PMID- 21553093 TI - [Successful methotrexate therapy of tubal pregnancy]. AB - Pathologists are well acquainted with the histopathologic features of a vital tubal pregnancy; however, tubal pregnancy successfully treated with medication is seen much less often, since these patients do not usually undergo surgery. We report a rare case of this type, in which no trophoblast tissue was found at histopathologic examination. Intratubal granulation tissue represented the remaining non-vital pregnancy tissue. PMID- 21553094 TI - School context protective factors against peer ethnic discrimination across the high school years. AB - Ethnically diverse high school contexts present unique social opportunities for youth to form interethnic relationships, but they may also subject students to certain social challenges such as peer ethnic discrimination. With a sample of 1,072 high school students (55% girls; 54% Latino, 20% African American, 14% Asian, 12% White) attending 84 high schools, school context factors that protect students' exposure to peer ethnic discrimination across the high school years were investigated with a three-level hierarchical linear model. Each spring for four consecutive years (grades 9-12), self-reported peer ethnic discrimination, interracial climate at school, and perceived school ethnic composition were assessed. At the school level, objective high school ethnic composition data were collected. Peer ethnic discrimination was found to decline slightly across the high school years. Above and beyond this decline, more positive perceptions of the school interracial climate and both objective and perceived numerical ethnic majority status predicted lower levels of peer ethnic discrimination. Taken together, the results highlight the significance of both objective (e.g., ethnic composition) and subjective (e.g., interracial climate) aspects of the school ethnic context to students' high school social experiences. PMID- 21553095 TI - System-level change in cultural and linguistic competence (CLC): how changes in CLC are related to service experience outcomes in systems of care. AB - As US demographic trends shift toward more diversity, it becomes increasingly necessary to address differential needs of diverse groups of youth in mental health service systems. Cultural and linguistic competence (CLC) is essential to providing the most appropriate mental health services to youth and their families. The successful implementation of CLC often begins at the system level. Though various factors may affect change and system-level factors set the tone for broad acceptance of CLC within systems, there is limited empirical evidence linking culturally competent practices to outcomes. The purpose of the present study was to examine system-level CLC changes over time within systems of care and their associations with service experiences among youth and their families. Participants were 4,512 youth and their families enrolled in the national evaluation of the Children's Mental Health Initiative (CMHI). Results suggest that implementation of CLC at the system level improves over time in funded systems of care. Further, variation exists in specific system-level components of CLC. In addition, the changes in CLC at the system level are related to family/caregiver participation in treatment. Implications for supporting positive changes in CLC among systems of care communities, and specific strategies for community psychologists, are discussed. PMID- 21553096 TI - "Just beyond my front door": public discourse experiences of children adopted from China. AB - The phenotypic differences between children and their adoptive parents in transracial adoptions make the child's adoptive status readily apparent in public. Consequently, adoptees field more frequent questions and comments about the adoption. The present study examines the nature of public conversations about ethnicity and adoption of 41 elementary school age girls adopted from China and the ecological factors related to less frequent occurrences of such conversations and to the positive nature of these experiences. Results indicate that family structure (single parent vs. two parents) and parental bicultural competence predict membership in the favorable condition (reporting fewer public interaction experiences and reporting more positive experiences, respectively). Child's age and racial diversity of the town of residence do not predict these outcomes. Implications for families, adoption professionals, teachers and researchers are discussed. PMID- 21553097 TI - Dexmedetomidine as sole agent for awake fiberoptic intubation in a patient with local anesthetic allergy. AB - A series of case reports acknowledges the efficacy of dexmedetomidine as a sole sedative for awake intubations in managing a critical airway. However, most case reports documented in the literature used topicalization of the oropharynx either via nebulized lidocaine or the spray-as-you-go technique with either 2% or 4% lidocaine spray to achieve successful intubation. The following case report presents an intensive care unit (ICU) patient with a critical airway who had a true documented allergy to local anesthetics. This case report demonstrates that dexmedetomidine appears to be useful for sedation during awake intubations in critical airways, without the need for airway topicalization. The ability of dexmedetomidine to act as a sedative, anxiolytic, analgesic, and antisialagogue without causing respiratory depression is promising to the field of anesthesiology. Additional studies are needed to elucidate its potential role as the sole agent for awake fiberoptic intubation. PMID- 21553098 TI - A compound heterozygous mutation of CYP27A1 gene in a Taiwanese patient with cerebrotendinous xanthomatosis. PMID- 21553099 TI - Bipolar hip arthroplasty for subtrochanteric femoral nonunion in an adult with autosomal dominant osteopetrosis type II. PMID- 21553100 TI - Prediction of ambulation ability following total hip arthroplasty. AB - BACKGROUND: In early postoperative rehabilitation after THA, it is essential to clarify some factors related to future ambulation ability. The aim of this study was to examine whether it is possible to predict ambulation ability for patients with THA at 6 months postoperatively. METHODS: The subjects of this study were 123 patients who had undergone unilateral THA. The hip abductor and knee extensor strength was assessed, and a timed up and go (TUG) test was performed at 4 weeks after the operation. Then, the patients were divided into two groups according to their ability to walk and to go up and down stairs at 6 months postoperatively: the good ambulatory group (n = 64) and the non-good ambulatory group (n = 59). RESULTS: The discriminating criteria between the two groups were 0.47 (Nm/kg) for hip abductor strength, 1.07 (Nm/kg) for knee extensor strength, and 10 s for TUG test. By multiple logistic regression, knee extensor strength and TUG test at 4 weeks were significantly associated with the categorization at 6 months. CONCLUSIONS: The results of this study suggest that the TUG test and knee extensor strength at an early stage after THA were useful indicators for predicting patients' ambulation ability at 6 months postoperatively. PMID- 21553101 TI - Alternation of trunk movement after arthroplasty in patients with osteoarthritis of the knee. AB - OBJECTIVE: Trunk movement is important but still little understood after total knee arthroplasty. The alternation of trunk movement was analyzed for use in a postoperative rehabilitation program in the short-term after arthroplasty. MATERIALS AND METHODS: The subjects were 25 patients with knee osteoarthritis (4 males, 21 females). The femorotibial angle was evaluated on standing anteriorposterior radiographs and recorded at pre- and post-arthroplasty. Using three-dimensional motion capture, the gait parameters (cadence, walking speed, stride length, step length, step width), range of motion of lower extremity joints (hip, knee, and ankle), and trunk movement parameters (angle, speed, and displacement) were measured and compared between the pre- and 4th post arthroplasty week. RESULTS: The femorotibial angles of the arthroplasty side were improved from an average of 189 degrees to 175 degrees after arthroplasty. At the 4th post-arthroplasty week, the range of motion of the hip and knee flexion, hip adduction on the arthroplasty side, and ankle dorsiflexion on the non arthroplasty side were significantly increased compared to pre-arthroplasty. Among gait parameters, only the stride length increased significantly. Regarding the trunk movement in the coronal plane, the maximal trunk speed to the non arthroplasty side and maximal trunk displacement to the arthroplasty side were both reduced in a medio-lateral direction; the upward maximal trunk speed on the arthroplasty side increased and the maximal trunk displacement on the non arthroplasty side decreased significantly in an up-down direction. CONCLUSION: The recovery of hip adduction during the standing phase caused by improvement of knee alignment contributed the reduction of trunk movement to the operated side. In the early post-arthroplasty period, the reduction of trunk movement in the coronal plane is beneficial to maintain trunk balance and prevent falls. Functional recovery of the lower extremities is a long-term process, and sustained functional training is necessary. PMID- 21553102 TI - Prevalence and clinical course of Clostridium difficile infection in a tertiary care hospital: a retrospective analysis. AB - The spectrum of Clostridium difficile-associated diarrhea (CDAD) is changing. Apart from antibiotic use, other risk factors such as use of proton pump inhibitors (PPI) and immunosuppressive agents, intensive care unit (ICU) stay and inflammatory bowel disease are being recognized. We retrospectively analyzed data on patients whose stool samples were tested for C. difficile toxin (CDT) by enzyme linked immunosorbent assay between June 2006 and May 2008. Demographic and clinical data, and risk factors (antibiotic use, underlying malignancy, chemotherapy, use of PPI, ICU stay) were noted. The details of treatment for CDAD, response, complication and follow up were recorded. Patients whose stool samples were CDT-positive were grouped as study subjects and those with negative stool samples were included in the control group. Of the 99 patients (mean age 46.7 years; 58 men) whose stool samples were tested during this period, 17 (17%) were positive for CDT. As compared with control subjects (n = 82), study subjects were more likely to have fever, prolonged ICU stay, underlying malignancy, and exposure to immunosuppressive and chemotherapeutic agents. On multivariate analysis, exposure to immunosuppressive agents was the only risk factor associated with CDAD. Fifteen patients were treated with metronidazole and two with vancomycin. Two patients did not respond to metronidazole but responded to vancomycin. No patient developed any complication. The prevalence of C. difficile toxin in diarrheal stools sent for C. difficile toxin testing was 17%. Exposure to immunosuppressive agents was a risk factor for the infection. Metronidazole was effective in a majority of patients. PMID- 21553103 TI - Prognostic significance of galectin-3 and cyclin D1 expression in undifferentiated nasopharyngeal carcinoma. AB - Galectin-3 was shown to be involved in various biological events, including cell growth, adhesion, differentiation, angiogenesis, apoptosis, tumorigenesis, and metastasis. The prognostic significance of galectin-3 expression has already been evaluated in several cancers. However, its prognostic role has not been investigated in nasopharyngeal carcinoma. The loss of cell cycle control is one of the critical steps in the development of nasopharyngeal carcinoma. Cyclin D1 is one of the key proteins involved in cell cycle control and is essential for G1/S phase transition. Overexpression of cyclin D1 has been observed in several human cancers. In the present study, the expression of galectin-3 and cyclin D1 was evaluated with immunohistochemical analysis in 45 patients diagnosed as undifferentiated nasopharyngeal carcinoma and expression of these proteins was correlated with clinicopathological parameters and prognosis. Multivariate analysis showed that older age (>50 vs. <=50) (P = 0.028), distant metastasis at presentation (M(1) vs. M(0)) (P = 0.001), and increased galectin-3 expression (>5% vs. <=5%) (P = 0.025) were independently correlated with poor overall survival. We found no statistically significant correlation between cyclin D1 immunoexpression and disease outcome. The Spearman's correlation coefficient revealed a significant correlation between galectin-3 and cyclin D1 expression (r = 0.425; P = 0.004). Our findings suggested that the immunohistochemical analysis of galectin-3 might be useful in predicting prognosis in nasopharyngeal carcinoma. PMID- 21553104 TI - A retrospective statistical analysis of high-grade soft tissue sarcomas. AB - Soft-tissue sarcomas have a mortality rate ranging from 40-60% for high-grade lesions. Prior identified risk factors for post-surgical mortality include tumor size, lesion histology, and margin status at resection. A better understanding of prognostic factors is needed to guide patient counseling and treatment. Data were collected from 129 patients surgically treated for high-grade extremity soft tissue sarcomas during 2002-2010. The primary endpoint was death related to high grade soft tissue sarcoma. Thirteen variables were investigated: age, gender, race, tumor size, margin status, location, estimated blood loss, operative blood transfusions, pre-operative metastatic disease, pre-operative radiation, post operative radiation, pre-operative chemotherapy, and post-operative chemotherapy. A Cox Survival Analysis model was created to determine the best predictors of survival time. Tumor size and the presence of pre-surgical metastasis were statistically significant predictors of overall survival. Patients with a tumor greater than 8 cm in any cross section had a 3.15 times greater chance of death. Presence of pre-surgical metastasis carried a 3.47 greater chance of death. The remaining variables did not predict patient outcomes in a statistically significant manner. The hazard ratios calculated add new data and can be used to more effectively guide patients in prognosis and treatment regimens. PMID- 21553105 TI - Carbohydrate antigen 242 highly consists with carbohydrate antigen 19-9 in diagnosis and prognosis of colorectal cancer: study on 185 cases. AB - The objective of the study was to compare the clinical value of preoperative serum carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 242 (CA242) in diagnosis and prognosis for 5-year recurrence-free survival (RFS) in patients with colorectal cancer (CRC). Preoperative serum CA19-9 and CA242 concentrations were detected by C12 protein chip diagnostic system in 185 patients with CRC, and informative data were collected during 5-year follow-up periods. The value of CA19-9 and CA242 in diagnosis and prognosis for 5-year RFS as well as their consistencies and correlations were comparatively analyzed. The sensitivities of CA19-9 and CA242 were only 19.5 and 20%, respectively; the efficiencies of two TMs were 53.9 and 54.2%, respectively; and two TMs increased significantly with advancing clinical stages (P < 0.0001). Preoperative CA19-9 and CA242 levels correlated with stage (r, 0.411 and 0.408) and CEA concentration (r, 0.553 and 0.630). The concentrations of two TMs closely correlated with each other (r = 0.829), and two TMs had a very strong consistency in diagnosis (kappa = 0.931). Among 88 of 185 cases with complete follow-up information on RFS, patients with positive preoperative serum CA19-9 or CA242 had higher 5-year recurrent rates (72.2% vs. 44.3%, P = 0.034; 76.5% vs. 43.7%, P = 0.015) and reduced median RFS (14 vs. 36 months, 12 vs. 36 months) compared with those with negative TMs. The consistency of predicting prognosis for RFS of two TMs was extremely strong (kappa = 0.964). ROC curves analysis showed that CA242 test performed better than CA19-9 test (AUC, 0.648 vs. 0.605). Univariate analysis showed that preoperative serum status of both TMs was correlated with 5-year RFS (P < 0.05), whereas multivariate Cox regression model analysis revealed that none of them were independent prognostic factors for RFS. Both CA19-9 and CA242 had strong consistencies in diagnosis and prognosis for predicting 5-year RFS. CA242 demonstrated superior value to CA19-9 in CRC. PMID- 21553106 TI - Major ecosystems in China: dynamics and challenges for sustainable management. AB - Ecosystems, though impacted by global environmental change, can also contribute to the adaptation and mitigation of such large scale changes. Therefore, sustainable ecosystem management is crucial in reaching a sustainable future for the biosphere. Based on the published literature and publicly accessible data, this paper discussed the status and trends of forest, grassland, and wetland ecosystems in China that play important roles in the ecological integrity and human welfare of the nation. Ecological degradation has been observed in these ecosystems at various levels and geographic locations. Biophysical (e.g., climate change) and socioeconomic factors (e.g., intensive human use) are the main reasons for ecosystem degradation with the latter factors serving as the dominant driving forces. The three broad categories of ecosystems in China have partially recovered from degradation thanks to large scale ecological restoration projects implemented in the last few decades. China, as the largest and most populated developing nation, still faces huge challenges regarding ecosystem management in a changing and globalizing world. To further improve ecosystem management in China, four recommendations were proposed, including: (1) advance ecosystem management towards an application-oriented, multidisciplinary science; (2) establish a well-functioning national ecological monitoring and data sharing mechanism; (3) develop impact and effectiveness assessment approaches for policies, plans, and ecological restoration projects; and (4) promote legal and institutional innovations to balance the intrinsic needs of ecological and socioeconomic systems. Any change in China's ecosystem management approach towards a more sustainable one will benefit the whole world. Therefore, international collaborations on ecological and environmental issues need to be expanded. PMID- 21553107 TI - Soil carbon sequestration potential for "Grain for Green" project in Loess Plateau, China. AB - Conversion of cropland into perennial vegetation land can increase soil organic carbon (SOC) accumulation, which might be an important mitigation measure to sequester carbon dioxide from the atmosphere. The "Grain for Green" project, one of the most ambitious ecological programmes launched in modern China, aims at transforming the low-yield slope cropland into grassland and woodland. The Loess Plateau in China is the most important target of this project due to its serious soil erosion. The objectives of this study are to answer three questions: (1) what is the rate of the SOC accumulation for this "Grain for Green" project in Loess Plateau? (2) Is there a difference in SOC sequestration among different restoration types, including grassland, shrub and forest? (3) Is the effect of restoration types on SOC accumulation different among northern, middle and southern regions of the Loess Plateau? Based on analysis of the data collected from the literature conducted in the Loess Plateau, we found that SOC increased at a rate of 0.712 TgC/year in the top 20 cm soil layer for 60 years under this project across the entire Loess Plateau. This was a relatively reliable estimation based on current data, although there were some uncertainties. Compared to grassland, forest had a significantly greater effect on SOC accumulation in middle and southern Loess Plateau but had a weaker effect in the northern Loess Plateau. There were no differences found in SOC sequestration between shrub and grassland across the entire Loess Plateau. Grassland had a stronger effect on SOC sequestration in the northern Loess Plateau than in the middle and southern regions. In contrast, forest could increase more SOC in the middle and southern Loess Plateau than in the northern Loess Plateau, whereas shrub had a similar effect on SOC sequestration across the Loess Plateau. Our results suggest that the "Grain for Green" project can significantly increase the SOC storage in Loess Plateau, and it is recommended to expand grassland and shrub areas in the northern Loess Plateau and forest in the middle and southern Loess Plateau to enhance the SOC sequestration in this area. PMID- 21553108 TI - Nitric oxide enhances aluminum tolerance by affecting cell wall polysaccharides in rice roots. AB - Nitric oxide (NO) is a key signal molecule involved in many physiological processes in plants. To study the mechanisms of exogenous NO contribution to alleviate the aluminum (Al) toxicity, roots of rice (Oryza sativa) seedlings pre treated with sodium nitroprusside (SNP, a NO donor) were used to investigate the effect of Al in this study. Results indicated that NO alleviated the lipid peroxidation induced by Al and promoted the root elongation, whereas butylated hydroxyanisole (BHA), an efficient lipophilic antioxidant, alleviated the lipid peroxidation only. Rice seedling roots pre-treated with SNP followed by Al treatment had lower contents of pectin and hemicellulose, lower Al accumulation in root tips and cell walls, higher degree of methylation of pectin and lower wall Al-binding capacity than the roots with Al treatment only. Therefore, the decreased Al accumulation in the cell walls of rice roots is likely to be the reason for the NO-induced increase of Al tolerance in rice, and it seems that exogenous NO enhanced Al tolerance in rice roots by decreasing the contents of pectin and hemicellulose, increasing the degree of methylation of pectin, and decreasing Al accumulation in root cell walls. PMID- 21553109 TI - Isolation and promoter analysis of a chalcone synthase gene PtrCHS4 from Populus trichocarpa. AB - As perennial plants, Populus species are constantly exposed to environmental stresses, such as wounding and pathogen attack, which lead to production of compounds including lignin, flavonoids and phytoalexins. Chalcone synthase (CHS) is a key enzyme in the flavonoid biosynthesis pathway. In this study, a cDNA clone encoding CHS was isolated from Populus trichocarpa by reverse transcription polymerase chain reaction (RT-PCR). The full-length cDNA, named PtrCHS4, was 1,314 bp with a 1,173 bp open reading frame that corresponded to a deduced protein of 391 amino acid residues. Multiple sequence alignments showed that PtrCHS4 shared high homology with CHS proteins from other plants. Phylogenetic analysis revealed that PtrCHS4 was most closely related to PhCHS from Petunia hybrida and NaCHS from Nicotiana attenuata. Semi-quantitative RT-PCR analysis identified that the PtrCHS4 gene was abundantly expressed in the leaves and stems, while its expression was drastically reduced in the roots. Transcript abundance of PtrCHS4 was stimulated by 2.5-fold within 24 h of wounding treatment. Promoter analysis confirmed that the PtrCHS4 promoter was capable of directing expression of the GUS reporter in both wounded and unwounded leaves of transgenic Chinese white poplar (P. tomentosa Carr.), indicating that the PtrCHS4 promoter is systemically responsive to wounding stimuli. Furthermore, promoter deletion analysis showed that the proximal 1,592 bp from the transcription start site were required for promoter activation by jasmonic acid and the -1,096 to 148 region was proved to be necessary for establishing wound-induced pattern of expression. PMID- 21553110 TI - Is acoustic evaluation in a non-primate mammal, the tree shrew, affected by context? AB - Sound categorisation plays a crucial role for processing ecological and social stimuli in a species' natural environment. To explore the discrimination and evaluation of sound stimuli in human babies and nonhuman primates, a reciprocal habituation-dishabituation paradigm has been successfully introduced into auditory research. We applied the reciprocal paradigm for the first time to a non primate mammal, the tree shrew (Tupaia belangeri), to examine to what extent non primate mammals share the ability to evaluate communication calls with primates. Playback stimuli were three types of communication calls, differing distinctively in context and acoustic structure, as well as two artificial control sounds, differing solely in frequency. We assessed the attention towards the playback stimuli by the latency to respond to the test stimulus. Subjects evaluated pairs of communication call types as well as the artificial playback stimuli. Attention towards the test stimuli differed significantly in strength for one pair of communication calls, with subjects dishabituating faster to one category than the other. The comparison of a second pair of communication calls did not show significant differences. Interestingly, subjects also evaluated the artificial control sounds. Findings are only partly in line with results on human and non human primates. They provided first evidence that in non-primate mammals acoustic evaluation is not solely affected by the sound-associated context but is also linked to unusualness and acoustic cues, such as peak frequency. PMID- 21553111 TI - Communication between domestic dogs and humans: effects of shelter housing upon the gaze to the human. AB - It is widely known that gaze plays an essential role in communicative interactions. Domestic dogs tend to look at the human face in situations of conflict and uncertainty. This study compares the gaze of shelter and pet dogs during acquisition and extinction phases in a situation involving a reward in sight but out of reach. Even though no significant differences between the groups were recorded during acquisition, gaze duration decreased in both groups during extinction, with shelter dogs showing a significant shorter duration. This could be related to their different living conditions and to the fact that through their ordinary everyday interactions, pet dogs have more opportunities to learn to persist in their communicative responses when they do not get what they want. These results highlight the relevance of learning experiences during ontogeny, which would therefore modulate communicative responses. PMID- 21553112 TI - Single-dose-dexketoprofen-induced acute kidney injury due to massive rhabdomyolysis. AB - A 70-year-old male patient was admitted complaining of weakness and pain in his arms and lower limbs. His serum creatine kinase and serum creatinine were markedly elevated (36,248 IU/L and 2.8 mg/dL, respectively). He had taken dexketoprofen trometamol because of a common cold, which had developed the previous night. Acute kidney injury caused by dexketoprofen-induced rhabdomyolysis was diagnosed by ruling out other possible causes, such as dermato/polymyositis, myxedema, brucellosis, and hepatitis. Dexketoprofen administration was stopped. As diuresis did not restore spontaneously, the patient was treated with I.V. alkaline solutions and mannitol. Hemodialysis was performed because of anuria and severe metabolic acidosis. The patient's renal function later recovered. In conclusion, dexketoprofen may be a potential risk factor for acute kidney injury and rhabdomyolysis. PMID- 21553113 TI - The primary arteriovenous fistula failure-a comparison between diabetic and non diabetic patients: glycemic control matters. AB - OBJECTIVES: Presence of diabetes mellitus has been shown to be related with the occurrence of primary arteriovenous fistula (AVF) failure in some but not in all studies. In the current study, we examined whether glycemic control as evaluated by HbA1c is independently related with primary AVF failure. METHODS: We recorded sociodemographic, clinical, and laboratory parameters of the patients from medical records and hospital charts prior to AVF surgery. Primary AVF failure was described as a complication of the AVF before the first successful cannulation for HD treatment. RESULTS: Our study comprised of 160 non-diabetic (Group1) and 73 diabetic patients. Among diabetic patients, 37 had HbA1c values <7% (Group 2) and 36 patients had HbA1c values >=7% (Group 3). In total, 74 (31.8%) patients had a history of primary AVF failure. The percentages of primary AVF failure were 27.5, 29.7, and 52.8% in Group 1, Group 2, and Group 3, respectively (P: 0.013). The percentage of patients with primary AVF failure was significantly lower in Group 1 and Group 2 than in Group 3 (P:0.003 and P:0.045, respectively). There was no difference with respect to primary AVF failure between Group 1 and Group 2 patients. CONCLUSIONS: We suggest that poor glycemic control as assessed by HbA1c may be an important factor for the development of primary AVF failure among diabetic subjects. It is possible that differences with respect to AVF failure between diabetic and non-diabetic patients may be partly attributed to glycemic control. PMID- 21553114 TI - Urinary tract dysfunction in Parkinson's disease: a review. AB - INTRODUCTION: Parkinson's disease is an extrapyramidal neurological disorder. Although motor symptoms are a predominant feature of the condition, non-motor symptoms have also been recognized. Urinary symptoms are frequently present in patients affected with Parkinson's disease (PD). Symptoms such as urgency, frequency, nocturia and urge incontinence significantly impact the patient's quality of life. We discuss the urinary dysfunction seen in patients with Parkinson's disease and consider the pathophysiology, important differentials, the investigations and management options for such patients. MATERIALS AND METHODS: An extensive search was performed using the PubMed((r))/EMBASE((r)) databases to identify the available literature on urinary disturbances and Parkinson's disease. Reference was also made to current national guidelines on Parkinson's disease. RESULTS: Urinary disturbances are frequently observed in sufferers of Parkinson's disease resulting in significant impact to the individual's quality of life. Studies report that storage symptoms are present in 57-83% of patients, whereas voiding symptoms are seen in 17-27% patients. Out of all the urinary symptoms, nocturia is the most common complaint in >60% patients with PD. Urgency occurs in 33-54% of patients, whilst frequency is experienced by 16-36% of patients. Detrusor overactivity (DO) is the commonest cystometric abnormality in patients with PD. The rate of neurogenic DO in patients with PD is 45-93%. The main differential to consider is Multiple System Atrophy (MSA) in which all patients are ultimately afflicted with urinary disturbance. It is well recognized that patients initially diagnosed with PD may in fact have MSA, and it is important to distinguish the two as their urological management is different. Patients presenting with refractory LUTS with concurrent PD should undergo full urodynamic investigation including cystometry, flowmetry and ultrasonography before treatment is initiated. DISCUSSION: Referral to a urologist is advised in those with persistent or refractory urinary complaints. Urodynamic evaluation allows determination of the underlying bladder disorder; however, post-void residuals suffice in the uncomplicated patient. The pathophysiology of urinary dysfunction and current investigation and treatment modalities are discussed. PMID- 21553115 TI - A single plasmid transfection that offers a significant advantage associated with puromycin selection, fluorescence-assisted cell sorting, and doxycycline inducible protein expression in mammalian cells. AB - Although there are several inducible expression systems for mammalian cells, the most reliable one is the tetracycline-regulated expression system. This system is well-established and widely used by many researchers. Although Clontech provides several types of cells that stably express reverse tetracycline transactivator (rtTA), the cells that are not provided can be generated with pTet-On-Advanced by first integrating this plasmid into the require type of cell and then introducing the genes of interest. These processes are experimental bottlenecks. To improve this situation, we synthesized an all-in-one vector, termed pMAK17, which enables constitutive expression of puromycin N-acetyltransferase, modified Discosoma red fluorescent protein, and rtTA, as well as P(Tight)-driven enhanced green fluorescent protein (EGFP). The pMAK17-transfected cells could be successfully induced to express EGFP, were selectable by fluorescence-activated cell sorting, and displayed puromycin resistance. PMID- 21553116 TI - Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials. AB - Compared to tamoxifen, the efficacy and side effects of toremifene in adjuvant endocrine therapy for breast cancer were not very clear. This meta-analysis was conducted to give a more precise estimation of the efficacy and severe side effects of toremifene given in the adjuvant setting in comparison to tamoxifen. The electronic database PubMed was searched for randomized trials comparing toremifene with tamoxifen as adjuvant therapies. Four randomized trials published in three articles were eligible, including 1,890 pooled cases treated with toremifene and 1,857 cases treated with tamoxifen. Compared to patients in tamoxifen group, patients in toremifene group did not have a significantly different overall survival rate (risk ratio (RR): 1.07, 95% confidence interval (CI): 0.97-1.19, P = 0.994 for heterogeneity) or a disease-free survival (DFS) rate (RR: 1.05, 95% CI: 0.95-1.17, P = 0.431 for heterogeneity) at the end of the follow-up time. The rates of thromboembolic events in toremifene group, including deep vein thrombosis (odds ratio (OR): 0.68, 95% CI: 0.40-1.17, P = 0.926 for heterogeneity), cerebrovascular accident (OR: 0.59, 95% CI: 0.32-1.09, P = 0.438 for heterogeneity), and pulmonary embolism (OR: 0.91, 95% CI: 0.42-2.01, P = 0.618 for heterogeneity), were not significantly different from those in tamoxifen group. The rates of endometrial polyps and endometrial cancer between the two groups were almost the same. This meta-analysis suggested that toremifene was as effective as tamoxifen in the adjuvant setting for both perimenopausal and postmenopausal breast cancer patients with similar severe adverse effects to tamoxifen. Toremifene was a convincing and safe change for tamoxifen in adjuvant endocrine therapy. PMID- 21553117 TI - The influence of travel time on breast cancer characteristics, receipt of primary therapy, and surveillance mammography. AB - Travel time has been shown to influence some aspects of cancer characteristics at diagnosis and care for women with breast cancer, but important gaps remain in our understanding of its impact. We examined the influence of travel time to the nearest radiology facility on breast cancer characteristics, treatment, and surveillance for women with early-stage invasive breast cancer. We included 1,012 women with invasive breast cancer (stages I and II) who had access to care within an integrated health care delivery system in western Washington State. The travel times to the nearest radiology facility were calculated for all the U.S. Census blocks within the study area and assigned to women based on residence at diagnosis. We collected cancer characteristics, primary and adjuvant therapies, and surveillance mammography for at least 2.5 years post diagnosis and used multivariable analyses to test the associations of travel time. The majority of women (68.6%) lived within 20 min of the nearest radiology facility, had stage I disease (72.7%), received breast conserving therapy (68.7%), and had annual surveillance mammography the first 2 years after treatment (73.7%). The travel time was not significantly associated with the stage or surveillance mammography after adjusting for covariates. Primary therapy was significantly related to travel time, with greater travel time (>30 min vs. <= 10 min) associated with a higher likelihood of mastectomy compared to breast conserving surgery (RR = 1.53; 95% CI, 1.16-2.01). The travel time was not associated with the stage at diagnosis or surveillance mammography receipt. The travel time does seem to influence the type of primary therapy among women with breast cancer, suggesting that women may prefer low frequency services, such as mastectomy, if geographic access to a radiology facility is limited. PMID- 21553118 TI - Patient and tumor characteristics of bilateral breast cancer at screening mammography in the Netherlands, a population-based study. AB - Few data are available on bilateral breast cancer in the screening population. The aim of this study was to determine patient and tumor characteristics of women with bilateral breast cancer at screening mammography. We included all 350,637 screening mammography examinations of women participating in a biennial screening program in a southern screening region of the Netherlands between May 1998 and January 2010. For referred women, all breast imaging reports, biopsy results, and surgery reports during one year after referral were collected. We compared patient and tumor characteristics of referred women with a diagnosis of bilateral breast cancer or unilateral breast cancer at workup. Bilateral or unilateral breast cancer had been diagnosed in respectively 40 (2.2%) and 1766 (97.8%) of 1806 referred women. Women with bilateral or unilateral breast cancer did not differ significantly in mean age, mammographic breast density, family history of breast cancer, or use of hormone replacement therapy. Compared with index cancers, contralateral cancers comprised significantly more lobular cancers (P = 0.02). Tumor size, mitotic activity, and estrogen receptor status were comparable for both groups, but contralateral cancers had a significantly lower risk of lymph node metastases (P = 0.03). Compared to unilateral breast cancer, contralateral malignancies in women with bilateral breast cancer comprised significantly more lobular cancers (P = 0.004) and lymph node negative cancers (P = 0.01). Contralateral breast cancers detected at screening comprise more lobular cancers and show less nodal involvement than index cancers or unilateral cancers. No differences are observed with respect to other patient and tumor characteristics. PMID- 21553119 TI - Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing. AB - In order to adequately evaluate the clinical relevance of genetic testing in sporadic breast and ovarian cancer patients, we offered comprehensive BRCA1/2 mutation analysis in patients without a family history for the disease. We evaluated the complete coding and splice site regions of BRCA1/2 in 193 sporadic patients. In addition, a de novo mutation was further investigated with ultra deep sequencing and microsatellite marker analysis. In 17 patients (8.8%), a deleterious germline BRCA1/2 mutation was identified. The highest mutation detection ratio (3/7 = 42.9%) was obtained in sporadic patients diagnosed with breast and ovarian cancer after the age of 40. In 21 bilateral breast cancer patients, two mutations were identified (9.5%). Furthermore, 140 sporadic patients with unilateral breast cancer were investigated. Mutations were only identified in patients diagnosed with breast cancer before the age of 40 (12/128 = 9.4% vs. 0/12 with Dx > 40). No mutations were detected in 17 sporadic male breast cancer and 6 ovarian cancer patients. BRCA1 c.3494_3495delTT was identified in a patient diagnosed with breast and ovarian cancer at the age of 52 and 53, respectively, and was proven to have occurred de novo at the paternal allele. Our study shows that the mutation detection probability in specific patient subsets can be significant, therefore mutation analysis should be considered in sporadic patients. As a consequence, a family history for the disease and an early age of onset should not be used as the only criteria for mutation analysis of BRCA1/2. The relatively high mutation detection ratio suggests that the prevalence of BRCA1/2 may be underestimated, especially in sporadic patients who developed breast and ovarian cancer. In addition, although rare, the possibility of a de novo occurrence in a sporadic patient should be considered. PMID- 21553120 TI - Prolonged mammosphere culture of MCF-7 cells induces an EMT and repression of the estrogen receptor by microRNAs. AB - Mammosphere culture has been used widely for the enrichment of mammary epithelial stem cells and breast cancer stem cells (CSCs). Epithelial-to-mesenchymal transition (EMT) also induces stem cell features in normal and transformed mammary cells. We examined whether mammosphere culture conditions per se induced EMT in the epithelial MCF-7 breast cancer cell line. MCF-7 cells were cultured as mammospheres for 5 weeks, with dispersal and reseeding at the end of each week. This mammosphere culture induced a complete EMT by 3 weeks. Return of the cells to standard adherent culture conditions in serum-supplemented media generated a cell population (called MCF-7(M) cells), which displays a stable mesenchymal and CSC-like CD(44+)/CD(24-/low) phenotype. EMT was accompanied by a stable, marked increase in EMT-associated transcription factors and mesenchymal markers, and a decrease in epithelial markers and estrogen receptor alpha (ERalpha). MCF-7(M) cells showed increased motility, proliferation and chemoresistance in vitro, and produced larger tumors in immunodeficient mice with or without estrogen supplementation. MicroRNA analysis showed suppression of miR-200c, miR-203, and miR-205; and increases in miR-222 and miR-221. Antisense hairpin RNA inhibitor targeting miR-221 resulted in re-expression of ERalpha in MCF-7(M) cells. This study provides the first example of mammosphere culture conditions inducing EMT and of EMT regulating microRNAs that target ERalpha. PMID- 21553121 TI - 1H, 13C and 15N NMR assignments of the Escherichia coli Orf135 protein. AB - Escherichia coli Orf135 protein is thought to be an enzyme that efficiently hydrolyzes oxidatively damaged nucleotides such as 2-hydroxy-dATP, 8-hydroxy-dGTP and 5-hydroxy-CTP, in addition to 5-methyl-dCTP, dCTP and CTP, thus preventing mutations in cells caused by unfavorable base pairing. Nucleotide pool sanitization by Orf135 is important since organisms are continually subjected to potential damage by reactive oxygen species produced during respiration. It is known that the frequency of spontaneous and H(2)O(2)-induced mutations is two to threefold higher in the orf135(-) strain compared with the wild-type. Orf135 is a member of the Nudix family of proteins which hydrolyze nucleoside diphosphate derivatives. Nudix hydrolases are characterized by the presence of a conserved motif, although they recognize various substrates and possess a variety of substrate binding pockets. We are interested in delineating the mechanism by which Orf135 recognizes oxidatively damaged nucleotides. To this end, we are investigating the tertiary structure of Orf135 and its interaction with substrate using NMR. Herein, we report on the (1)H, (13)C and (15)N resonance assignments of Orf135, which should contribute towards a structural understanding of Orf135 and its interaction with substrate. PMID- 21553122 TI - X-chromosome inactivation: molecular mechanisms from the human perspective. AB - X-chromosome inactivation is an epigenetic process whereby one X chromosome is silenced in mammalian female cells. Since it was first proposed by Lyon in 1961, mouse models have been valuable tools to uncover the molecular mechanisms underlying X inactivation. However, there are also inherent differences between mouse and human X inactivation, ranging from sequence content of the X inactivation center to the phenotypic outcomes of X-chromosome abnormalities. X linked gene dosage in males, females, and individuals with X aneuploidies and X/autosome translocations has demonstrated that many human genes escape X inactivation, implicating cis-regulatory elements in the spread of silencing. We discuss the potential nature of these elements and also review the elements in the X inactivation center involved in the early events in X-chromosome inactivation. PMID- 21553123 TI - Environmental regulation of stomatal response in the Arabidopsis Cvi-0 ecotype. AB - The Arabidopsis Cape Verde Islands (Cvi-0) ecotype is known to differ from other ecotypes with respect to environmental stress responses. We analyzed the stomatal behavior of Cvi-0 plants, in response to environmental signals. We investigated the responses of stomatal conductance and aperture to high [CO2] in the Cvi-0 and Col-0 ecotypes. Cvi-0 showed constitutively higher stomatal conductance and more stomatal opening than Col-0. Cvi-0 stomata opened in response to light, but the response was slow. Under low humidity, stomatal opening was increased in Cvi-0 compared to Col-0. We then assessed whether low humidity affects endogenous ABA levels in Cvi-0. In response to low humidity, Cvi-0 had much higher ABA levels than Col-0. However, epidermal peels experiments showed that Cvi-0 stomata were insensitive to ABA. Measurements of organic and inorganic ions in Cvi-0 guard cell protoplasts indicated an over-accumulation of osmoregulatory anions (malate and Cl-). This irregular anion homeostasis in the guard cells may explain the constitutive stomatal opening phenotypes of the Cvi-0 ecotype, which lacks high [CO2]-induced and low humidity-induced stomatal closure. PMID- 21553124 TI - MALDI mass spectrometry based molecular phenotyping of CNS glial cells for prediction in mammalian brain tissue. AB - The development of powerful analytical techniques for specific molecular characterization of neural cell types is of central relevance in neuroscience research for elucidating cellular functions in the central nervous system (CNS). This study examines the use of differential protein expression profiling of mammalian neural cells using direct analysis by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). MALDI-MS analysis is rapid, sensitive, robust, and specific for large biomolecules in complex matrices. Here, we describe a newly developed and straightforward methodology for direct characterization of rodent CNS glial cells using MALDI-MS based intact cell mass spectrometry (ICMS). This molecular phenotyping approach enables monitoring of cell growth stages, (stem) cell differentiation, as well as probing cellular responses towards different stimulations. Glial cells were separated into pure astroglial, microglial, and oligodendroglial cell cultures. The intact cell suspensions were then analyzed directly by MALDI-TOF-MS, resulting in characteristic mass spectra profiles that discriminated glial cell types using principal component analysis. Complementary proteomic experiments revealed the identity of these signature proteins that were predominantly expressed in the different glial cell types, including histone H4 for oligodendrocytes and S100-A10 for astrocytes. MALDI imaging MS was performed, and signature masses were employed as molecular tracers for prediction of oligodendroglial and astroglial localization in brain tissue. The different cell type specific protein distributions in tissue were validated using immunohistochemistry. ICMS of intact neuroglia is a simple and straightforward approach for characterization and discrimination of different cell types with molecular specificity. PMID- 21553125 TI - Analysis of membrane and hydrophilic proteins simultaneously derived from the mouse brain using cloud-point extraction. AB - In this study, a temperature-induced phase fractionation known as cloud-point extraction (CPE) with the non-ionic surfactant Triton X-114 was used to simultaneously extract, concentrate, and fractionate hydrophobic and hydrophilic proteins from mouse brain tissue. Two bottom-up proteomic techniques were used to comprehensively identify the extracted proteins. The first "shotgun"-based approach included tryptic digestion of the proteins followed by reversed-phase nanoliquid chromatography (RP-nanoLC) in combination with electrospray ionization (ESI) tandem mass spectrometry (MS/MS). In the second approach, the extracted intact proteins were first separated by one-dimensional (1D) gel electrophoresis and then in-gel digested with trypsin and analyzed with nanoLC-MS/MS. In total, 1,825 proteins were unambiguously identified and the percentage of membrane proteins was 26% which is at the reported genome expression levels of 20-30%. The protein overlap between the two approaches was high. The majority (77%) of the identifications in the first approach was also found by the second method. The protein overlap between the CPE-extracted hydrophilic and hydrophobic fractions was rather small (16-23%) for both methods, which indicates a good phase separation. A quantitative evaluation of the CPE with iTRAQ labeling and nanoLC ESI-MS/MS analysis gave iTRAQ ratios at the expected levels and an overall variation of the entire method at 17-31%. The results indicate very reproducible sample preparation and analysis methods that readily can be applied on large scale sample sets. PMID- 21553126 TI - Visual stimuli that elicit appetitive behaviors in three morphologically distinct species of praying mantis. AB - We assessed the differences in appetitive responses to visual stimuli by three species of praying mantis (Insecta: Mantodea), Tenodera aridifolia sinensis, Mantis religiosa, and Cilnia humeralis. Tethered, adult females watched computer generated stimuli (erratically moving disks or linearly moving rectangles) that varied along predetermined parameters. Three responses were scored: tracking, approaching, and striking. Threshold stimulus size (diameter) for tracking and striking at disks ranged from 3.5 deg (C. humeralis) to 7.8 deg (M. religiosa), and from 3.3 deg (C. humeralis) to 11.7 deg (M. religiosa), respectively. Unlike the other species which struck at disks as large as 44 deg, T. a. sinensis displayed a preference for 14 deg disks. Disks moving at 143 deg/s were preferred by all species. M. religiosa exhibited the most approaching behavior, and with T. a. sinensis distinguished between rectangular stimuli moving parallel versus perpendicular to their long axes. C. humeralis did not make this distinction. Stimulus sizes that elicited the target behaviors were not related to mantis size. However, differences in compound eye morphology may be related to species differences: C. humeralis' eyes are farthest apart, and it has an apparently narrower binocular visual field which may affect retinal inputs to movement sensitive visual interneurons. PMID- 21553128 TI - High serum zinc and serum testosterone levels were associated with excessive erythrocytosis in men at high altitudes. AB - Chronic mountain sickness (CMS), a lack of adaptation to altitude characterized by excessive erythrocytosis (EE), is a health problem associated with life at high altitude. The erythropoietic process is regulated by both erythropoietin and testosterone. Zinc (Zn) is known to be related with testosterone and hemoglobin levels; meanwhile, nitric oxide was also associated with adaptation to high altitude. The aim of this study was to determine the relationship of hemoglobin and CMS score with serum levels of zinc, total testosterone (TT), calculated free testosterone (cFT), bioavailable testosterone (BAT), hemoglobin, and nitric oxide in men at high altitude with or without EE. Men residing in Lima (150 m) and Cerro de Pasco (4,340 m), Peru, were divided into three groups: (1) low altitude, (2) high altitude without EE (hemoglobin < 21 g/dl), and (3) high altitude with EE (hemoglobin >= 21 g/dl). Adjusted multivariable regression models showed that serum testosterone (total or free) and Zn levels were independently correlated with increased hemoglobin levels. Similarly, hemoglobin was positively related with signs/symptoms of CMS; however, both increased the serum Zn and the nitric oxide levels correlated with reduced risk for signs/symptoms of CMS. In conclusion, higher serum testosterone levels and Zn levels were associated with EE, and low scores of signs/symptoms of CMS were associated with higher Zn and nitric oxide levels. PMID- 21553130 TI - ULBP4/RAET1E is highly polymorphic in the Old World monkey. AB - Natural-killer group 2 member D (NKG2D) is an activating receptor that plays an important role in the immune response mediated by NK cells, gammadelta(+) T cells, and CD8(+) T cells. In humans, MHC class I chain-related genes and UL-16 binding protein (ULBP)/retinoic acid early transcript 1 (REAT1) gene family encode ligands for NKG2D. The rhesus and crab-eating macaques, which belong to the Old World monkeys, are widely used as non-human primate models in medical researches on the immunological process. In the present study, we investigated the polymorphisms of ULBP4/RAET1E, a member of the ULBP/RAET1 family, and found 25 and 14 alleles from the rhesus and crab-eating macaques, respectively, of which diversities were far more extended than in humans. A phylogenetic study suggested that the allelic diversification of ULBP4/RAET1E predated the divergence of rhesus and crab-eating macaques. PMID- 21553131 TI - Cardioprotective effects of hesperetin against doxorubicin-induced oxidative stress and DNA damage in rat. AB - Doxorubicin is a widely used chemotherapeutic agent; however, its clinical uses are limited due to its cardiotoxicity associated with an induction of oxidative stress. This study was aimed to investigate the protective effect of hesperetin against doxorubicin-induced cardiotoxicity in rats. Doxorubicin was administered at the dosage of 4 mg/kg bw/week, ip for a period of 5 consecutive weeks. Hesperetin was administered at the dosages of 25, 50 and 100 mg/kg bw, po by gavage for 5 consecutive days in a week for 5 weeks. The animals were killed 1 week after the last injection of doxorubicin. Hesperetin at the doses of 50 and 100 mg/kg bw significantly reduced MDA and increased GSH levels in the doxorubicin-treated animals. Further, hesperetin significantly reduced doxorubicin-induced DNA damage as well as apoptosis at 25, 50, and 100 mg/kg bw as evident from the comet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays, respectively. Thus, hesperetin ameliorated doxorubicin induced cardiotoxicity by reducing oxidative stress, abnormal cellular morphology and DNA damage in rat. Moreover, nuclear factor-kappa B, p38, and caspase-3 play a role in the hesperetin-mediated protection against doxorubicin-induced cardiotoxicity. This study indicates the protective effect of hesperetin against doxorubicin-induced cardiotoxicity. PMID- 21553132 TI - Times to drink: cross-cultural variations in drinking in the rhythm of the week. AB - OBJECTIVES: The time of drinking in terms of daytime versus evening and weekday versus weekend is charted for regular drinkers in 14 countries in Europe, Asia, Latin America, Africa and Oceania. METHODS: National or regional adult population surveys from the GENACIS project. RESULTS: The weekly rhythm of drinking varies greatly between societies. Drinking was generally more likely after 5 p.m. and on weekends. To this extent, alcohol consumption is now regulated by a universal clock. The relation of time of day and of the week of drinking to problems from drinking varied between societies. Drinking at specific times was more likely to predict problems among men than women, though for men the particular time varied, while weekday evenings were the most problematic time for women. The relation of drinking at a particular time to problems in part reflected that heavy drinkers were more likely to be drinking at that time. CONCLUSIONS: There are commonalities across cultures in drinking by time of day and day of the week, but the implications of the timing for alcohol-related problems are fairly culture specific. PMID- 21553133 TI - Virtual reality goes to war: a brief review of the future of military behavioral healthcare. AB - Numerous reports indicate that the incidence of posttraumatic stress disorder (PTSD) in returning OEF/OIF military personnel is creating a significant healthcare challenge. These findings have served to motivate research on how to better develop and disseminate evidence-based treatments for PTSD. Virtual Reality delivered exposure therapy for PTSD has been previously used with reports of positive outcomes. This article details how virtual reality applications are being designed and implemented across various points in the military deployment cycle to prevent, identify and treat combat-related PTSD in OIF/OEF Service Members and Veterans. The summarized projects in these areas have been developed at the University of Southern California Institute for Creative Technologies, a U.S. Army University Affiliated Research Center, and this paper will detail efforts to use virtual reality to deliver exposure therapy, assess PTSD and cognitive function and provide stress resilience training prior to deployment. PMID- 21553134 TI - [Zenker's diverticulum: pro endoscopic treatment]. AB - Zenker's diverticulum occurs as a result of impaired relaxation of the cricopharyngeal muscle primarily causing dysphagia. Affected are elderly patients with several comorbidities. By means of endoscopic intervention the septum is divided between the diverticulum and esophagus which allows unobstructed passage of food and liquids to the diverticulum into the esophagus. Advantages of this technique are manifold: usually general anesthesia is not required, the intervention can be performed in an outpatient setting or if necessary, hospital stay is short and the complication rate is low. Therefore, it is a suitable option for multimorbid patients. In approximately 90% of interventions symptoms of dysphagia are improved after the first treatment resulting in excellent effective medium term results in most cases. PMID- 21553135 TI - Development of the STAR evaluation system for football helmets: integrating player head impact exposure and risk of concussion. AB - In contrast to the publicly available data on the safety of automobiles, consumers have no analytical mechanism to evaluate the protective performance of football helmets. The objective of this article is to fill this void by introducing a new equation that can be used to evaluate helmet performance by integrating player head impact exposure and risk of concussion. The Summation of Tests for the Analysis of Risk (STAR) equation relates on-field impact exposure to a series of 24 drop tests performed at four impact locations and six impact energy levels. Using 62,974 head acceleration data points collected from football players, the number of impacts experienced for one full season was translated to 24 drop test configurations. A new injury risk function was developed from 32 measured concussions and associated exposure data to assess risk of concussion for each impact. Finally, the data from all 24 drop tests is combined into one number using the STAR formula that incorporates the predicted exposure and injury risk for one player for one full season of practices and games. The new STAR evaluation equation will provide consumers with a meaningful metric to assess the relative performance of football helmets. PMID- 21553136 TI - [Vascular interventions in the head and neck region. part 2: procedures for vessel occlusion]. AB - As a result of continuing progress in the development of intervention materials but also due to growing understanding of pathophysiological relationships, the prevalence and significance of endovascular interventions in the head and neck region have continued to increase. This applies to procedures for recanalization, which were addressed in detail in an earlier article, as well as to techniques used for vessel occlusion. This contribution first presents the techniques and materials employed in embolization in the head and neck region. Based on this description the application of endovascular procedures for vessel occlusion are explained with respect to different disease entities in the head and neck region. In this context particular attention is given to the treatment of intracranial aneurysms, cerebral arteriovenous malformations, dural AV fistulae, vascular malformations, and tumors in the head and neck region. PMID- 21553137 TI - [Reconstruction of the elbow with the deep circumflex iliac artery. Multicomponent free flap plasty after a gunshot wound]. AB - A 20-year-old woman sustained massive elbow trauma from a gunshot wound. After initial surgery soft tissue coverage, reconstruction of the proximal third of the ulna, of the ulnar collateral ligament and of the triceps tendon was performed by one multicomponent microvascular free flap. There were no complications, the elbow is stable and reached full weight bearing 11 months after trauma. Active range of motion for extension and flexion is 0-20 degrees -80 degrees . PMID- 21553138 TI - [Diagnosis and therapy of hip abductor insufficiency after hip arthroplasty]. AB - Abductor insufficiency after hip arthroplasty is a difficult and challenging problem whereby conservative therapy is often insufficient and surgical therapy is known to have failures with re-ruptures. Alternative approaches and arthroscopic surgery are proposed but in many cases they do not fulfill the expectations of patients.Our experience with temporary explantation of implants and transosseous refixation is good resulting in a pain-free patient in a high number of cases but the method is quite demanding and needs a cooperative patient. A functionless abductor muscle is not amenable to surgical treatment but only a surgical exploration can confirm the clinical suspicion. PMID- 21553139 TI - [Selected interventional methods for the treatment of chronic pain: Part 1: peripheral nerve block and sympathetic block]. AB - Approximately 5-8 million people in Germany suffer from chronic pain. Some patients can obtain relief from specific interventional techniques. In detail these are blocks of the sympathetic chain and peripheral nerve blocks, regional anesthetic techniques close to the spinal cord and neuromodulation. Part 1 of this article presents peripheral nerve blocks using the example of intercostal blocks and blocks of the sympathetic chain. Peripheral nerve blocks are important for postoperative pain treatment. Only a few methods are used for chronic pain and this applies primarily to the intercostal block which is used for the treatment of pain occurring after thoracotomy, intercostal neuralgia and pain associated with infiltration of cancer. Blocks of the vegetative nervous system are accomplished on the ganglions of the head and the sympathetic chain and are therefore most commonly applied to treat headache, neuropathic and sympathetic pain in the area of abdomen and the extremities. PMID- 21553140 TI - Expression profiling of difficult-to-diagnose thyroid histologic subtypes shows distinct expression profiles and identify candidate diagnostic microRNAs. AB - BACKGROUND: The incidence of thyroid cancer is increasing worldwide. The findings of up to 30% of thyroid fine-needle aspiration biopsies (FNAB) are inconclusive, primarily as a result of several thyroid histologic subtypes with overlapping cytologic features. MicroRNAs (miRNAs) are small noncoding RNAs and have been implicated in carcinogenesis. We hypothesized that there are miRNAs that are differentially expressed between benign and malignant thyroid tumors that are difficult to distinguish by FNAB. METHODS: The expression of 1263 human miRNAs was profiled in 47 tumor samples representing difficult to diagnose histologic subtypes of thyroid neoplasm (21 benign, 26 malignant). Differentially expressed miRNAs were validated by quantitative real-time reverse transcriptase-polymerase chain reaction. The area under the receiver operating characteristic curve (AUC) was used to determine the diagnostic accuracy of differentially expressed miRNAs. RESULTS: Supervised hierarchical cluster analysis demonstrated grouping of 2 histologies (papillary and follicular thyroid carcinoma). A total of 34 miRNAs were differentially expressed in malignant compared to benign thyroid neoplasms (P<0.05). A total of 25 of the 34 nonproprietary miRNAs were selected for validation, and 15 of the 25 miRNAs were differentially expressed between benign and malignant samples with P-value<0.05. Seven miRNAs had AUC values of >0.7. miR 7 and miR-126 had the highest diagnostic accuracy with AUCs values of 0.81 and 0.77, respectively. CONCLUSION: To our knowledge, this is the first study to evaluate the diagnostic accuracy of miRNAs in thyroid histologies that are difficult to distinguish as benign or malignant by FNAB. miR-126 and miR-7 had high diagnostic accuracy and could be helpful adjuncts to thyroid FNAB. PMID- 21553141 TI - Clinical implications of bilateral lateral cervical lymph node metastasis in papillary thyroid cancer: a risk factor for lung metastasis. AB - BACKGROUND: Distant metastasis to the lung in papillary thyroid cancer (PTC) is rarely detected, but it is known to be an important prognostic factor associated with survival. We investigated risk factors for lung metastasis in PTC. MATERIALS AND METHODS: We performed a retrospective review of patients with PTC (n=977) who were treated from January 2006 to August 2009. Enrolled patients received radioablation therapy followed by a radioiodine whole body scan. Lung metastasis was screened out with whole body scan or positron emission tomography/computed tomography (PET/CT) and confirmed with chest CT. Age, gender, extrathyroidal extension, central lymph node metastasis, lateral lymph node metastasis, and bilateral lateral cervical lymph node metastasis (BLNM) were investigated to analyze the relationship with lung metastasis. RESULTS: In total, 949 patients were enrolled. The median age was 49 years (+/-13 years) with 829 women. Lung metastasis was found in 20 patients (2.1%). Patients were divided into three groups by tumor size (<=1 cm, 1-2 cm, >2 cm); the groups comprised 47.3%, 28.5%, and 24.1% of the patients, respectively. BLNM was identified in 4.4% (n=43). In a univariate analysis, male gender, old age, large tumor, extrathyroidal extension, lymph node metastasis, lateral lymph node metastasis, and BLNM were significantly related to lung metastasis (P<0.05). In a multivariate analysis, BLNM appeared to be the only significant risk factor for lung metastasis (P=0.026; odds ratio=10.219). CONCLUSIONS: BLNM may be a risk factor for lung metastasis. This indicates that careful examinations, including chest CT and positron emission tomography (PET), are recommended during the follow-up period when BLNM is suspected. PMID- 21553142 TI - Selective organ preservation in operable locally advanced head and neck squamous cell carcinomas guided by primary site restaging biopsy: long-term results of two sequential brown university oncology group chemoradiotherapy studies. AB - OBJECTIVES: The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. METHODS: A total of 65 patients were treated with CRT consisting of carboplatin (AUC=1/week) and paclitaxel (60 or 40 mg/m2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. RESULTS: Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long term failure rates were: 6% local, 6% regional, and 32% distant. CONCLUSIONS: This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups. PMID- 21553143 TI - Butylidenephthalide suppresses human telomerase reverse transcriptase (TERT) in human glioblastomas. AB - BACKGROUND: Telomerase is widely expressed in most human cancers, but is almost undetectable in normal somatic cells and is therefore a potential drug target. Using the human telomerase promoter platform, the naturally occurring compound butylidenephthalide (BP) was selected for subsequent investigation of antitumor activity in vitro and in vivo. METHODS: We treated human glioblastoma cells with BP and found a dose-dependent decrease in human telomerase reverse transcriptase (hTERT) mRNA expression and a concomitant increase in p16 and p21 expression. Because c-Myc and Sp1 are involved in transcriptional regulation of hTERT, the effect of BP on c-Myc and Sp1 expression was examined. RESULTS: Using electrophoretic mobility shift assays and western blotting, we showed that BP represses hTERT transcriptional activity via downregulation of Sp1 expression. Using the telomerase repeat amplification protocol, an association between BP concentration and suppression of telomerase activity, induction of human glioblastoma senescence, and inhibition of cellular proliferation was identified. This was supported by a mouse xenograft model, in which BP repressed telomerase and inhibited tumor proliferation, resulting in tumor senescence. Overexpression of hTERT restored telomerase activity in human glioblastoma cells and overcame replicative senescence. CONCLUSIONS: These findings suggest that BP inhibits proliferation and induces senescence in human glioblastomas by downregulating hTERT expression and consequently telomerase activity. This is the first study to describe regulation of telomerase activity by BP in human glioblastomas. PMID- 21553144 TI - Evaluating patient adherence to antidepressant therapy among uninsured working adults diagnosed with major depression: results of the Texas Demonstration to Maintain Independence and Employment study. AB - This study examined antidepressant adherence and persistence among uninsured working adults diagnosed with major depression enrolled in the Texas Demonstration to Maintain Independence and Employment (DMIE) program. Antidepressant adherence was measured between intervention and control cohorts using proportion of days covered (PDC) during a 365-day observation period. Persistence examined duration of time from drug initiation to discontinuation based on a >=35-day refill supply gap. Older, non-minority patients with higher education were more adherent or persistent to antidepressant therapy. Adjusting for covariates, results showed no significant difference in PDC at the end of 12 months between intervention and control participants (b = .07, P = .054, semi partial eta (2) = .02). Exploratory analysis found subgroup differences in PDC among the study recruitment cohorts. No significant difference between intervention and control groups was found in persistence between the groups. Follow-up investigation is planned to assess the longer term impact of the DMIE program on antidepressant adherence and persistence. PMID- 21553145 TI - Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why? AB - Tumor-infiltrating T lymphocytes (TILs) are observed in a number of human primary or metastatic tumors. Recently, gene expression profiling experiments suggested that the presence of T cells in metastatic melanomas before vaccinating the patients with tumor antigens could be a biomarker for clinical benefit from the vaccines. In this context, we review results pertaining to TILs in human melanomas, their prognostic value, and some possible reasons why their presence could help in selecting melanoma patients for vaccination against tumor-specific antigens. PMID- 21553146 TI - Increased PRAME antigen-specific killing of malignant cell lines by low avidity CTL clones, following treatment with 5-Aza-2'-Deoxycytidine. AB - The cancer testis antigen Preferentially Expressed Antigen of Melanoma (PRAME) is overexpressed in many solid tumours and haematological malignancies whilst showing minimal expression in normal tissues and is therefore a promising target for immunotherapy. HLA-A0201-restricted peptide epitopes from PRAME have previously been identified as potential immunogens to drive antigen-specific autologous CTL responses, capable of lysing PRAME expressing tumour cells. CTL lines, from 13 normal donors and 10 melanoma patients, all of whom were HLA-A0201 positive, were generated against the PRAME peptide epitope PRA(100-108). Specific killing activity against PRA(100-108) peptide-pulsed targets was weak compared with CTL lines directed against known immunodominant peptides. Moreover, limiting dilution cloning from selected PRAME-specific CTL lines resulted in the generation of a clone of only low to intermediate avidity. Addition of the demethylating agent 5-aza-2'-Deoxycytidine (DAC) increased PRAME expression in 7 out of 11 malignant cell lines including several B lineage leukaemia lines and also increased class I expression. Pre-treatment of target cells was associated with increased sensitivity to antigen-specific killing by the low avidity CTL. When CTL, as well as of the target cells, were treated, the antigen-specific killing was further augmented. Interestingly, one HLA-A0201-negative DAC-treated line (RAJI) showed increased sensitivity to killing by clones despite a failure of expression of PRAME or HLA-A0201. Together these data point to a general increased augmentation of cancer immunogenocity by DAC involving both antigen specific and non-specific mechanisms. PMID- 21553147 TI - Evaluation of factors affecting post-treatment quality of life in oral and oropharyngeal cancer patients primarily treated with curative surgery: an exploratory study. AB - The aim was to explore the impact of important clinico-demographic factors on the post-treatment quality of life (QOL) in surgically treated oral and oropharyngeal cancer patients. 63 consecutive follow-up oral and oropharyngeal cancer patients treated primarily with surgery were recruited. 55 patients sent the completed questionnaires and finally included in this study. QOL and important sub-domains of the QOL were assessed. Mean QOL scores (SD) were computed, level of significance was set at P < 0.05. The mean composite QOL score and standard deviation (SD) for oral and oropharyngeal cancer patients were 76.6 (15.2) and 73.4 (13.9), respectively. Patients with higher T-stage (T3 and T4) and higher overall-stage (III and IV) had lower mean QOL scores as against early T (T1 and T2) and overall early-stage (I and II); mean scores (SD) 64.3 (13.6) and 72.3 (13.8), and 76.6 (13.6) and 81.7 (14.1), respectively. Younger patients had lower mean scores (SD) than older patients; mean QOL scores (SD) 69.7 (14.0) and 79.6 (SD), respectively. Patients with reconstruction had lower mean QOL scores as compared to those without reconstruction; mean scores (SD) 67.6 (16.0) and 77.4 (12.5), respectively. In conclusion, tumor-stage, overall-stage, age of patients, and reconstruction had a significant direct effect on the post-treatment QOL of oral and oropharyngeal cancer patients. PMID- 21553148 TI - Review on clinical trials of targeted treatments in malignant mesothelioma. AB - PURPOSE: Malignant mesothelioma (MM) is an aggressive tumor of the serosal surfaces with a poor prognosis. Advances in the understanding of tumor biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. This article is a comprehensive review of all clinical trials evaluating the effect of targeted treatments in MM. METHODS: An extensive literature search was performed in January 2011 using pubmed and medline. No constraints on publication date were applied. RESULTS: Thirty-two trials exploring 17 different targeted agents in MM were found. Treatment in first- and second-line targeted agents induced response rates ranging from 0-14% and 0-16%, respectively. The tyrosine kinase inhibitor sunitinib induced partial response in 10% and stable disease in 66% of MPM patients as second-line treatment. A preliminary analysis of a phase II/III trial suggests that addition of bevacizumab to pemetrexed and cisplatin first-line treatment significantly improves disease control (CR + PR + SD) in the bevacizumab arm (73.5%) compared with treatment with pemetrexed and cisplatin without bevacizumab (43.2%) (P = 0.010). Another phase II trial did not observe any significant clinical benefit of adding of bevacizumab to gemcitabine and cisplatin. CONCLUSIONS: Disease stabilization is reported in some patients with several targeted treatments and might be beneficial in subgroups of patients or in combination with classic chemotherapy. None of the hitherto explored targeted treatments can currently be recommended as standard treatment in MM. PMID- 21553149 TI - Brief report: faces cause less distraction in autism. AB - Individuals with autism have difficulties interpreting face cues that contribute to deficits of social communication. When faces need to be processed for meaning they fail to capture and hold the attention of individuals with autism. In the current study we illustrate that faces fail to capture attention in a typical manner even when they are non-functional to task completion. In a visual search task with a present butterfly target an irrelevant face distracter significantly slows performance of typical individuals. However, participants with autism (n = 28; mean 10 years 4 months) of comparable non-verbal ability are not distracted by the faces. Interestingly, there is a significant relationship between level of functioning on the autism spectrum and degree of face capture or distraction. PMID- 21553150 TI - Sequence variants of Toll-like receptor 4 (TLR4) and the risk of prostate cancer in Korean men. AB - PURPOSE: Chronic inflammation has been considered a potential risk factor for prostate cancer. Toll-like receptors (TLRs) are important in the innate immune response to pathogens and in cross talk between innate immunity and adaptive immunity. In this study, sequence variants in the TLR4 gene were investigated to determine whether they were associated with prostate cancer risk in a Korean cohort. METHODS: An association study between 11 single-nucleotide polymorphisms (SNPs) of the TLR4 gene and prostate cancer was performed in 463 Korean male subjects including 240 prostate cancer patients and 223 healthy controls. SNPs were genotyped using the TaqMan assay, and their association with the risk of prostate cancer was evaluated using logistic regression analysis. RESULTS: The statistical analysis revealed that one SNP at the 3'UTR (rs11536889) showed significant association with the risk of prostate cancer (P (corr) = 0.005, OR = 1.81). One common haplotype (ht2) was also significantly associated with the risk of prostate cancer (P (corr) = 0.009, OR = 1.77). However, further analysis showed no association between any of the SNPs and prostate cancer prognostic factors such as the Gleason score or tumor stage. CONCLUSIONS: The findings of this study suggest that polymorphisms of the TLR4 gene might be associated with the risk of prostate cancer in Korean men. PMID- 21553151 TI - The ethical self-fashioning of physicians and health care systems in culturally appropriate health care. AB - Diverse advocacy groups have pushed for the recognition of cultural differences in health care as a means to redress inequalities in the U.S., elaborating a form of biocitizenship that draws on evidence of racial and ethnic health disparities to make claims on both the state and health care providers. These efforts led to federal regulations developed by the U.S. Office of Minority Health requiring health care organizations to provide Culturally and Linguistically Appropriate Services. Based on ethnographic research at workshops and conferences, in-depth interviews with cultural competence trainers, and an analysis of postings to a moderated listserv with 2,000 members, we explore cultural competence trainings as a new type of social technology in which health care providers and institutions are urged to engage in ethical self-fashioning to eliminate prejudice and embody the values of cultural relativism. Health care providers are called on to re-orient their practice (such as habits of gaze, touch, and decision-making) and to act on their own subjectivities to develop an orientation toward Others that is "culturally competent." We explore the diverse methods that cultural competence trainings use to foster a health care provider's ability to be self-reflexive, including face-to-face workshops and classes and self-guided on-line modules. We argue that the hybrid formation of culturally appropriate health care is becoming detached from its social justice origins as it becomes rationalized by and more firmly embedded in the operations of the health care marketplace. PMID- 21553152 TI - Clinical subjectivation: anthropologies of contemporary biomedical training. PMID- 21553153 TI - Change in action: using positive deviance to improve student clinical performance. AB - At our medical college many students have lower ratings in their clinical performance once they start their clinical years (third year). This is contrary to their results in other written exams. Some students demonstrate better clinical performance. We used the six-step Positive Deviance (PD) Conceptual Framework to identify and disseminate the strategies employed by the successful students to improve group clinical performance. Fifty 3rd year students (of a 5 year MBBS program) rotating through internal medicine were assessed mid-rotation with mini-CEX and 360 degrees evaluations. Twenty students (40%) who performed well were invited for in depth interviews in order to identify positive deviant behavior in their clinical skills learning practices. The seven students (14%) who reported novel behaviors were asked to develop strategies for dissemination of their learning behavior in their peers. They decided to work in small groups with their peers, using the identified PD behaviors to encourage learning of history taking and examining skills in their peers. Group performance was assessed at the end of rotation, using mini-CEX and 360 degrees evaluation in comparison to a subsequent group of students in the same year that did not work in PD peer learning groups. For the 360 degrees evaluation the EP(2) (generalizability coefficient) was 0.92 and for the mini-CEX the EP(2) was 0.95, taking into account the variances between participants, groups, time and the interactions effects; thus indicating good reliability of both the assessment methods. A statistically significant difference (p < 0.05) was seen for improvement in medical interviewing skills and clinical judgment on the mini-CEX exam and 360 evaluation (p < 0.0001) in the PD group. Positive Deviance approach can help highlight behaviors among medical students, which contribute to success but may go unnoticed. Learning strategies based on the PD framework can improve student's group performance. PMID- 21553154 TI - Association of steroid use with complicated sigmoid diverticulitis: potential role of activated CD68+/CD163+ macrophages. AB - BACKGROUND: Immunosupression and, especially, intake of steroids have previously been identified as risk factors for complicated types of sigmoid diverticulitis. However, little is known about the underlying molecular and cellular mechanisms. We aimed to elucidate the potential role of activated macrophages in this respect. METHODS: A consecutive series of n = 101 patients having undergone surgical resection for sigmoid diverticulitis at our institution was analyzed regarding the inflammatory infiltrate and prevalence of comorbid diseases as well as risk factors, including steroid use. Fifty-seven patients had complicated types of diverticulitis with severe inflammation (group A). Forty-four patients had moderate inflammation, most of whom had been operated for chronically recurrent diverticulitis (group B). Randomly selected 50 patients (n = 20/group A/n = 30 group B) underwent immunolabelling against CD68 and CD163. RESULTS: Using immunofluorescence double labeling experiments we found a strong positive correlation of CD68 expression with CD163 expression (t = 0.934). High CD68 expression (x >= 23%) and high CD163 expression (x >= 22%) within stromal cells of the lamina propria was significantly associated with steroid use (CD68, p = 0.012 and CD163, p = 0.004, respectively) and complicated sigmoid diverticulitis with severe inflammation (CD68, p = 0.0001 and CD163, p = 0.001, respectively). CONCLUSIONS: Inflammation, especially mediated by activated (CD68+/CD163+) macrophages in histopathological specimen might resemble the cellular link between steroid use and complicated types of sigmoid diverticulitis. Macrophages might be a suitable target for future supportive/preventive therapies. However, as long as we are lacking such strategies, we must bear in mind that steroid intake is a risk factor for complicated diverticulitis, especially when indicating surgical resection. PMID- 21553155 TI - Development of fluorapatite cement for dental enamel defects repair. AB - In order to restore the badly carious lesion of human dental enamel, a crystalline paste of fluoride substituted apatite cement was synthesized by using the mixture of tetracalcium phosphate (TTCP), dicalcium phosphate anhydrous (DCPA) and ammonium fluoride. The apatite cement paste could be directly filled into the enamel defects (cavities) to repair damaged dental enamel. The results indicated that the hardened cement was fluorapatite [Ca(10)(PO(4))(6)F(2), FA] with calcium to phosphorus atom molar ratio (Ca/P) of 1.67 and Ca/F ratio of 5. The solubility of FA cement in Tris-HCl solution (pH = 5) was slightly lower than the natural enamel, indicating the FA cement was much insensitive to the weakly acidic solutions. The FA cement was tightly combined with the enamel surface, and there was no obvious difference of the hardness between the FA cement and natural enamel. The extracts of FA cement caused no cytotoxicity on L929 cells, which satisfied the relevant criterion on dental biomaterials, revealing good cytocompatibility. In addition, the results showed that the FA cement had good mechanical strength, hydrophilicity, and anti-bacterial adhesion properties. The study suggested that using FA cement was simple and promising approach to effectively and conveniently restore enamel defects. PMID- 21553157 TI - The new era of risk reclassification in cardiovascular imaging. PMID- 21553156 TI - Characterization of and host response to tyramine substituted-hyaluronan enriched fascia extracellular matrix. AB - Naturally-occurring biomaterial scaffolds derived from extracellular matrix (ECM) have been previously investigated for soft tissue repair. We propose to enrich fascia ECM with high molecular weight tyramine substituted-hyaluronan (TS-HA) to modulate inflammation associated with implantation and enhance fibroblast infiltration. As critical determinants of constructive remodeling, the host inflammatory response and macrophage polarization to TS-HA enriched fascia were characterized in a rat abdominal wall model. TS-HA treated fascia with cross linking had a similar lymphocyte (P = 0.11) and plasma cell (P = 0.13) densities, greater macrophage (P = 0.001) and giant cell (P < 0.0001) densities, and a lower density of fibroblast-like cells (P < 0.0001) than water treated controls. Treated fascia, with or without cross-linking, exhibited a predominantly M2 pro remodeling macrophage profile similar to water controls (P = 0.82), which is suggestive of constructive tissue remodeling. Our findings demonstrated that HA augmentation can alter the host response to an ECM, but the appropriate concentration and molecular weight needed to minimize chronic inflammation within the scaffold remains to be determined. PMID- 21553158 TI - PET imaging of aortic atherosclerosis: Is combined imaging of plaque anatomy and function an amaranthine quest or conceivable reality? AB - Traditionally, blood vessels have been studied using contrast luminography to determine the site, extent and severity of luminal compromise by atherosclerotic deposits. Similar anatomical data can now be acquired non-invasively using ultrasound, computed tomography or magnetic resonance imaging. Plaque stability is an important determinant of subsequent vascular events and currently functional data on the stability of plaque is less well provided by these methods. The search for non-invasive techniques to image combined plaque anatomy and function has been pursued with visionary anticipation. This expectation may soon be realised as imaging with radionuclide-labelled atheroma-targeted contrast agents has demonstrated that plaque functional characteristics can now be shown. Increasingly positron emission tomography/computed tomography (PET/CT) imaging with (18)F fluorodexoyglucose (FDG) and other radionuclides is being used to determine culprit plaques in complex clinically scenarios. Clinically, this information may prove extremely valuable in the assessment of stable and unstable patients and its use in prime time medical practice is eagerly awaited. We will discuss the current clinical applications of functional atheroma imaging in the aorta and highlight the promising preclinical data on novel image biomarkers of plaque instability. If clinical science is able to successfully translate these advances in vascular imaging from the bench to the bedside, a new paradigm will be achieved in cardiovascular diagnostics. PMID- 21553159 TI - Cardiac tamponade on ECG-gated dipyridamole PET perfusion imaging. PMID- 21553160 TI - Current state of hybrid imaging: attenuation correction and fusion. PMID- 21553161 TI - Effect of body mass index on the efficacy, side effect profile, and plasma concentration of fixed-dose regadenoson for myocardial perfusion imaging. AB - BACKGROUND: There are limited data on the effect of body mass index (BMI) on the actions of fixed-dose regadenoson. The purpose of this study was to determine the effect of BMI on the efficacy, side effects, and plasma concentration of regadenoson for Myocardial Perfusion Imaging (MPI). METHODS AND RESULTS: The study included 2,015 subjects from the ADVANCE MPI trials. Initial adenosine MPI was followed by randomization to regadenoson (400-MUg bolus injection) or adenosine (6-minute infusion) MPI. Subjects were classified according to BMI into six categories from underweight (<20 kg/m(2)) to extremely obese (>=40 kg/m(2)). PK modeling was used to predict the effect of BMI on plasma regadenoson concentration (PRC). Adenosine-regadenoson agreement rates for the presence and extent of reversibility were similar across BMI categories (P > .05). The incidence of side effects was also similar across BMIs (P >= .06). Subjects were less likely to feel very or extremely uncomfortable after regadenoson vs adenosine in all groups with BMI >= 25 kg/m(2), but this trend was not statistically significant in subjects with BMI 20-24 kg/m(2) (P > .05). PRC was inversely related to BMI with 19% higher PRC in the underweight and 36% lower PRC in the extremely obese compared with a normal weight subject. CONCLUSIONS: BMI does not alter the efficacy of regadenoson MPI despite lower PRC in high BMI subjects, or its side effect profile despite higher PRC in low BMI subjects. Regadenoson is better tolerated than adenosine but this benefit seems to lose statistical significance in subjects with BMI < 25 kg/m(2). PMID- 21553162 TI - Emergent embolization of arterial bleeding after vacuum-assisted breast biopsy. AB - Vacuum-assisted core breast biopsy has become important in evaluating patients with suspicious breast lesions. It has proven to be a relatively safe procedure that in rare cases can result in vascular complications. These are the first reported cases of transcatheter embolization of uncontrolled breast hemorrhage after vacuum-assisted breast biopsy. With increased use of biopsy and larger gauge devices, breast imaging groups may consider embolotherapy as a safe alternative for treatment of hemorrhage in a select group of patients. PMID- 21553163 TI - Successful thrombolysis and spasmolysis of acute leg ischemia after accidental intra-arterial injection of dissolved flunitrazepam tablets. AB - A 37-year-old man with known intravenous drug abuse presented in the surgical ambulatory care unit with acute leg ischemia after accidental intra-arterial injection of dissolved flunitrazepam tablets into the right femoral artery. A combination of anticoagulation, vasodilatation, and local selective and superselective thrombolysis with urokinase was performed to salvage the leg. As a result of the severe ischemia-induced pain, the patient had to be monitored over the complete therapy period on the intensive care unit with permanent administration of intravenous fluid and analgetics. We describe the presenting symptoms and the interventional technique, and we discuss the recent literature regarding the management of accidental intra-arterial injection of dissolved flunitrazepam tablets. PMID- 21553164 TI - A kinetic study of the polymorphic transformation of nimodipine and indomethacin during high shear granulation. AB - The objective of the present study was to investigate the mechanism, kinetics, and factors affecting the polymorphic transformation of nimodipine (NMD) and indomethacin (IMC) during high shear granulation. Granules containing active pharmaceutical ingredient, microcrystalline cellulose, and low-substituted hydroxypropylcellulose were prepared with ethanolic hydroxypropylcellulose solution, and the effects of independent process variables including impeller speed and granulating temperature were taken into consideration. Two polymorphs of the model drugs and granules were characterized by X-ray powder diffraction analysis and quantitatively determined by differential scanning calorimetry. A theoretical kinetic method of ten kinetic models was applied to analyze the polymorphic transformation of model drugs. The results obtained revealed that both the transformation of modification I to modification II of NMD and the transformation of the alpha form to the gamma form of IMC followed a two dimensional nuclei growth mechanism. The activation energy of transformation was calculated to be 7.933 and 56.09 kJ.mol(-1) from Arrhenius plot, respectively. Both the granulating temperature and the impeller speed affected the transformation rate of the drugs and, in particular, the high shear stress significantly accelerated the transformation process. By analyzing the growth mechanisms of granules in high-shear mixer, it was concluded that the polymorphic transformation of NMD and IMC took place in accordance with granule growth in a high-shear mixer. PMID- 21553165 TI - Injectability evaluation: an open issue. AB - The current work aimed to propose a system of scoring to rationalize and support the selection of the optimal diameter and length of needles. Four formulations at different viscosity and needles ranging from 21 to 26 G and length ranging from 16 to 40 mm were used. Plunger-stopper breakloose force, maximum force (F(max)), and dynamic glide force were measured by a texture analyzer at the crosshead speed of 1 mm/s. Testing was carried out into air or human subcutaneous tissue. The manual injectability of the highest viscosity product was assessed by ten evaluators. The comparison of the panel test score and the quantitative measurements of the forces permitted to score a given needle-syringe-formulation system keeping also in consideration the pressure created in the subcutaneous space and muscles at the injection site. In particular, the following relationship was drawn: at the F(max) up to 250 mPa, the injection was practically impossible; at F(max) ranging from 160 to 250 mPa, the injection was very difficult; at F(max) in the 125-160 mPa range, the injection was feasible, though with some difficulty; when the values of F(max) were lower 125 mPa, the injection went smoothly. On the basis of these preliminary data, a system of scoring the needle-syringe-formulation system is proposed to rationalize and support the selection of the optimal diameter and length of needles, keeping also in consideration the pressure created in the subcutaneous space and muscles at the injection site. PMID- 21553166 TI - [Aspects of inner ear trauma in CI treatment]. PMID- 21553167 TI - Accidental insertion of a percutaneous venovenous cannula into the persistent left superior vena cava of a patient undergoing liver transplantation. AB - PURPOSE: Persistent left superior vena cava (PLSVC) is a rare congenital vascular abnormality found in 0.3% of the general population. We report herein a rare complication involving the accidental insertion of a large bore cannula into the PLSVC during liver transplantation (LT). CLINICAL FEATURES: A 63-yr-old man with primary sclerosing cholangitis presented for LT. Given the existence of a tunnelled dialysis catheter in the right internal jugular vein (IJV) and a triple lumen catheter via the left IJV, insertion of an 18 French cannula for venovenous bypass (VVB) was performed via the left IJV using the existing triple lumen cannula as a conduit for a guidewire. Upon initiation of VVB, profound systemic hypotension occurred, and liver transplantation was completed without the further use of VVB. A chest x-ray confirmed a malposition of the VVB cannula with a large left hemothorax. A mini-sternotomy was performed for removal of the VVB cannula, which was found to be inserted in the PLSVC. Retrospectively, the presence of PLSVC was not anticipated due to a normal superior vena cava and a left innominate vein, as revealed by the course of a pre-existing left internal jugular vein triple lumen catheter on a preoperative chest x-ray, and due to a normal-sized coronary sinus on preoperative echocardiography. CONCLUSION: Malpositioning of a venous cannula in a PLSVC should be anticipated as one of the potential complications of vascular access via the left internal jugular vein. PMID- 21553168 TI - Controlled release systems containing solid dispersions: strategies and mechanisms. AB - In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system. PMID- 21553169 TI - Effectiveness of endoclips for the treatment of stigmata of recent hemorrhage in the colon of patients with acute lower gastrointestinal tract bleeding. AB - AIMS AND METHODS: Coaptive thermo coagulation (CTC) for the treatment of stigmata of recent hemorrhage (SRH) in the colon is risky. We evaluated the safety and effectiveness of endoclips in 13 patients with acute lower gastrointestinal bleeding (GIB). Thirty-day re-bleeding and complication rates were comparable to a historical cohort of 41 patients (group 2) who underwent CTC/IE (injection epinephrine) for the management of acute lower GIB. RESULTS: There was no difference in the 30-day re-bleeding rates in the two groups. In group I, immediate hemostasis was successful in all patients. Three of 13 patients (23.1%) developed re-bleeding. In group II, 41 patients from six prior studies underwent CTC and/or IE for the treatment of HRS where 12 (29.3%) developed re-bleeding. There were no immediate complications. CONCLUSIONS: Endoclip deployment is as effective as CTC and/or IE for treatment of SRH in the colon. PMID- 21553170 TI - Evaluation of two sources of calcium sulfate for a local drug delivery system: a pilot study. AB - BACKGROUND: Local drug delivery has substantial potential to prevent infections compared with systemic delivery. Although calcium sulfate (CaSO(4)) has been studied for local drug delivery and two types are commercially available, it is unknown whether they differentially release antibiotics. QUESTIONS/PURPOSES: We determined the differences between two sources of CaSO(4) and the K(2)SO(4) catalyst's presence on the degradation, daptomycin elution, and activity against Staphylococcus aureus. METHODS: We formed pellets from synthetic and naturally sourced (from gypsum) CaSO(4) and loaded with 5% daptomycin and 3% or 0% K(2)SO(4). We used in vitro experiments to determine the daptomycin concentration and degradation profiles over 10 days. Turbidity assays were used to evaluate the activity of the daptomycin eluates against S. aureus. RESULTS: All pellets exhibited a bolus release with the highest daptomycin concentration on Day 1 with the sourced CaSO(4) pellets. The synthetic CaSO(4) pellets with 3% K(2)SO(4) exhibited a slower drug release compared with the synthetic CaSO(4) pellets with 0% K(2)SO(4), which degraded and eluted daptomycin too quickly to inhibit S. aureus. Turbidity assays demonstrated that all CaSO(4) pellets inhibit S. aureus for expected lengths of time. CONCLUSIONS: Our preliminary in vitro data suggest differences in the degradation, elution, and activity properties between sourced and synthetic CaSO(4) pellets. The addition of K(2)SO(4) appeared beneficial when using synthetic CaSO(4). Synthetic CaSO(4) may be effective when slow degradation and longer elution times are needed. CLINICAL RELEVANCE: Local delivery of eluted daptomycin can be tailored through material selection and K(2)SO(4) addition. PMID- 21553171 TI - Infection control rate of irrigation and debridement for periprosthetic joint infection. AB - BACKGROUND: Irrigation and debridement with retention of prosthesis is commonly performed for periprosthetic joint infection. Infection control is reportedly dependent on timing of irrigation and debridement relative to the index procedure. QUESTIONS/PURPOSES: We therefore (1) compared the ability of irrigation and debridement to control acute postoperative, acute delayed, and chronic infections and (2) determined whether any patient-related factors influenced infection control. PATIENTS AND METHODS: We retrospectively reviewed the records of 136 patients (138 joints) from two institutional databases treated with irrigation and debridement between 1996 and 2007. Mean age at time of treatment was 64 years (range, 18-89 years); 77 (56%) joints were in women. Three subgroups were extracted: acute postoperative infections, occurring within 4 weeks (52 joints), acute delayed infections occurring after 4 weeks with acute onset of symptoms (50 joints), and chronic infections (36 joints). Minimum followup was 12 months (average, 54 months; range, 12-115 months). Failure to control infection was reported as the need for any subsequent surgical intervention and/or use of long-term suppressive antibiotics. RESULTS: Infection control was not achieved in 90 joints (65%; 82 requiring return to surgery and eight remaining on long-term suppressive antibiotics). Failure rates were 69% (36 of 52), 56% (28 of 50), and 72% (26 of 36) for acute postoperative, acute delayed, and chronic infections, respectively. Of the 10 variables considered as potential risk factors, only Staphylococcal organisms predicted failure. CONCLUSIONS: Irrigation and debridement is unlikely to control periprosthetic joint infection, including acute infections. Our data suggest surgeons should be cautious using this procedure as a routine means to address periprosthetic joint infection. For most patients, we recommend irrigation and debridement be reserved for an immunologically optimized host infected acutely with a non-Staphylococcal organism. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21553172 TI - Natural orifice translumenal endoscopic surgery (NOTES((r))): a technical review. AB - INTRODUCTION: The clinical NOTES literature continues to grow. This review quantifies the published human NOTES experience to date, examines instrument use in detail, and compiles available perioperative outcomes data. METHODS: A PubMed search for all articles describing human NOTES cases was performed. All articles providing a technical description of procedures, excluding cases limited to diagnostic procedures, specimen extraction, fluid drainage or gynecological procedures, were reviewed. Two reviewers systematically cataloged the technical details of each procedure and performed a frequency analysis of instrument use in each type of case. Available outcomes data were also compiled. RESULTS: Forty three discrete articles were reviewed in detail, describing a total of 432 operations consisting of transvaginal (n = 355), transgastric (n = 58), transesophageal (n = 17), and transrectal (n = 2) procedures, with 90% of cases performed in hybrid fashion with laparoscopic assistance. Cholecystectomy (84% of cases) was the most common procedure. Analysis of key steps included choice of endoscope, establishment of peritoneal access, dissection, specimen extraction, and closure of the access site. Analysis of instrument use during transvaginal cholecystectomy revealed variation in the choice of endoscope and the technique for establishment of access. A majority of these procedures relied heavily on the use of rigid and transabdominal instrumentation. Closure of the vaginotomy site was found to be well standardized, performed with an open suturing technique. Similar analysis for transgastric procedures revealed consistency in the choice of flexible endoscope as well as access and closure techniques. Perioperative outcomes from NOTES procedures were reported, but the data are currently limited due to small case numbers. CONCLUSIONS: NOTES is most commonly performed using a hybrid, transvaginal approach. Although some aspects of these procedures appear to be well standardized, there is still significant variability in technique. More outcomes data with standardized reporting are needed to determine the actual risks and benefits of NOTES. PMID- 21553173 TI - Totally laparoscopic sigmoid colectomy with transanal specimen extraction. AB - BACKGROUND: Conventional techniques for laparoscopic-assisted colectomy (LAC) require abdominal minilaparotomy for extraction of the specimen. Abdominal wound complications often increase the invasiveness of LAC. To decrease the incidence of wound complications, natural orifice specimen extraction (NOSE) has been reported. However, only a few devices that allow smooth extraction and reduced intracorporeal contamination have been reported previously. We performed totally laparoscopic sigmoid colectomy using transanal specimen extraction (TASE) and the Alexis((r)) wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA). We document this simple and safe technique and its short-term results. METHODS: We prospectively collected data on 18 patients who underwent totally laparoscopic sigmoid colectomy with TASE from April 2009 to July 2010. Lymph node dissection and transection of proximal and distal colon were performed in conventional manner. The transected rectal stump was opened transversely, and a long Babcock grasper was inserted transanally through the opened rectal stump. One of a pair of Alexis rings was held and pulled out of the anus. The other ring was placed in the opened rectal stump. The specimen was then extracted transanally through the Alexis. After the Alexis had been removed, the rectal opening was reclosed with a linear stapler. End-to-end colorectal anastomosis was then performed using the double-stapling technique. RESULTS: Transanal extraction was achieved in 17 cases. We switched to conventional LAC in a case involving a bulky specimen. In 16 cases not including the combined cholecystectomy case, mean operation time was 241 min. One case was complicated by anastomotic leakage and wound infection, while another had enterocolitis. Median hospital stay was 6 days. All patients remained disease free. Mean Wexner score at 12 months after operation was 2.3. CONCLUSION: Totally laparoscopic sigmoid colectomy using TASE and the Alexis appears to be feasible, safe, and oncologically acceptable for selected cases. PMID- 21553174 TI - Endoscopic surgery through single-port incision: time for a trial? PMID- 21553175 TI - External valve deformity: correction by composite flap elevation and mattress sutures. AB - BACKGROUND: Deformities of the external valve (lateral crus) are an occasional problem following rhinoplasty. One of the most notable problems is when the posterior aspect of the lateral crus curls around into the vestibule. It not only obstructs the airway but can be aesthetically displeasing to the patient. Traditional correction including grafts works can be complicated and often leaves the lateral wall bulky. METHODS: A U-shaped incision is made around the lateral crus creating a medially based composite flap. This flap contains most of the lateral crus and is delivered into the vestibule for the application of one or more horizontal mattress sutures to the convex surface of the cartilage. These sutures act to straighten out the lateral crus prior to replacing it in its bed. RESULTS: Seven patients with a deformity of the posterior aspect of the lateral crus received correction by composite flap elevation and mattress suture application. Follow-up ranged from 10 to 33 months. All but one patient had their aesthetic and functional symptoms corrected; this required a symmetry procedure secondary to the loss of alar groove depth. CONCLUSION: Exposure of the entire lateral curs with the use of a medially based composite flap containing most of the lateral crus is an excellent means to control its shape. Mattress sutures applied to the surface of the cartilage will result in increased stiffness and strength. The net result is a simple correction of what might otherwise be a complicated problem. PMID- 21553176 TI - The impact of ignoring random features of predictor and moderator variables on sample size for precise interval estimation of interaction effects. AB - The influence of the joint distribution of predictor and moderator variables on the identification of interactions has been well described, but the impact on sample size determinations has received rather limited attention within the framework of moderated multiple regression (MMR). This article investigates the deficiency in sample size determinations for precise interval estimation of interaction effects that can result from ignoring the stochastic nature of continuous predictor and moderator variables in MMR. The primary finding of our examinations is that failure to accommodate the distributional properties of regressors can lead to underestimation of the necessary sample size and distortion of the desired interval precision. In order to take account of the randomness of regressor variables, two general and effective procedures for computing sample size estimates are presented. Moreover, corresponding programs are provided to facilitate use of the suggested approaches. This exposition helps to correct drawbacks in the existing techniques and to advance the practice of reporting confidence intervals in MMR analyses. PMID- 21553177 TI - The prediction of intelligence in preschool children using alternative models to regression. AB - Statistical prediction of an outcome variable using multiple independent variables is a common practice in the social and behavioral sciences. For example, neuropsychologists are sometimes called upon to provide predictions of preinjury cognitive functioning for individuals who have suffered a traumatic brain injury. Typically, these predictions are made using standard multiple linear regression models with several demographic variables (e.g., gender, ethnicity, education level) as predictors. Prior research has shown conflicting evidence regarding the ability of such models to provide accurate predictions of outcome variables such as full-scale intelligence (FSIQ) test scores. The present study had two goals: (1) to demonstrate the utility of a set of alternative prediction methods that have been applied extensively in the natural sciences and business but have not been frequently explored in the social sciences and (2) to develop models that can be used to predict premorbid cognitive functioning in preschool children. Predictions of Stanford-Binet 5 FSIQ scores for preschool aged children is used to compare the performance of a multiple regression model with several of these alternative methods. Results demonstrate that classification and regression trees provided more accurate predictions of FSIQ scores than does the more traditional regression approach. Implications of these results are discussed. PMID- 21553178 TI - Nanoscale-engineered cytochrome p450 system with a branch structure. AB - Most of the bacterial cytochrome P450 s require two kinds of electron transfer proteins, ferredoxin and ferredoxin reductase, and thus P450 s do not show catalytic activity by themselves. A microbial transglutaminase-mediated site specific cross-linking enables the formation of fusion P450 protein with a branched structure, which is generated from a genetic fusion protein of P450 ferredoxin reductase and ferredoxin, an interactive nanoscale protein structure. This fusion P450 system is self-sufficient due to intramolecular electron transfer, which means the system does not require additional electron transferring proteins. Because some components of bacterial cytochrome P450 system are interchangeable, this self-sufficient system can be applied to non natural combination of P450 and electron transfer proteins from different species of bacteria. PMID- 21553179 TI - Chemically induced self-assembly of enzyme nanorings. AB - Continued exploration into the field of chemically induced dimerization (CID) has revealed a number of applications for its use in a broader context as a method of structural assembly (1-4). In particular, the use of CID technology to generate self-assembled (and selectively disassembled) protein toroids serves as a key advancement toward developing stable and controllable protein-based platforms. Such structures have broad application to the development of novel therapeutics, lab-on-a-chip technologies, and multi-enzyme assemblies (5, 6). This chapter describes a method of developing an enzymatically active protein nanostructure incorporating both a CID-based assembly region containing dihydrofolate reductase (DHFR) and an enzymatic region consisting of histidine triad nucleotide binding protein 1 (Hint1). Details of both the production and the characterization of this structure are provided. PMID- 21553180 TI - Self-assemblies of polymer-enzyme conjugates at oil-water interfaces for interfacial biocatalysis. AB - Many biocatalysts have been shown powerful in enabling reactions among a broad range of substrates possessing very different hydrophilicity/hydrophobicity. Biphasic reaction systems, especially oil-water biphasic systems, have been commonly adopted to mediate such reactions. The greatest challenge in conducting an efficient reaction between two substrates that have to be hosted in two immiscible liquid phases is the mass transfer resistance across interfaces. Imaginably, the substrates afford the most extensive interactions at the interfacial region. The interfacial assembled enzymes, developed by conjugating water-soluble enzymes with hydrophobic polymers, are therefore expected to be efficient in catalyzing biotransformation at the organic-aqueous interfaces. This chapter describes a method in preparing and applying of such interface-assembling enzymes. A model enzyme, alpha-chymotrypsin (CT), is grafted with polystyrene (PS) to introduce an organic affinity, thus leading to a surfactant-like structure. The characterization of the activity and stability of the interface assembled enzyme is also presented. PMID- 21553181 TI - Molecular assembly-assisted biocatalytic reactions in ionic liquids. AB - Room temperature ionic liquids (RTILs), having no measurable vapor pressure, represent an interesting class of tunable designer solvents. Due to their many unique properties, ILs have been used as attractive alternatives to environmentally harmful ordinary organic solvents in a wide range of applications including enzymatic biotransformation. Compared to conventional organic solvents, ILs offer many advantages for biocatalysis such as enhanced conversion rates, high enantioselectivity, better enzyme stability, and improved catalyst recoverability and recyclability. However, biocatalysis in ILs has not yet fully achieved its potential because many biocatalysts are insoluble in most ILs. This limitation could be overcome by the formation of nano/micrometer-sized aqueous microemulsion droplets in an IL continuous phase (referred to as water-in-IL microemulsions) stabilized by a layer of surfactants. Enzymes can be dissolved in such water droplets and protected from the unfavorable effect of ILs by the surfactant layer. In this chapter, a simple and effective method for the development of aqueous microemulsion droplets in a hydrophobic IL comprising an anionic surfactant sodium bis(2-ethyl-1-hexyl) sulfosuccinate (AOT) is presented. For this approach, we have synthesized a hydrophobic IL [C(8)mim][Tf(2)N] (1 octyl-3-methyl imidazolium bis(trifluoromethyl sulfonyl) amide) containing a long pendant hydrocarbon chain to facilitate the dissolution of AOT molecules. A detailed description of the procedure for the potential use of this newly developed water-in-IL reverse microemulsion for biocatalysis is also included. PMID- 21553182 TI - Organic-soluble enzyme nano-complexes formed by ion-pairing with surfactants. AB - The solubilization of enzymes in organic solvents for non-aqueous biocatalysis has attracted considerable attention since the homogeneous distribution accounts for a drastically improved reaction efficiency compared to enzymes dispersed as aggregates in an organic phase. This chapter highlights ion-pairing as a valuable and facile method to make enzymes soluble in organic solvents. Ion-pairing denotes the formation of a nano-complex, in which a single enzyme molecule in the core is surrounded by counter-charged surfactant molecules. The special architecture of this nano-complex exposes the surfactant hydrophobic group toward the bulk solvent and renders the complex sufficiently soluble in organic media. This chapter also describes the underlying principle of ion-pairing as well as simple preparation and characterization techniques to yield highly active enzyme surfactant nano-complexes. The general applicability of this technique is demonstrated on the base of the hydrolytic enzyme alpha-chymotrypsin (alpha-CT) and the redox enzyme glucose oxidase (GO( x )). PMID- 21553183 TI - Enzyme-immobilized CNT network probe for in vivo neurotransmitter detection. AB - Glutamate is the principal excitatory neurotransmitter in the brain, and its excessive release plays a key role in neuronal death associated with a wide range of neural disorders. Real-time monitoring of extracellular glutamate levels would be very helpful in understanding the excitotoxic process of neurotransmitters on brain injury. Toward the detection of L: -glutamate, we describe in this chapter the preparation of carbon nanotube (CNT) network probes with immobilized L: glutamate oxidase (GLOD) by using a non-covalent functionalized method. Such GOLD CNT network probes are evaluated with real-time electronic responses corresponding to standard glutamate solutions in vitro and a 11-vessel occlusion (11 VO) rat model in vivo. The ultrahigh sensitivity, selectivity, and fast response time of GLOD-CNT network probes are greatly promising for the real-time electronic detection of extracellular glutamate levels in brain. PMID- 21553184 TI - Kinesin I ATPase manipulates biohybrids formed from tubulin and carbon nanotubes. AB - This chapter describes a method for the formation of novel protein-nanotube hybrid conjugates. Specifically, we took advantage of the self-assembly and self recognition properties of tubulin cytoskeletal protein immobilized onto carbon nanotubes to form nanotube-based biohybrids. Further biohybrid hierarchical integration in assemblies enabled molecular-level manipulation on engineered surfaces, as demonstrated with biocatalyst kinesin 1 ATPase molecular motor. The method presented herein can be extended for the preparation of biocatalyst-based or protein-based assemblies to be used as sensors or biological templates for nanofabrication. PMID- 21553185 TI - Reversible his-tagged enzyme immobilization on functionalized carbon nanotubes as nanoscale biocatalyst. AB - Common enzyme immobilization methods on nanomaterials (adsorption, covalent binding, crosslinking, encapsulation) often generate problems in enzyme leaching, 3D structure change and diffusion resistance. We show here a detailed site specific enzyme immobilization method that overcomes the foresaid limitations. It is based on the specific interaction between His-tagged enzyme and single-walled carbon nanotubes modified with N (alpha) ,N (alpha)-bis(carboxymethyl)-L: -lysine hydrate. This method does not require enzyme purification and the resulting nanoscale biocatalyst can maintain high enzyme activity and stability. The enzyme loading capacity is also comparable with the reported immobilization capacity on carbon nanotubes by either covalent binding or adsorption. Furthermore, the immobilization is reversible for several cycles while maintaining high enzyme activity and the nanoscale biocatalyst can be regenerated easily. PMID- 21553186 TI - A TiO2 nanoparticle system for sacrificial solar H2 production prepared by rational combination of a hydrogenase with a ruthenium photosensitizer. AB - A hybrid system comprising a hydrogenase and a photosensitizer co-attached to a nanoparticle serves as a rational model for fast dihydrogen (H(2)) production using visible light. This chapter describes a stepwise procedure for preparing TiO(2) nanoparticles functionalized with a hydrogenase from Desulfomicrobium baculatum (Db [NiFeSe]-H) and a tris(bipyridyl)ruthenium photosensitizer (RuP). Upon irradiation with visible light, these particles produce H(2) from neutral water at room temperature in the presence of a sacrificial electron donor - a test-system for the cathodic half reaction of water splitting. In particular, we describe how a hydrogenase and a photosensitizer with desired properties, including strong adsorption on TiO(2), can be selected by electrochemical methods. The catalyst Db [NiFeSe]-H is selected for its high H(2) production activity even when H(2) and traces of O(2) are present. Adsorption of Db [NiFeSe] H and RuP on TiO(2) electrodes results in high electrochemical and photocatalytic activities that translate into nanoparticles exhibiting efficient light harvesting, charge separation, and sacrificial H(2) generation. PMID- 21553187 TI - Preparation and characterization of single-enzyme nanogels. AB - Enzymes have been incorporated in nanostructures in order to provide robust catalysts for valuable reactions, particularly those performed under harsh and denaturing conditions. This chapter describes the encapsulation of enzymes in polyacrylamide nanogels by a two-step in situ polymerization process for preparing robust biocatalysts. The first step in this process is the generation of vinyl groups on the enzyme surface, while the second step involves in situ polymerization using acrylamide as the monomer. Encapsulation of the enzyme in the hydrophilic, porous, and flexible polyacrylamide gel of several nanometers thick would help to both give a significantly enhanced thermostability and prevent the removal of essential water by polar solvents. The hydrophilic flexible polymer shell also allows the protein structure to undergo necessary conformational transitions during the catalytic reaction and, at the same time, impose marginal mass transfer restrictions for the substrates entering across the polymer shell. The effectiveness of this method is demonstrated with horseradish peroxidase (HRP), carbonic anhydrase, and lipase. The impacts of such an encapsulation on the activity and stability of enzymes are also discussed. PMID- 21553188 TI - Fabrication and characterization of bioactive thiol-silicate nanoparticles. AB - Here we describe a new method for the production of thiol-silicate particles and the entrapment of enzymes within the thiol particles as they are formed. When bio inspired polymers (polyethyleneimine) are combined with a silicic acid source and phosphate buffer under pH neutral conditions, formation of silicate particles occurs. In the method presented here the silica source contains a thiol group and so therefore the silicate particles are pre-functionalized with thiol groups. We have termed the silicate particles produced "thiol particles" and the characterization of these thiol particles is also presented in this chapter. As enzymes can be entrapped during fabrication, it means that the thiol particles can not only attach to metal surfaces but also catalyse certain reactions depending on the enzyme used. This means that there are many future possibilities for the use of thiol particles containing enzymes, as they may be used in a wide range of processes and devices which require catalytic functionalized surfaces, such as biosensors and biocatalytic reactors. PMID- 21553189 TI - Immobilization of enzymes on fumed silica nanoparticles for applications in nonaqueous media. AB - Enzymatic catalysis in nonaqueous media is considered as an attractive tool for the preparation of a variety of organic compounds of commercial interest. This approach is advantageous for numerous reasons including the enhanced stability of some substrates and products in solvents, sometimes improved selectivity of the enzyme, and reduction of unwanted water-dependent side reactions since little water is present. Due to the poor solubility of enzymes in these media, mass transfer limitations are sometimes present, leading to low apparent catalytic activity. Immobilization on solid supports has been successfully applied to overcome enzyme solubility issues by increasing the accessibility of substrates to the enzymes' active sites. We have developed a simple immobilization protocol that uses fumed silica as support. Fumed silica is an inexpensive nanostructured material with unique properties including large surface area and exceptional adsorptive affinity for organic macromolecules. Our protocol is performed in two main steps. First, the enzyme molecules are physically adsorbed on the surface of the non-porous fumed silica nanoparticles with the participation of silanol groups (Si-OH) and second, water is removed by lyophilization. The protocol has been successfully applied to both s. Carlsberg and Candida antarctica lipase B (CALB). The resulting fumed silica-based nanobiocatalysts of these two enzymes were tested for catalytic activity in hexane. The transesterification of N-acetyl L: -phenylalanine ethyl ester was the model reaction for s. Carlsberg nanobiocatalysts. The simple esterification of geraniol and the enantioselective transesterification of (RS)-1-phenylethanol were the model reactions for CALB nanobiocatalysts. The observed catalytic activities were remarkably high and even exceeded those of commercially available preparations. PMID- 21553190 TI - Microencapsulation of bioactive nanoparticles. AB - Supported or modified enzymes in the form of mobile nanoparticles are designed for enhanced activities and stabilities; however, their practical operations are dwarfed due to their tiny size which always makes recycling an arduous task and a potential risk to the environment. To overcome such drawbacks, this chapter describes a method for the preparation of a new form of microcapsules, possessing single-cavity compartments and nano-pores in the shell, to encage nanoparticle based biocatalysts and form cell-like microreactors (CLMRs). The encaged nanoscale catalysts are maintained their high activities as in a bulk-phase solution, while they could be handled as materials of sizes hundreds-fold larger. PMID- 21553191 TI - Engineering the logical properties of a genetic AND gate. AB - Synthetic biology promises to enhance our ability to control biological systems by creating a systematic approach for the construction of genetic circuits that reliably program cellular function. As part of this approach, efficient methods are needed for the tuning of genetic circuits so as to allow for optimization of a design despite varying cellular contexts and incomplete understanding of in vivo biological interactions. Here we outline an optimization method that we have used to improve the logical responses of a genetic AND logic gate derived from components of the LuxI-LuxR bacterial quorum-sensing system. Basing our approach on the idea of evolutionary design, we improved the properties of our genetic AND logic gate by using directed evolution and a two-step screening process to alter the activities of the LuxR transcriptional activator. Using this method, we were able to rapidly enhance the AND gate's logical responses and have increased the specificities of these responses by ~1.5-fold. PMID- 21553192 TI - Strain engineering strategies for improving whole-cell biocatalysis: engineering Escherichia coli to overproduce xylitol as an example. AB - This chapter provides an overview of key tools and methodologies available to practitioners of biocatalysis interested in using microorganisms to carry out biotransformations and describes specific examples of applying genetic modification strategies for strain design. We focus on the use of the polymerase chain reaction (PCR) for gene amplification, plasmid DNA for recombinant gene cloning and expression, and homologous recombination and phage transduction for modifying chromosomal DNA. Specifically we use Escherichia coli as the host organism, and the overproduction of xylitol by reduction of xylose represents the biotransformation of interest. PMID- 21553193 TI - Enzyme-carrying electrospun nanofibers. AB - Compared to other nanomaterials as supports for enzyme immobilization, nanofibers provide a promising configuration in balancing the key factors governing the catalytic performance of the immobilized enzymes including surface area-to-volume ratio, mass transfer resistance, effective loading, and the easiness to recycle. Synthetic and natural polymers can be fabricated into nanofibers via a physical process called electrospinning. The process requires only simple apparatus to operate, yet has proved to be very flexible in the selection of feedstock materials and also effective to control and manipulate the properties of the resulting nanofibers such as size and surface morphology, which are typically important parameters for enzyme immobilization supports. This chapter describes a protocol for the preparation of nanofibrous enzyme, involving the synthesis and end-group functionalization of polystyrene, production of electrospun nanofibers, and surface immobilization of enzyme via covalent attachment. PMID- 21553194 TI - Uniform lab-scale biocatalytic nanoporous latex coatings for reactive microorganisms. AB - This chapter describes a method for generating uniform lab-scale biocatalytic nanoporous latex coatings. Nearly everything we come into contact with on a daily basis has been coated with some polymer material. High-speed waterborne polymer coating and ink-jet printing techniques are mature technologies. Methods for immobilizing microorganisms in lab-scale waterborne latex biocatalytic coatings draw on existing coating technologies for generating precision industrial paint and paper coatings and would therefore be amenable to scale up in future applications. An inherent problem for many lab-scale techniques is coating uniformity. The method described here has been developed to dramatically increase the uniformity of multiple individual small surface area coatings derived from a single coating template by minimizing edge effects due to emulsion drying adjacent to the edge of the mask. PMID- 21553195 TI - Entrapment of enzymes in nanoporous sol-gels. AB - The prerequisite for many successful enzyme-based biotechnologies is the preparation of highly stable and active biocatalysts, which can be achieved effectively by immobilization. This chapter introduces the immobilization of enzymes by entrapment in nanoporous silica particles made in a sol-gel process. These easily tailorable materials have been proven very beneficial for a broad variety of applications of biocatalysts. Besides the spatial confinement in silica sol-gels, another advantage is given by the easy possibility of fine tuning the physicochemical properties of the matrix itself to provide the ideal environment for the reaction and the biocatalyst. Preparation details are demonstrated using the process of immobilizing a lipase in a sol-gel matrix, which is chemically modified by using methyl-, ethyl-, propyl-, and i butyltrimethoxysilane. The transesterification of canola oil with methanol is used as a model reaction. PMID- 21553196 TI - Effectiveness assessment of vaccination policy against measles epidemic in Japan using an age-time two-dimensional mathematical model. AB - OBJECTIVES: In 2007, measles prevailed among the youth and young adult population in Japan, creating in a serious social problem. Among the developed countries, Japan has a relatively high incidence of measles. The objective of this study was to assess the effect of improvements in the vaccination policy against measles through simulations. METHODS: We developed an age-time two-dimensional model for the transmission of measles to reflect an age structure, enabling contact rate to be selected by age. Introduction of the maternal immunity class into the model allowed natural infection and vaccination to be discriminated along the course of an infant's mother acquiring the immunity, thereby resulting in an improved accuracy of the simulations in infants. Several vaccination scenarios were attempted in order to assess the influence of various vaccination policies on the prevention of a measles epidemic. RESULTS: The results of this quantitative study indicated that suppression of a measles outbreak requires the maintenance of high vaccine coverage and that a decline in vaccine coverage may result in a measles epidemic. CONCLUSIONS: The present standard immunization program for measles will maintain an acceptable level of immunity and is therefore associated with a low risk of an epidemic after discontinuation of the third and fourth stages as scheduled--as long as at least 90% vaccine coverage of the first and second is maintained. The simulation results show that discontinuation of the third and fourth stages of vaccination as scheduled should be accompanied by endeavors to maintain appropriate high vaccine coverage of the first and second stages. PMID- 21553197 TI - Possible organizational effect of sex steroids on the stabilization of manual preference in female common marmosets (Callithrix jacchus). AB - Handedness has been widely studied in nonhuman primates. However, few studies investigate this behavior throughout ontogenetic development. To determine the influence of developmental stage in common marmoset (Callithrix jacchus) females, we used six animals, which were observed in food-reaching tests involving hand use preference from the infantile to the adult phase. During this period, fecal samples were collected for sexual hormone analysis (estrogen and progesterone). The results point to correlations between age and stabilization of manual preference across the developmental phases. A relationship between progesterone and the intensity of hand use asymmetry was observed during the pubertal period, when the data was grouped into three phases: prepubertal, pubertal, and postpubertal. These data show increasing strength of hand preference during ontogenetic development and that sexual hormones may be involved in females. PMID- 21553199 TI - [Posttraumatic laryngotracheal separation]. AB - Laryngotracheal trauma is rare and may lead to airway obstruction and life threatening situations. We present a case report of laryngotracheal separation after a horse riding accident. In this case, early intubation secured the respiratory passage and the life of the patient. PMID- 21553200 TI - Excision and primary closure using the Karydakis flap for the treatment of pilonidal disease: outcomes from a single institution. AB - BACKGROUND: Chronic pilonidal disease is a debilitating condition that typically affects young adults. There is a wide variety of available therapeutic strategies reflecting the inconsistent outcomes attributed to the various operative approaches. The majority involve excision of the sinus tract followed by either primary closure or healing by secondary intention. A variety of closure approaches exist. There remains uncertainty as to which is more effective. The aim of the current study was to determine subjective and objective outcomes following excision and Karydakis flap closure in a unit where this technique is the standard of care in the management of chronic pilonidal disease. METHODS: This study involving consecutive patients with chronic pilonidal disease was conducted over a 4-year period. A tailored patient satisfaction questionnaire was given to each patient. Postoperative primary and secondary outcomes were evaluated. The mean follow-up time was 30 months. RESULTS: One hundred six consecutive patients (33 female, 73 male) underwent excision and primary closure using the Karydakis flap. Ninety-two completed questionnaires were returned (87% response rate). Patients consulted their general practitioner 2.8 times (mean) and 46% received empirical oral antimicrobial therapy prior to referral for a surgical opinion. The mean time lost to work/school following the Karydakis flap repair was 13 days (range 3-33). Successful treatment was achieved in 96.3% of cases and 92% of patients were satisfied with their operative result. CONCLUSION: Excision and primary closure with Karydakis flap is an effective treatment for chronic pilonidal disease. It is associated with low morbidity, early return to premorbid functioning, and a high degree of patient satisfaction (92%). PMID- 21553201 TI - Value of polyclonal human immunoglobulin tagged with 99mTc for detecting acute appendicitis in patients with intermediate probability of appendicitis. AB - BACKGROUND: The aim of this study was to assess the value of a technetium ((99m)Tc)-polyclonal antibody to detect acute appendicitis in patients with intermediate probability of appendicitis. METHODS: A total of 40 patients with mean age of 24.6 +/- 6.9 years with intermediate probability of appendicitis according to the Alvarado scoring system (score 5 or 6) were studied. After intravenous injection of 740 MBq of (99m)Tc-immunoglobulin G (IgG), a flow and blood pool image was obtained followed by two planar images and single photon emission tomography (SPECT) scan from the lower abdominal and pelvic regions. The images were subjected to visual and quantitative analysis. Patients were followed clinically, and the surgeon decided to operate on or observe the patient depending on the clinical findings. The pathology results were considered the gold standard if patients underwent an operation. If patients improved without surgery, it was considered negative for appendicitis. RESULTS: Altogether, 31 patients were operated on, and 21 patients had acute appendicitis. Nine patients were discharged from hospital and had no symptoms during follow-up. The sensitivity of the planar images for diagnosing appendicitis was 19-24% and specificity was 100%. The sensitivity of SPECT for diagnosis of appendicitis was 62%, the specificity was 68%, and the negative predictive value (NPV) was 62%. Quantitative analysis showed that using a cutoff of >1.2 for the mean right-to left count per voxel ratio, the sensitivity of the test for detection of appendicitis was 54%, and the specificity was 86%. CONCLUSIONS: (99m)Tc polyclonal IgG scanning has low sensitivity and moderate NPV for detecting appendicitis. Therefore, it is not a suitable tracer for excluding appendicitis. PMID- 21553202 TI - Long-term health-related quality of life for disease-free esophageal cancer patients. AB - BACKGROUND: Health-related quality of life (HRQL) has been studied extensively during the first year following esophagectomy, but little is known about HRQL in long-term survivors. The aim of this study was to investigate HRQL in patients alive at least 1 year after surgical resection for esophageal cancer using validated European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaires (QLQ). METHODS: Eligible patients, without known disease recurrence and at least 1 year after esophagectomy, were identified from a prospectively maintained database. Patients completed general (QLQ-C30) and esophageal cancer-specific (QLQ-OES18, OG25) questionnaires. A numeric score (0-100) was computed in each conceptual area and compared with validated cancer (n = 1031) and age-matched (n = 7802) healthy populations using two-tailed unpaired t-tests. A cohort of 80 patients had pretreatment scores recorded. RESULTS: Altogether, 132 of 156 eligible patients (84%) completed the self-rated questionnaire, 105 (67.3%) were men, and the mean age was 62 years (range 29-84 years). The mean time since esophagectomy was 70.3 months (12-299 months). Global health status was significantly reduced at least 1 year after esophagectomy (mean +/- SD score 48.4 +/- 18.6) when compared with patients with esophageal cancer prior to treatment (55.6 +/- 24.1) and the general population (71.2 +/- 22.4) (p < 0.0001). In a prospective cohort of eighty patients, symptoms related to swallowing difficulty, reflux, pain, and coughing significantly decreased in the long term (p < 0.0001). The degree of subjective swallowing dysfunction was highly correlated with a poor QOL (Spearman's rho = 0.508, p < 0.01). CONCLUSIONS: Global health status remains significantly reduced in long-term survivors after esophagectomy compared with population controls, and swallowing dysfunction is highly associated with this compromised QOL. PMID- 21553203 TI - Oscillatory vagal maneuvers produce ventricular entrainment in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained dysrhythmia and appears to be an independent predictor of sudden cardiac death. The irregular ventricular rhythm contains both linear and non-linear patterns; however, it remains unclear whether vagally mediated effects are present within these patterns. OBJECTIVE: We sought to determine if (1) power spectral analysis of heart rate can detect changes in vagal activity in patients with AF and (2) if the vagus modulates ventricular response during AF. METHODS: Time and frequency domain parameters of heart rate variability (HRV) were calculated during forced vagal oscillations at 0.125 and 0.25 Hz imposed by neck suction and deep breathing in five AF patients. RESULTS: There was a significant increase in SDRRI during deep breathing/neck suction combined compared to baseline (p=0.01) and deep breathing (p=0.03). Neck suction significantly increased SDRRI compared to baseline (p=0.03). Deep breathing/neck suction significantly increased spectral power compared to baseline (p=0.02) and deep breathing (p=0.03). Neck suction significantly increased spectral power compared to baseline (p=0.03). Deep breathing did not significantly increase HRV compared to baseline (p>0.20). In addition, SDRRI and spectral power were significantly correlated during deep breathing (r=0.91, p=0.03) and deep breathing/neck suction combined (r=0.92, p=0.02). INTERPRETATION: These data suggest that (1) power spectral analysis can detect vagal influences on heart rate in AF patients, and (2) oscillatory vagal maneuvers produce ventricular entrainment during AF. PMID- 21553204 TI - Retraction. Applications of radiotherapy and radiosurgery in the management of pediatric Cushing's disease: a review of the literature and our experience. J Neurooncol (2008) 90:117-24. PMID- 21553205 TI - No guns at children: not even a toy one! PMID- 21553206 TI - Amyloidosis in a child with leucocyte adhesion deficiency type-1: an unusual association. AB - Leucocyte adhesion deficiency type I (LAD I) is a rare autosomal recessive disorder of leucocyte function, characterized by delayed separation of the umblical cord, recurrent bacterial and fungal infections, defective wound healing and impressive constant blood neutrophilia. The authors report a child with genetic diagnosis of leucocyte adhesion deficiency (LAD) type I, who succumbed to his illness and developed amyloidosis preterminally. To the best of author's knowledge this is the first case of leucocyte adhesion deficiency type I associated with amyloidosis among the human LAD cases worldwide. PMID- 21553207 TI - Empyema thoracis: analysis of 150 cases from a tertiary care centre in North East India. AB - OBJECTIVES: To analyze the clinical characteristics, microbiological profile, management, complications and outcome of cases with empyema thoracis. METHODS: All cases diagnosed as 'empyema thoracis' over a period from January 2006 through June 2010 were identified from the inpatient records and discharge summaries. Of the 160 cases identified, 150 cases were taken up for analysis and the rest 10 cases, of which two had significant predisposing co-morbidity and eight cases diagnosed as tubercular empyema thoracis were excluded from the analysis. RESULTS: Mean age of presentation was 4.74 +/- 3.53 years and two thirds of the children were under 5 years with male to female ratio of 1.42:1. Pus culture was positive in 32% (48 cases) with Streptococcus pneumoniae being the commonest organism isolated (31 cases, 64.6%) followed by Staphylococcus aureus (11 cases, 22.9%), Klebsiella pneumoniae (3 cases, 6.3%), Haemophilus influenzae type b (2 cases, 4.2%) and Enterococcus (1 case, 2%). Clustering was seen in the hot and humid months from April to July (63.3%). Fever was the commonest presentation (96.7%) followed by cough (90%), breathing difficulty (66.7%), chest pain (26.7%) and pain abdomen (10.7%). Ampicillin and cloxacillin was used as the first line antibiotic in 57.3% cases. Average duration of intercostal water seal drainage (ICWSD) in situ was 13.5 +/- 8.05 days and 59 patients (39.3%) received fibrinolytic therapy. The commonest complications were collapse (18%), thickened pleura (16.7%), pericardial effusion (8%), cardiac tamponade (3.3%) and bronchopleural fistula (3.3%). Surgical procedures involved in this case series were decortication (14 cases, 9.3%), pericardiocentesis (5.3%), pericardiostomy (2.7%) and pericardiectomy (1.6%). Mortality was 3.3%. CONCLUSIONS: This is the first report of empyema thoracis from the north eastern region of India. Streptococcus pneumoniae was found to be the leading cause of empyema thoracis in this case series. Conservative management with ICWSD and antibiotics or early use of fibrinolytic therapy if indicated are effective modalities of treatment. PMID- 21553208 TI - Initial assessment and triage in ER. AB - Triage refers to quick assessment of a patient in the Emergency Room with a view to define urgency of care and priorities in management. Triage evaluation can be completed in an organized and systematic manner using Pediatric Assessment Triangle (PAT), which refers to immediate visual and auditory assessment of appearance, breathing and circulation. At the end of PAT, patient's illness is categorized as either stable or unstable. Unstable conditions are further classified into life threatening and non life threatening. Patients in the former category include those in need of immediate resuscitation e.g. cardiac arrest, cardio-respiratory failure, decompensated shock, deep coma, severe stridor etc. Once a child is on the way to stabilization, the primary assessment (assessment pentagon),which takes 1-3 min follows. It involves the detailed physical examination/assessment of airway (A), breathing (B), circulation(C), neurologic abnormalities (D) and head to- toe examination (Exposure). After the primary assessment, patient's illness severity is triaged into 5 levels of acuity based on the physiological abnormalities: those in need of Resuscitation, Emergent care, Urgent care, Less urgent and Non-urgent care. PMID- 21553209 TI - Neonatal lupus erythematosus associated with unilateral pectoralis major atrophy. AB - Neonatal lupus erythematosus (NLE), in most cases, presents with cardiac and dermatological manifestation due to transferred IgG auto antibodies (anti Ro/SSA and anti La/SSB) from the mother. Some unusual associations with myelopathy, vasculopathy, transient myasthenia gravis, congenital nephrotic syndrome, chondrodysplasia punctata etc. are also reported. Here, the authors present a case of NLE with isolated left sided pectoralis major muscle atrophy, which has not been reported earlier. PMID- 21553210 TI - Treatment of acute myeloid leukemia in children: experience from a tertiary care hematology centre in India. AB - OBJECTIVE: To assess the treatment and outcome of children with acute myeloid leukemia. The Primary objectives were to assess remission rates, treatment related toxicity and disease free survival. Secondary objective was to assess prognostic factors associated with poor outcome. METHODS: A retrospective analysis of all treated patients with acute myeloid leukemia, less than 18 year of age from Sept 2005 to Aug 2009 was done. Clinical laboratory, treatment and follow up records retrieved to calculate remission rate, treatment related toxicity, disease free survival and poor prognostic factors. RESULTS: This analysis included thirty five patients (male : female; 23:12), twenty seven (77.1%) achieved remission after one 3 + 7 induction and seven required two inductions. High dose cytosine arabinoside consolidation was given in thirty one patients while one underwent allogenic stem cell transplantation. Two patients died during chemotherapy (TRM- 5.7%), two did not complete the therapy, seventeen relapsed (48.5%) with 80% of relapses occurring within first year of remission and no relapse occurred after 2 years. Fourteen patients are in remission (40%, follow up 5-54 months) and cumulative median disease free survival is of 13 months. CONCLUSIONS: The present data suggests that 3 + 7 induction, followed by high dose cytarabine consolidation has low treatment related toxicity and resource utilization; however, relapse free survival is inferior to more intensive regimens, highlighting the need to intensify chemotherapy regimen once the treatment related mortality has been minimized. PMID- 21553211 TI - Elephantine but not elephantiasis: Subcutaneous zygomycosis. AB - Subcutaneous zygomycosis is an unusual disorder caused by a rare fungus, Basidiobolus ranarum. We report this entity in a 4- yr- old boy. Biopsy showed the Splendore Hoeppli phenomenon and the culture yielded Basidiobolus ranarum. The child responded to saturated solution of potassium iodide within 1 month of starting treatment. PMID- 21553212 TI - Systemic arterial and venous determinants of renal hemodynamics in congestive heart failure. AB - Heart and kidney interactions are fascinating, in the sense that failure of the one organ strongly affects the function of the other. In this review paper, we analyze how principal driving forces for glomerular filtration and renal blood flow are changed in heart failure. Moreover, renal autoregulation and modulation of neurohumoral factors, which can both have repercussions on renal function, are analyzed. Two paradigms seem to apply. One is that the renin-angiotensin system (RAS), the sympathetic nervous system (SNS), and extracellular volume control are the three main determinants of renal function in heart failure. The other is that the classical paradigm to analyze renal dysfunction that is widely applied in nephrology also applies to the pathophysiology of heart failure: pre-renal, intra renal, and post-renal alterations together determine glomerular filtration. At variance with the classical paradigm is that the most important post-renal factor in heart failure seems renal venous hypertension that, by increasing renal tubular pressure, decreases GFR. When different pharmacological strategies to inhibit the RAS and SNS and to assist renal volume control are considered, there is a painful lack in knowledge about how widely applied drugs affect primary driving forces for ultrafiltration, renal autoregulation, and neurohumoral control. We call for more clinical physiological studies. PMID- 21553213 TI - 14-3-3 protein beta/alpha as a urinary biomarker for renal cell carcinoma: proteomic analysis of cyst fluid. AB - Although various samples, including tissue, cells, serum, and urine, from patients with renal cell carcinoma (RCC) have been analyzed, biomarkers with diagnostic value have yet to be identified. We used a proteomics approach to analyze cyst fluid in cases of cyst-associated RCC to identify accessible and abundant proteins that are overexpressed and/or secreted by RCC cells. Proteins in the cyst fluid were separated by reverse-phase high-performance liquid chromatography and agarose two-dimensional gel electrophoresis and were identified by tandem mass spectrometry. We conducted a National Center for Biotechnology Information search and a MEDLINE search to predict the function of these identified proteins and to select a tumor-marker candidate protein. Our search resulted in the identification and selection of the differentially regulated protein known as 14-3-3 protein beta/alpha, which was overexpressed in cyst fluid from cyst-associated RCC but has not been previously associated with RCC. We then measured its incidence through Western blotting of various normal and RCC samples (serum, urine, tissue, and cyst fluid). The expression levels of 14-3-3 protein beta/alpha were higher in urine samples from patients with RCC than in samples from healthy volunteers. Receiver operating characteristic (ROC) curve analyses were performed to assess this potential biomarker; these data (area under the ROC curve value was 0.8813) indicate a high degree of accuracy for this screening method. 14-3-3 Protein beta/alpha may be a diagnostically useful biomarker for early diagnosis of RCC. PMID- 21553215 TI - Accurate mass measurements and ultrahigh-resolution: evaluation of different mass spectrometers for daily routine analysis of small molecules in negative electrospray ionization mode. AB - Six mass spectrometers based on different mass analyzer technologies, such as time-of-flight (TOF), hybrid quadrupole-TOF (Q-TOF), orbitrap, Fourier transform ion cyclotron resonance (FT-ICR), and triple quadrupole (QqQ), installed at independent laboratories have been tested during a single day of work for the analysis of small molecules in negative electrospray ionization (ESI) mode. The uncertainty in the mass measurements obtained from each mass spectrometer has been determined by taking the precision and accuracy of replicate measurements into account. The present study is focused on calibration processes (before, after, and during the mass measurement), the resolving power of the mass spectrometers, and the data processing for obtaining elemental formulae. The mass range between m/z 100 and 600 has been evaluated with a mix of four standards. This mass range includes small molecules usually detected in food and environmental samples. Negative ESI has been tested as there is almost no data on accurate mass (AM) measurements in this mode. Moreover, it has been used because it is the ESI mode for analysis of many compounds, such as pharmaceutical, herbicides, and fluorinated compounds. Natural organic matter has been used to demonstrate the significance of ultrahigh-resolution in complex mixtures. Sub millidalton accuracy and precision have been obtained with Q-TOF, FT-ICR, and orbitrap achieving equivalent results. Poorer accuracy and precision have been obtained with the QqQ used: 11 mDa root-mean-square error and 6-11 mDa standard deviation. Some advice and requirements for daily AM routine analysis are also discussed here. PMID- 21553216 TI - Evaluation of different adsorbents for large-volume pre-concentration for analyzing atmospheric persistent organic pollutants at trace levels. AB - This paper investigates the performance of some adsorbents, Carbopack B, Tenax GC, and XAD-2, in a SPE and GC analytical method for sampling and determining some persistent organic pollutants such as benzene, toluene, o-, m-, and p xylenes, naphthalene, anthracene, fluorene, fluoranthene, benzo(i,k)fluorene, pyrene and benzo(a)pyrene, aldrin, dieldrin, endrin, endosulfan, and PCB congeners (nos. 1, 15, 44, 77, and 209). Adsorbents evaluated in this study are Carbopack B, Tenax-GC, and XAD-2. Before applying the analytical method to air samples, it was widely investigated in laboratory: the sampler is constituted by a glass pyrex vial home-filled with 300 mg (sampling section) and 50 mg of adsorbent material (backup section). The re-extraction is performed by CS(2) (1-2 mL) and analysis is performed by GC-FID and GC-ECD. The evaluation of breakthrough volumes and desorption efficiencies shows the XAD-2 performance in the enrichment of different organic species present in atmosphere at trace levels (ppt) to be more advantageous than the other two materials in terms of analytical and technical parameters. One of the advantages is the high volume of sampled air with high concentration factor and limited loss of analytes (breakthrough volumes are higher than 5,000 L g(-1) for high-boiling compounds and higher than 400 L g( 1) for low-boiling solutes). Another advantage is the possibility of easy and speed re-extraction of analytes using small volumes of solvent (a few milliliters). The recoveries are about 100% with a RSD <= 2.3 for low-boiling compounds, and between 77% and 109% with a RSD <= 5.7% for high-boiling species. The XAD-2 adsorbent was applied to real air samples collected in different polluted areas (urban, industrial, rural, and remote locations) demonstrating the wide application of such methodology in various environmental situation. PMID- 21553217 TI - Effect of atmosphere on collinear double-pulse laser-induced breakdown spectroscopy. AB - Double-pulse laser-induced breakdown spectroscopy (DP-LIBS) has been shown to enhance LIBS spectra. Several researchers have reported significant increases in signal-to-noise and/or spectral intensity compared to single-pulse (SP) LIBS. In addition to DP-LIBS, atmospheric conditions can also increase sensitivity. Thus, in this study, a collinear DP-LIBS scheme was used along with manipulation of the atmospheric conditions. The DP-LIBS scheme consisted of an initial 45-mJ pulse at 1,064-nm fired into a sample contained in a controlled atmospheric/vacuum chamber. A second analytical 45-mJ pulse at 1,064-nm was then fired 0 to 200 MUs after and along the same path of the first pulse. Ar, He, and air at pressures ranging from atmospheric pressure to 1 Torr are introduced during DP-LIBS and SP LIBS experiments. For a brass sample, significant increases in the spectral intensities of Cu and Zn lines were observed in DP-LIBS under Ar compared to DP LIBS in air. It was also found that Cu and Zn lines acquired with SP-LIBS in Ar are nearly as intense as DP-LIBS in air. While collinear DP-LIBS is effective for increasing the sensitivity for some reduced atmospheres (i.e., Ar and air at 630 to 100 Torr and He at 300 Torr), the enhanced spectral intensity ultimately dropped off as the pressure was reduced below 10 Torr for all atmospheric compositions in the experimental arrangement used in this study. At all pressures of air and Ar, the plasma temperature remained rather constant with increased inter-pulse delays; however, the plasma temperature was more variable for different He gas pressures and inter-pulse delays. PMID- 21553218 TI - Solution to nuclear Overhauser effect challenge. PMID- 21553219 TI - Living cell spectroscopy challenge. PMID- 21553220 TI - Self-assessment and controlled examination in analytical chemistry by use of the EChemTest. PMID- 21553221 TI - Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in hematological parameters. AB - Research on hematological disorders relies on suitable animal models. We retrospectively evaluated the use of the hematological parameters hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell count (WBC), and platelet count (PLT) in the phenotype-driven Munich N-ethyl-N-nitrosourea (ENU) mouse mutagenesis project as parameters for the generation of novel animal models for human diseases. The analysis was carried out on more than 16,000 G1 and G3 offspring of chemically mutagenized inbred C3H mice to detect dominant and recessive mutations leading to deviations in the levels of the chosen parameters. Identification of animals exhibiting altered values and transmission of the phenotypic deviations to the subsequent generations led to the successful establishment of mutant lines for the parameters MCV, RBC, and PLT. Analysis of the causative mutation was started in selected lines, thereby revealing a novel mutation in the transferrin receptor gene (Tfrc) in one line. Thus, novel phenotype-driven mouse models were established to analyze the genetic components of hematological disorders. PMID- 21553222 TI - The association between GSTM1 polymorphism and gastric cancer risk: a meta analysis. AB - Relationship of gastric cancer with the GSTM1 polymorphism was reported with inconsistent results. The objective of this study was to quantitatively evaluate the association between GSTM1 polymorphism and gastric cancer susceptibility. Relevant studies were identified from PubMed and references of retrieved articles. A meta-analysis was performed, which included 38 studies with 6,605 gastric cancer cases and 11,311 controls. The combined result based on all studies showed there was a significant link between GSTM1 null genotype and gastric cancer (OR=1.20, 95%CI: 1.08-1.34). When stratifying for the race, the phenomenon was found that gastric cancer case had a significantly higher frequency of GSTM1 null genotype than control in Asians (OR=1.27, 95%CI: 1.10 1.47). However, there was not enough evidence to show there was a significant difference in GSTM1 null genotype distribution between gastric cancer case and control in Caucasians (OR=1.13, 95%CI: 0.96-1.32). This meta-analysis indicated that GSTM1 null genotype might be associated with increased gastric cancer risk in Asians. However, this meta-analysis did not provide an evidence of confirming association between GSTM1 polymorphism and gastric cancer in Caucasians. PMID- 21553223 TI - PNAS4 knockout does not induce obviously neurocytes apoptosis and abnormal development in mice brain. AB - Apoptosis is one kind of programmed cell death and contributes to development of a variety of organs such as brain. PNAS4 has been reported to be a novel apoptosis-related gene. Overexpression and knocking down of PNAS4 would cause zebrafish and Xenopus lavis developmental abnormalities. But its function and apoptotic mechanism in mammals are still unknown. Here, we first reported that established PNAS4 CKO (conditional knock out) mice using recombineering technology. We prepared its polyclonal antibodies which recognized both myc-PNAS4 overexpression protein and WT and CKO mice brain tissue and MEFS cells with high titre and specificity. Further we detected that PNAS4 was highly expressed in the embryonic period. However, we observed neither neural structural abnormality nor apoptosis signal in PNAS4 CKO mice brain. Our data suggested that PNAS4 was not involved in mice brain development and apoptosis. PMID- 21553224 TI - A meta-analysis of beta1-adrenergic receptor gene polymorphisms in idiopathic dilated cardiomyopathy. AB - Published data on the association between beta1-adrenergic receptor gene polymorphisms and idiopathic dilated cardiomyopathy (IDCM) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 12 case-control studies including 2642 cases and 3136 controls provided data on the association between beta1-adrenergic receptor gene polymorphisms and susceptibility to IDCM. Overall, no significantly elevated risk was associated with Arg389Gly polymorphisms for all genetic models. In the subgroup analysis by ethnicity, no statistically increased risk was found for Gly389Gly versus Arg389Arg (OR 0.73; 95% CI 0.54-0.99; Ph=0.35) and Gly389Gly versus Arg389Arg+Arg389Gly (OR 0.75; 95% CI 0.55-1.01; Ph=0.52) among Europeans. Meanwhile, significantly increased risk was found among Asians based on the relatively small sample size. Further, significantly elevated IDCM risk was associated with Ser49Gly polymorphisms for all genetic models. When stratified by ethnicity, statistical association was found among Asians for Gly49Gly versus Ser49Ser (OR 4.56; 95% CI 1.36-15.23; Ph=0.10) and Gly49Gly versus Ser49Ser+Ser49Gly (OR 4.49; 95% CI 1.33-15.15; Ph=0.12), but not among Europeans. In summary, this meta-analysis suggests that no statistically increased risk was found between beta1-adrenergic receptor gene polymorphisms and susceptibility to IDCM among Europeans. PMID- 21553225 TI - The cyclophosphamide metabolite, acrolein, induces cytoskeletal changes and oxidative stress in Sertoli cells. AB - The aim of this study is to explore the mechanism by which acrolein (ACR), a metabolite of cyclophosphamide (CP), induces immature Sertoli cell cytoskeletal changes. Sertoli cells obtained from rats were cultivated and treated with 50 and 100 MUM ACR. XTT assays were performed to detect cell viability. Activities of superoxide dismutase (SOD), glutathione peroxidases (GSH-Px), and catalase (CAT), as well as total anti-oxidation competence (T-AOC) were examined. Superoxide anion levels were detected by a fluorescent probe. Cell ultrastructure changes were observed by transmission fluorescent microscope. Actin filament (F-actin) distribution was detected by immunofluorescence, and ERK and p38MAPK expression were detected by western blot analysis. ACR significantly decreased the viability of Sertoli cells in a dose- and time-dependent manner. T-AOC and the antioxidant activity of SOD, CAT and GSH-Px, were decreased in ACR-treated groups compared with the control group. The levels of reactive oxygen species (ROS) in ACR treated Sertoli cells were increased. In addition, characteristics of cell apoptosis such as mitochondrial swelling, aggregated chromatin, condensed cytoplasm, nuclei splitting, and nuclei vacuolization were observed in ACR treated cells. Furthermore, ACR-treatment also induced microfilament aggregation, marginalization and regionalization. The expression levels of ERK and p38MAPK were also increased in ACR-treated cells in a dose- and time-dependent manner. ACR, a major CP metabolite, impairs the cytoskeleton which is likely caused by induction of the oxidative stress response through up-regulation of ERK and p38MAPK expression. PMID- 21553226 TI - Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism. AB - We aimed to investigate the association between manganese superoxide dismutase (MnSOD) Ala-9-Val gene polymorphism and the initiation and/or progression of prostate cancer (PCa) as well as to evaluate its potential interactions with advanced age and smoking status. MnSOD Ala-9-Val gene polymorphism was carried out in 134 (mean age 64.1+/-7.48) PCa patients and 159 (mean age 62.5+/-7.53) healthy controls with serum prostate specific antigen (PSA) levels (<4 ng/ml) and normal digital rectal examination (DRE) findings in this prospectively designed study. PCa patients were classified as low stage disease (T1 or T2 and N0M0 stages) and high stage disease (T3 or T4 and N0M0 or N1 or M1 stages). Genotypes for MnSOD Ala-9-Val gene polymorphism were identified by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFPL). Despite lack of association between different genotypes of MnSOD Ala-9-Val gene polymorphism and the presence of PCa, patients with Ala/Ala genotype were at an increased risk of high stage disease compared with those with the Val/Val genotype [odds ratio (OR), 3.77; 95% CI, 1.30-10.94; P=0.012]. However, no significant difference was observed in the distribution of each genotype among PCa patients, with respect to tumor grade. On the other hand, smoking status and aging did not seem to change the association between genotypes and PCa risk. Ala/Ala genotype of MnSOD polymorphism may have an effect on adverse features of PCa such as high stage disease. PMID- 21553227 TI - General and specific determinants of the selective interactions between SRC-1 NR box-2 and target nuclear receptors. AB - Nuclear receptors (NRs) associate with various coactivator proteins via direct interaction with a short LXXLL motif (also called NR box) that is present among coactivators. Here we identified the critical residues within or outside NR box-2 or -3 of SRC-1, which are required for the optimal interaction with LXR/RXR heterodimers using the yeast one- plus two-hybrid screening system. The critical residues of NR box-2 were broadly located from position -4 to +5 of the NR box (where +1 is the first L of LXXLL motif), whereas those of NR box-3 were located between -1 and +5. We assessed the functional and physical interactions between the isolated NR box-2 mutants and various NRs. Among the NR box-2 mutants, H-3Q, I-1T/V and H+2P mutants evidenced different interaction profiles depending on the target NRs, thereby indicating that these residues are the specific determinants required for the selective interaction between the SRC-1 NR box-2 and a given receptor. PMID- 21553228 TI - Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. AB - The aim of this study was to determine whether the interleukin-10 (IL-10) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-10 -1082 G/A, -592 C/A, -892 C/T and IL-10.R polymorphisms and RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 16 studies (19 comparisons) involving 2647 RA patients and 3383 controls were considered in the meta-analysis. Meta-analysis of the IL-10 -1082 G/A polymorphism showed no association with RA in the study subjects, or in European or Asian subjects. However, meta-analysis of the -1082 G allele in 4 studies in Hardy-Weinberg equilibrium showed a significant association with RA (OR=1.217, 95% CI=1.027 1.442, P=0.0236). In contrast, meta-analysis of the C allele, the CC genotype, and of the CC versus the AA genotype of the IL-10 -592 C/A polymorphism showed significant associations with RA. The overall ORs of the associations between the C allele and RA were 0.684 and 0.758 (95% CI=0.494-0.946, P=0.022; 95% CI=0.475 1.210, P=0.045) in all study subjects and Asians. Meta-analysis of the CC+CT versus TT genotype and of the CC versus TT genotype of the IL-10 -892 C/T polymorphism revealed significant associations with RA. The overall OR of the association between the C allele carrier and RA was 0.552 (95% CI=0.375-0.812, P=0.003). No association was found between the IL10.R2 alleles and RA. This meta analysis suggests that the IL-10 -592 C/A polymorphism confers susceptibility to RA in Asians and that the IL-10 -1082 G/A and -892 C/T polymorphisms are associated with RA susceptibility. These findings suggest the IL-10 genes confer susceptibility to RA. PMID- 21553229 TI - IL-10R1 S138G loss-of-function polymorphism is associated with extrapulmonary tuberculosis risk development in Tunisia. AB - There is considerable evidence that host genetic factors are important in determining susceptibility to mycobacterial infections. More recently, functional genetic mutations affecting IL-10 receptor 1 (IL-10R1) were described. In this study, we investigated the relationship of IL-10R1 S138G loss-of-function polymorphism (A536G: rs3135932) with susceptibility to active tuberculosis (TB) in Tunisian patients. A total of 168 patients with pulmonary TB, 55 with extrapulmonary TB, and 150 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL 10R1 gene by multiplex allele-specific polymerase chain reaction. Associations between G allele [odds ratio OR=5.01; 95% confidence intervals CI=2.58-9.77; P=10(-7)], GG genotypes [OR=9.06; 95% CI (1.58-67.33); correcting P-values using the Bonferroni method for multiple tests Pc=0.015] and AG genotype [OR=3.75; 95% CI (1.62-8.7); Pc=0.0012] with the risk development of active extrapulmonary TB were found. In contrast, the AA genotype was found to be associated with resistance to extrapulmonary TB [OR=0.19; 95% CI (0.09-0.42); Pc=6.10(-6)]. No association was found between S138G SNP and pulmonary TB. In conclusion, our study suggested the possible role of IL-10R1 S138G loss-of-function polymorphism in extrapulmonary TB susceptibility-resistance in Tunisia. PMID- 21553230 TI - Enucleation in pancreatic surgery: indications, technique, and outcome compared to standard pancreatic resections. AB - PURPOSE: Pancreatic surgery is a technically challenging intervention with high demands for preoperative diagnostics and perioperative management. A perioperative mortality rate below 5% is achieved in high-volume centers due to the high level of standardization in surgical procedures and perioperative care. Besides standard resections, certain indications may require individualized surgical concepts such as tumor enucleations. The aim of the study was to evaluate the indications, technique, and outcome of this limited local approach compared to major resections. MATERIALS AND METHODS: Data from patients undergoing pancreatic surgery were prospectively recorded. All patients with tumor enucleations were compared with classical resections (pancreaticoduodenectomy or left resection) in a matched-pair analysis (1:2). Tumor type, localization, operative parameters, complications, and outcome were evaluated. RESULTS: Fifty-three patients underwent pancreatic tumor enucleation between October 2001 and December 2009. Indications included cystic lesions, IPMNs, and neuroendocrine pancreatic tumors. Enucleations were associated with shorter operation time, less blood loss as well as shorter ICU and hospital stay compared to pancreaticoduodenectomy and left resections. The overall surgical morbidity of enucleations was 28.3% without major complications. Leading clinical problems were ISGPF type A fistulas (20.8%) requiring prolonged primary drainage. No surgical revisions were necessary, and no deaths occurred. CONCLUSIONS: Pancreatic tumor enucleations can be carried out with good results and no mortality. Decisions regarding enucleations are highly individual compared to standard resections, underlining the importance of treatment in experienced high volume institutions. Enucleations should be carried out whenever possible and oncologically feasible to prevent the typical complications of major pancreatic resection. PMID- 21553231 TI - Significantly high expression of platelet-derived growth factor (PDGF) in benign nodules of the thyroid: relevance in the development of goitre recurrence? AB - PURPOSE: Platelet-derived growth factor (PDGF) is a critical regulator of cell proliferation and influences the development of tumors. The role of PDGF in benign thyroid diseases is presently not well-determined. The purpose is to evaluate PDGF isoforms and receptors in primary culture of thyrocytes isolated from human thyroid tissue. METHODS: Forty patients with uninodular (n = 11), multinodular (n = 15) and recurrent goitre (n = 14) were investigated. Nodular and corresponding paranodular thyroid tissues were characterized. RNA and protein were extracted from primary thyrocyte monoculture. RT-PCR, western blot and ELISA were performed to evaluate PDGF isoforms AA, BB, CC, DD and PDGF receptors alpha and beta. RESULTS: Significantly higher mRNA expression of PDGF-AA, -BB, -CC and PDGFR molecules alpha and beta was measured by RT-PCR in thyrocytes from uninodular and recurrent nodular tissue compared with corresponding paranodular tissue. Elevated PDGF protein and PDGFR-alpha and -beta were confirmed by western blot. Likewise, higher secretion of PDGF-AA and -BB was detected in the supernatant of thyrocyte culture from all nodular tissue compared with paranodular tissue. Interestingly, comparison of nodular and corresponding paranodular tissues in multinodular goitre did not show significant difference of expression levels of PDGF isoforms or receptors. CONCLUSION: These findings suggest that the overexpression of PDGF isoforms and receptors may play a crucial role in the development of thyroid nodules and recurrent goitre. PMID- 21553233 TI - Peptide antigens for gamma/delta T cells. AB - gammadelta T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region of TCR V-J junctions, especially in the delta chain, which should enable the gammadelta TCRs to distinguish differences in small epitopes. Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported. Responses to small non-peptides known as phospho-antigens are multi-clonal yet limited to a single gammadelta T cell subset in humans and non-human primates. Responses to small peptides are multi-clonal or oligo-clonal, include more than one subset of gammadelta T cells, and occur in rodents and primates. However, less effort has been devoted to investigate the peptide responses. To settle the questions of whether peptides can be ligands for the gammadelta TCRs, and whether responses to small peptides might occur normally, peptide binding will have to be demonstrated, and natural peptide ligands identified. PMID- 21553234 TI - LAPTM4A interacts with hOCT2 and regulates its endocytotic recruitment. AB - Human organic cation transporter 2 (hOCT2) is involved in the transport of endogenous and exogenous organic cations mainly in cells of the kidney and the brain. Here, we focus on the regulation of hOCT2 by direct protein-protein interaction. Screening within a mating-based split-ubiquitin-yeast-two-hybrid system (mBSUS) revealed the lysosomal-associated protein transmembrane 4 alpha (LAPTM4A) as a potential interacting protein. Interaction of LAPTM4A and hOCT2 was confirmed by pulldown assays, FRET microscopy analysis and immunofluorescence microscopy. Functionally, overexpression of LAPTM4A significantly decreased ASP(+) uptake in HEK293 cells stably transfected with hOCT2, suggesting a negative regulation of hOCT2-mediated transport. Furthermore, overexpression of LAPTM4A leads to a significantly decreased hOCT2 plasma membrane expression in surface biotinylation experiments. In addition, significant expression of LAPTM4A in human kidney was demonstrated by immunoblotting and immunofluorescence.In this work, LAPTM4A has been identified as interaction partner of hOCT2. LAPTM4A regulates the function of hOCT2 by influencing its trafficking to/from the cell membrane and processing it via the intracellular sorting machinery. PMID- 21553232 TI - Melanocortin control of energy balance: evidence from rodent models. AB - Regulation of energy balance is extremely complex, and involves multiple systems of hormones, neurotransmitters, receptors, and intracellular signals. As data have accumulated over the last two decades, the CNS melanocortin system is now identified as a prominent integrative network of energy balance controls in the mammalian brain. Here, we will review findings from rat and mouse models, which have provided an important framework in which to study melanocortin function. Perhaps most importantly, this review attempts for the first time to summarize recent advances in our understanding of the intracellular signaling pathways thought to mediate the action of melanocortin neurons and peptides in control of longterm energy balance. Special attention will be paid to the roles of MC4R/MC3R, as well as downstream neurotransmitters within forebrain and hindbrain structures that illustrate the distributed control of melanocortin signaling in energy balance. In addition, distinctions and controversy between rodent species will be discussed. PMID- 21553235 TI - Kinetics of CEA and CA15-3 correlate with treatment response in patients undergoing chemotherapy for metastatic breast cancer (MBC). AB - The aim of this retrospective analysis is to determine the correlation between tumour marker kinetics (TMK) like carcinoembryonic antigen (CEA) and/or cancer antigen (CA) 15-3 and imaging concerning effectiveness of chemotherapy in metastatic breast cancer (MBC) patients. TMK (CEA, AxSYM, Abbott; CA15-3, Elecsys, Roche) were evaluated in MBC patients (n=77) at the beginning of chemotherapy (pre-treatment value=A), after 20-30 days (first intermediate value=B), after 40-60 days (second intermediate value=C) and at the time the effectiveness of chemotherapy was evaluated with imaging (D). Response to treatment was assessed by standard WHO criteria criteria. For the assessment of biochemical progression and response, four criteria based on TMK were established. The first criterion of progression required that there was an increase >= 25% after 40-60 days (C) and the slope per day from B to C exceeds the slope from A to B. The second criterion of progression required that, at the time of staging, the value be >= 25% of the pre-treatment value (A), and also, increasing values from C until staging (D) were required. The first criterion of response required that the second intermediate value (C) be decreased by >= 25% compared to A (pre-treatment value) and C be lower than B (first intermediate value). The second criterion of response required that D be <= 25% of B and D be lower than C. Fifty-four (70%) patients showed a correlation between TMK and imaging results during chemotherapy. In 10 (13%) patients, no correlation was obtained, and in 13 (17%) patients, no biochemical statement was possible because of divergent TMK. In summary, after 1 month, no statement about treatment response was possible by using TMK. The effectiveness or ineffectiveness of treatment could be determined correctly in 40% of patients after 2 months and in 70% of patients after approximately 3 months. The data presented support the hypothesis that TMK are clinically relevant tools to monitor treatment response. Further improvements on their sensitivity can be probably achieved by a prospective study design and by combining with other biomarkers like CA-125 and HER2 shed antigen. PMID- 21553236 TI - Telomerase reverse transcriptase catalytic subunit expression and proliferation index in Wilms tumor. AB - Telomerase activity provides telomere maintenance in chromosomes. It prevents cells from entering senescence. Telomerase activity is one of the crucial steps in various cancers. Wilms tumor (nephroblastoma) is one of the most common solid tumors of childhood. Hitherto, telomerase reverse transcriptase (TERT) catalytic subunit expression in Wilms tumor has not been investigated widely. The aim of this study was to explore the expression level of human TERT in Wilms tumor and to correlate with some clinical prognosis factors such as tumor weight, stage, histology, and Ki67 expression. This study included 41 nephroblastoma cases of childhood. The telomerase catalytic subunit expression and proliferation index was determined using an immunohistochemical method on archival paraffin-embedded tissue sections. Statistical analysis was done on SPSS 9.05 by Mann-Whitney U test and Spearman's correlation analysis. TERT expression was negative in 11 cases (26.8%), weakly positive in 14 cases (34.1%), and strongly positive in 16 cases (39%). The proliferation index was found to be 20 to 90 (mean 58.9 +/- 26.8). Using Spearman correlation analysis, both the TERT expression (p=0.032) and Ki67 index (p=0.048) were found to be correlated with survival rate. Similarly, both the telomerase expression (p=0.011) and the Ki67 index (0.040) were correlated with the weight and dimension of the tumor. But there was no relationship between telomerase expression and Ki67 index (p=0.429). The mean survival time for telomerase negative cases was 56.6 +/- 27.3 months, while it was 34.67 +/- 28.36 months for positive cases. The Mann-Whitney U test revealed that levels of telomerase (p=0.040) significantly affected the survival rate. In the present study, we showed that the presence of TERT expression correlated with both tumor size and survival time. These findings suggest that senescence may play an important role in WT evolution, and determination of telomere maintenance will be useful to predict survival and follow-up of patients with Wilms tumor. PMID- 21553237 TI - Mucosal changes induced by ischemia-reperfusion injury in a jejunal loop transplanted in oropharynx. AB - Tissues exposed to ischemia and reperfusion develop an inflammatory response. We investigate the morphological and immunological changes occurring in the mucosa of a jejunal loop transplanted in the oropharynx of a man undergoing circular pharyngolaryngectomy. Jejunal biopsies were collected during the transplantation procedures (cold and warm ischemia, reperfusion), during the 7 post-operative days through an exteriorized jejunal segment for flap monitoring, and 45 days after transplantation through an upper endoscopy. Matrix metalloproteinase (MMP) 3 and MMP-12 increase was accompanied by a parallel rise in apoptotic enterocytes, and by a concomitant reduction of surface area to volume ratio and enterocyte height. Goblet cell hyperplasia is coupled with Paneth cell disappearance at the crypt base. CD8-positive intraepithelial lymphocytes initially decrease, then they increase in accordance with the peak of enterocyte apoptosis. We identified alterations in lymphocyte infiltration, mucosal architecture and epithelial cell turnover, which may give a window to mechanisms of small bowel ischemia-reperfusion in humans. PMID- 21553238 TI - Improved survival in patients with inoperable chronic thromboembolic pulmonary hypertension. AB - Patients with inoperable chronic thromboembolic pulmonary hypertension (Inop CTEPH) treated with conventional therapy have a poor survival. We compare the 3 year survival between those treated with conventional therapy and those treated with conventional therapy and a combination of novel drugs. We also evaluate the clinical course. A total of 34 Inop-CTEPH consecutive patients were evaluated from 1991 to 2009 including right heart catheterization (RHC) and perfusion lung scan (PLS): 7 underwent surgical treatment while 27 were confirmed inoperable. Of these 27 patients, 12 evaluated from 1991 to 2003 (Group 1) were treated with conventional therapy and 15 evaluated from 2004 to 2009 (Group 2) were treated with conventional and novel therapies. At baseline, no group difference emerged at RHC. Based on clinical course, novel drugs and oxygen supplementation were given to patients of Group 2. Seven of these who had worse clinical course repeated RHC and four of them also PLS during therapy. Those without repeat RHC had baseline pulmonary artery mean pressure and brain natriuretic peptide (NT proBNP) lower and mixed venous saturation (SvO2) and exercise test higher (p = 0.022, 0.015, 0.044 and 0.003, respectively). During therapy, those with repeat RHC had total pulmonary vascular resistance reduced (p = 0.012), base excess increased (p = 0.002) and significant redistribution of pulmonary blood flow at PLS. At the 3-year follow-up, survival was 86% in Group 2 and 31% in Group 1 (p = 0.031). In Inop-CTEPH patients, the clinical course may help to select drugs and the level of oxygen supply that can improve hemodynamics, gas exchange and long term survival. PMID- 21553239 TI - Recent advances in understanding Crohn's disease. AB - Crohn's disease is a chronic inflammatory bowel disorder resulting from an inappropriate innate and acquired immune response to commensal microorganisms in genetically susceptible individuals. This disease has a fluctuating course, with alternating periods of remission and relapses, and it is characterized by a remarkable clinical heterogeneity; it may be complicated by perianal fistulas, abscesses, and intestinal strictures leading to obstructions, besides several systemic manifestations. However, a complete resolution of the disease is currently not possible, yet Crohn's disease can be managed with established and novel therapies, which achieve long-term remission and acceptable quality of life. This review is focused on novel advances in basic and clinical aspects of Crohn's disease, although it also deals with new trends in diagnosis and treatment. PMID- 21553240 TI - Evidence for a cognitive bias of interpretation toward threat in individuals with a Type D personality. AB - Biological and behavioral mediators link Type D personality with a poor prognosis in heart disease. However, the mediator role of cognitive biases is still unknown. This study tested whether Type D individuals exhibit an interpretative bias for ambiguous social situations. For this aim we examined Type D and non Type D individuals' evaluations of written social situations that varied in terms of situations' clarity (clear, ambiguous) and social judgment (neutral, negative). A convenience sample of 42 young, healthy adults rated each situation in relation to the difficulty of formulating a verbal response, anticipated distress, and perceived threat, and they completed the Type D personality scale (DS14; Denollet, 2005). Results showed an interpretation bias among Type D individuals, as they rated ambiguous or neutral situations as significantly more distressing compared to non-Type D individuals. Only clearly negative situations were rated similarly by Type D and non-Type D individuals. The discussion suggests that this interpretation bias in Type D individuals would increase their vulnerability to perceived stress. PMID- 21553241 TI - Cadmium accumulation and antioxidant responses in Sparus aurata exposed to waterborne cadmium. AB - Cadmium (Cd), a nonessential trace element, is rapidly accumulated by most living organisms and subsequently exerts its toxicity at different molecular levels. This study exposed gilthead sea bream (Sparus aurata) to waterborne 0.1 mg/l Cd for 11 days and investigated the Cd accumulation pattern, lipid oxidation, and response of antioxidant defences. At the end of the experiment, mean Cd concentrations in gills and liver, the organs most prone to metal accumulation, were 209.4 and 371.7 ng/g ww, respectively. Muscle did not show any Cd retention during the 11 days of exposure. In liver, the cytosolic fraction of the metal was chelated into the nontoxic form by metallothionein (MT), a specific Cd-inducible protein. Zn and Cu concentrations were not influenced by Cd exposure. Glutathione (GSH) concentrations and the antioxidant enzyme activities of GSH reductase and GSH peroxidase showed an overall decreasing trend. In addition, lipid and aqueous hydroperoxide levels did not show any significant variation. Oxidative stress indirectly generated by Cd seems to be compensated for by the different biochemical systems tailored to decrease cellular damage. In particular, the negative effects of Cd accumulation in tissues were probably counteracted by the induction of MT. PMID- 21553242 TI - Zinc alleviates mercury-induced oxidative stress in Pfaffia glomerata (Spreng.) Pedersen. AB - The possible role of zinc (Zn) to reverse the oxidative stress caused by mercury (Hg) was investigated in Pfaffia glomerata plantlets. Thirty-day-old acclimatized plantlets of P. glomerata were exposed to four treatments: control, 50 MUM Zn, 50 MUM Hg and 50 MUM Zn + 50 MUM Hg for 9 days. In Zn + Hg treatment, shoot and root Hg concentrations were 59 and 24% smaller than that plants exposed to 50 MUM Hg added alone. An increase in the Zn concentration in the shoot of plants exposed to Zn + Hg occurred, although in the roots Zn concentration was not altered, when compared to the control. Fresh and dry weights, as well as the activity of delta aminolevulinic acid dehydratase (delta-ALA-D) in Hg-treated plants were significantly reduced. Percentage survival, fresh and dry weights and delta-ALA-D activity of plants treated by 50 MUM Zn + 50 MUM Hg were greater than of that treated by Hg alone. Moreover, Zn treatment reduced the lipid peroxidation caused by Hg, being this effect related to increased root superoxide dismutase activity, and shoot catalase and ascorbate peroxidase activities. In conclusion, the presence of Zn in the substrate caused a significant reduction in the oxidative stress induced by Hg. PMID- 21553243 TI - Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. AB - Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (?ISR[AUC]) to incremental area under the glucose curve (?G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60-120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 +/- 0.6 vs. 0.72 +/- 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 +/- 0.2 and 0.19 +/- 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT. PMID- 21553244 TI - Optimal response to chemotherapy for a mathematical model of tumor-immune dynamics. AB - An optimal control problem for cancer chemotherapy is considered that includes immunological activity. In the objective a weighted average of several quantities that describe the effectiveness of treatment is minimized. These terms include (i) the number of cancer cells at the terminal time, (ii) a measure for the immunocompetent cell densities at the terminal point (included as a negative term), (iii) the overall amount of cytotoxic agents given as a measure for the side effects of treatment and (iv) a small penalty on the terminal time that limits the overall therapy horizon which is assumed to be free. This last term is essential in obtaining a well-posed problem formulation. Employing a Gompertzian growth model for the cancer cells, for various scenarios optimal controls and corresponding responses of the system are calculated. Solutions initially follow a full dose treatment, but then at one point switch to a singular regimen that only applies partial dosages. This structure is consistent with protocols that apply an initial burst to reduce the tumor volume and then maintain a small volume through lower dosages. Optimal controls end with either a prolonged period of no dose treatment or, in a small number of scenarios, this no dose interval is still followed by one more short burst of full dose treatment. PMID- 21553245 TI - Cellular localization of human p53 expressed in the yeast Saccharomyces cerevisiae: effect of NLSI deletion. AB - The tumor suppressor p53 plays a central role in the regulation of cellular growth and apoptosis. In Saccharomyces cerevisiae, over-expression of the human wtp53 leads to growth inhibition and cell death on minimal medium. In the present work, we showed that deletion of the nuclear localization signal (NLSI) of p53 restores the yeast growth. In this heterologous context, the level of p53?NLSI was low and the protein mainly located in the cytoplasm while the wtp53 was observed in both the cytoplasmic and nuclear compartments. Interestingly, the wtp53 protein was observed in the mitochondria, whereas the p53?NLSI protein failed to localize in mitochondria. Moreover, mitochondrial morphology defect and release of cytochrome c in the cytosol were noticed only in the yeast strain expressing the wtp53. In conclusion, our results provide evidence that the human wtp53 is active in S. cerevisiae probably through dependent and independent transcriptional mechanisms leading to cell death. The deletion of the NLSI sequence decreases p53 nuclear translocation as well as its mitochondrial localization and consequently its effect on yeast growth. PMID- 21553247 TI - BIT/SHPS-1 promotes antiapoptotic effect of BDNF on low potassium-induced cell death of cultured cerebellar granule neurons. AB - Brain immunoglobulin-like molecule with tyrosine-based activation motifs/SHP substrate 1 (BIT/SHPS-1) is a neuronal adhesion molecule that is highly expressed in cerebellar granule neurons (CGNs); however its function in CGNs remains unclear. Our previous studies indicated that BIT/SHPS-1 is able to modulate the antiapoptotic effect of brain-derived neurotrophic factor (BDNF) on CNS neurons by cell type-specific mechanisms. In this article, we have studied the role of BIT/SHPS-1 in the antiapoptotic function of BDNF on low potassium (LK)-induced cell death of cultured CGNs which is an in vitro model system of neuronal apoptosis during brain development. Cultured rat CGNs were transduced with wild type rat BIT/SHPS-1 (BIT/SHPS-1(WT)), its 4F-mutant (BIT/SHPS-1(4F), in which all cytoplasmic tyrosine residues were substituted with phenylalanine), or nuclear localization signal-attached beta-galactosidase (NLS-LacZ, as control)-expressing adenoviruses. Expression of BIT/SHPS-1(WT) and BIT/SHPS-1(4F) alone did not affect steady-state cell viability. Tyrosine phosphorylation of BIT/SHPS-1 was only detected in BIT/SHPS-1(WT)-expressing cultures in the presence and the absence of BDNF. When subjected to LK in the presence of BDNF, BIT/SHPS-1(WT)- and BIT/SHPS-1(4F)-expressing cultures showed a significant resistance to cell death, while the control virus-transfected culture did not. In addition, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, attenuated the antiapoptotic effect of BDNF on BIT/SHPS-1(WT)-, and BIT/SHPS-1(4F)-expressing cultures. These results demonstrated that in both tyrosine phosphorylation independent and PI3-K-dependent manners, BIT/SHPS-1 promotes the antiapoptotic effect of BDNF on the LK-induced cell death of CGNs. PMID- 21553249 TI - Bioaccumulation of trace elements in different tissues of three commonly available fish species regarding their gender, gonadosomatic index, and condition factor in a wetland ecosystem. AB - In the present research, accumulation of Cd, Co, Cr, Cu, Mn, Ni, Pb, V, and Zn were determined in sediments and fillet, liver, kidney, gonads, and gills of three commonly fish species in the largest wetland ecosystem that is located in southwest of Iran; Shadegan wetland. Shadegan is one of the most important wetland that posses various fauna and flora but suffers inputs from agricultural and industrial activities. So, sediment samples and fish species including Barbus grypus, Barbus sharpeyi, and Cyprinus carpio were collected during winter 2009. Results showed that mean concentrations of trace elements (except Ni and Co) were high in liver and gills of B. grypus. Also trace elements had the most accumulation in liver of B. sharpeyi except for Cd (0.26 mg kg(- 1) d.w.) and Mn (13.45 mg kg(- 1) d.w.) that were high in gills. Beside, kidney is determined as target tissue for Ni and V in B. grypus and for Pb in C. carpio, due to their high concentration. Zn levels in all tissues of C. carpio showed the highest concentrations in comparison to other fish species. Generally, accumulations of most of the studied elements in B. grypus and B. sharpeyi were higher in females than in males, while in fillet and gonads of C. carpio, this trend was inverted. Bioaccumulation factors (BAFs) were determined for different tissues of fish species with respect to elemental concentrations in sediment. BAFs results indicated that Zn, Pb, and Cu have higher BAF than other elements. Also this investigation demonstrated that trace elements have different affinities with condition factor of studied fish species. Gonadosomatic index (GSI) and Pb showed positive correlation together in both B. sharpeyi and B. grypus, respectively, in females and males. Moreover, females of C. carpio showed significantly positive relation of GSI and all studied elements. PMID- 21553248 TI - Brain tumor microvesicles: insights into intercellular communication in the nervous system. AB - Brain tumors are heterogeneous tumors composed of differentiated tumor cells that resemble various neural cells and a small number of multipotent cancer stem cells. These tumors modify normal cells in their environment to promote tumor growth, invasion and metastases by various ways. Recent publications show that glioblastoma cells release microvesicles that contain a select subset of cellular proteins and RNAs. These microvesicles are avidly taken up by normal cells in cell culture and can change the translational profile of these cells through delivery of tumor-derived mRNAs, which are translated into functional proteins. In addition to mRNA and proteins, microvesicles have been shown to contain microRNAs, non-coding RNAs and DNA. This commentary explores the recent advances in this novel intercellular communication route and discusses the potential physiological role of microvesicles in brain tumorigenesis. PMID- 21553250 TI - Comparison of some quality properties of soils around land-mined areas and adjacent agricultural fields. AB - When agricultural lands are no longer used for agriculture and allowed to recover its natural vegetation, soil organic carbon can accumulate in the soil. Measurements of soil organic carbon and aggregate stability changes under various forms of land use are needed for the development of sustainable systems. Therefore, comparison of soil samples taken from both agricultural and nearby area close to land-mined fields where no agricultural practices have been done since 1956 can be a good approach to evaluate the effects of tillage and agriculture on soil quality. The objective of this study was to compare tillage, cropping and no tillage effects on some soil-quality parameters. Four different locations along the Turkey-Syria border were selected to determine effects of tillage and cropping on soil quality. Each location was evaluated separately because of different soil type and treatments. Comparisons were made between non tilled and non-cropped fallow since 1956 and adjacent restricted lands that were tilled about every 2 years but not planted (T) or adjacent lands tilled and planted with wheat and lentil (P). Three samples were taken from the depths of 0 20 and 20-40 cm each site. Soil organic carbon (SOC), pH ,electrical conductivity, water soluble Ca(++), Mg(++), CO3-2 and HCO3-, extractable potassium (K(+)) and sodium (Na(+)), soil texture, ammonium (NH4+-N) and nitrate (NO(3)-N), extractable phosphorous and soil aggregate stability were determined. While the SOC contents of continuous tillage without cropping and continuous tillage and cropping were 2.2 and 11.6 g kg(-1), respectively, it was 30 g kg(-1) in non-tilled and non-planted site. Tillage of soil without the input of any plant material resulted in loss of carbon from the soil in all sites. Soil extractable NO(3)-N contents of non-tilled and non-cropped sites were greatest among all treatments. Agricultural practices increased phosphorus and potassium contents in the soil profile. P(2)O(5) contents of planted soils were approximately 20 to 39 times greater than those of non-tilled and non-cropped soils at different sites. FTIR spectra showed that never tilled sites had greater phenol, carboxylic acid, amide, aromatic compounds, polysaccharide and carbohydrates than other treatments. PMID- 21553251 TI - A primer for nonresponse in the US forest inventory and analysis program. AB - Nonresponse caused by denied access and hazardous conditions are a concern for the USDA Forest Service, Forest Inventory and Analysis (FIA) program, whose mission is to quantify status and trends in forest resources across the USA. Any appreciable amount of nonresponse can cause bias in FIA's estimates of population parameters. This paper will quantify the magnitude of nonresponse and describe the mechanisms that result in nonresponse, describe and qualitatively evaluate FIA's assumptions regarding nonresponse, provide a recommendation concerning plot replacement strategies, and identify appropriate strategies to pursue that minimize bias. The nonresponse rates ranged from 0% to 21% and differed by land owner group; with denied access to private land the leading cause of nonresponse. Current FIA estimators assume that nonresponse occurs at random. Although in most cases this assumption appears tenable, a qualitative assessment indicates a few situations where the assumption is not tenable. In the short-term, we recommend that FIA use stratification schemes that make the missing at random assumption tenable. We recommend the examination of alternative estimation techniques that use appropriate weighting and auxiliary information to mitigate the effects of nonresponse. We recommend the replacement of nonresponse sample locations not be used. PMID- 21553252 TI - Prevention needs of HIV-positive men and women awaiting release from prison. AB - Greater understanding of barriers to risk reduction among incarcerated HIV+ persons reentering the community is needed to inform culturally tailored interventions. This qualitative study elicited HIV prevention-related information, motivation and behavioral skills (IMB) needs of 30 incarcerated HIV+ men and women awaiting release from state prison. Unmet information needs included risk questions about viral loads, positive sexual partners, and transmission through casual contact. Social motivational barriers to risk reduction included partner perceptions that prison release increases sexual desirability, partners' negative condom attitudes, and HIV disclosure-related fears of rejection. Personal motivational barriers included depression and strong desires for sex or substance use upon release. Behavioral skills needs included initiating safer behaviors with partners with whom condoms had not been used prior to incarceration, disclosing HIV status, and acquiring clean needles or condoms upon release. Stigma and privacy concerns were prominent prison context barriers to delivering HIV prevention services during incarceration. PMID- 21553253 TI - Optimizing the analysis of adherence interventions using logistic generalized estimating equations. AB - Interventions aimed at improving HIV medication adherence could be dismissed as ineffective due to statistical methods that are not sufficiently sensitive. Cross sectional techniques such as t tests are common to the field, but potentially inaccurate due to increased risk of chance findings and invalid assumptions of normal distribution. In a secondary analysis of a randomized controlled trial, two approaches using logistic generalized estimating equations (GEE)-planned contrasts and growth curves-were examined for evaluating percent adherence data. Results of the logistic GEE approaches were compared to classical analysis of variance (ANOVA). Robust and bootstrapped estimation was used to obtain empirical standard error estimates. Logistic GEE with either planned contrasts or growth curves in combination with robust standard error estimates was superior to classical ANOVA for detecting intervention effects. The choice of longitudinal model led to key differences in inference. Implications and recommendations for applied researchers are discussed. PMID- 21553254 TI - Levels of insulin-like growth factor during pregnancy and maternal cancer risk: a nested case-control study. AB - Previous studies have suggested that pregnancy measures of insulin-like growth factors (IGFs) may be related to breast cancer risk in mothers. IGFs may also be important in cervical cancer etiology. We conducted a nested case-control study (69 breast cancer cases, 151 cervical cancer cases, 443 controls) among mothers of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Over 70% of blood samples was taken prior to 15 weeks' gestation; the remainder before 30 weeks. Logistic regression, controlling for maternal age, gestational age, and sample type (plasma/serum) was used to model the association between IGFs and maternal cancer risk. Neither IGF-I nor IGF-II were associated with breast or cervical cancer. IGF-binding protein (BP)-3 was not related to breast cancer, but there was a suggestion that women in the highest compared to lowest quartile of IGFBP-3 had reduced risk of cervical cancer, OR 0.43 (95% CI 0.21-0.86). In conclusion, the importance of IGFs measured in pregnancy and later breast and cervical cancer remains unclear, though IGFBP-3 may be a marker of lowered risk. PMID- 21553255 TI - Hesperidin, a flavone glycoside, as mediator of neuronal survival. AB - Flavonoids comprise the most common group of plant polyphenols and provide much of the flavor and color to fruits and vegetables. More than 5,000 different flavonoids have been described. The biological activities of flavonoids cover a very broad spectrum, from anticancer and antibacterial activities to inhibition of bone reabsorption and neuroprotection effect. Although emerging evidence suggests that flavonoids have an important role on brain development, little is known about their mechanisms of action. In the present work, we performed a screening of flavonoid actions by analyzing the effects of these substances (hesperidin and rutin) on neural progenitors and neuronal morphogenesis in vitro. We demonstrated that treatment of neural progenitors with the flavonoid hesperidin enhanced neuronal population as revealed by an 80% increase in the number of beta-tubulin III cells. This effect was mainly due to modulation of neuronal progenitor survival. Pools of astrocyte and oligodendrocyte progenitors were not affected by hesperidin whereas rutin had no effect on neuronal population. We also demonstrated that the flavonoid hesperidin modulates neuronal cell death by activating MAPK and PI3K pathways. This opens the possibility of using flavonoids for potential new therapeutic strategies for neurodegenerative diseases. PMID- 21553256 TI - Effects of adrenalectomy and replacement therapy of corticosterone on cell proliferation and neuroblast differentiation in the rat dentate gyrus. AB - Newly generated neurons in the dentate gyrus differentiate into mature granule cells. In the present study, we observed the effects of adrenalectomy (ADX) and corticosterone replacement therapy (CRT) on cell death, cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus (SZDG). For this, the animals received vehicle or CRT after ADX, and were sacrificed 5 or 42 days later. Plasma corticosterone levels were very low in the adrenalectomized groups, whereas CRT after ADX significant increased serum corticosterone levels at 42 days, not 5 days, after ADX. ADX induced some neuronal damage in the dentate gyrus at 5 days post-ADX. CRT did not significantly reduce the neuronal damage at 5 days post-ADX; however, neuronal damage was not shown at 42 post-ADX with CRT. Ki67 (a marker for cell proliferation) and doublecortin (DCX, a marker for neuronal differentiation) immunoreaction was detected in the SZDG. ADX transiently increased cell proliferation and neuroblast differentiation 5 days after ADX, not 42 days, after ADX, and the CRT 42 days after ADX prominently decreased cell proliferation and neuroblast differentiation in the dentate gyrus. These results suggest that adrenal corticosteroid hormone is not essential for cell proliferation and neuroblast differentiation in long-term period after ADX. PMID- 21553257 TI - A novel hypothesis about mechanisms affecting conduction velocity of central myelinated fibers. AB - The hypothesis that gap junctions are implicated in facilitating axonal conduction has not yet been experimentally demonstrated at the electrophysiological level. We found that block of gap junctions with oleammide slows down axonal conduction velocity in the hippocampal Schaffer collaterals, a central myelinated pathway. Moreover, we explored the possibility that support by the oligodendrocyte to the axon involves energy metabolism, a hypothesis that has been recently proposed by some of us. In agreement with this hypothesis, we found that the effect of oleammide was reversed by pretreatment with creatine, a compound that is known to increase the energy charge of the tissue. Moreover, conduction velocity was also slowed down by anoxia, a treatment that obviously decreases the energy charge of the tissue, and by ouabain, a compound that blocks plasma membrane Na/K-ATPase, the main user of ATP in the brain. We hypothesize that block of gap junctions slows down conduction velocity in central myelinated pathways because oligodendrocytes synthesize ATP and transfer it to the axon through gap junctions. PMID- 21553258 TI - Bone fluoride concentrations of eastern grey kangaroos (Macropus giganteus) resident near an aluminium smelter in south-eastern Australia. AB - Lesions of skeletal and dental fluorosis have been described recently in eastern grey kangaroos (Macropus giganteus). The present study further examined the epidemiology of skeletal fluorosis in this species. Bone fluoride concentrations were obtained from a range of skeletal sites of animals from a high (Portland Aluminium) and a low (Cape Bridgewater) fluoride environment in Victoria, Australia. Age, but not sex, affected the mean bone fluoride concentration of kangaroos. For a given age, bone fluoride concentrations were significantly higher in kangaroos from Portland than Cape Bridgewater. Concentrations varied between skeletal sites examined, with samples containing cancellous bone having higher fluoride concentrations than those containing only cortical bone. PMID- 21553259 TI - The role of weather in mediating the effect of mercury exposure on reproductive success in tree swallows. AB - Mercury is a heavy metal that has contaminated countless ecosystems throughout the world. A large body of literature has documented reproductive, physiological, and behavioral impairments associated with mercury exposure in laboratory settings, but whether and how such effects are manifest in free-living populations remains poorly understood. The purpose of this study was to evaluate whether tree swallow (Tachycineta bicolor) breeding success at a site with high mercury exposure varied with ambient temperature or precipitation at various points in the breeding cycle. Tree swallows nesting along the South River had significantly elevated blood total mercury (mean +/- SE: 3.03 +/- 0.15 MUg/g) compared to swallows breeding on reference sites (mean +/- SE: 0.16 +/- 0.005 MUg/g). These high levels of mercury were associated with reduced hatching and fledging success, and contaminated birds produced approximately one less fledgling per nest than their reference counterparts. The magnitude of this difference was weather-dependent: unusually high ambient temperatures encountered early in the nestling period were associated with reduced reproductive output in contaminated, but not in reference, birds. In contrast, little effect of mercury on success of nestlings was observed when temperatures were cooler, and precipitation also had no detectable interaction with mercury. These results provide insight into mechanisms underlying reproductive effects of mercury. In addition, these findings underscore the importance of considering variable environmental conditions when assessing effects of contaminants on free-living wildlife. In particular, projections about the effects of global climate change on ecotoxicological impacts must take into account the kinds of weather-mediated effect demonstrated here. PMID- 21553260 TI - The kinase DYRKIA regulates pre-mRNA splicing in spermatogonia and proliferation of spermatogonia and Sertoli cells by phosphorylating a spliceosomal component, SAP155, in postnatal murine testes. AB - SAP155 is an essential component of the spliceosome and its phosphorylation is required for splicing catalysis, but little is known concerning its function and regulation during spermatogenesis in postnatal murine testes. We report that inhibition of dual-specificity tyrosine-phosphorylation regulated kinase (DYRK) IA strongly suppressed the mitogen-stimulated SAP155 phosphorylation and constitutive splicing of IkappaB pre-mRNA as well as the proliferation of spermatogonial and Sertoli cells in cultures of the 6-day post partum testes and a spermatogonial cell line, but not in a Sertoli cell line. Our findings suggest that the active spliceosome, containing SAP155 phosphorylated by DYRKIA, performs pre-mRNA splicing in spermatogonia during testicular development. PMID- 21553261 TI - Mechanisms of chloride in cardiomyocyte anoxia-reoxygenation injury: the involvement of oxidative stress and NF-kappaB activation. AB - During anoxia/reoxygenation (A/R) injury, intracellular chloride ion concentration ([Cl(-)](i)) homeostasis may play a role in maintaining the normal physiological function of cardiomyocytes. Various chloride transport systems could have influenced the concentration of chloride ion, but what kinds of chloride transport systems could play an important role in cardiomyocytes subjected to A/R injury and its mechanism are unknown. The aim of our study was to clarify the contributions of various chloride transport systems to anoxia/reoxygenation in rat neonatal cardiac myocytes and further to investigate the involved mechanisms. Oxidative stress and redox-sensitive transcription factor (NF-kappaB) activation are believed to play an important role in the A/R injury. To assess whether oxidative stress and NF-kappaB involve [Cl(-)](i) changes resulting in cardiomyocytes injury, the anoxia-reoxygenation (A/R) injury model was successfully established and administered with inhibitors of various chloride transport systems. Administration with Cl(-)-substitution and Cl( )/HCO(3) (-) exchange inhibitor(SITS) has been shown to produce a protective effect against A/R injury by decreasing [Cl(-)](i) concentration, lipid peroxidation (malondialdehyde (MDA)) levels, and NF-kappaB activity, and by increasing antioxidant enzyme (glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase(CAT)) activity. However, inhibitors for the Cl(-) channel (9-AC) and Na(+)-K(+)-2Cl(-) co-transporter (bumetanide) had no effects. Our results indicate that Cl(-)/HCO(3) (-) exchange system plays an important role in the cardiocyte A/R injury by influencing [Cl(-)](i) concentration. The protective effects of SITS and Cl(-)-substitution on cardiomyocytes may be due to the attenuation of oxidative stress and inhibition of NF-kappaB activation. PMID- 21553262 TI - Heterotopic low-frequency stimulation induces nociceptive LTD within the same central receptive field in man. AB - Electrical low-frequency stimulation (LFS) evokes long-term depression (LTD) of nociception. Human studies suggested a strictly homotopic organization. This study hypothesizes that even heterotopic LFS evokes LTD within the same receptive field (RF). In 33 healthy volunteers, painful electrical test stimulation and LFS were applied to the low back by a concentric electrode (ExpBack) and to the forearm by a multiarray electrode (ExpArm). Volunteers rated pain perception during test stimulation that was applied before and after LFS. In ExpBack, test stimuli were administered within the right T12 dermatome. LFS was applied heterotopically within the same RF or remote in dermatome T8. In ExpArm, test stimulation was carried out in the center of the RF whereas LFS was applied to the center, margin, or outside the RF. In ExpBack (n = 20), pain ratings decreased significantly stronger in T12 than in T8 dermatome (P < 0.01). In ExpArm (n = 20), LFS to the center of the RF induced a stronger pain reduction than LFS applied outside the RF (P < 0.001). This study demonstrates a heterosynaptic organization of LTD within the same RF. Profound knowledge about RF involvement on LTD seems crucial in order to judge the quality of LFS as a possible neuromodulatory treatment of pain. PMID- 21553263 TI - Bodily self: an implicit knowledge of what is explicitly unknown. AB - We tested the hypothesis that the body self-advantage, i.e., the facilitation in discriminating self versus other people's body-effectors, is the expression of an implicit and body-specific knowledge, based mainly on the sensorimotor representation of one's own body-effectors. Alternatively, the body self advantage could rely on visual recognition of pictorial cues. According to the first hypothesis, using gray-scale pictures of body-parts, the body self advantage should emerge when self-body recognition is implicitly required and should be specific for body-effectors and not for inanimate-objects. In contrast, if the self-advantage is due to a mere visual-perceptual facilitation, it should be independent of the implicit or explicit request (and could be extended also to objects). To disentangle these hypotheses, healthy participants were implicitly or explicitly required to recognize either their own body-effectors or inanimate objects. Participants were more accurate in the implicit task with self rather than with others' body-effectors. In contrast, the self-advantage was not found when an explicit recognition of one's own body-effectors was required, suggesting that the body self-advantage relies upon a sensorimotor, rather than a mere visual representation of one's own body. Moreover, the absence of both self/other and implicit/explicit effects, when processing inanimate-objects, underlines the differences between the body and other objects. PMID- 21553264 TI - Amino acid uptake by temperate tree species characteristic of low- and high fertility habitats. AB - The relationship between inorganic nitrogen (N) cycling and plant productivity is well established. However, recent research has demonstrated the ability of plants to take up low molecular weight organic N compounds (i.e., amino acids) at rates that often rival those of inorganic N forms. In this study, we hypothesize that temperate forest tree species characteristic of low-fertility habitats will prefer amino acids over species characteristic of high-fertility habitats. We measured the uptake of (15)N-labeled amino acids (glycine, glutamine, arginine, serine), ammonium (NH(4)(+)), and nitrate (NO(3)(-)) by four tree species that commonly occur in eastern North America, where their abundances have been correlated with inorganic N availability. Specific uptake rates of amino acids were largely similar for all tree species; however, high-fertility species took up NH(4)(+) at rates more than double those of low-fertility species, rendering amino acid N relatively more important to the N nutrition of low-fertility species. Low-fertility species acquired over four times more total N from arginine compared to NH(4)(+) and NO(3)(-); high-fertility species acquired the most N from NH(4)(+). Arginine had the highest uptake rates of any amino acid by all species; there were no significant differences in uptake rates of the remaining amino acids. Our results support the idea that the dominant species in a particular habitat are those best able to utilize the most available N resources. PMID- 21553265 TI - Benchmarks in organism performance and their use in comparative analyses. AB - Evaluating the response of organisms to stress assumes that functional benchmarks are available against which the response can be gauged, but this expectation remains unfulfilled for many taxa. As a result, attempts to describe the organismic effects of environmental degradation and physiological stress can prove misleading. Functional benchmarks and the effects of stress are particularly germane to coral reefs that globally are exposed to significant environmental challenges, and in this study, we compiled data on scleractinian corals to describe a reference against which stress responses can be gauged. Based on this construct, we tested the veracity of well-established contrasts- involving differences in physiological function among depths and families--to evaluate the capacity of available data to support synthetic analyses. Our analysis used 126 papers describing 37 genera, and at least 73 species, and described 13 traits, first independent of depth, and second, by depth. Data appropriate for these analyses were so sparse that depth- and family-level effects were inconspicuous, although the depth contrast revealed a decline in dark respiration and an increase in calcification (both normalized to area) in deeper water. Our analyses of scleractinian literature revealed limitations of the data available for synthetic analyses, as well for describing functional benchmarks within this taxon. We attribute some of these effects to differences in the physical environment under which measurements were made, and suspect that such problems are commonplace for other taxa. Dynamic Energy Budget (DEB) models provide one means to overcome some of these problems, and they can be used for any taxon to quantitatively summarize data for comparative analyses of stressor responses. The suitability of these models is illustrated for scleractinian corals by predicting from first principles the ratio of Symbiodinium to holobiont carbon and the respiration. PMID- 21553266 TI - Patients with single-ventricle physiology: prognostic implications of stress testing. AB - This study used a retrospective analysis of adults with single-ventricle physiology to ascertain the predictive power of cardiopulmonary stress-testing parameters in determining patients at increased risk of suffering from adverse clinical outcomes. We found that the specific parameters of percent of maximum predicted heart rate achieved and maximum oxygen consumption were significantly correlated with adverse clinical outcomes in patients with single-ventricle congenital heart disease. PMID- 21553267 TI - High-dose sotalol is safe and effective in neonates and infants with refractory supraventricular tachyarrhythmias. AB - Our objective was to assess the efficacy and safety of high-dose sotalol in neonates and infants with refractory supraventricular tachycardia (SVT). SVT in neonates and infants can be refractory to primary therapies; therefore, secondary agents, e.g., sotalol, are often required to obtain control of SVT. Age-factor nomogram dosing of sotalol is widely used; however, our institution uses greater doses based on body surface area (approximately 150-200 mg/m(2)/d). A retrospective review of 78 inpatients receiving sotalol, after failing another antiarrthymic medication, at our institution from 2001 to 2008 was performed. Corrected QT intervals (QTc), 24-h Holter-monitoring results, and outpatient records were reviewed to assess safety and efficacy for patients <= 2 years of age. Median patient age at the time of initiation of therapy was 24 days (range 3 728). Forty-eight patients (62%) were neonates, and 36 (46%) had congenital heart disease. The median sotalol dosage was 152 mg/m(2)/day (range 65-244). The SVT of 70 patients (90%) was controlled with sotalol. No patients experienced significant QTc prolongation or proarrhythmia. Mean duration of follow-up was 3.3 +/- 0.24 years. High-dose sotalol allows for safe and rapid control of refractory tachyarrhythmias in this young age group. PMID- 21553268 TI - Bilateral abducens nerve palsy by compression from bilateral anterior inferior cerebellar artery. PMID- 21553269 TI - Response to immunotherapy in CLIPPERS syndrome. PMID- 21553270 TI - Quadrupedal coordination of bipedal gait: implications for movement disorders. AB - During recent years, evidence has come up that bipedal locomotion is based on a quadrupedal limb coordination. A task-dependent neuronal coupling of upper and lower limbs allows one to involve the arms during gait but to uncouple this connection during voluntarily guided arm/hand movements. Hence, despite the evolution of a strong cortico-spinal control of hand/arm movements in humans, a quadrupedal limb coordination persists during locomotion. This has consequences for the limb coordination in movement disorders such as in Parkinson's disease (PD) and after stroke. In patients suffering PD, the quadrupedal coordination of gait is basically preserved. The activation of upper limb muscles during locomotion is strong, similar as in age-matched healthy subjects although arm swing is reduced. This suggests a contribution of biomechanical constraints to immobility. In post-stroke subjects a close interactions between unaffected and affected sides with an impaired processing of afferent input takes place. An afferent volley applied to a leg nerve of the unaffected leg leads to a normal reflex activation of proximal arm muscles of both sides. In contrast, when the nerve of the affected leg was stimulated, neither on the affected nor in the unaffected arm muscles EMG responses appear. Muscle activation on the affected arm becomes normalized by influences of the unaffected side during locomotion. These observations have consequences for the rehabilitation of patients suffering movement disorders. PMID- 21553271 TI - Risk of marginal mandibular nerve injury in neck dissection. AB - The immediate and permanent frequency of injury to the marginal mandibular branch of the facial nerve (MMN) after neck dissection has only scarcely been addressed in the medical literature. We investigated the risk of injury in 159 consecutive patients after neck dissection for various reasons in level I B and level II A, respectively. In 95 patients with oral cancer 13 (14%) of the cases had malfunction of the lower lip domain 2 weeks after neck dissection in level I B indicating paresis to the MMN. Follow-up analyses 1-2 years after the operation showed permanent paralysis in 4 to 7% of the cases in whom two of them had the nerve sacrificed for oncologic reasons during the operation. In 18 patients with parotic cancer the corresponding permanent frequency of MMN paralysis was 11.1%. In 46 patients with neck dissection in level II A but not in level I B, no paresis of the MMN was registered. Recognition of the MMN during the operation, pre- or postoperative radiation therapy, re-operation for deep hemorrhage, age, gender or postoperative infection did not have any statistically significant influence on the frequency of MMN injury. In conclusion we found a moderate risk of injury to the MMN after neck dissection in level I B whereas the corresponding risk after level II A dissection was negligible. PMID- 21553272 TI - Concentrations of mercury and other toxic elements in orange roughy, Hoplostethus atlanticus, from the Mid-Atlantic Ridge. AB - Concentrations of the elements mercury, arsenic, cadmium and lead were measured in the muscle tissue of Orange roughy (Hoplostethus atlanticus) obtained from the Mid-Atlantic Ridge during the MAR: -ECO: expedition in the North Atlantic Ocean in 2004. The age of the fish varied from 1 to 139 years. To the best of our knowledge, the concentration of the heavy metals presented here is for one of the oldest fish in the literature, in addition to the fact that very little information on arsenic in Orange roughy has been previously published. The concentration of mercury in the fillet of the fish varied between 0.06 and 1.1 MUg g-1 w.w. Mercury was the only element that was positively correlated to the age. The concentrations of mercury were found to be below the maximum limits for Orange roughy set by EU at 1.0 MUg g-1 w.w, except for a 134 year fish sample with a concentration of 1.1 MUg g-1 w.w. PMID- 21553273 TI - Determination of the anal position in newborns and in children with chronic constipation: comparative study in two European healthcare centres. AB - INTRODUCTION: The objective of this study was to determine the normal anal position index (API) in neonates and in a group of older children with chronic constipation, and to identify the incidence of anterior ectopic anus (AEA) in the two groups. MATERIALS AND METHODS: A prospective random study was carried out in two European hospitals determining the API in 1,012 neonates (529 in Group A, and 483 in Group B) and in 64 children suffering chronic constipation of ages between 3 months and 12 years (Group C). The API is defined as the ratio between the fourchette-anal and fourchette-coccygeal distances in girls and the scroto-anal and scroto-coccygeal distances in boys. The gestational age, weight, meconium evacuation and anal calibre were recorded in Groups A and B, and age, sex, and API in Group C. Statistical comparisons were made using Student's t test and Welch's t test for independent sample groups. RESULTS: The mean API in Group A was 0.53 +/- 0.06 in males and 0.40 +/- 0.05 in females, and in Group B 0.51 +/- 0.06 in males and 0.39 +/- 0.08 in females, with significant differences between the sexes (p < 0.0001) in both groups; 1.7% of the neonates in Group A and 2.4% of Group B presented AEA. 4/13 newborns females with AEA presented with severe constipation during their first months of life. For the 64 patients in Group C: 59.3% were female; the mean API was 0.47 +/- 0.1 in males and 0.36 +/- 0.1 in females (p < 0.0001). The incidence of AEA was 47% in females and 35% in males. CONCLUSIONS: In the neonates (Groups A and B), the position of the anus in the perineum was more anterior in females than in males (p < 0.0001); 31% of the newborns females with AEA presented with constipation in their first months of life. In the Group C patients, there was a high incidence of AEA, especially in the females, and we consider it to be the probable cause of this defecation disorder. PMID- 21553274 TI - Efficacy of bladder irrigation and surveillance program in prevention of urinary tract infections and bladder calculi in children with an ileocystoplasty and bladder neck repair. AB - PURPOSE: In children with bladder augmentation and particularly in those with bladder neck repair (BNR), urinary tract infections (UTI) and bladder calculi are a recognised problem. Bladder irrigation potentially prevents these complications. Our aim was to investigate the efficacy of bladder irrigation supported by a surveillance program in prevention of UTI and bladder calculi in these children. METHODS: A cohort of children subjected to ileocystoplasty with a stoma for clean intermittent self catheterisation with or without BNR was retrospectively analysed. The children were subjected to bladder irrigation and monitored by Clinical Nurse Specialists (CNS) according to a protocol. Patients' demographics, treatment methods and postoperative management were reviewed. Compliance to bladder irrigation was assessed with questionnaires. UTI recurrence and bladder calculi during follow-up were assessed. RESULTS: 28 children were included in this study. The median follow-up was 48 months (range 6-87). Compliance could be assessed in all children, except in one child (3.5%). There was no recurrent UTI reported, bladder calculi occurred in two children (7%). CONCLUSION: Our bladder irrigation regime resulted in a low incidence of calculi by preventing recurrent UTI. The surveillance program resulted in high compliance rates in children with an augmented bladder with or without BNR. PMID- 21553275 TI - Multicystic dysplastic kidney: our experience in non-surgical management. AB - INTRODUCTION: Although multicystic dysplastic kidney (MDK) is a common renal anomaly, the management of this condition remains controversial. The purpose of this study was to focus on its regression by ultrasound (US) scan for MDK managed conservatively. MATERIALS AND METHODS: Between 1990 and 2010, 50 children with MDK were retrospectively studied. All patients were submitted to radioisotope scan to confirm the diagnosis, and a micturating cystogram to exclude other uropathies. RESULTS: Of the 50 patients, 19 underwent nephrectomy, and the other 31 were conservatively managed with clinical and US scan follow-up. The mean follow-up time (range 6 months to 11 years) in the non-operated group was 6.2 years. Of the 31 children with nonsurgical management, 17 (54.8%) showed total involution on US scan, 7 (22.6%) showed a partial regression, and 7 (22.6%) were unchanged at the time of this study. The mean time to complete disappearance on US scan was 2.5 years (1-4 years). No children developed hypertension or tumors. DISCUSSION: The natural history of MDK is usually benign, but patients must have long-term follow-up with US scan. In addition, many studies confirmed that the disappearance of it on a US scan does not mean a total involution of the affected kidney. We recommend a strict follow-up even when US scan shows an undetectable kidney. PMID- 21553276 TI - Role of imaging and biopsy to assess local recurrence after definitive treatment for prostate carcinoma (surgery, radiotherapy, cryotherapy, HIFU). AB - PURPOSE: Defining the site of recurrent disease early after definitive treatment for a localized prostate cancer is a critical issue as it may greatly influence the subsequent therapeutic strategy or patient management. METHODS: A systematic review of the literature was performed by searching Medline from January 1995 up to January 2011. Electronic searches were limited to the English language, and the keywords prostate cancer, radiotherapy [RT], high intensity focused ultrasound [HIFU], cryotherapy [CRIO], transrectal ultrasound [TRUS], magnetic resonance [MRI], PET/TC, and prostate biopsy were used. RESULTS: Despite the fact that diagnosis of a local recurrence is based on PSA values and kinetics, imaging by means of different techniques may be a prerequisite for effective disease management. Unfortunately, prostate cancer local recurrences are very difficult to detect by TRUS and conventional imaging that have shown limited accuracy at least at early stages. On the contrary, functional and molecular imaging such as dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI), offers the possibility of imaging molecular or cellular processes of individual tumors. Recently, PET/CT, using 11C-choline, 18F-fluorocholine or 11C-acetate has been successfully proposed in detecting local recurrences as well as distant metastases. Nevertheless, in controversial cases, it is necessary to perform a biopsy of the prostatic fossa or a biopsy of the prostate to assess the presence of a local recurrence under guidance of MRI or TRUS findings. CONCLUSION: It is likely that imaging will be extensively used in the future to detect and localize prostate cancer local recurrences before salvage treatment. PMID- 21553277 TI - Tm:YAG laser en bloc mucosectomy for accurate staging of primary bladder cancer: early experience. AB - INTRODUCTION: Exact pathological staging of bladder cancer is crucial for determination of further treatment. One limiting factor is the surgical 'incise and scatter' technique that might contribute to tumour recurrence. En bloc resection techniques are en emerging issue. We present initial results with Thulium:YAG (Tm:YAG) en bloc resection of bladder tumours for treatment and accurate staging of solitary transitional cell carcinoma of the bladder. MATERIALS AND METHODS: From June through October 2010, six patients were treated by TmLRBT (Thulium laser resection of bladder tumour). Inclusion criteria were solitary lesions, treatment naive patients and tumour localisation of the lower bladder wall and trigonum. En bloc resection was applied on all of the tumours. Two cold-cut biopsies from the tumour base were extracted. On five of the six patients, a re-resection was performed after 6 weeks. RESULTS: Pathological evaluation revealed 1 patient with pTa G1, 2 patients with pTa G2 and 3 patients with pT1 G3. All of the resected specimens provided detrusor muscle, and all biopsies were positive for muscle cells. No intra-, peri- or post-operative complications were observed. Bladder irrigation was mandatory in only 50% of the patients. All patients were negative for residual TCC in re-resection 6 weeks after initial treatment. CONCLUSION: TmLRBT has been proven safe and effective for both, treatment and pathological staging of primary TCC of the bladder. Tm:YAG en bloc resection therefore could be an appropriate tool for accurate staging with possibly lower scattering potential for the assessment and treatment of patients with TCC. PMID- 21553278 TI - The use of low-dose etanercept as an alternative therapy for treatment of ankylosing spondylitis: a case series. AB - During recent decades, biological medications play a crucial role for treating rheumatologic disorders and thus are strongly recommended for initial treatment of ankylosing spondylitis. However, because of high cost of biological drugs, the use of these drugs has been limited. In current series, we tried to assess safety of low-dose etanercept as a common usable biological drug in patients with ankylosing spondylitis. In a case-series study, 4 men with ankylosing spondylitis were treated with low-dose etanercept (25 mg/2 weeks) plus methotrexate (10 mg/week). Safety was assessed by measuring rate of differences in severity of clinical manifestations and level of C-reactive protein (CRP). After the completion of treatment with low-dose etanercept, inflammatory low back pain and morning stiffness was reduced lower than 30 min in all patients. Only one patient had baseline high serum ESR and positive CRP that was changed to negative following treatment protocol. At one-year follow-up, all participants continued their regular treatment regimen with the etanercept survival rate 100%. Neither side effects related to drug nor clinical complications were observed within the follow-up period. Our findings suggest that low-dose etanercept (25 mg/2 weeks) has an acceptable safety and effectiveness profile in individuals with ankylosing spondylitis and can be good alternative instead of conventional therapy with etanercept (25 mg two times per week). PMID- 21553279 TI - Prevalence of osteochondritis among preparatory and primary school children in an Egyptian governorate. AB - Epiphyseal osteochondritis is a localized disorder in childhood. Vascular insufficiency is thought to be the most significant etiologic factor. This study had been carried on Primary and Preparatory school children in Zagazig City and surrounding villages in Sharkia Governorate, Egypt. Total number of studied children were 16,060, 7,380 males, 8,680 females. The mean age was 11.41 +/- 1.99. Our results showed that the prevalence of osteochondritis was 21:10,000. Distribution of Sever's and Osgood-Shlatter diseases were significantly high compared with other osteochondritis. Regarding the sex distribution, osteochondritis was frequent in males. Our results showed that there was history of trauma especially in Sever's and Osgood-Schlatter diseases. PMID- 21553280 TI - Standard or extended-duration prophylaxis in medical patients? A review of the evidence. AB - Acutely ill medical patients are at significant risk of venous thromboembolism (VTE). Thromboprophylaxis can substantially reduce the incidence of VTE, but to be optimally effective must consist of the correct choice of agent, at an appropriate dose, and for sufficient duration. Increasing evidence suggests that VTE risk persists beyond the standard period of prophylaxis. Although there is evidence that extended-duration prophylaxis is beneficial in preventing late VTE complications in high-risk surgical patients, few data exist in medical patients. The recent EXCLAIM study demonstrated that, subsequent to a standard prophylaxis regimen of 10 +/- 4 days with enoxaparin 40 mg once daily, extended-duration prophylaxis (28 +/- 4 days) with enoxaparin reduced total VTE events compared with placebo: 2.5% versus 4.0%; (absolute risk difference -1.53%; 95.8% confidence interval [CI] -2.54 to -0.52), with parallel increases in major bleeding rates (0.8% vs. 0.3%; absolute risk difference 0.51%; 95% CI 0.12 0.89%). The reduction in total VTE was principally driven by a decrease in symptomatic deep-vein thrombosis (absolute risk difference -0.60%; 95.8% CI -1.00 to -0.19%). Favorable benefit-to-risk ratios were observed in certain high-risk patient groups: level 1 immobility, women, and age >75 years. In addition to their underlying medical condition, medical patients often have multiple risk factors, placing them at sustained risk of VTE. Extended-duration prophylaxis might be most relevant in such patients. The development of appropriate risk assessment tools could help identify medical patients at greatest risk of late VTE events who might benefit most from extended-duration prophylaxis. PMID- 21553281 TI - Taurine: a novel tumor marker for enhanced detection of breast cancer among female patients. AB - INTRODUCTION: The antioxidant Taurine found to display antineoplastic effect through down regulation of angiogenesis and enhancement of tumor cell apoptosis. It has been found that progressive inhibition of apoptosis and induction of angiogenesis may contribute to tumor initiation, growth and metastasis in the pathogenesis of breast cancer. AIM OF THE STUDY: To correlate taurine level with the levels of some bioomolecules operating in both angiogenesis (VEGF, CD31) and apoptosis (TNF-alpha and Caspas-3) which could help for breast cancer pronostication and to evaluate a possible role of serum taurine level as an early marker for breast cancer in Egyptian patients. PATIENTS AND METHODS: Four groups of a total 85 female candidates were studied in this work. The first group consists of 50 female patients at National Cancer Institute (NCI), Cairo University were diagnosed and undergoing surgery for breast carcinoma. In the second group 10 having benign breast lesions, were included. The third group consists of five cases, with positive family history. Twenty healthy females were also recruited as control. A preoperative blood sample were taken from each patient to measure serum level of VEGF; Taurine; CA15.3 and TNF- alpha. Sample of fresh tumor and their corresponding safety margins were obtained from the first and second groups, for determination of caspase-3; histopathological examination and immunohistochemical assay of VEGF and CD31. RESULT: No significant differences in the serum level of CA15.3 between the breast cancer patients, the high risk and the control group. TNF-alpha (apoptotic biomolecule) level showed a significant difference only between breast cancer group and control group. The VEGF (angiogenic biomarker) showed a highly significant difference between breast cancer patients, the high risk and the control group. Regarding the antioxidant taurine (antiangiogenic biomolecule) serum level in breast cancer group exhibited a value strongly lower than the high risk and control group. Also the correlative ratio between the angiogenic/apoptotic biomarker (VEGF/TNF-alpha) showed a highly significant difference between the main previous three groups. Same observation were also noticed in the correlation between angiogenic/antiangiogenic (VEGF/taurine) ratio in the same groups. Moreover the enzymatic activities of Casp-3 in the tissue homogenate were statistically higher in adjacent normal tissues than in malignant tissues. The result of immunohistochemical investigation showed a significant increase in the density of intracellular VEGF and microvessel density expressed as CD31 in cancer cases compared to normal adjacent tissue. CONCLUSION: It is suggested that assessment of taurine level in sera of patients with high risk for breast cancer are of great value in the early diagnosis of malignant changes in the breast. PMID- 21553282 TI - An automated high throughput screening-compatible assay to identify regulators of stem cell neural differentiation. AB - The use of Embryonic Stem Cells (ESCs) holds considerable promise both for drug discovery programs and the treatment of degenerative disorders in regenerative medicine approaches. Nevertheless, the successful use of ESCs is still limited by the lack of efficient control of ESC self-renewal and differentiation capabilities. In this context, the possibility to modulate ESC biological properties and to obtain homogenous populations of correctly specified cells will help developing physiologically relevant screens, designed for the identification of stem cell modulators. Here, we developed a high throughput screening-suitable ESC neural differentiation assay by exploiting the Cell(maker) robotic platform and demonstrated that neural progenies can be generated from ESCs in complete automation, with high standards of accuracy and reliability. Moreover, we performed a pilot screening providing proof of concept that this assay allows the identification of regulators of ESC neural differentiation in full automation. PMID- 21553283 TI - Immunotherapy eradicates metastases with reversible defects in MHC class I expression. AB - Tumor or metastatic cells lose MHC class I (MHC-I) expression during cancer progression as an escape mechanism from immune surveillance. These defects in MHC I may be reversible by cytokines or different agents (soft lesions) or irreversible due to structural defects (hard lesions). The nature of these MHC-I alterations might determine the success or failure of immunotherapy treatments. In this study, we have used an MHC-I-positive murine fibrosarcoma tumor clone, GR9-A7, which generates multiple lung and lymph node metastases with reversible MHC-I alterations after treatment with IFN-gamma. Four different antitumor treatments were carried out after primary tumor excision to determine their capacity to inhibit spontaneous metastatic colonization of the GR9-A7 tumor clone. We found that 2 different immunotherapy protocols (CpG plus autologous irradiated-GR9-A7 cells and protein-bound polysaccharide K (PSK) and 1 chemoimmunotherapy (docetaxel plus PSK) induced eradication of metastases. In contrast, chemotherapy with docetaxel alone produced only partial reduction in the number of metastases. Flow cytometric analysis of lymphocyte populations showed an immunosuppression in GR9-A7 tumor-bearing host, which could be reverted by immunotherapy treatments. Our results suggest that irreversible or reversible MHC-I alterations in tumor target cells may determine its progression or regression independently of the type of immunotherapy used. PMID- 21553284 TI - Decisive role of tumor necrosis factor-alpha for spongiosis formation in acute eczematous dermatitis. AB - Apoptosis of single keratinocytes (KC) is a characteristic feature of spongiosis formation, the histopathologic hallmark of acute eczematous dermatitis. In acute eczema, activated dermis-infiltrating T cells secrete several proinflammatory cytokines which might be decisive for KC apoptosis or survival. We analyzed the role of tumor necrosis factor alpha (TNF-alpha) in the determination of KC fate during spongiosis formation in acute eczematous dermatitis. Supernatants of activated human CD4(+) T cells induced apoptosis in primary KC, which could be fully inhibited by individual blockade of interferon-gamma (IFN-gamma) and CD95 but not by neutralization of TNF-alpha activity. As compared to CD95-triggering alone, synchronous CD95 and TNF receptor cross-linking in the presence of IFN gamma only marginally enhanced KC apoptosis. Importantly, pre-treatment of KC with TNF-alpha followed by CD95 stimulation, but not vice versa, significantly amplified KC apoptosis as compared to CD95 stimulation alone. This TNF-alpha mediated sensitization to CD95-induced KC cell death could be abrogated by blocking TNF receptor 1 (TNF-R1) but not TNF-R2 mAb. In eczematous dermatitis, the CD95 receptor was expressed throughout the epidermis, whereas immunohistological detection of TNF-R1 was rather restricted to KC around spongiotic vesicle formation. Thus, TNF-alpha primes KC for CD95-mediated signals which results in an increased susceptibility to apoptosis. TNF-R1 expression and spatial action of TNF-alpha restricted to spongiotic vesicles promote both CD95 induced KC apoptosis and limitation of spreading KC damage. PMID- 21553285 TI - 5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases. AB - PURPOSE: 5-Fluorouracil (5-FU) is a mainstay for treating various solid tumours in adults, including digestive and head and neck cancers. 5-FU-related toxicities usually include haematological, digestive and cutaneous features. Additionally, 5 FU has been described as being potentially neurotoxic in patients, but these side effects are quite rare in clinical practice. Here, we report two cases of sudden and unpredictable drug-induced neurotoxicities that occurred in patients undergoing their first course of 5-FU-based chemotherapy. PATIENTS AND METHODS: None of these patients had any previous neurological disorder history, and both were treated following standard regimen (LV-5-FU2 and TPF for patient 1 and 2, respectively). Neurotoxicity included drowsiness, acute confusion plus dysarthria for the first patient and seizure, confusion and signs of metabolic encephalopathy for the second one. In addition, typical 5-FU-related severe toxicities (e.g. neutropenia and mucosities) were observed. Both patients slowly recovered from these neurological toxicities under supportive treatment. It was assumed that overexposure to 5-FU could explain the severe toxicities encountered. To test this hypothesis, we retrospectively evaluated the dihydropyrimidine dehydrogenase (DPD) activity of these patients on a phenotypic basis. RESULTS: Evaluation of the uracil-to-di-hydrouracil (U/UH2) ratio in plasma revealed a profound DPD deficiency syndrome in both patients. CONCLUSION: These cases suggest that 5-FU standard dosage administration may lead to strong overexposure, responsible for the severe toxicities observed, including the neurological features. It implies that DPD deficiency can cause neurotoxicity in 5-FU-treated patients and advocates for the prospective screening of DPD deficiency before starting any 5-FU-containing chemotherapy so as to prevent such side effects in the future. PMID- 21553286 TI - Preclinical evaluation of the novel multi-targeted agent R1530. AB - PURPOSE: This study describes the antiproliferative activity of the multikinase inhibitor R1530 in vitro and its antitumor and anti-angiogenic activity, pharmacokinetics, and tolerability in vivo. METHODS: The antiproliferative activity of R1530 was investigated in a range of human tumor, endothelial and fibroblast cell lines. Tolerability and antitumor activity were assessed in mice bearing a range of human tumor xenografts, and anti-angiogenic properties were established in the murine corneal pocket assay. R1530 pharmacokinetics in mice were established. RESULTS: R1530 strongly inhibited human tumor cell proliferation. Growth factor-driven proliferation of endothelial and fibroblast cells was also inhibited. Significant tumor growth inhibition was demonstrated in a lung cancer xenograft model with a range of once daily, weekly and twice-weekly doses of R1530 (3.125-50 mg/kg qd, 100 mg/kg qw, 100 mg/kg biw). Daily doses were most effective in the lung cancer model and also had significant growth inhibitory effects in models of colorectal, prostate, and breast tumors. Tumor regression occurred in all models treated with the maximum tolerated daily dose (50 mg/kg). The doses of 25 and 50 mg/kg qd resulted in biologically significant increased survival in all tested models. After oral administration in nude mice, R1530 showed good tissue penetration. Exposure was dose dependent up to 100 mg/kg with oral administration. CONCLUSIONS: R1530 has demonstrated activity against a range of tumor models in vitro and in vivo and is an effective inhibitor of angiogenesis. These findings support the approach of targeting multiple pathways in the search for potential agents with improved anticancer properties. PMID- 21553287 TI - Targeting and sensing cancer cells with ZnO nanoprobes in vitro. AB - A new class of zinc oxide quantum dots (ZnO QDs) was investigated as nanoprobes for targeting cancer cells in vitro. ZnO nanoparticles were synthesized using conventional sol-gel method and encapsulated using trimethoxy aminopropyl silane. Transferrin, the ligand targeting the cancer cells, was conjugated to the ZnO QDs. In vitro imaging studies using MDA-MB-231 showed the biocompatible ZnO nanoprobe selectively binding to the cell surface receptor and internalizing through receptor-mediated endocytosis. Time-lapsed photobleaching studies indicate the ZnO QDs to be resistant to photobleaching, making them suitable for long term imaging purpose. Investigation of the ZnO nanoprobe as a platform for sensitive bioassays indicates that it can be used as an alternative fluoroprobe for cancer cell targeting and sensing applications. PMID- 21553288 TI - Small interfering RNAs screened from random siRNA library direct neuronal differentiation. AB - Directed neuronal differentiation is crucial for development of cell therapy and investigation of neurogenesis. However, limited differentiation-inducing agents are available and most of current differentiation regimens are complicated. Here we carried out a combinatorial high-throughput screen with a random siRNA library on murine P19 cell differentiation toward neuronal lineage. Two siRNAs screened from the library were able to direct neuronal differentiation, determined by nestin, neurofilament-M and MAP-2 up-regulation. This is the first trial of a screening procedure for neuronal differentiation-directing agents arising from a random siRNA library and demonstrates that a random siRNA library can be considered as a new resource in efforts to seek new agents for directed differentiation. As the random siRNA library has a broad coverage for the entire genome, screening using random siRNA library can be expected to greatly augment the repertoire of siRNAs for directed differentiation. PMID- 21553289 TI - Genetic characterisation of genes involved in the upper pathway of carbazole metabolism from the putative Kordiimonas sp. AB - The car genes from a carbazole (CAR)-degrading bacterium, Kordiimonas sp. OC9, were functionally and transcriptionally analysed. The enzymatic activity for the protein coded by carBaBb using pBOC93 (carAaAcBa), pBOC93-2 (carAaAcBb), and pBOC94 (carAaAcBaBb) was confirmed. Resting cells using Escherichia coli harbouring pBOC95 (carAaAcBaBbC) revealed the function of the carC gene product in the conversion of CAR to anthranilic acid by expressing it with CarAaAcBaBb. The pathway of CAR metabolism to anthranilic acid in marine CAR-degraders was elucidated. Transcriptional analysis using RT-PCR revealed that car genes are related to CAR degradation in response to CAR exposure in strain OC9. RT-PCR analysis of the operon structure showed that the car gene cluster of strain OC9 has two distinct operons in one car gene cluster. The localisation of the car gene cluster of strain OC9 was also determined. PMID- 21553290 TI - Overexpression of ligase defective E6-associated protein, E6-AP, results in mammary tumorigenesis. AB - E6-associated protein (E6-AP) is a dual function protein. It acts as an E3 ubiquitin-protein ligase enzyme and coactivator of steroid hormone receptors such as estrogen (ERalpha) and progesterone (PR) receptors. It promotes the degradation of ERalpha and PR through the ubiquitin-proteasome pathway. Furthermore, it has been shown that the levels of E6-AP are inversely associated with that of ERalpha in human breast tumors. But the role of wild-type human E6 AP and its ubiquitin-protein ligase activity in mammary tumorigenesis is still unknown. To investigate this role, the authors utilized transgenic mice lines that specifically overexpress either the wild-type human E6-AP (E6-AP(WT)) or the ubiquitin-protein ligase defective E6-AP that contains C833S mutation (E6 AP(C833S)) in the mammary gland. To further substantiate the role of E6-AP in the development of breast tumorigenesis, it was also examined the expression of E6-AP in a large cohort of human breast cancer samples. The transgenic mice that overexpress wild-type E6-AP (E6-AP(WT)) fail to develop mammary tumors. Unlike the E6-AP(WT) mice, the E6-AP(C833S) mice that overexpress ubiquitin-protein ligase defective E6-AP protein develop mammary hyperplasia with a median latency of 18 months. These observations suggest that the inactivation of the ubiquitin protein ligase function of E6-AP is sufficient to initiate the process of mammary tumor development. Furthermore, the data also suggests that E6-AP exerts its effects on target cells by modulating the protein levels and functions of ERalpha and PR. In addition, it was found in human breast cancer patients that the level of E6-AP is decreased in invasive breast tumors compared to normal breast tissue. Moreover, the authors also show that the survival patterns for E6-AP negative patients were worse compared to E6-AP positive patients. Taken together, these data suggests that E6-AP may act as a tumor suppressor in breast. PMID- 21553291 TI - The association of reproductive factors and breastfeeding with long term survival from breast cancer. AB - Reproductive factors that influence breast cancer risk may also have an impact on survival, once the disease is diagnosed. In this study, 2,640 women were diagnosed with invasive breast cancer during follow-up after a breast cancer screening that took place in 1956-1959. Survival was assessed in relation to age at menarche, age at first birth, parity, history of breastfeeding, age at menopause, and the effect of BMI was assessed in a subset of patients. It is a special feature that the patients of this study have not been subjected to organized mammography screening and their use of exogenous hormones has been negligible. By the end of follow-up (2008), 2,301 (87%) of the patients had died and 1,022 (44%) of the deaths were caused by breast cancer. Breast cancer survival was not associated with age at menarche, parity or time since last birth, but survival was consistently poorer with increasing age at first birth (P for trend 0.03): comparing a first birth after 35 years with 25-29 years, the hazard ratio was 1.32 (95% CI 1.02-1.72). There was no evidence for a dose related effect of breastfeeding, but BMI measured many years prior to diagnosis was inversely associated with survival (P for trend <0.01). The main finding was that reproductive factors, including breastfeeding, appear to have little influence on the survival of breast cancer patients. Age at first birth may be an exception to this, since we found a gradually poorer survival with increasing age at first birth. We also found that overweight and obesity, as measured many years prior to diagnosis, were associated with poorer survival. PMID- 21553292 TI - Prospective randomized trial of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus paclitaxel and FAC (TFAC) in patients with operable breast cancer: impact of taxane chemotherapy on locoregional control. AB - A previous randomized trial (CALGB 9344/Intergroup 0148) compared four cycles of adjuvant doxorubicin/cyclophosphamide (AC) to four cycles of AC plus four cycles of paclitaxel (AC + T) and demonstrated that the addition of paclitaxel improved locoregional control (LRC) in patients with node-positive breast cancer. However, it could not be determined whether it was the paclitaxel or the increased duration of chemotherapy that led to this improvement. The present study aimed to analyze whether the addition of paclitaxel to a doxorubicin-based regimen improves LRC in a cohort of patients who all received eight total cycles of chemotherapy. Five hundred eleven women with operable breast cancer were randomized on a single-institution prospective trial to receive 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) * 8 cycles (n = 252) or FAC * 4 cycles plus paclitaxel * 4 cycles (TFAC) (n = 259). Rates of LRC and overall survival (OS) were analyzed. Median follow-up was 124 months (range 5-167 months). The 10-year LRC rate was 92.6 versus 93.1% in the FAC versus TFAC arms, respectively (P = 0.26). The LRC between treatment arms did not differ when analyzed by locoregional treatment group: breast conservation therapy (BCT), mastectomy alone (M), and mastectomy + radiation (M + RT). The 10-year LRC rates were 95.1% (FAC) versus 91.2% (TFAC) after BCT (P = 0.98), 89.5% (FAC) versus 93.4% (TFAC) after M (P = 0.24), and 94.7% (FAC) versus 96.5% (TFAC) after M + RT (P = 0.59). Additionally, there was no difference in OS between the treatment arms, with 10 year OS rates of 78.4% (FAC) versus 81.7% (TFAC) (P = 0.93). The addition of paclitaxel to a doxorubicin-based regimen had no impact on LRC, regardless of the type of local therapy received. Historically inferior LRC with AC chemotherapy alone versus AC + T may have been due to an inadequate duration of systemic therapy and not due to the absence of paclitaxel. PMID- 21553293 TI - Second primary breast, endometrial, and ovarian cancers in Black and White breast cancer survivors over a 35-year time span: effect of age. AB - Breast cancer incidence increases with age and exhibits a Black-to-White crossover around age 45. Breast cancer survivors are at a significantly elevated risk of developing a second primary breast or gynecological cancer compared with the general population. The purpose of this study was to determine whether a similar crossover occurs in hormonally related second primary breast, endometrial, or ovarian cancers in Black and White women. The Surveillance, Epidemiology, and End Results' Registry 9 was used to follow 415,664 White and 39,887 Black female breast cancer survivors, diagnosed at age 19 or older, for a second primary breast, endometrial, or ovarian cancer between 1973 and 2007. Cumulative incidence curves were generated; Pepe and Mori's test was used to test for significance. Second primary breast cancer followed the incidence pattern of the first primary breast cancer in Black and White women diagnosed before age 45. It was opposite of the pattern of first primary breast cancer in Black and White women diagnosed at age 45 or later. Second primary endometrial and ovarian cancers paralleled the incidence pattern of first primaries of the same anatomic site among Black and White women, independent of the age at diagnosis of the first primary breast cancer. Despite the Black-to-White crossover of first primary breast cancer around age 40, the incidence of hormonally related second primaries does not appear affected by the age at diagnosis of the first primary. PMID- 21553294 TI - Associations of objectively assessed physical activity and sedentary time with biomarkers of breast cancer risk in postmenopausal women: findings from NHANES (2003-2006). AB - Physical activity reduces the risk of postmenopausal breast cancer through multiple inter-related biologic mechanisms; sedentary time may contribute additionally to this risk. We examined cross-sectional associations of objectively assessed physical activity and sedentary time with established biomarkers of breast cancer risk in a population-based sample of postmenopausal women. Accelerometer, anthropometric and laboratory data were available for 1,024 (n = 443 fasting) postmenopausal women in the U.S. National Health and Nutrition Examination Survey 2003-2006. Associations of quartiles of the accelerometer variables (moderate- to vigorous-intensity activity, light-intensity activity and sedentary time per day; average length of active and sedentary bouts) with the continuous biomarkers were assessed using linear regression models. Following adjustment for potential confounders, including sedentary time, moderate- to vigorous-intensity activity had significant (P < 0.05), inverse associations with all biomarker outcomes (body mass index, waist circumference, C-reactive protein, fasting plasma glucose, fasting insulin and homeostasis model assessment of insulin resistance). Light-intensity activity and sedentary time were significantly associated in fully adjusted models with all biomarkers except fasting glucose. Active bout length was associated with a smaller waist circumference and lower C-reactive protein levels, while sedentary bout length was associated with a higher BMI. The associations of objectively assessed moderate- to vigorous-intensity activity with breast cancer biomarkers are consistent with the established beneficial effects of self-reported exercise on breast cancer risk. Our findings further suggest that light-intensity activity may have a protective effect, and that sedentary time may independently contribute to breast cancer risk. PMID- 21553296 TI - Association of XPC polymorphisms with breast cancer risk. PMID- 21553295 TI - Correlates of fear of cancer recurrence in women with ductal carcinoma in situ and early invasive breast cancer. AB - Fear of cancer recurrence (FCR) is a common and persistent concern among breast cancer survivors. Little is known about factors associated with FCR in women with ductal carcinoma in situ (DCIS) or early invasive breast cancer (EIBC). Women with first primary DCIS, or stages I-IIA breast cancer were prospectively enrolled in a quality-of-life study and completed interviews at 4-6 weeks, 6 months, and 2 years after definitive surgical treatment. In three stepwise multivariable linear regression models, including both time-independent and time varying variables measured at each respective interview, we identified independent correlates of mean FCR scores (range 1-6) using four items from the Concern About Recurrence Scale (CARS) at 2-year follow-up. Of 506 disease-free patients at 2-year follow-up (mean [SD] age, 58 [10] years; 81% White; 34% DCIS), the average FCR score of 2.0 was low. However, 145 (29%) reported moderate-to high levels of FCR (scores 3.0-6.0). All three models showed that younger age, stage IIA breast cancer (vs. DCIS), lower social support, and elevated anxiety were consistently associated with higher FCR at 2-year follow-up (each P < 0.05; final models R (2) = 0.25-0.32). DCIS patients reported lower FCR than stage IIA patients (each P <= 0.01) but had similar FCR as stage I patients. Although mean FCR was low, 29% of DCIS and EIBC survivors reported moderate-to-high levels of FCR at 2-year follow-up. Management of anxiety, provision of social support, and patient education may help reduce FCR among DCIS and EIBC survivors, especially among younger survivors. PMID- 21553297 TI - Subtleties of explanatory language: what is meant by "mediation"? PMID- 21553298 TI - Increases in Australian cutaneous abscess hospitalisations: 1999-2008. AB - Staphylococcus aureus is the most common cause of skin and soft tissue infections (SSTIs). Such infections have increased in several countries recently and at a time when community-associated methicillin-resistant S. aureus (CA-MRSA) strains have emerged globally. We examined changes in Australian hospitalisations for the treatment of cutaneous abscesses between 1999 and 2008, a period when increased numbers of CA-MRSA infections were being reported. National hospitalisation data for cutaneous abscess treatment (1999-2008) were examined. Hospitalisation numbers were collated and age-specific admission rates calculated and examined for changes over time. Yearly admissions for the treatment of cutaneous abscesses increased by 48%, from 8,849 (1999-2000) to 13,126 (2007-2008). The crude annual hospitalisation rate per 100,000 population rose from 46 to 62 respectively. However, increases in admission rates were limited to the 10 to 54 years age range. Incidence rate ratios (IRRs) for final versus baseline year admission rates for these age groups ranged from 1.36 (95% confidence interval [CI] 1.04 1.78) for those aged 10-14 years to 1.64 (95% CI 1.26-2.12) for those aged 45-49 years; p<0.05. Increases in hospitalisation for cutaneous abscess treatment have occurred in Australia during the last decade. Research into the underlying causes and prevention of these infections is a public health priority. PMID- 21553299 TI - Opportunistic invasive fungal pathogen Macrophomina phaseolina prognosis from immunocompromised humans to potential mitogenic RBL with an exceptional and novel antitumor and cytotoxic effect. AB - With the ever-increasing risk for fungal infections, one can no longer ignore fungi. It is imperative that clinical manifestations "presume fungus" with their epidemiologic and pathogenic features when evaluating a potentially infected patient. In the high-risk patient groups, fungi with intrinsic resistance to antifungal agents already exist, with a tendency to emerge as opportunistic pathogens. One of the smart pathogens is Macrophomina phaseolina, with the potential to disarm plant, animal, and human immunity. The response prophylaxis may vary from antifungal therapy and surgical measures to biochemical (Rhizoctonia bataticola lectin [RBL] with antitumor and cytotoxic nature) and gene therapeutics. PMID- 21553300 TI - Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. AB - Olfactory dysfunction is a frequent and early feature of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) and is very uncommon in patients with frontotemporal dementia (FTD). Mechanisms underlying this clinical manifestation are poorly understood but the premature deposition of protein aggregates in the olfactory bulb (OB) of these patients might impair its synaptic organization, thus accounting for the smell deficits. Tau, beta-amyloid and alpha-synuclein deposits were studied in 41 human OBs with histological diagnosis of AD (n = 24), PD (n = 6), FTD (n = 11) and compared with the OB of 15 control subjects. Tau pathology was present in the OB of all patients, irrespective of the histological diagnosis, while beta-amyloid and alpha-synuclein protein deposit were frequently observed in AD and PD, respectively. Using stereological techniques we found an increased number of dopaminergic periglomerular neurons in the OB of AD, PD and FTD patients when compared with age-matched controls. Moreover, volumetric measurements of OBs showed a significant decrease only in AD patients, while the OB volume was similar to control in PD or FTD cases. The increased dopaminergic tone created in the OBs of these patients could reflect a compensatory mechanism created by the early degeneration of other neurotransmitter systems and might contribute to the olfactory dysfunction exhibited by patients with neurodegenerative disorders. PMID- 21553301 TI - Biochemical and histological liver changes occurred after iron supplementation and possible remediation by garlic consumption. AB - Iron liver excess is associated to biochemical and histological liver perturbations. Our aim was to know even if fresh garlic consumption can remediate these problems. Three groups of rats were utilized: control group A, iron overload group B and garlic and iron overload group C. Important morphological and biochemical modifications were obtained in group B rats comparatively to control group A. Indeed, body and liver weights and liver iron contents increased, respectively, by 12.5 +/- 0.06%; 17 +/- 0.25% and 35 +/- 0.11% comparatively to controls. Radical cation scavenging ability in liver cytosol of group B rats was significantly low (54 +/- 0,1%) in comparison to group A. Garlic consumption allowed the group C to achieve an increase by 46 +/- 0,11 and 75 +/- 0,14% of total antioxidant capacity comparatively to group A and B rats. For the serum ALAT, ASAT, triglyceride and LDH levels, they increased in iron-treated rats, respectively, by 25 +/- 0.21; 15 +/- 0.12; 30 +/- 0.14 and 22 +/- 0.16% comparatively to controls. These perturbations were accompanied by deep histological changes. After food fresh garlic supplementation, we had found a deep regulation of all modified parameters showing a hepatoprotective effect of garlic against iron liver excess. Garlic chemical compounds have curative effects on iron liver excess. PMID- 21553302 TI - Epicardial adipose tissue thickness in type 1 diabetic patients. AB - Insulin resistance is getting important in the course of type 1 diabetes mellitus. Visceral fat depot is associated with insulin resistance and assessment of epicardial fat thickness is a way of measuring visceral fat. The aim of the study was to measure epicardial adipose tissue (EAT) thickness and to determine its relationship with waist-hip-ratio (WHR) and estimated glucose disposal rate (eGDR) in adult type 1 diabetic patients. Thirty-six type 1 diabetic patients (aged 31+/-8 years; Female/Male: 22/14) and 43 age, gender and BMI matched healthy controls were included. Fasting blood glucose (FBG), hemoglobin A1c, and lipid profiles were measured. Waist-hip-ratio (WHR) was calculated. Daily insulin dose/kg of patients were recorded and eGDR of all subjects was calculated. Epicardial adipose tissue (EAT) thickness was evaluated by echocardiography. EAT thickness of the type 1 diabetic patients was significantly higher than controls (3.30+/-1.06 vs. 2.30+/-0.34 mm, P<0.0001). EAT thickness was correlated with age (P=0.05; r=0.35), WHR (P=0.003; r=0.67), daily insulin dose/kg (r=0.45, P=0.005), and eGDR (r=-0.55, P=0.0004). Multivariate analysis revealed WHR and eGDR to be related to EAT among age, WHR, daily insulin dose/kg, eGDR, FBG, and hemoglobin A1c (r2 of the model=0.64). Epicardial adipose tissue thickness is increased in type 1 diabetic patients compared to controls and is related to WHR and eGDR in this group of patients. This measurement may point to the presence of insulin resistance in type 1 diabetic patients. PMID- 21553303 TI - A 5-year prospective quality of life analysis following laparoscopic adjustable gastric banding for morbid obesity. AB - BACKGROUND: In addition to actual weight loss and the possible resolution of obesity-related co-morbidities following bariatric surgery, another widely recognized important outcome measure is the improvement of quality of life (QOL). METHODS: Disease-specific quality of life (DSQOL) and general health-related quality of life (HRQOL) were measured preoperatively and at 1 and 5 years postoperatively following laparoscopic adjustable gastric banding (LAGB) for morbid obesity. The Moorehead-Ardelt questionnaire was used for DSQOL assessments and a generic 15-dimensional questionnaire (15D) was used for HRQOL measurements. In addition, HRQOL was compared with that of the age- and gender-standardized general population. RESULTS: DSQOL scores were significantly improved on all domains after 1 year from the operation and this improvement was maintained at 5 years. This improvement was also seen in the total HRQOL scores. Despite this improvement, the HRQOL after LAGB remained worse compared to the age- and gender standardized general population. CONCLUSIONS: DSQOL and HRQOL improve both significantly after LAGB. This QOL improvement is maintained at 5-year follow-up although QOL does not reach the level of the general population. PMID- 21553304 TI - Adjustable intragastric balloons: a 12-month pilot trial in endoscopic weight loss management. AB - Intragastric balloons are associated with (1) early period intolerance, (2) diminished effect within 3-4 months, and (3) bowel obstruction risk mandating removal at 6 months. The introduction of an adjustable balloon could improve comfort and offer greater efficacy. A migration prevention function, safely enabling prolonged implantation, could improve efficacy and weight maintenance post-extraction. The first implantations of an adjustable balloon with an attached migration prevention anchor are reported. The primary endpoint was the absence of bowel perforation, obstruction, or hemorrhage. Eighteen patients with mean BMI of 37.3 were implanted with the Spatz Adjustable Balloon system (ABS) for 12 months. Balloon volumes were adjusted for intolerance or weight loss plateau. Mean weight loss at 24 weeks was 15.6 kg with 26.4% EWL (percent of excess weight loss) and 24.4 kg with 48.8% EWL at 52 weeks. Sixteen adjustments were successfully performed. Six downward adjustments alleviated intolerance, yielding additional mean weight loss of 4.6 kg. Ten upward adjustments for weight loss plateau yielded a mean additional weight loss of 7 kg. Seven balloons were removed prematurely. Complications necessitating early removal included valve malfunction (1), gastritis (1), Mallory-Weiss tear (1), NSAID (2* dose/2 weeks) perforating ulcer (1), and balloon deflation (1). Two incidents of catheter shear from the chain: one passed uneventfully and one caused an esophageal laceration without perforation during extraction. The Spatz ABS has been successfully implanted in 18 patients. (1) Upward adjustments yielded additional weight loss. (2) Downward adjustments alleviated intolerance, with continued weight loss. (3) Preliminary 1-year implantation results are encouraging. PMID- 21553305 TI - NMR assignment and secondary structure of the C-terminal DNA binding domain of Arabidopsis thaliana VERNALIZATION1. AB - VERNALIZATION1 (VRN1) is a multidomain DNA binding protein from Arabidopsis thaliana that is required for the acceleration of flowering time in response to prolonged cold treatment; a physiological process called vernalization. VRN1 is a 39 kDa protein comprised of two B3 domains flanking a putative nuclear localization sequence and two PEST domains. Here we report the (1)H, (13)C and (15)N resonance assignments of the 134 residue C-terminal region of VRN1, comprising a B3 DNA binding domain of the REM family and an upstream region that is highly conserved among VRN1 homologs from other dicotyledonous plant species. PMID- 21553306 TI - Assessment of dietary restraint: psychometric properties of the revised restraint scale in Hong Kong adolescents. AB - BACKGROUND: The psychometric properties of the Revised Restraint Scale (RRS) have been well established in western populations but not in Chinese adolescents. PURPOSE: This study investigated the psychometric properties of RRS and its validity in different subgroups for Hong Kong Chinese adolescents. METHOD: In 2007, 909 Hong Kong students aged 12 to 18 years (55.3% boys) completed a questionnaire including demographic items, RRS, Eating Attitudes Test (EAT-26), and Motivation for Eating Scale (MFES)-physical. Moreover, subjects' height and weight were measured. To examine the factor structure of RRS, the whole sample was randomly split into two groups (sample 1: N=454 and sample 2: N=455) for exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), respectively. Convergent and discriminant validity of RRS were investigated by correlating the RRS with EAT-26 and MFES-physical. Multigroup CFA was conducted to test the three-factor model of RRS in different sex, age, and weight status subgroups. RESULTS: Results of EFA for sample 1 revealed three strongly correlated factors for the RRS construct, and were supported by the CFA results in sample 2. Multigroup CFA further suggested that the three-factor model of RRS was stable across sex, age, and weight status subgroups. CONCLUSIONS: A new three factor model is proposed for Hong Kong adolescents in this study. In general, RRS is a reliable and valid measure of restrained eating for adolescents, regardless of sex, age, and weight status. PMID- 21553307 TI - Efficacy of combined pegylated interferon and ribavirin therapy in Jewish patients of Israel suffering from chronic hepatitis C. AB - BACKGROUND AND PURPOSE: The efficacy and safety of pegylated interferon and ribavirin treatment for chronic hepatitis C (CHC) in the Jewish population has not been previously ascertained. The aims of our study were to determine the efficacy of pegylated interferon and ribavirin therapy in an Israeli outpatient practice. METHODS: The medical records of 331 consecutive naive patients with CHC infection treated with pegylated interferon and ribavirin between 2003 and 2010 were reviewed in order to document the virological response to the combination therapy. We used logistic regression to identify predictors for the sustained virological response (SVR). Variable selection in multivariable modeling was based on clinical and statistical significance and performed in a hierarchical fashion. First demographic characteristics, then patient clinical characteristics, viral characteristics, and finally adherence to the therapy were introduced into the model. RESULTS: The overall SVR was 57.1% (42.5% in genotype 1, 87.5% in genotype 2, 81.6% in genotype 3, and 100% in genotype 4). SVR was significantly associated with genotype 2 (OR 3.77, 95% CI 1.04-13.60, P = 0.04), genotype 3 (OR 9.72, 95% CI 4.07-23.20, P < 0.001), baseline viral load lower than 400,000 IU/mL (OR 23.1, 95% CI 8.23-64.98, P < 0.001), and adherence to the 80/80/80 rule (OR 36.22, 95% CI 11.14-117.72, P < 0.001). CONCLUSIONS: Combined pegylated interferon and ribavirin therapy was of similar or even higher efficacy in the Israeli population as compared to that reported by international trials in Caucasian, Hispanic, and African American populations. PMID- 21553308 TI - Culture-dependent and culture-independent diversity surveys target different bacteria: a case study in a freshwater sample. AB - Compared with culture-independent approaches, traditionally used culture dependent methods have a limited capacity to characterize water microbiota. Nevertheless, for almost a century the latter have been optimized to detect and quantify relevant bacteria. A pertinent question is if culture-independent diversity surveys give merely an extended perspective of the bacterial diversity or if, even with a higher coverage, focus on a different set of organisms. We compared the diversity and phylogeny of bacteria in a freshwater sample recovered by currently used culture-dependent and culture-independent methods (DGGE and 454 pyrosequencing). The culture-dependent diversity survey presented lower coverage than the other methods. However, it allowed bacterial identifications to the species level, in contrast with the other procedures that rarely produced identifications below the order. Although the predominant bacterial phyla detected by both approaches were the same (Proteobacteria, Actinobacteria, Bacteroidetes), sequence similarity analysis showed that, in general, different operational taxonomical units were targeted by each method. The observation that culture-dependent and independent approaches target different organisms has implications for the use of the latter for studies in which taxonomic identification has a predictive value. In comparison to DGGE, 454 pyrosequencing method had a higher capacity to explore the bacterial richness and to detect cultured organisms, being also less laborious. PMID- 21553309 TI - Fungal associates of the lodgepole pine beetle, Dendroctonus murrayanae. AB - Bark beetles are well known vectors of ophiostomatoid fungi including species of Ophiostoma, Grosmannia and Ceratocystis. In this study, the most common ophiostomatoid fungi associated with the lodgepole pine beetle, Dendroctonus murrayanae, were characterized. Pre-emergent and post-attack adult beetles were collected from lodgepole pines at four sites in British Columbia, Canada. Fungi were isolated from these beetles and identified using a combination of morphology and DNA sequence comparisons of five gene regions. In all four populations, Grosmannia aurea was the most common associate (74-100% of all beetles) followed closely by Ophiostoma abietinum (29-75%). Other fungi isolated, in order of their relative prevalence with individual beetles were an undescribed Leptographium sp. (0-13%), Ophiostoma ips (0-15%), Ophiostoma piliferum (0-11%), a Pesotum sp. (0 11%) and Ophiostoma floccosum (0-1%). Comparisons of the DNA sequences of Leptographium strains isolated in this study, with ex-type isolates of G. aurea, Grosmannia robusta, Leptographium longiclavatum, and Leptographium terebrantis, as well as with sequences from GenBank, revealed a novel lineage within the Grosmannia clavigera complex. This lineage included some of the D. murrayane isolates as well as several isolates from previous studies referred to as L. terebrantis. However, the monophyly of this lineage is not well supported and a more comprehensive study will be needed to resolve its taxonomic status as one or more novel taxa. PMID- 21553311 TI - Differential expression of HINT1 in schizophrenia brain tissue. AB - Recent findings in the literature suggest a relation between histidine triad nucleotide-binding protein-1 (HINT1) and psychiatric disorders such as major depression, anxiety, and schizophrenia, although its physiological roles are not completely comprehended. Using Western blot, we compared HINT1 protein expression in the postmortem dorsolateral prefrontal cortex and thalamus of schizophrenia patients and healthy controls for contributing to elucidate the role of HINT1 in schizophrenia pathophysiology. HINT1 was found to be downregulated in the dorsolateral prefrontal cortex and upregulated in the thalamus. Our results combined to previous studies in human samples and preclinical models support the notion that HINT1 must be more explored as a potential target for psychiatric disorders. PMID- 21553312 TI - Matrix proteins are inefficiently imported into Arabidopsis peroxisomes lacking the receptor-docking peroxin PEX14. AB - Mutations in peroxisome biogenesis proteins (peroxins) can lead to developmental deficiencies in various eukaryotes. PEX14 and PEX13 are peroxins involved in docking cargo-receptor complexes at the peroxisomal membrane, thus aiding in the transport of the cargo into the peroxisomal matrix. Genetic screens have revealed numerous Arabidopsis thaliana peroxins acting in peroxisomal matrix protein import; the viable alleles isolated through these screens are generally partial loss-of-function alleles, whereas null mutations that disrupt delivery of matrix proteins to peroxisomes can confer embryonic lethality. In this study, we used forward and reverse genetics in Arabidopsis to isolate four pex14 alleles. We found that all four alleles conferred reduced PEX14 mRNA levels and displayed physiological and molecular defects suggesting reduced but not abolished peroxisomal matrix protein import. The least severe pex14 allele, pex14-3, accumulated low levels of a C-terminally truncated PEX14 product that retained partial function. Surprisingly, even the severe pex14-2 allele, which lacked detectable PEX14 mRNA and PEX14 protein, was viable, fertile, and displayed residual peroxisome matrix protein import. As pex14 plants matured, import improved. Together, our data indicate that PEX14 facilitates, but is not essential for peroxisomal matrix protein import in plants. PMID- 21553313 TI - Prospective evaluation of the incidence of delayed nausea and vomiting in patients with colorectal cancer receiving oxaliplatin-based chemotherapy. AB - PURPOSE: This study sought to prospectively determine the frequency of delayed nausea and vomiting with oxaliplatin-based chemotherapy following day 1 prophylaxis with a 5-HT-(3) receptor antagonist and dexamethasone. METHODS: Patients with colon cancer, >= age 18, with a performance status <= 2, receiving oxaliplatin (85-100 mg/m(2)) as part of a standard folinic acid, 5-fluorouracil, oxaliplatin regimen for the first time were eligible. All patients received a 5 HT(3) receptor antagonist and dexamethasone 20 mg on day 1 prior to oxaliplatin. No routine prophylaxis for delayed emesis was given. Antiemetic outcome was recorded in patient-completed diaries for the 120-h study period following oxaliplatin administration. Primary endpoint was frequency of delayed (24-120 h) emesis (vomiting/retching). RESULTS: Forty-one patients were enrolled and 39 are evaluable. Median age was 70 (34-85) and the female/male ratio was 20:19. Four patients (10%) experienced vomiting or retching during the delayed period. One patient vomited during the first 24 h after oxaliplatin. The overall (120 h) no emesis rate was 87% (34/39). Twenty-one patients (54%) developed delayed nausea. Nine patients had moderate or severe nausea. Eighteen patients (46%) took rescue antiemetics during the delayed period. Delayed and overall complete response (no emesis or use of rescue antiemetics) rates were 54% and 49%, respectively. CONCLUSIONS: The use of a 5-HT(3) antagonist and dexamethasone prior to oxaliplatin results in excellent control of nausea and vomiting (CR-90%) during the 24 h after chemotherapy. However, without further antiemetic treatment, complete response in the delayed period decreased to 54%. This study supports the need for routine antiemetic prophylaxis for delayed nausea and vomiting following oxaliplatin-based chemotherapy. PMID- 21553314 TI - Compression garments versus compression bandaging in decongestive lymphatic therapy for breast cancer-related lymphedema: a randomized controlled trial. AB - BACKGROUND: Lymphedema as a result of curative surgery for breast cancer can lead to long-term morbidity. Decongestive lymphatic therapy (DLT) is recognized as an optimal management strategy for patients with moderate symptomatologies, but there is little data in regard to the most effective means of providing compression therapy within a DLT protocol. We conducted a randomized trial of two forms of compression therapy within the initial treatment phase of a DLT protocol for breast cancer-related lymphedema. METHODS: Subjects were required to have mild-moderate lymphedema (10-40% volume difference) acquired as a result of curative breast cancer surgery and were randomized to compression bandaging or garments within the initial treatment phase of a DLT protocol. Primary endpoint was change in affected limb volume assessed via volumetry, and secondary endpoints were symptom control and upper extremity function assessed via visual analogue scales and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, respectively. Endpoints were assessed at day 10 of treatment and at 3 months and compared to baseline. RESULTS: Twenty-one subjects were available for analysis. The group receiving bandaging experienced greater median volume reductions at 10 days (70 vs. 5 mL; p = 0.387) and at 3 months (97.5 vs. 50 mL; p = 0.182). The bandaging group also experienced a greater increase in median DASH scores at 10 days (+20.9 vs. +5; p = 0.143) and at 3 months (+18.4 vs. +3.3; p = 0.065). CONCLUSION: Within the initial treatment phase of a DLT protocol for acquired, breast cancer-related lymphedema, compression bandaging may lead to greater volume reduction but worse upper extremity functional status (higher DASH scores) as compared to compression garments. PMID- 21553315 TI - Current microbiology of percutaneous endoscopic gastrostomy tube (PEG tube) insertion site infections in patients with cancer. AB - PURPOSE: Percutaneous endoscopic gastrostomy (PEG) is frequently used to provide enteral access in cancer patients who are unable to swallow. Infection is an important complication in this setting. Current microbiological data are needed to guide infection prevention and treatment strategies. METHODS: The microbiological records of our institution (a 550-bed comprehensive cancer center) were retrospectively reviewed over an 8-month study period in order to identify patients who developed PEG tube insertion site infections, and review their microbiological details and susceptibility/resistance data. RESULTS: Fifty eight episodes of PEG tube insertion site infections were identified. Of these, 31 (53%) were monomicrobial, and the rest were polymicrobial. The most common organisms isolated were Candida species, Staphylococcus aureus, and Pseudomonas aeruginosa. All infections were local (cellulitis, complicated skin, and skin structure infections including abdominal wall abscess) with no cases of concomitant bacteremia being documented. Most of the organisms isolated were susceptible to commonly used antimicrobial agents, although some quinolone resistant and some multidrug-resistant organisms were isolated. CONCLUSIONS: This retrospective study provides descriptive data regarding PEG tube insertion site infections. These data have helped us update institutional guidelines for infection prevention and treatment as part of our focus on antimicrobial stewardship. PMID- 21553316 TI - Dynamic telecytologic evaluation of imprint cytology samples from CT-guided lung biopsies: a feasibility study. AB - OBJECTIVE: This study assessed the feasibility of telecytological evaluation of samples from CT-guided lung biopsies using a dynamic telecytological system in which the microscope was operated by personnel from the radiology department at the site of the biopsy and a cytologist off-site diagnosed the biopsy sample. MATERIALS AND METHODS: 45 imprint samples from CT-guided biopsies of lung lesions were reviewed by two cytologists using a telecytological microscope (Olympus BX51, Tokyo, Japan). The telecytological microscope was operated by one radiologist and one radiology technician. The cytological samples were classified by a cytologist into four categories: benign, malignant, atypical cells of undetermined significance, and non-diagnostic. The results were compared with those of a previous consensus reading of two independent cytologists (gold standard). RESULTS: When the radiologist was operating the microscope, the diagnostic accuracy was 100% as both cytologists came to the correct diagnosis in all samples. When the technician operated the microscope, two diagnoses of cyotologist 1 differed from the gold standard. Thus, the accuracy for the technician was 95.56%. CONCLUSION: Telecytological evaluation of imprint samples from CT-guided lung biopsies is feasible because it can be performed with high diagnostic accuracy if personnel from the radiology department operate the microscope. PMID- 21553317 TI - Atypical adult medulloblastoma. AB - Medulloblastomas are malignant primitive neuro-ectodermal neoplasms of childhood. In adults, clinical manifestations, imaging and prognosis can be different from that observed in children. Three adult patients with confirmed diagnoses of medulloblastoma are discussed in this report. They presented with unusually prolonged clinical courses and with imaging more suggestive of L'hermitte-Duclos disease. Medulloblastoma should be considered in all adults with posterior fossa masses despite having clinical and radiological features suggestive of a low grade tumour. Definitive diagnosis requires histological confirmation in all cases. PMID- 21553318 TI - A role of diffusion tensor imaging fiber tracking in deep brain stimulation surgery: DBS of the dentato-rubro-thalamic tract (drt) for the treatment of therapy-refractory tremor. AB - INTRODUCTION: Deep brain stimulation (DBS) can alleviate tremor of various origins. A number of regions are targeted. In recent work our group was able to show the involvement of the dentato-rubro-thalamic tract (drt) in tremor control with fiber tracking techniques. Here we report for the first time the successful use of magnetic resonance tractography in combination with traditional landmark based targeting techniques to perform the implantation of a bilateral DBS system in a patient with dystonic head tremor. METHODS: We report on a 37-year-old female with long-standing pure head tremor from myoclonus dystonia. She was identified as a candidate for thalamic DBS. The use of head fixation in a stereotactic frame would blur target symptoms (head tremor) during surgery and was therefore avoided. Her dentate-rubro-thalamic tracts were visualized with preoperative diffusion tensor imaging (DTI) and tractography, and then directly targeted stereotactically with DBS electrodes. RESULTS: Three months after implantation, tremor control was excellent (>90%). A close evaluation of the active electrode contact positions revealed clear involvement of the drt. CONCLUSION: This is the first time that direct visualization of fiber tracts has been employed for direct targeting and successful movement disorder tremor surgery. In the reported case, additional knowledge about the position of the drt, which previously has been shown to be a structure for modulation to achieve tremor control, led to a successful implantation of a DBS system, although there was a lack of intra-operatively testable tremor symptoms. In concordance with studies in optogenetic neuromodulation, fiber tracts are the emerging target structures for DBS. The routine integration of DTI tractography into surgical planning might be a leading path into the future of DBS surgery and will add to our understanding of the pathophysiology of movement disorders. Larger study populations will have to prove these concepts in future research. PMID- 21553319 TI - Dissection of both frontal and parietal branches of the superficial temporal artery for bypass surgery through a single linear skin incision. AB - BACKGROUND: Double superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery has typically involved more than one linear incision. In this report, we demonstrate how the procedure can be performed through a single linear skin incision over the parietal branch of the STA. METHODS: Initial dissection of the parietal branch and creation of a subcutaneous cavity along the frontal branch were performed using the conventional microscopic method. Detailed additional dissection and isolation of the frontal branch were accomplished with the aid of an endoscopic retractor. RESULTS: This procedure was performed in five patients for harvesting of approximately 8- and 5-cm lengths of the parietal and frontal branches, respectively. The resultant lengths of the harvested vessels were sufficient for anastomotic revascularization of MCA recipient arteries in both the frontal and temporal lobes. CONCLUSION: This method can be safely performed with achievement of a less invasive dissection of the STA and an overall improved cosmetic outcome. PMID- 21553320 TI - Preventive care in prostate cancer patients: following diagnosis and for five year survivors. AB - INTRODUCTION: Prostate cancer is the most common male cancer. Survival rates are high, making preventive care maintenance important. Factors associated with prostate-cancer cases' preventive care in the short-term (Year 1) and long-term (Year 5), and how survivors' care compares to non-cancer controls, require study. METHODS: This retrospective, controlled SEER-Medicare study included loco regional prostate cancer cases age >= 66 in fee-for-service Medicare diagnosed in 2000 and surviving >= 12 months, and non-cancer controls matched to cases on socio-demographics and survival. Outcomes included influenza vaccination, cholesterol screening, and colorectal cancer screening. Independent variables were number of physician visits, physician specialties visited, initial prostate cancer treatment, socio-demographic characteristics, and case-control status. RESULTS: There were 13,507 cases and 13,507 controls in Year 1, and 10,482 cases and 10,482 controls in Year 5. In Years 1 and 5, total number of visits (6/6 outcomes) and primary care provider (PCP) visits (5/6 outcomes) were most consistently associated with preventive care receipt. In Year 1, prostate cancer cases were more likely than controls to receive influenza vaccination (48% vs. 45%) but less likely to receive colorectal cancer screening (29% vs. 31%) (both p < 0.0001). In Year 5, prostate cancer cases remained more likely than controls to receive influenza vaccination (46% vs. 44%; p < 0.0001). CONCLUSIONS: Differences in survivors' short-term preventive care did not lead to worse long term preventive care. The number of physician visits, particularly PCP visits, are important factors associated with appropriate care. IMPLICATIONS FOR CANCER SURVIVORS: PCP involvement in prostate cancer patients' care is critical both during treatment and for long-term survivors. PMID- 21553321 TI - Serum adiponectin complexes and cardiovascular risk in children with chronic kidney disease. AB - In contrast to the general population, patients with chronic kidney disease (CKD) experience increased total adiponectin levels despite an increased prevalence of cardiovascular disease. Adiponectin circulates as trimer, low molecular weight (LMW), and high molecular weight (HMW) complexes. The distribution and role of each subfraction in CKD is unknown. This cross-sectional analysis examined the association of serum adiponectin and its subfractions with known cardiovascular risk factors in 105 children (median age 12 years; 56% male) enrolled into the Chronic Kidney Disease in Children (CKiD) study, an observational cohort study of children with CKD stage 2-4.HMW accounted for 46% of total adiponectin, followed by LMW (34%) and trimer (20%). In multivariable analysis, LMW was independently associated with iohexol glomerular filtration rate (GFR) (p = 0.004) and was higher in pubertal versus prepubertal children (p = 0.005). HMW/LMW ratio was independently associated with age and iohexol GFR (all p < 0.001). Unexpectedly, systolic blood pressure was positively correlated with HMW (p = 0.01), and HMW/LMW ratio (p = 0.007) and inversely correlated with LMW (p = 0.009). Among subfractions, only LMW was significantly correlated with left ventricular mass (LVM) index (p = 0.05). In multivariable analysis, decreased LMW was independently associated with higher LVM index [beta= -0.25, 95% confidence interval (CI) -0.50, -0.03, p=0.04) after adjustment for body mass index (BMI), age, and blood pressure.The higher total adiponectin levels in children with CKD are associated with higher HMW and lower LMW. This imbalance may be an important biomarker for increased cardiovascular risk despite higher levels of total adiponectin in children with CKD. PMID- 21553322 TI - Elevated plasma advanced oxidation protein products in children with Henoch Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is a systemic vasculitis characterized by involvement of skin, joints, gastrointestinal tract (GIT), and kidney; its pathogenesis is still controversial. The aim of our study was to investigate the role of oxidative stress in the pathogenesis of HSP. Plasma advanced oxidation protein products (AOPP) level was measured in 29 children with HSP at the onset of the disease and during remission in comparison with 30 healthy subjects. Patients at the active stage had significantly higher AOPP levels than those at the remission stage of HSP and the controls (42.9 +/- 25.7, 30.6 +/- 11.8, 27.9 +/- 11.2 mmol/l; P = 0.027 and P = 0.023 respectively). The mean AOPP levels of the patients with arthritis and/or arthralgia were significantly higher those than without joint involvement (48.3 +/- 26.0 and 22.3 +/- 9.3, P = 0.036 respectively). However, AOPP levels were similar in patients with and without gastrointestinal involvement. Plasma AOPP levels were positively correlated with leukocyte and thrombocyte count at disease onset, whereas they were found to be negatively correlated with serum glucose and sodium levels. The mean thrombocyte count was the only independent predictor of increased level of AOPP in regression analysis (beta = 0.407; P = 0.029). In conclusion, this study showed that increased oxidative stress may play an important role in the pathogenesis of HSP. Also, we suggest that higher platelet count might be an indirect indicator of oxidative stress in these patients. Further research is required to identify the potential association between oxidative stress and increased thrombocyte count in children with HSP. PMID- 21553323 TI - Natural history of adolescent-onset cystinosis. AB - Cystinosis is a rare autosomal recessive disease caused by mutations of the CTNS gene in which cystine accumulates throughout the body as a result of a defective efflux of cystine from lysosomes. Three phenotypic forms have been described according to the age of onset and the severity of the clinical symptoms: infantile, intermediate, and ocular non-nephropathic cystinosis. Here we report the natural history of cystinosis in a 55-year-old man with intermediate nephropathic cystinosis diagnosed at 9 years of age. Although tubulopathy was unnoticed in the early years, he required transplantation at age 16. Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 21 bp in-frame deletion in exon 5 (c. 198_218del21), resulting in an in-frame deletion of 7 amino acids from the N-terminal domain of the cystinosin protein. Our patient has had relatively mild extra-renal disease despite lack of early cysteamine therapy. He has been able to attend university and pursue a professional career into the 6th decade. PMID- 21553324 TI - Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome. AB - Oral steroid treatment is the first line of therapy for childhood nephrotic syndrome (NS). Nonetheless, some patients are resistant to this treatment. Many efforts have been made to explain the differences in the response to steroid treatment in patients with NS based on the genetic background. We have investigated single nucleotide polymorphisms of the MDR1 [C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642)] and MIF (G-173C, rs755622) genes in 170 children with NS. Of these children, 69 (40.6%) were initial steroid non responders, and 23 (13.5% of total) developed chronic kidney disease. Renal biopsy findings, which were available for 101 patients, showed that 35 patients had minimal change lesion and 66 had focal segmental glomerulosclerosis. The frequencies of the MDR1 1236 CC (18.8 vs 7.2%) or TC (53.5 vs 43.5%) genotype and C allele (45.5 vs 29.0%) were significantly higher in the initial steroid responders than in the non-responders. Analysis of MDR1 three-marker haplotypes revealed that the frequency of the TGC haplotype was significantly lower in the initial steroid responders than in the non-responders (15.8 vs 29.0%). There was no association between the MIF G-173C polymorphism and clinical parameters, renal histological findings, and steroid responsiveness. These data suggest that the initial steroid response in children with NS may be influenced by genetic variations in the MDR1 gene. PMID- 21553325 TI - Hox genes and kidney development. AB - The adult mammalian kidney is generated by the differentiation and integration of several distinct cell types, including the nephrogenic mesenchyme, ureteric epithelium, stromal and endothelial cells. How and where these cell types are generated and what signals lead to their differentiation and integration into a functional organ system is a main focus of current studies. Herein, we review the formation of distinct cell types within the adult mammalian kidney; what is understood regarding their origin and the signaling pathways that lead to their formation and integration; morphogenetic changes the metanephric kidney undergoes during development; and what is known regarding the role of Hox genes in these processes. PMID- 21553326 TI - Renal FMD may not confer a familial hypertensive risk nor is it caused by ACTA2 mutations. AB - Renal fibromuscular dysplasia (FMD) can cause hypertension, and previous reports suggest that FMD is familial. We hypothesized that, in families containing an individual with proven FMD, relatives of index cases would have an increased risk of hypertension. ACTA2 mutations cause a spectrum of extra-renal arteriopathy, leading to our second hypothesis that mutations are implicated in FMD. The blood pressure of first-degree relatives was measured using standard devices and, when indicated, with 24-h ambulatory monitoring. Leucocyte DNA was obtained from FMD index cases and ACTA2 sequenced. Thirteen unrelated index cases, aged 2-32 (median 15) years, were recruited. Blood pressure was assessed in 40 first-degree relatives, comprising 22 parents aged 28-58 (median 44) years and 18 siblings aged 3-30 (median 13) years. Hypertension was evident in six (27%) parents but in none of the eight adult siblings. Of the ten screened siblings aged less than 18 years, one teenager was pre-hypertensive (90th-95th centile), the remainder being normotensive. No ACTA2 mutations were found in 13 index cases. Hypertension was evident in 20% of all assessed adult first-degree relatives and is therefore not increased relative to 25% of the adult population. Although hypertensive parents did not undergo angiography to assign FMD status, this observation, together with the lack of hypertension in 18 siblings, indicates that FMD is unlikely to confer an excess hypertension risk in first-degree relatives up to middle-age. Furthermore, in our cohort, FMD was not caused by ACTA2 mutations. PMID- 21553327 TI - Transcription of the Hsp30, Hsp70, and Hsp90 heat shock protein genes is modulated by the PalA protein in response to acid pH-sensing in the fungus Aspergillus nidulans. AB - Heat shock proteins are molecular chaperones linked to a myriad of physiological functions in both prokaryotes and eukaryotes. In this study, we show that the Aspergillus nidulans hsp30 (ANID_03555.1), hsp70 (ANID_05129.1), and hsp90 (ANID_08269.1) genes are preferentially expressed in an acidic milieu, whose expression is dependent on the palA (+) background under optimal temperature for fungal growth. Heat shock induction of these three hsp genes showed different patterns in response to extracellular pH changes in the palA(+) background. However, their accumulation upon heating for 2 h was almost unaffected by ambient pH changes in the palA (-) background. The PalA protein is a member of a conserved signaling cascade that is involved in the pH-mediated regulation of gene expression. Moreover, we identified several genes whose expression at pH 5.0 is also dependent on the palA (+) background. These results reveal novel aspects of the heat- and pH-sensing networks of A. nidulans. PMID- 21553328 TI - The direct cost of acute hip fracture care in care home residents in the UK. AB - Data on the true acute care costs of hip fractures for patients admitted from care homes are limited. Detailed costing analysis was undertaken for 100 patients. Median cost was L9,429 [10,896], increasing to L14,435 [16,681], for those requiring an upgrade from residential to nursing home care. Seventy-six percent of costs were attributable to hospital bed days, and therefore, interventions targeted at reducing hospital stay may be cost effective. INTRODUCTION: Previous studies have estimated the costs associated with hip fracture, although these vary widely, and for patients admitted from care homes, who represent a significant fracture burden, there are limited data. The primary aim of this study was to perform a detailed assessment of the direct medical costs incurred and secondly compare this to the actual remuneration received by the hospital. METHODS: One hundred patients presenting from a care home in 2006 were randomly selected and a detailed case-note costing analysis was undertaken. This cost was then compared to the actual remuneration received by the hospital. RESULTS: Median cost per patient episode was L9,429 [10,896] (all patients) range L4,292-162,324 [4,960-187,582] (subdivided into hospital bed day costs L7,129 [8,238], operative costs L1,323 [1,529] and investigation costs L977 [1,129]). Twenty-two percent of the patients admitted from a residential home required upgrading to a nursing home. In this group, the median length of stay was 31 days (mean 38, range 10-88) median cost L14,435 [16,681]. Average remuneration received equated to L6,222 [7,190] per patient. This represents a mean loss in income, compared to actual calculated costs of L3,207 [3,706] per patient. CONCLUSION: The median cost was L9,429 [10,896], increasing to L14,435 [16,681], for those requiring an upgrade from residential to nursing home care at discharge. Significant cost differences were seen comparing the actual cost to remuneration received. Interventions targeted at reducing length of stay may be cost effective. PMID- 21553329 TI - Creative solution for implementation of experiential, competency-based palliative care training for internal medicine residents. AB - To graduate internal medicine residents with basic competency in palliative care, we employ a two-pronged strategy targeted at both residents and attending physicians as learners. The first prong provides a knowledge foundation using web based learning programs designed specifically for residents and clinical faculty members. The second prong is assessment of resident competency in key palliative care domains by faculty members using direct observation during clinical rotations. The faculty training program contains Competency Assessment Tools addressing 19 topics distributed amongst four broad palliative care domains designed to assist faculty members in making the clinical competency assessments. Residents are required to complete their web-based training by the end of their internship year; they must demonstrate competency in one skill from each of the four broad palliative care domains prior to graduation. Resident and faculty evaluation of the training programs is favorable. Outcome-based measures are planned to evaluate long-term program effectiveness. PMID- 21553330 TI - Cervical cancer screening: attitudes and behaviors of young Asian American women. AB - Compared to other racial/ethnic groups, Korean, Filipino, and Vietnamese American women experience high incidence rates of cervical cancer but low rates of cervical cancer screenings. This study examines the behaviors and attitudes towards screening in young Korean, Filipino, and Vietnamese American women (n = 304) in the San Francisco Bay Area. Results indicated Vietnamese American (OR = 2.51) and Filipino American (OR = 2.31) women had greater odds of ever having a Pap test than Korean American women. Those older (OR = 1.55), born in the USA (OR = 2.64), and those comfortable with the test (OR = 3.41) also had greater odds of ever having a Pap test. Correct knowledge of cervical cancer and the human papillomavirus did not significantly affect the odds of having a Pap test. Interventions to increase Pap testing in these populations should focus on increasing levels of comfort and should target those younger and foreign born. PMID- 21553331 TI - Qualitative evaluation of a new tobacco cessation training curriculum for patient navigators. AB - Treatments for tobacco dependence exist but are underutilized, particularly among low-income and minority smokers. Patient navigation has been shown to help patients overcome barriers to quality care. In preparation for testing the feasibility of integrating tobacco cessation patient navigation into primary care, this paper describes the development and qualitative evaluation of a new curriculum for training patient navigators to address cessation treatment barriers faced by low-income, minority smokers who are advised to quit by their physicians. Thematic text analysis of transcripts obtained from focus groups with experienced patient navigators (n = 19) was conducted. Participants endorsed patient navigation as a relevant strategy for addressing tobacco cessation treatment barriers and made several recommendations regarding the knowledge, core competencies, and skills needed to conduct tobacco cessation patient navigation. This curriculum could be used by existing patient navigation training centers or made available as a self-guided continuing education program for experienced navigators who wish to expand their navigation interventions to include a tobacco cessation focus. PMID- 21553332 TI - Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. AB - Production of cytokines by immune cells in response to stimuli and the binding of cytokines to specific receptors on target cells is a central feature of the immune response. The IL-12 cytokine family is particularly influential in determining the fate of T cells and is characterized by the sharing of cytokine and receptor subunits. A thorough understanding of the molecular interactions within this family will be a key to the development of therapeutic inhibitors or enhancers of IL-12 family function. While the current structural and molecular data for IL-12 family members is limited, there is ample information on the structurally related IL-6 cytokine family. This review will summarize the current structural and mutagenesis data within the IL-12 family and will attempt to utilize similarities between the IL-6 and IL-12 families to understand molecular interactions between IL-12 family subunits and with receptor components. PMID- 21553333 TI - Convective heat transfer from a nude body under calm conditions: assessment of the effects of walking with a thermal manikin. AB - The present experimental work is dedicated to the analysis of the effect of walking on the thermal insulation of the air layer (I (a)) and on the convective heat transfer coefficients (h (conv)) of the human body. Beyond the standing static posture, three step rates were considered: 20, 30 and 45 steps/min. This corresponds to walking speeds of approximately 0.23, 0.34 and 0.51 m/s, respectively. The experiments took place in a climate chamber with an articulated thermal manikin with 16 independent parts. The indoor environment was controlled through the inner wall temperatures since the objective of the tests was restricted to the influence of the walking movements under calm conditions. Five set points were selected: 10, 15, 20, 25 and 30 degrees C, and the operative temperature within the test chamber varied between 11.9 and 29.6 degrees C. The highest and lowest I ( a ) values obtained were equal to 0.87 and 0.71 clo, respectively, and the reduction in insulation due to walking ranged between 9.8 and 11.5%. The convective coefficients (h (conv)) for the whole body and for the different body segments were also determined for each step rate. In the case of the whole body, for the standing static reference posture, the mean value of h (conv) was equal to 3.3 W/m(2) degrees C and a correlation [Nu = Nu(Gr)] for natural convection is also presented in good agreement with previous results. For the other postures, the values of h (conv) were equal to 3.7, 3.9 and 4.2 W/m(2) degrees C, respectively for 20, 30 and 45 steps/min. PMID- 21553334 TI - Spatial structure of the abiotic environment and its association with sapling community structure and dynamics in a cloud forest. AB - Analyzing the relationship between the spatial structures of environmental variables and of the associated seedling and sapling communities is crucial to understanding the regeneration processes in forest communities. The degree of spatial structuring (i.e., spatial autocorrelation) of environmental and sapling community variables in the cloud forest of Teipan, S Mexico, were analyzed at a 1 ha scale using geostatistical analysis; after fitting semivariogram models for each set of variables, the association between the two sets was examined through cross-variograms. Kriging maps of the sapling community variables (density, cover, species richness, and mortality and recruitment rates) were obtained through conditional simulation method. Canopy openness, total solar radiation, litter depth, soil temperature and soil moisture were spatially structured, as were sapling density, species richness and sapling mortality rate. Mean range in semivariograms for environmental and sapling community variables were 13.14 +/- 3.67 and 12.68 +/- 5.71 m (+/-SE), respectively. The spatial structure of litter depth was negatively associated with the spatial structures of sapling density, species richness, and sapling community cover; in turn, the spatial structure of soil moisture was positively associated with the spatial structure of recruitment rate. These associations of the spatial structures of abiotic and sapling community variables suggest that the regeneration processes in this cloud forest is driven by the existence of different microsites, largely characterized by litter depth variations, across which saplings of tree species encounter a range of opportunities for successful establishment and survival. PMID- 21553335 TI - Using Self-Organising Maps (SOMs) to assess synchronies: an application to historical eucalypt flowering records. AB - Self-Organising Map (SOM) clustering methods applied to the monthly and seasonal averaged flowering intensity records of eight Eucalypt species are shown to successfully quantify, visualise and model synchronisation of multivariate time series. The SOM algorithm converts complex, nonlinear relationships between high dimensional data into simple networks and a map based on the most likely patterns in the multiplicity of time series that it trains. Monthly- and seasonal-based SOMs identified three synchronous species groups (clusters): E. camaldulensis, E. melliodora, E. polyanthemos; E. goniocalyx, E. microcarpa, E. macrorhyncha; and E. leucoxylon, E. tricarpa. The main factor in synchronisation (clustering) appears to be the season in which flowering commences. SOMs also identified the asynchronous relationship among the eight species. Hence, the likelihood of the production, or not, of hybrids between sympatric species is also identified. The SOM pattern-based correlation values mirror earlier synchrony statistics gleaned from Moran correlations obtained from the raw flowering records. Synchronisation of flowering is shown to be a complex mechanism that incorporates all the flowering characteristics: flowering duration, timing of peak flowering, of start and finishing of flowering, as well as possibly specific climate drivers for flowering. SOMs can accommodate for all this complexity and we advocate their use by phenologists and ecologists as a powerful, accessible and interpretable tool for visualisation and clustering of multivariate time series and for synchrony studies. PMID- 21553336 TI - Occipital horn syndrome in a woman: skeletal radiological findings. AB - Ehlers-Danlos type IX syndrome, also called occipital horn syndrome (OHS), is a milder and rare form of Menkes disease where the patient reaches adulthood. As an X-linked disease, it typically occurs in male subjects, while female subjects are usually healthy carriers. OHS is mainly characterized by connective tissue disorders and slightly subnormal intelligence or signs of autonomic dysfunction are the only apparent neurological abnormalities, in connection with molecular defects in copper metabolism. Our purpose is to report on radiological skeletal findings that may be incidental or investigated when OHS is suspected and to underline the possible involvement and expression in the female. Moreover, the impact of skeletal findings is also highlighted in the prevention of serious complications of the disease. PMID- 21553337 TI - The relationship between prevalent medial meniscal intrasubstance signal changes and incident medial meniscal tears in women over a 1-year period assessed with 3.0 T MRI. AB - OBJECTIVE: Intrasubstance meniscal signal changes not reaching the articular surface on fast spin echo (FSE) sequences are considered to represent mucoid degeneration on MRI. The aim of this study was to evaluate the association of prevalent intrasubstance signal changes with incident tears of the medial meniscus detected on 3.0 T MRI over a 1-year period. MATERIALS AND METHODS: A total of 161 women aged >= 40 years participated in a longitudinal 1-year observational study of knee osteoarthritis. MRI (3.0 T) was performed at baseline and 12-month follow-up. The anterior horn, body, and posterior horn of the medial meniscus were scored by two experienced musculoskeletal radiologists using the Boston-Leeds Osteoarthritis Knee Score (BLOKS) system. Four grades were used to describe the meniscal morphology: grade 0 (normal), grade 1 (intrasubstance signal changes not reaching the articular surface), grade 2 (single tears), and grade 3 (complex tears and maceration). Fisher's exact test and the Cochran Armitage trend test were performed to evaluate whether baseline intrasubstance signal changes (grade 1) predict incident meniscal tears/maceration (grades 2 and/or 3) in the same subregion of the medial meniscus, when compared to subregions without pathology as the reference group (grade 0). RESULTS: Medial meniscal intrasubstance signal changes at baseline did not predict tears at follow-up when evaluating the anterior and posterior horns (left-sided p-values 0.06 and 0.59, respectively). No incident tears were detected in the body. CONCLUSION: We could not demonstrate an association between prevalent medial meniscal intrasubstance signal changes with incident tears over a 1-year period. PMID- 21553338 TI - The aetiology behind torticollis and variable spine defects in patients with Mullerian duct/renal aplasia-cervicothoracic somite dysplasia syndrome: 3D CT scan analysis. AB - The aim of the article is fourfold; firstly, to detect the aetiology of torticollis in patients with Mullerian duct/renal aplasia-cervicothoracic somite dysplasia syndrome; secondly, spine pathology in Mullerian duct/renal aplasia cervicothoracic somite dysplasia syndrome varies considerably from one patient to another and there are remarkable differences in severity and localization; thirdly, mismanagement of congenital spine pathology is a frequent cause of morbid/fatal outcome; and fourthly, the application of prophylactic surgical treatment to balance the growth of the spine at an early stage is mandatory. Reformatted CT scans helped in exploring the craniocervical and the entire spine in these patients. The reason behind torticollis ranged between aplasia of the posterior arch of the atlas, assimilation of the atlas and extensive fusion of the lower cervical vertebrae (bilateral failure of segmentation) in four patients; in one patient, in addition to the hypoplastic posterior arch of the atlas, we observed ossification of the anterior and the posterior longitudinal spinal ligaments giving rise to a block vertebrae-like suggestive of early senile ankylosing vertebral hyperostosis (Forestier disease). Scoliosis at different spine levels was attributable to variable spine defects. Pelvic ultrasound showed the classical renal agenesis in four patients; whereas in one patient, the MRI showed pelvic cake kidney (renal fused ectopia) associated with ovarian, uterine and vaginal abnormalities. This is the first exploratory study on the craniocervical and the entire spine in a group of patients with MURCS association. PMID- 21553339 TI - Dual pathology as a result of spinal stenosis and vitamin B12 deficiency. AB - Vitamin B12 deficiency can confound the clinical assessment of patients presenting with features of spinal disorders. Speciality practice within spinal surgery may lead the clinician to a focus upon spinal explanations for symptoms and that belief may be reinforced by supporting imaging. In the presence of mainly sensory symptoms consideration and exclusion of non surgical causes needs to occur. This study aimed at identifying the prevalence of vitamin B12 deficiency; the presence of dual pathology on imaging performed; the implementation of replacement therapy and their subsequent clinical response as perceived by patients. This was performed through a retrospective review of patients presenting to specialist spine out-patient clinics over a 4-year period via access to pathology reports followed by a telephone survey. 457 patients were investigated of which 8.5% were vitamin B12 deficient. 70% of patients had repeat levels and 31% continued to be deficient. 26% of these patients were not placed on any supplemental therapy. 72% of patients on treatment had self perceived improved outcomes as compared with 55% not on treatment. 73% of patients underwent MRI/CT imaging. 59% of which had evidence of spinal stenosis. In older patients with sensory symptoms, the coexistence of B12 deficiency should be considered. Detection of deficiency with consequent treatment results in better global outcomes than no treatment. Unless the correct blood test is done, the pathology will remain undetected, and patients may continue with their primary symptoms despite high-risk spinal surgical procedures. PMID- 21553340 TI - One-compartmental biometric blood loss calculation after cesarean section. AB - Blood loss during cesarean section was calculated based on post-operative decrement of hemoglobin (Hb) and hematocrit (Hct) level. The model used for pregnant women was previously validated for non-pregnant women who underwent gynecological surgery. 1,068 pregnant women who underwent cesarean section and 517 women who underwent gynecological surgery were included in the study. Regression lines between collected (x) and calculated (y) blood loss in pregnant women (y = 0.164 + 0.602x) and non-pregnant (y = 0.255 + 0.750x) women were statistically parallel. This study confirmed the applicability of one compartmental model based on the drop in Hb levels for blood loss calculations for both gynecological surgery and cesarean section. Improved methods for calculating blood loss, V after cesarean section as V = [0.0115 * body weight (kg) * ln (preoperative Hb/postoperative Hb)] + [0.1905 * height3 (m) * ln (preoperative Hb/postoperative Hb)] + 0.3158 and after gynecological surgery V = [0.004 * body weight (kg) * ln (preoperative Hb/postoperative Hb)] + [0.4624 * height 3(m) * ln (preoperative Hb/postoperative Hb)] + 0.0472 were suggested. PMID- 21553342 TI - Preserved interhemispheric functional connectivity in a case of corpus callosum agenesis. PMID- 21553341 TI - Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity. AB - In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the head-group, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC). Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the head-group. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phase-transition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed. PMID- 21553343 TI - Study of the differentially expressed genes in pleomorphic adenoma using cDNA microarrays. AB - Recent studies have determined that gene expression profiling using microarray technology can be used to identify tumor-related molecules. The objective of this study was to screen the differentially expressed genes between pleomorphic adenoma (PA) and the normal tissue adjacent to PA using cDNA microarrays and to further validate the differentially expressed genes by real-time PCR. In this study, we selected five pairs of PA and the surrounding normal salivary gland tissues. The total RNA was isolated from tumor and normal tissues and purified to mRNA. The mRNA was reverse-transcribed to cDNA with the incorporation of fluorescent-labeled dUTP to prepare the hybridization probes. The mixed probes were hybridized to Whole Human Gene Expression Microarrays by Agilent. Tumor related genes were screened by analyzing the fluorescence intensity. As a result, a total of 447 genes were found to be differentially expressed between PA and normal tissue adjacent to PA. Among them, 185 genes were up-regulated and 262 genes were down-regulated in PA. By constructing a network from the differentially expressed genes, some genes, such as Gli2 and CTNNB1, were identified as being at the core of the network. In addition, differential gene expression was validated for 2 up-regulated genes, Gli2 and LOX, using real-time PCR and the results were consistent with those of the cDNA microarray analysis thus verifying the credibility of the microarray data. Therefore, our microarray data may provide clues for finding novel genes involved in the development of PA, and shed light on finding new targets for diagnosis and therapy of PA. Further characterization of these differentially expressed genes will be useful in understanding the genetic basis for PA. PMID- 21553344 TI - Anatomical single bundle anterior cruciate ligament reconstruction. AB - We present a review of the literature looking at the anatomy of the Anterior Cruciate Ligament, the biomechanical aspects of ACL reconstruction, review the outcomes of single and double bundle ACL reconstruction and present the current techniques for anatomic single bundle reconstruction. PMID- 21553345 TI - Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells. AB - Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 MUM:17.5 MUM or 17.5 MUM:10 MUM was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5 fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity. PMID- 21553346 TI - Effects of a parenting intervention on features of psychopathy in children. AB - This study examined whether Project Support, a parenting intervention shown to reduce child conduct problems, also exerts positive effects on features of psychopathy in children. Participants were 66 families (mothers and children) recruited from domestic violence shelters who participated in a randomized controlled trial evaluating Project Support. Each family included at least one child between the ages of 4 and 9 who was exhibiting clinical levels of conduct problems. Families were randomly assigned to the Project Support intervention condition or to an existing services comparison condition, and they were assessed on 6 occasions over 20 months, following their departure from the shelter. Children in families in the Project Support condition, compared with those in the comparison condition, exhibited greater reductions in features of psychopathy. Moreover, the changes in features of psychopathy remained after accounting for changes in conduct problems. Project Support's effects on features of psychopathy were mediated by improvements in mothers' harsh and inconsistent parenting. These findings on the effects of an intervention on features of psychopathy are the first from a randomized controlled trial. They inform the debate about whether features of psychopathy in children are responsive to intervention, and hold important implications for clinical practice. PMID- 21553347 TI - Activated immune cells in Parkinson's disease. AB - Recently, an interaction between neurodegenerative processes and the innate and adaptive immune responses has been increasingly recognized. Activation of microglia, infiltration of peripheral T lymphocytes, and T-cell interaction with microglia may strongly affect the progression of Parkinson's disease (PD) both in patients and in animal models of the disease. Here, we summarize the current knowledge regarding the role of microglia in the progression of PD. The plasticity of the microglial response is also discussed in the context of PD. In addition, we also focus on the influence of several peripheral T-cell subsets on PD progression as well as on possible pathways by which they might act. This review should help increase our understanding of the effects of innate and adaptive immune cells in the pathogenesis of PD. PMID- 21553348 TI - The unique characteristics and management of patients over 60 years of age with classic Hodgkin lymphoma. AB - In recent decades, the prognosis of Hodgkin lymphoma has been substantially improved, but these successes have been restricted to younger patients and could not be translated into a major benefit for older patients, especially those with advanced-stage disease. Major problems in treating older patients include a different biology, frailty, comorbidities, and poorer tolerance of therapy. Additionally, these patients are often excluded from randomized trials, so an evidence-based standard of care is lacking. Importantly, the proportion of older patients with HL will increase over the next 50 years. Currently, ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) is considered to be the gold standard, even though it has some toxicity in older patients and prospective data are not available. Thus, further studies are required, including the assessment of comorbidities and the incorporation of new drugs such as immunomodulatory agents, antibody-drug conjugates, mTOR inhibitors, or histone deacetylase (HDAC) inhibitors. PMID- 21553349 TI - Impaired cerebral vasoreactivity may cause cerebral blood volume dip following obstructive sleep apnea termination. PMID- 21553350 TI - Stem cell associated genes working with one miRNA cluster have different clinic pathologic values in gastric cancer. AB - Cancer stem cells are nowadays considered to be the origin of cancer. Also, stem cell associated genes are emerging as predictors of cancer malignancy. We investigated the association of several stemness genes (c-Myc, PTEN, p57 and p21) with clinic pathological parameters and survival in stomach cancer by performing immunohistochemistry on paraffin sections of gastric cancer patients who underwent surgical staging with following-up statistics. We discovered that expression of c-Myc was significantly related to distant metastasis, the combined expression of PTEN and p21 correlated positively to overall survival, while p57 was less useful in overall survival prediction in gastric cancer. Additionally, there is a positive correlation between expressions of p57 and p21. In conclusion, our present study indicated that expression of stemness genes (c-Myc, PTEN, p57 and p21) performed different predictive potential in the evaluation of clinical malignancy levels in gastric cancer. PMID- 21553351 TI - Acetyl salicylic acid treatment in neonatal Bartter syndrome. PMID- 21553352 TI - Slouching towards gene therapy for hypercholesterolemia. PMID- 21553353 TI - Adult cancer survivorship care: experiences from the LIVESTRONG centers of excellence network. AB - BACKGROUND: The objectives of this study were to characterize survivorship models of care across eight LIVESTRONG Survivorship Center of Excellence (COE) Network sites and to identify barriers and facilitators influencing survivorship care. METHODS: Using the framework of the Chronic Care Model (CCM), quantitative and qualitative methods of inquiry were conducted with the COEs. Methods included document reviews, key informant telephone interviews with 39 participants, online Assessment of Chronic Illness Care (ACIC) surveys with 40 participants, and three site visits. RESULTS: Several overarching themes emerged in qualitative interviews and were substantiated by quantitative methods. Health system factors supporting survivorship care include organization and leadership commitment and program champions at various levels of the health care team. System barriers include reimbursement issues, lack of space, and the need for leadership commitment to support changes in clinical practices as well as having program "champions" among clinical staff. Multiple models of care include separate survivorship clinics and integrated models as well as consultative models. COEs' scores on the ACIC survey showed overall "reasonable support" for survivorship care; however, the clinical information system domain was least developed. Although the ACIC findings indicated "reasonable support" for self-management, the qualitative analysis revealed that self-management support was largely limited to health promotion provided in clinic-based education and counseling sessions, with few COEs providing patients with self-management tools and interventions. CONCLUSIONS: The CCM framework captured experiences and challenges of these COEs and provided insight into the current state of survivorship care in the context of National Cancer Institute-designated comprehensive cancer centers. Findings showed that cancer patients and providers could benefit from clinical information systems that would better identify candidates for survivorship care and provide timely information. In addition, a crucial area for development is self-management support outside of clinical care. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivors may benefit from learning about the experience and challenges faced by the eight LIVESTRONG Centers of Excellence in developing programs and models for cancer survivorship care, and these findings may inform patient and caregiver efforts to seek, evaluate, and advocate for quality survivorship programs designed to meet their needs. PMID- 21553354 TI - Identification of biotransformation products of macrolide and fluoroquinolone antimicrobials in membrane bioreactor treatment by ultrahigh-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - Ultrahigh-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry was applied for the identification of transformation products (TPs) of fluoroquinolone (norfloxacin and ciprofloxacin) and macrolide (azithromycin, erythromycin, and roxitromycin) antimicrobials in wastewater effluents from a Zenon hollow-fiber membrane bioreactor (MBR). The detected TPs were thoroughly characterized using the accurate mass feature for the determination of the tentative molecular formulae and MS-MS experiments for the structural elucidation of unknowns. Several novel TPs, which have not been previously reported in the literature, were identified. The TPs of azithromycin and roxithromycin, identified in MBR effluent, were conjugate compounds, which were formed by phosphorylation of desosamine moiety. Transformation of fluoroquinolones yielded two types of products: conjugates, formed by succinylation of the piperazine ring, and smaller metabolites, formed by an oxidative break-up of piperazine moiety to form the 7-[(2-carboxymethyl)amino] group. A semi-quantitative assessment of these TPs suggested that they might have contributed significantly to the overall balance of antimicrobial residues in MBR effluents and thus to the overall removal efficiency. Determination of TPs during a period of 2 months indicated a conspicuous dynamics, which warrants further research to identify microorganisms involved and treatment conditions leading to their formation. PMID- 21553355 TI - Generation difficulty and memory for source. AB - The role of the word predictability from sentence context for reality monitoring and external source monitoring was examined in two experiments. In a reality monitoring task, discrimination of an internal source was better in the hard than in the easy condition. It is probable that extra cognitive operations engaged during word generation in the hard condition were effective cues for reality monitoring judgements. In contrast, in an external source-monitoring task (recognition memory of item's colour), the hard condition resulted in worse source memory for generated words than did the easy condition. This result is consistent both with an item-context trade-off hypothesis and a processing hypothesis. Greater effort involved at the time of generation might limit resources available for encoding of an external source. It is also possible that for generated words, the hard condition promoted conceptual processing instead of perceptual processing; therefore the item's colour was not effectively encoded. PMID- 21553356 TI - [Persisitent dysphonia and multiple vocal nodes in a female patient]. PMID- 21553357 TI - A gene polymorphism in acetyl-coenzyme A carboxylase beta may be associated with the C-reactive protein level in a prediabetic and diabetic population. AB - A recent study reported a significant association between the T-allele in intron 18 of the acetyl-coenzyme A carboxylase beta (ACACB) gene (C>T polymorphism) and nephropathy caused by diabetes mellitus (DM). Considering the involvement of chronic inflammation in the pathophysiology of DM, the present study investigated an association between the ACACB gene polymorphism and high-sensitivity C reactive protein (hsCRP) in a prediabetic and diabetic population. Anthropometric and biochemical variables including hsCRP were measured among 91 Japanese subjects (mean age: 69 years) with a hemoglobin A1c level of >=5.6% and no history of cardiovascular disease. All subjects were genotyped by an allele specific DNA assay. The subjects with the T-allele (n=32) showed significantly higher hsCRP levels than those without the T-allele (median level: 0.17 vs. 0.14 mg/dL, P<=0.05). Similarly, the hsCRP levels continued to differ significantly, independently of the other variables, between the subjects with and without the T allele after adjusting for multiple variables. The present data suggest that the ACACB gene C>T polymorphism may therefore be associated with chronic inflammation in this population. PMID- 21553358 TI - Primary hypothyroidism associated with acute mania: case series and literature review. AB - In the evaluation of patients presenting with altered mental function searching for underlying medical conditions is necessary. Abnormal thyroid function has long been implicated in mood changes with the classic associations of depression occurring together with hypothyroidism and of mania along with hyperthyroidism. We here report 3 patients who presented with symptoms consistent with acute manic episode diagnosed using DSM IV-TR criteria and who were found to have primary hypothyroidism biochemically. This led to a review of the literature on this phenomenon resulting in the identification of 10 reports of mania and associated thyroid profiles consistent with primary hypothyroidism. All 3 of our patients improved clinically after use of levothyroxine and psychotropic medications, consistent with the literature reports. This illustrates that thyroid function abnormalities including primary hypothyroidism should be considered and screened for when evaluating patients with acute manic episodes. PMID- 21553359 TI - Associations between metabolic syndrome and its components and alcohol drinking. AB - AIMS: The relationship between alcohol drinking and metabolic syndrome (MetS) and its components are not fully confirmed, we examined relationship between alcohol drinking and MetS and its components. METHODS: 2,538 Mongolian people aged 20 or more were included in this study. The data for demographic characteristics, lifestyle factors, family history of hypertension, blood pressure (BP) measurements and physical examination were obtained, and fasting plasma glucose (FPG) and lipids examined for all participants. Associations between MetS and its components and alcohol drinking were analyzed with Logistic regression. RESULTS: The risks of MetS associated with alcohol drinking and various drinking volume were not significant after adjustment for other variables. Alcohol drinking was significantly and positively associated with high BP and high TG, the multivariate adjusted OR (95% CI) of high BP and high TG for drinking were 1.399(1.109, 1.764) and 2.464(1.866, 3.252), respectively, compared with no drinking. However, drinking was inversely associated with low HDL-C, the multivariate adjusted OR (95% CI) of low HDL-C was 0.597(0.479, 0.745) for alcohol drinking compared with no drinking. CONCLUSIONS: Alcohol drinking was significantly and positively associated with high BP and high TG, while alcohol drinking inversely associated with low HDL-C. PMID- 21553360 TI - Long term clinical management of girls with Turner syndrome at a center of pediatric endocrinology. AB - AIM: To evaluate clinical management of patients with Turner syndrome in one center over a long period. METHODS: Retrospective analysis of 89 patients cared for between 1974 and 2004. Assessment of age and height at diagnosis, indications for karyotyping, induction of puberty and final height attainment. RESULTS: Average age at diagnosis was 8.21 years, with a significant decline over the observation period. Mean height SDS at diagnosis was -2.86. Main reasons for karyotyping were edema in youngest ages and growth retardation in ages older than 6 years. Puberty induction was started at a mean age of 13.93 years, with a significant decline over the observation period. Mean duration until menarche was 2.51 years. An appropriate clinical response with changes in Tanner stages was observed. Mean final height after GH therapy was 151.81 cm, height SDS for TS was increased by +1.82. CONCLUSIONS: In recent study years, Turner Syndrome is being diagnosed at younger ages and at heights closer to normal heights. The clinical spectrum warrants karyotyping at an early age. In spite of late diagnoses, puberty induction was started within a physiological age in recent years and was, just as GH therapy, successful to mimic physiological progress in most instances. PMID- 21553361 TI - "Menstrual irregularities in PCOS. Does it matter when it starts?". AB - BACKGROUND: PCOS is presented by a broad spectrum of menstrual irregularities appearing often at puberty or later on during the reproductive years in women suffering from this multifaceted syndrome. To our knowledge, there is no evidence to suggest whether the time of onset of menstrual irregularities (peri or post pubertal) indicates a differential metabolic and/or hormonal profile as well as ovarian ultrasonographic findings, in adulthood in women with PCOS. AIM OF THE STUDY: To compare anthropometric, hormonal-metabolic profile and ultrasound findings in PCOS women with peripubertal onset of menstrual disorders with the corresponding data obtained from PCOS patients with post pubertal onset of menstrual irregularities, matched for BMI and age. PATIENTS-METHODS: 89 PCOS women were evaluated cross-sectionally at the age of 25 years. In 49 subjects menstrual irregularities were present from menarche, whereas in 40 women the irregularities appeared at least 3 years post menarche. RESULTS: Anthropometric parameters were comparable between the 2 groups. The 2 groups did not differ on metabolic and hormonal profile as well as ovarian ultrasound findings. CONCLUSIONS: These data indicate that the timing of menstrual irregularities, do not appear to have an impact, on hormonal/metabolic profile and ovarian ultrasound morphology in patients diagnosed with PCOS, later in life. PMID- 21553362 TI - Novel PHEX nonsense mutation in a patient with X-linked hypophosphatemic rickets and review of current therapeutic regimens. AB - INTRODUCTION: The most common form of familial hypophosphatemic rickets is X linked. PHEX has been identified as the gene defective in this phosphate wasting disorder leading to decreased renal phosphate reabsorption, hypophosphatemia and inappropriate concentrations of 1,25-dihydroxyvitamin D in regard to hypophosphatemia. Clinical manifestation are skeletal deformities, short stature, osteomalacia, dental abscesses, bone pain, and loss of hearing. SUBJECTS AND METHODS: We report 3 cases of hypophosphatemic rickets with genetic mutational analysis of the PHEX gene. In 1 male patient an unknown nonsense mutation was found in exon 7, codon 245 (c.735T>G, Tyr245Term, Y245X). In both female patients known mutations were found: c.682delTC (exon 6, codon 228) and c.1952G>C (exon 19, codon 651, R651P). Age at diagnosis ranged from early childhood to the age of 35 years. Clinical complications were hip replacement in 1 patient, mild nephrocalcinosis in 2 patients and loss of hearing in 1 patient. All 3 patients have been treated with phosphate supplements and receive 1,25-dihydroxyvitamin D. Under this regimen all patients show stable biochemical markers with slight hyperparathyreoidism. In all patients at least one family member is affected by rickets, as well. CONCLUSIONS: We report a novel nonsense mutation of PHEX that has not been identified so far. The recent discovery of FGF23 and MEPE has changed our understanding of the kidney-bone metabolism, but also raises concerns about the efficacy of current therapeutic regimens that are reviewed in this context. PMID- 21553363 TI - Mortality after hip fracture in diabetic patients. AB - AIM: Type 2 diabetic patients have an increased incidence of hip fracture. In this study, we aimed to evaluate the mortality rate after hip fracture and determine the predictors of mortality in diabetic patients. METHODS: 356 patients who sustained a hip fracture between January 1997 and June 2008 were retrospectively reviewed for the study. Of the eligible 230 patients, 69 had type 2 diabetes. Each of these patients' medical and nursing notes were reviewed to ascertain additional information, including patient demographic factors, prior co morbidities, fracture type, length of post-fracture stay and post-operative complications, the presence and duration of diabetes, glucose levels, HbA1c levels, albumin and hemoglobin levels. RESULTS: 148 women (64.3%) and 82 men (35.7%) were included in the study. The mean age of the study group was 76.1 +/- 10.4 years. The mean age for diabetics was 76.1 +/- 12.0 years and was 75.1 +/- 9.4 years for non-diabetics ( P=0.343). Diabetic patients with hip fracture had a higher risk of mortality than the non-diabetic patients. One year survival probabilities of diabetic and non-diabetic patients were respectively 68.0% and 87.3% (p=0.033). In diabetic patients with a hip fracture, predictors of mortality were advanced age, the presence of postoperative complications and elevated HbA1c levels. CONCLUSIONS: Diabetic patients have an increased risk of mortality after hip fracture. The medical care in the post-operative period, including glycemic control and postoperative complications, should be optimized in diabetic patients suffering from hip fracture in order to decrease mortality in these patients. PMID- 21553364 TI - Anthropometric measurements for prediction of metabolic risk among Chinese adults in Pudong new area of Shanghai. AB - BACKGROUND: Numerous studies have demonstrated the ability of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) to predict the risk of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). This study aimed to evaluate the predictive value of these anthropometries for metabolic abnormalities and related diseases in Chinese adults. MATERIAL & METHODS: A cross-sectional study was conducted in 2 477 men and 3 107 women at 20-79 years old who were randomly selected from Pudong New Area of Shanghai, China, through a multistage sampling process. Anthropometric variables and blood pressure were measured according to a standardized protocol, and a fasting blood sample was collected from each subject for biochemical analysis. RESULTS: Prevalence of the metabolic syndrome was observed to increase with increasing BMI, WC, WHR and WHtR in both sexes. Participants with any metabolic abnormality had a higher body size than those without. The associations of anthropometries with each metabolic factor were significant and equal for BMI, WC, WHR and WHtR. Areas under the receiver operating characteristic curves (AUC) ranged from 0.59 to 0.72 across the 4 anthropometries in predicting individual and clusters of metabolic factors. However, none of the 4 anthropometries identified newly-diagnosed T2DM or hypertension with a high sensitivity or specificity. CONCLUSION: Our findings suggest that the independent use of BMI, WC, WHR, or WHtR may not be an effective tool to predict metabolic factors and related chronic diseases in Chinese adults. PMID- 21553365 TI - Effects of rat C-peptide-II on lipolysis and glucose consumption in cultured rat adipose tissue. AB - Existing data show that C-peptide (CP) prevents or ameliorates diabetes-related complications mainly by improving microcirculation and perhaps metabolism. Although effects of CP on muscle glucose consumption are relatively well studied, its effects on adipose tissue, a key organ involved in metabolism, are not well known. Therefore, the aim of this study was to examine the effects of CP on basal and stimulated lipolysis and glucose consumption in rat retroperitoneal (RP) adipose tissue, using an EX-VIVO organ culture setting. The RP adipose tissue was excised from adult male rats, minced and subjected to EX-VIVO culture for 24 h. The tissue fragments were then weighted and distributed into a 24-well culture plate. The wells were left untreated (basal) or treated with insulin or isoproternol (ISO, stimulated) and incubated in the absence or presence of CP, insulin or a combination of the both peptides. Levels of lipolysis and tissue glucose consumption were determined by glycerol and glucose concentrations measurement in the infranatant conditioned media collected from each well. The CP, like insulin, induced an insignificant reduction in basal lipolysis. While insulin significantly reduced the ISO-stimulated lipolysis, CP was ineffective. Tissue glucose consumption was significantly stimulated by insulin, but was not affected by CP. However, in the presence of CP, inhibitory effect on ISO stimulated lipolysis and stimulatory effect on glucose consumption of insulin were significantly diminished. Our data suggest that CP may conditionally modulate certain metabolic actions of insulin in RP adipose tissue. These modulations may contribute to fine-tuning of body metabolism under physiologic or pathologic conditions. PMID- 21553366 TI - Shwachman-Diamond syndrome and type 1 diabetes mellitus: more than a chance association? AB - Shwachman-Diamond syndrome is a rare clinical condition consisting of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. The majority of Shwachman-Diamond syndrome cases result from mutations in the Shwachman-Bodian-Diamond Syndrome gene. To date, type 1 diabetes mellitus has only been reported in 4 independent cases presenting with Shwachman-Diamond syndrome, 3 of them with molecular confirmation of the diagnosis. We describe 2 unrelated patients with clinical and molecular features typical of Shwachman Diamond syndrome and type 1 diabetes mellitus. In addition, we report the occurrence rate of type 1 diabetes mellitus in the Italian registry for Shwachman Diamond syndrome, which is low (3.23%) but increased at least 30-fold over the type 1 diabetes mellitus occurrence rate in the general population. No evidence of a direct correlation between Shwachman-Diamond syndrome and type 1 diabetes mellitus have been reported, therefore the presence of both diseases in the same patient might be a chance association, however we suggest that the defects in immune regulation of Shwachman-Diamond syndrome might play a role in the development of type 1 diabetes mellitus. PMID- 21553367 TI - The functional muscle-bone unit in obese children - altered bone structure leads to normal strength strain index. AB - Obese children have a twofold increased risk of fracture of the forearm compared to non-obese children. OBJECTIVE: To investigate bone strength and bone structure of the forearm, and the relationship between muscle and bone in obese children. METHODS: The study-group consisted of 84 (40 female) overweight children (mean (SD)) age 11.8 (3.2) years, BMI 29.0 (5.1) kg/m(2)). Bone geometry and strength were measured at the proximal radius of the non-dominant forearm (65% measurement site) by means of pQCT (XCT 2000). Bone mineral density and lean mass of the total body was determined by means of DXA (Lunar, DPXL/PED). Results were compared to reference values by calculating age (SDS(CA)) and height-age (SDS(HA)) dependent standard deviation scores (SDS). RESULTS: Cortical density, 1.11 (1.74) SDS(HA), -0.45 (1.52) SDS(CA); cortical thickness, -1.46 (1.33) SDS(HA), -1.01 (1.46) SDS(CA); cortical area, -0.42 (1.31) SDS(HA), 0.26 (1.58) SDS(CA); total bone area +2.21 (1.47) SDS(HA), 2.91 (1.80) SDS(CA), marrow area +3.12 (2.29) SDS(HA), 3.37 (2.38) SDS(CA); strength strain index +0.10 (1.10) SDS(HA), 0.95 (1.57) SDS(CA). These changes in bone structure were independent from pubertal stage. Measurements revealed correlations between muscle area and SSI (R(2)=0.67, p<0.001), and muscle mass and bone mineral content (DXA; R (2)=0.81, p<0.001). CONCLUSION: Low cortical density, normal cortical area and increased total bone area led to a normal strength strain index adjusted both for height and for age. We assume that this normal bone strength is not appropriate for the higher kinetic energy of impact in case of a fall in overweight children. PMID- 21553368 TI - The different phenotypes of polycystic ovary syndrome: no advantages for identifying women with aggravated insulin resistance or impaired lipids. AB - BACKGROUND: According to the classification of polycystic ovary syndrome (PCOS) published by the Androgen Excess Society (AES), 10 different phenotypes of the condition are possible. The question remains of whether using these phenotypes might enable us to identify women with impaired insulin resistance or an impaired lipid profile among patients with PCOS. MATERIALS AND METHODS: A prospective cohort analysis was performed of 313 women with diagnosed PCOS and 80 control individuals. The screening panel included a physical examination, weight and height measurement, ultrasonography of the ovaries, and hormone, glucose, lipid, and insulin resistance measurements. RESULTS: There were no statistically significant differences in insulin resistance parameters between the different phenotypes. There were no statistically significant differences in body mass index (BMI) in any of the groups, but BMI showed the best correlation with insulin resistance in all women with PCOS and controls. Sex hormone-binding globulin (SHBG) was inversely correlated with insulin resistance in women with PCOS and controls. High-density lipoprotein (HDL) was negatively correlated with insulin resistance, and free testosterone was positively correlated with it, only in women with PCOS. CONCLUSIONS: Using the different phenotypes described in the AES classification shows no advantages for identifying women with aggravated insulin resistance or impaired lipid profile among patients with PCOS. PMID- 21553369 TI - A rare case of duodenal atresia with apple-peel configuration of the small intestine and malrotation. PMID- 21553370 TI - Pancreatic serous cystadenoma in a child. PMID- 21553371 TI - [Arthrodesis with subsequent screw fixation in the treatment of diabetic Charcot hind- and midfoot arthropathy]. AB - BACKGROUND: Surgical reconstruction of Charcot arthropathy in diabetes is characterised by long consolidation periods and extensive osteosynthesis procedures. The different methods of osteosynthesis are difficult to compare. Studies differ in many aspects such as favourable outcome, timing of surgery, clinical features, severity and stage of the disease. Therefore uniformity and comparability of the studies is not given. An evidence-based therapy algorithm for the surgical reconstruction of Charcot feet does not exist. PATIENTS AND METHODS: A retrospective study of twelve patients with 13 affected feet who had undergone arthrodesis of the foot to treat Charcot deformity was performed. All surgical procedures were performed at Eichenholtz stage 3. Six patients showed an ulcer of the foot at the time of surgery, six patients were without pedal ulceration. Screw fixation was used for reconstruction and bone grafting was performed in all patients. Radiographic measurements were recorded preoperatively, immediately postoperatively, 3 months postoperatively and at the time of the last follow-up. Patients were evaluated clinically and radiographically at an average of 2.4 years. RESULTS: Complete osseous union was achieved in ten patients at an average of 4.3 months. There was one patient with a postoperative infection and an internal amputation, one patient with an unstable non-union, with recurrence of deformity. All pedal ulcers healed during the period of the osseous consolidation. All patients returned to an ambulatory status within 7 months. CONCLUSIONS: Open reduction and arthrodesis with the use of screw fixation alone for the surgical correction of Charcot arthropathy provide a good result compared to other fixation methods. PMID- 21553372 TI - [Total elbow arthroplasty as a treatment option in complex injuries of the elbow in elderly patients]. AB - AIM: The aim of this study was to evaluate the functional outcome of patients with severe elbow injuries treated by primary and secondary implantation of an elbow prosthesis using two different functional scores. METHOD: To determine whether or not total elbow replacement is an acceptable treatment option in such cases, we analysed the functional outcome of patients after primary or secondary implantation of the semi-constrained Coonrad-Morrey prosthesis. Between March 2005 and September 2009 we implanted 25 Coonrad-Morrey prostheses in 24 patients with acute or chronic elbow injuries. Eight patients had complex type C3 fractures according to the AO classification and were treated with primary implantation. 16 patients received a secondary implantation including 3 chronic luxations, 3 non-unions of the bone, 3 failed osteosyntheses, 7 patients with post-traumatic arthrosis and 1 reimplantation. The mean follow-up after the operation was 12 (+/- 8) months. The functional outcome was measured by assembling the "Mayo elbow prosthesis score" and the "Mayo elbow performance score". We had 15 female and 9 male patients with a mean age of 67 (+/- 6) years. RESULTS: All 24 patients achieved very good results based on the used scores with a mean of 97 points each with a maximum performance of 100 points. The mean range of motion concerning extension and flexion was 92 degrees (range 55 to 115 degrees), concerning pronation and supination 144 degrees (range 100 to 160 degrees). The mean flexion deformity was 19 degrees (range 10 to 50 degrees), the mean maximum flexion was 112 degrees (range 90 to 130 degrees). During the follow up we had two partial ruptures of the triceps tendon, one temporary lesion of the ulnar nerve with complete recovery after surgical revision and one postoperative haematoma which needed surgical treatment. One patient needed revision surgery and resection arthroplasty due to a deep infection, but received a new prosthesis after two months. We recorded no radiographic loosening or other mechanical problems. CONCLUSIONS: Due to the good functional outcome and pain relief of patients treated by total elbow replacement, we suggest that total elbow arthroplasty is a reasonable treatment option for complex acute and chronic injuries of the elbow in elderly patients. PMID- 21553373 TI - [Taking the objectives of the law seriously!]. PMID- 21553374 TI - [A new treatment model for psychoses in Havelland]. PMID- 21553377 TI - [Outpatient psychiatric institute care in Germany - challenges and prospects]. PMID- 21553379 TI - Identification and functional analysis of novel genes expressed in the Anterior Visceral Endoderm. AB - During early vertebrate development, the correct establishment of the body axes is critical. The anterior pole of the mouse embryo is established when Distal Visceral Endoderm (DVE) cells migrate to form the Anterior Visceral Endoderm (AVE). Symmetrical expression of Lefty1, Cer1 and Dkk1 determines the direction of DVE migration and the future anterior side. In addition to the establishment of the Anterior-Posterior axis, the AVE has also been implicated in anterior neural specification. To better understand the role of the AVE in these processes, we have performed a differential screening using Affymetrix GeneChip technology with AVE cells isolated from cer1P-EGFP transgenic mouse embryos. We found 175 genes which were upregulated in the AVE and 36 genes in the Proximal posterior sample. Using DAVID software, we characterized the AVE cell population regarding cellular component, molecular function and biological processes. Among the genes that were found to be upregulated in the AVE, several novel genes were identified. Four of these transcripts displaying high-fold change in the AVE were further characterized by in situ hybridization in early stages of development in order to validate the screening. From those four selected genes, one, denominated Adtk1, was chosen to be functionally characterized by targeted inactivation in ES cells. Adtk1 encodes for a serine/threonine kinase. Adtk1 null mutants are smaller and present short limbs due to decreased mineralization, suggesting a potential role in chondrogenesis during limb development. Taken together, these data point to the importance of reporting novel genes present in the AVE. PMID- 21553380 TI - Cell-based cardiovascular repair and regeneration in acute myocardial infarction and chronic ischemic cardiomyopathy-current status and future developments. AB - Ischemic heart disease is the main cause of death and morbidity in most industrialized countries. Stem- and progenitor cell-based treatment approaches for ischemic heart disease are therefore an important frontier in cardiovascular and regenerative medicine. Experimental studies have shown that bone-marrow derived stem cells and endothelial progenitor cells can improve cardiac function after myocardial infarction, clinical phase I and II studies were rapidly initiated to translate this concept into the clinical setting. However, as of now the effects of stem/progenitor cell administration on cardiac function in the clinical setting have not met expectations. Thus, a better understanding of causes of the current limitations of cell-based therapies is urgently required. Importantly, the number and function of endothelial progenitor cells is reduced in patients with cardiovascular risk factors and/or coronary artery disease. These observations may provide opportunities for an optimization of cell-based treatment approaches. This review provides a summary of current evidence for the role and potential of stem and progenitor cells in the pathophysiology and treatment of ischemic heart disease, including the properties, and repair and regenerative capacities of various stem and progenitor cell populations. In addition, we describe modes of stem/progenitor cell delivery, modulation of their homing as well as potential approaches to "prime" stem/progenitor cells for cardiovascular cell-based therapies. PMID- 21553381 TI - Characterization and expression pattern analysis of the facilitative glucose transporter 10 gene (slc2a10) in Danio rerio. AB - The SLC2A10 gene located on chromosome 20q13.1 encodes the facilitative glucose transporter 10 (GLUT10), a class III member of the SLC2A facilitative glucose transporter family. Mutations in the human SLC2A10 gene cause arterial tortuosity syndrome (ATS), a rare autosomal recessive connective tissue disorder. In this work, we report the characterization of the slc2a10 ortholog gene in zebrafish (Danio rerio) and its expression pattern during embryonic development and in adult tissues. The slc2a10 gene consists of 5 exons, spanning 8 kb and mapping to a region on chromosome 11 that exhibits conserved synteny with human chromosome 20. The gene encodes Glut10, a 513 amino acid protein that maintains the 12 transmembrane domain structure typical of the GLUTs family, and shares the specific functional motifs involved in sugar transport with the vertebrate GLUT10. RT-PCR analysis showed that two specific splice variants, both including the 5'-UTR region, were expressed during embryogenesis and in different adult zebrafish tissues and organs. In situ hybridization analyses demonstrated a maternal origin of the total slc2a10 mRNA and its ubiquitous distribution until the early somitogenesis stage. In later embryonic stages, slc2a10 mRNA was detected in the otic vesicles, hatching gland cells, pectoral fin, posterior tectum and swim bladder. Overall, these results suggest a wide role of slc2a10 during zebrafish development. PMID- 21553382 TI - Limited inner ear morphogenesis and neurosensory development are possible in the absence of GATA3. AB - Haploinsufficiency of Gata3 causes hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome in mice and humans. Gata3 null mutation leads to early lethality around embryonic day (E)11.5, but catecholamine precursor administration can rescue Gata3 null mutants to E16.5. At E11.5, GATA3 deficiency results in the development of an empty otocyst with an endolymphatic duct. However, using rescued mice we found that some morphogenesis and neurosensory development is possible in the ear without Gata3. Extending previous studies, we find that at E16.5, Gata3 mutant inner ears can undergo partial morphogenesis and develop an endolymphatic duct, a utricular and saccular recess, and a shortened cochlear duct. In addition to the obvious morphogenic aberrations, these studies demonstrate that a subset of neurons develop and connect a fragmented sensory patch of MYO7A-positive hair cells to the vestibular nuclei of the brainstem. In situ hybridization studies reveal altered expression of several transcription factors relevant to ear development and we hypothesize that this may relate to the observed dysmorphia and restricted neurosensory development. While a cochlear duct can form, there is no concurrent cochlear neurosensory development, observations consistent with specific hearing defects encountered by HDR patients and mice with Gata3-associated expression alterations. Gata3 null mutant phenocopies the otic maldevelopment (cochlear duct formation in the absence of neurosensory development) seen in Foxg1cre mediated conditional deletion of microRNA processing enzyme, Dicer1. Finally, while GATA3 is expressed in the developing vestibulo-cochlear efferent (VCE) neurons, and its absence in the null mutants disrupts VCE projections to the ear, loss of GATA3 does not affect VCE progenitor cell migration. PMID- 21553383 TI - Visualization, characterization and modulation of calcium signaling during the development of slow muscle cells in intact zebrafish embryos. AB - Intact zebrafish embryos were used as an in vivo animal model to investigate the role of Ca2+ signaling during the differentiation of slow muscle cells (SMCs) within forming skeletal muscle. Transgenic zebrafish were generated using an a actin promoter that targeted apoaequorin expression specifically to muscle cells. Two distinct Ca2+ signaling periods (CSPs) were visualized in the developing SMCs: between ~17.5-19.5 hours post-fertilization (hpf) and after ~23 hpf, separated by a ~3.5 h Ca2+ signaling quiet period. Further spatial characterization of these Ca2+ signals using confocal fluorescent microscopy and calcium green-1 dextran as a reporter, indicated that the earlier CSP displayed distinct nuclear and cytoplasmic components, whereas the later CSP was predominantly cytoplasmic. Both CSPs consisted of a series of oscillating Ca2+ waves generated at distinct frequencies, while the earlier CSP also displayed a slow rise then fall in the Ca2+ baseline-level. Imaging of cyclopamine- and forskolin-treated wild-type, or smo-/- mutant embryos, where SMCs do not form, confirmed the specific cell population generating the signals. Treating embryos with antagonists indicated that both IP3Rs and RyRs are responsible for generating the temporal characteristics of the Ca2+ signaling signature, and that the latter plays a necessary role in SMC differentiation and subsequent myotome patterning. Together, these data support and extend the proposition that specific spatiotemporal patterns of spontaneous Ca2+ signals might be used for different as well as combinatorial regulation of both nuclear and cytosolic signal transduction cascades, resulting in myofibrillogenesis in SMCs as well as myotome patterning. PMID- 21553384 TI - Multi-probe in situ hybridization to whole mount Arabidopsis seedlings. AB - In situ RNA-RNA hybridization (ISH) is a molecular method for localization of gene transcripts at the cellular level and is widely used to provide spatial and temporal information regarding gene expression. However, standard protocols are complex and laborious to implement, restricting analysis to one or a few genes at any one time, each one observed on separate ISH preparations. Multi-probe whole mount in situ hybridization is a powerful technique to compare the expression patterns of two or more genes simultaneously in the same tissue or organ. We describe for the first time in plants, the detection of three different mRNAs in a single fixed whole mount Arabidopsis seedling. A combination of bright fluorescent secondary antibodies was used for the detection of riboprobes differentially labeled by digoxigenin, biotin and fluorescein. The 3-D detection of each of the multiple fluorescent hybridization signals or in combination was obtained through confocal laser-scanning microscopy. The reliability of the method was tested in the root, using the PINFORMED (PIN) genes with non overlapping temporal and spatial expression patterns. In the shoot, a class-I KNOTTED -like homeobox gene from Arabidopsis (KNAT1) with expression restricted to the shoot apical meristem was used in combination with ELONGATOR3 (ELO3) gene. In addition, the expression patterns of ELONGATOR complex gene (ELO2, ELO3) and HISTONE MONOUBIQUITINATION1 (HUB1) genes were analyzed in both shoot and root and a partial overlapping was observed. The whole procedure takes only 6 days. PMID- 21553385 TI - Identification of side population cells in mouse primordial germ cells and prenatal testis. AB - In mammals, the stem cells of spermatogenesis are derived from an embryonic cell population called primordial germ cells (PGCs). Spermatogonial stem cells displaying the "side population" (SP) phenotype have been identified in the immature and adult mouse testis, but noting is known about the expression of the SP phenotype during prenatal development of germ cells. The SP phenotype, defined as the ability of cells to efflux fluorescent dyes such as Hoechst, is common to several stem/progenitor cell types. In the present study, we analyzed and characterized the Hoechst SP via cytofluorimetric analysis of disaggregated gonads at different time points during embryonic development in mice. To directly test the hypothesis that the SP phenotype is a feature of germ cell lineage, experiments were performed on transgenic animals expressing enhanced green fluorescent protein (EGFP) under the control of the Oct4 promoter, to identify early germ cells up to PGCs. We found that prenatal gonads contain a fraction of SP cells at each stage analyzed, and the percentage of cells in the SP fraction decreases as development proceeds. Surprisingly, more than 50% of the PGCs displayed the SP phenotype at 11.5 dpc (days post coitum). The percentage of germ cells with the SP phenotype decreased steadily with development, to less than 1% at 18.5 dpc. Cytofluorimetric analysis along with immunocytochemistry performed on sorted cells indicated that the SP fraction of prenatal gonads, as in the adult testis, was heterogeneous, being composed of both somatic and germ cells. Both cell types expressed the ABC transporters Abcg2, Abcb1a, Abcb1b and Abcc1. These findings provide evidence that the SP phenotype is a common feature of PGCs and identifies a subpopulation of fetal testis cells including prospermatogonia whose differentiation fate remains to be investigated. PMID- 21553386 TI - [Reconstructive urethroplasty using porcine acellular matrix (SIS): evolution of the grafting technique and results of 10-year experience]. AB - INTRODUCTION: Long tract urethral reconstruction still has no other resolution than two-stage techniques or graft and flap procedures, that are neither simple nor trouble-free. Tissue engineering simplifies this surgery using porcine acellular matrix, obtained from small intestine submucosa (SIS): thin but strong, ready for grafting, it is not immunogenic, being deprived of cells. It is a biological bridge for reconstruction, promoting the regeneration of surrounding tissue. We report our experience using SIS for urethroplasty. MATERIALS AND METHODS: After coronal or perineal-scrotal incision and penile degloving, the urethra is rotated of 180 degrees and opened through the entire restricted tract. The graft is sutured dorsally and reinforced by the contact with the cavernous bodies to prevent pouching. From 1999 to 2005 we performed this grafting procedure in 36 men and 4 women. Afterwards, 16 more surgeries performed were with direct ventral graft procedure, without urethra isolation and rotation, with worthy simplification. RESULTS: A 10-year follow-up shows satisfactory urodynamic and subjective outcomes for both procedures, assessed by voiding urethrography, uroflowmetry, International Prostate Symptom Score, and Quality of Life perception. At urethroscopy the graft appears completely homogeneous to the native tissue, as confirmed by the histological examination. The ventral direct graft represents the more consistent innovation: we did not observe pouching and the results remained effective. For penile urethra, in a few patients, periodic dilatations were necessary. CONCLUSIONS: SIS can be considered as an alternative to more difficult grafting procedures, which are probably no more indispensable in urethral enlargement, even for critical strictures PMID- 21553387 TI - [Urinary incontinence after radical prostatectomy. Neurophysiological and urodynamic diagnosis]. AB - OBJECTIVES: Urinary incontinence after radical prostatectomy presents different clinical features. We propose to clarify the etiology and the therapeutic approaches. METHODS: 51 patients with urinary incontinence after radical prostatectomy underwent urodynamics, perineal EMG, perineal EMG frequency analysis and study of computerized sensory pudendal somatosensory evoked potentials. RESULTS: 18 patients (35%) were suffering from urinary incontinence secondary to overactive bladder, 14 patients (28%) had both an overactive bladder and a sphincter failure associated with Wallerian degenerative axonal neuropathy or segmental demyelination, 3 patients (6%) showed no significant urodynamics alterations but had signs of an incompetent sphincter neurapraxia, while 16 patients (31%) had urinary incontinence secondary to a degenerative neuropathy. CONCLUSIONS: Urinary incontinence after radical prostatectomy shows an etiologic diversification and therefore requires different therapeutic approaches PMID- 21553388 TI - [Reorganizing the management of specialist uro-andrologic ultrasound health-care service: impact on professional quality]. AB - INTRODUCTION: The process of organizing a ultrasound service nowadays can be improved by properly managing the user's request, the speed of response and safety, the standardization of methods and skills. MATERIALS AND METHODS: The outpatients at our uro-andrologic ultrasound clinic (O.U. of Urology in Ferrara) received a questionnaire each; we administered a total of 640 questionnaires. The number of questionnaires collected was 532. Patients were asked to give an assessment of services using a qualitative method according to a 4-parameter response scale: very satisfied, satisfied, dissatisfied, very dissatisfied. RESULTS: The identification of indicators to be monitored by the user's perceived quality was accomplished by establishing the correlation coefficient between different parameters of analysis and an overall rating of the sample. Some of these parameters were: the relationship with the practitioner, the availability of doctors, the ability of doctors for reassurance, the completeness of information and facilities hygiene conditions. When these parameters vary, positively or negatively, also the citizen's overall opinion changes. CONCLUSIONS: The customer satisfaction is an important component of the quality of care, it represents both an indicator of the effectiveness of health intervention and the ability to meet quality requirements of the health service organization. The objective of an ultrasound service should be to provide, within a reasonable timeframe, the supply of high quality with qualified personnel, with adequate tools and procedures. PMID- 21553389 TI - [2,8-dihydroxyadenine urolithiasis: case report and literature review]. AB - INTRODUCTION: 2,8-Dihydroxyadenine (DHA) urolithiasis is a rare type of urinary stone disease secondary to deficiency of adenine phosphoribosyltransferase (APRT) activity, a rare, inherited autosomal recessive disease with an incidental rate from 0.4 to 1.2%. The prevalence is higher among Japanese than other ethnic groups. APRT normally catalyzes the conversion of adenine to adenosine monophosphate and its deficiency results in 2,8-dihydroxyadenine (2,8-DHA) accumulation. This compound is extremely insoluble and its crystallization can lead to stone formation and renal failure. We report the case of 2,8 dihydroxyadenine (DHA) urolithiasis in a 52-year-old male patient. MATERIAL AND METHODS: In December 2008 a 52-year-old Caucasian man was admitted to our hospital with sudden pain in the left lumbar region. Abdominal X-ray did not show any radiopaque urinary stone. I.V. pielography showed a radiolucent left lumbar ureteral (0.6 mm) and renal (1.5 cm) stone. After therapy with tamsulosin, the ureteral stone was excreted. Successful ESWL treatment was performed for renal stone. He presented a clinical history of several episodes of bilateral renal colic and two prior ESWL treatment for radiolucent stones. Chemolitholysis was never successful. RESULTS. Stone analysis by infrared spectroscopy and microscopic examination of urine reveal typical 2,8-DHA crystals. APRT deficiency was detected in the hemolysate of erythrocyte. Partial deficiency of APRT in the patient's relatives showed heterozygosity of the enzyme defect. Allopurinol therapy successfully prevented further stone formation. 20 months later the patient remains stone free. CONCLUSION: Two types of deficit are commonly distinguished, depending on the level of residual APRT activity. Type I is complete enzyme deficiency. Type II shows residual activity in cell lysates, but enzyme activity is not demonstrable in intact cells. About 78% of the Japanese patients belong to type II. The diagnosis of the disease is based on stone analysis by infrared spectroscopy or microscopic examination of urine, which may reveal typical 2,8-DHA crystals. Molecular approach can identify mutations, which are responsible of this inherited disease. Excessive water intake, restriction of foods with high adenine contents and administration of allopurinol are useful treatments. APRT deficiency is a rare disease but we can consider this pathology in case of recurrent radiolucent stones after chemolitolysis. PMID- 21553390 TI - [Alternative tests to PSA for prostate cancer diagnosis]. AB - Prostate specific antigen (PSA) is still the most useful tool to select the population requiring prostatebiopsy. The main downsides of PSA are an inadequate sensitivity to be used in screening and a low specificity for cancer detection. So far, a limited value for PSA derivates (velocity, density, free, proisoforms and doubling time) has been recognised. We present a short review of the literature describing a selection of the most promising alternatives to PSA being studied currently: PCA3, serum kallikreins, serum detectable prostate specific membrane antigen, the nuclear matrix protein EPCA, EPCA-2, prostatic acid phosphatase, urine detectable GSTP1, anti-AMACR antibodies, sarcosine, plasminogen activating urokinase, IGFBP, TGF beta 1,PSP94, IL6, plasmatic DNA, serum autoantibodies, neuroendocrine markers, proteomic analysis. PMID- 21553391 TI - Ultrasound-guided central venous cannulation in infants weighing less than 5 kilograms. AB - PURPOSE: Recent reports suggest that ultrasound-guided central venous cannulation may also be safe and effective in infants. This study aimed to evaluate the success and complications rate of this technique in infants weighing less than 5 kg. METHODS: We studied 45 infants, weighing less than 5 kg (mean weight: 2.9 +/- 1.1 kg, median: 3.1) needing a central venous access for intensive care treatment. In all patients, venous access was obtained by ultrasound-guided cannulation of the internal jugular vein (IJV). RESULTS: Central venous cannulation was successful in all 45 infants. The right internal jugular vein (IJV) was used in most cases (92%). The IJV was antero-lateral to the carotid artery in 66% of patients, lateral in 28% and anterior in 6%. Although we recorded 10 complications (22.2%), only one was clinically relevant (one pneumothorax). The other complications were repeated venipunctures (n=4), kinking of the guidewire (n=3) and local venous hematomas (n=2). The time required for completing the procedure was 7 +/- 4.3 min, while the mean time of central venous catheter permanence was 5.5 +/- 8 days. There was a negative correlation between the patient's weight and the time needed for cannulation (p<0.01). Complications occurred in infants with a lower body weight (p<0.01). CONCLUSIONS: Our experience suggests that ultrasound-guided central vein cannulation can be performed by well-trained physicians in infants weighing less than 5 kg without relevant risks. PMID- 21553392 TI - Corneal clarity restoration after Descemet stripping automated endothelial keratoplasty with edematous corneal graft. AB - PURPOSE: To report a case of a patient who underwent Descemet stripping automated endothelial keratoplasty (DSAEK) with implantation of a precut edematous corneal graft, and restored corneal clarity 3 months postoperatively. METHODS: Case report. RESULTS: A 54-year-old woman underwent DSAEK due to Fuchs endothelial dystrophy. An edematous appearance of the donor graft was unveiled upon graft preparation but the surgeon decided not to abort the procedure. The severity of graft opacity was not unveiled until implantation. During the first 2 postoperative months recipient cornea and graft continued to appear edematous. After the first 3 postoperative months the patient's cornea had restored its clarity with corrected distance visual acuity (CDVA) of 20/63. No residual graft edema was observed while 9 months postoperatively CDVA was improved to 20/32. CONCLUSIONS: Corneal clarity in a post-DSAEK patient with implantation of edematous graft could be restored after the first 3 postoperative months. PMID- 21553393 TI - Cellular fura-2 manganese extraction assay (CFMEA). AB - Cellular manganese (Mn) uptake and transport dynamics can be measured using a cellular fura-2 manganese extraction assay (CFMEA). The assay described here uses immortalized murine striatal cell line and primary cortical astrocytes, but the method is equally adaptable to other cultured mammalian cells. An ultrasensitive fluorescent nucleic acid stain for quantification of double-stranded DNA (dsDNA) in solution, Quant-iT PicoGreen, has been utilized for normalization of Mn concentration in the cultured cells, following Mn (II) chloride (MnCl(2)) exposure. Depending on the cell type and density, other methods, e.g., protein determination assays or cell counts, may also be used for normalization. Methods are described for rapidly stopping Mn uptake and transport processes at specified times, extraction, and quantification of cellular Mn content, and normalization of Mn levels to dsDNA concentration. PMID- 21553394 TI - Fluorescence correlation spectroscopy: detecting and interpreting the mobility of transmembrane proteins in vivo. AB - Mobility of proteins is crucial for their functionality. Fluorescence correlation spectroscopy (FCS) is a sensitive tool for assessing dynamics in vivo. It can reveal properties of diffusing proteins, as well as of the surrounding medium. Hence, subtle changes in the dynamics after treatment with toxic substances can be visualized. On biological membranes, the high concentration of transmembrane and peripheral membrane proteins leads to molecular crowding, and thus to a change in the diffusion behavior, i.e., to anomalous diffusion of membrane proteins. Presented here is a protocol for conducting and evaluating FCS measurements of membrane proteins before and after treatment. PMID- 21553395 TI - High-throughput assays for assessing mitochondrial dysfunction caused by compounds that impair mtDNA-encoded protein levels in eukaryotic cells. AB - Compounds that impair the synthesis of either mitochondrial DNA (mtNDA) or mtDNA encoded proteins reduce the levels of 13 proteins essential for oxidative phosphorylation, leading to a decrease in mitochondrial ATP production. Toxicity caused by these compounds is seldom identified in 24 to 72 hr cytotoxicity assays due to the low turnover rates of both mtDNA and mtDNA-encoded proteins. Here, we describe three high-throughput screening assays that detect compounds that affect mtDNA-encoded protein levels. All three assays measure the levels of two proteins, one a mtDNA-encoded protein synthesized on mitochondrial ribosomes and the other, a nuclear DNA-encoded protein synthesized on cytosolic ribosomes. The first assay measures the levels of these two proteins by quantitative image analysis and requires a high-content imaging system. The second assay is an in cell immunoassay that utilizes infrared dyes for detection of the two proteins and, thus, requires a LI-COR Odyssey system. The third assay is an in-cell immunoassay that utilizes colorimetric detection of the two proteins and requires an absorbance microplate reader. PMID- 21553397 TI - [Good care at the heart of patients' rights]. PMID- 21553396 TI - Aldehyde reduction by cytochrome P450. AB - This protocol describes the procedure for measuring the relative rates of metabolism of the alpha,beta-unsaturated aldehydes 9-anthracene aldehyde (9-AA) and 4-hydroxy-trans-2-nonenal (4-HNE). More specifically, these assays measure the aldehyde reduction reactions of cytochrome P450s (CYPs). They can be performed using liver microsomal or other tissue fractions, spherosome preparations of recombinant CYPs, or recombinant CYPs from other sources. The method for reduction of 9-AA (a model alpha,beta-unsaturated aldehyde) by CYPs was adapted from an assay for 9-anthracene oxidation published by Marini et al. (2003). For reduction of the endogenous aldehyde 4-HNE, the substrate was incubated with CYP in the presence of oxygen and NADPH, and the metabolites were separated by HPLC, using an adaptation of the method by Srivastava et al. (2010). For both 9-AA and 4-HNE, the first step involves incubation of the substrate with the CYP in an appropriate medium. This is followed by quantification of metabolites through by spectrofluorometry (9-AA) or HPLC coupled with a radiometric assay (4-HNE). Metabolite identification can be achieved by HPLC GC/MS analysis. Inhibitors of cytochrome P450 can be utilized to show the role of the hemoprotein or other enzymes in these reduction reactions. The reduction of CYPs is not inhibited by either anaerobiosis or inclusion of CO in the gaseous phase of the reaction mixture. These characteristics are similar to those reported for some cytochrome P450-catalyzed azo reduction reactions. PMID- 21553398 TI - [Campaign against resistance to antimicrobial drugs]. PMID- 21553399 TI - National survey of drinking and driving attitudes and behaviors: 2008. PMID- 21553400 TI - Understanding patient compliance and persistence with osteoporosis therapy. AB - Chronic non-terminal diseases, including postmenopausal osteoporosis, are associated with poor treatment compliance and persistence. The longer a patient with osteoporosis complies and persists with treatment, the lower the risk of fracture. Retrospective studies with emphasis on real-world data have led to a greater understanding of the factors affecting medication compliance and persistence, and their association with improved treatment outcomes. However, these data do not contain information about patient choices of medication or patient commitment to particular medication regimens. Patient preferences can affect compliance and persistence behaviours. While recent evidence questions the importance of dosing regimen in patient preferences, other recent data show that medication efficacy and safety remain the most important determinants of patient preference. Informed patient decision making about treatment options, adverse effects and outcomes can have a beneficial impact on medication-taking behaviour. Healthcare professionals play a crucial role in the management of factors associated with poor compliance and persistence with osteoporosis therapies. Education about disease consequences and differences among treatment options, as well as treatment monitoring and positive reinforcement, are crucial to improving medication compliance and persistence in osteoporotic patients. PMID- 21553401 TI - Proceedings of the First Acta Nordic Cancer Rehabilitation Symposium. Copenhagen, Denmark. September 21-22, 2010. PMID- 21553402 TI - Stem cells: T cell opposition. PMID- 21553403 TI - Proceedings of the 7th International Conference on Homocysteine Metabolism. June, 21-25, 2009. Prague, Czech Republic; and the Annual International Meeting on Inborn Errors of Metabolism. Fulda, Germany. PMID- 21553404 TI - Immunology: Pro-metastatic T(Reg)cells get RANKed. PMID- 21553405 TI - Preface. The evidence for the clinical role of linezolid beyond its licence. PMID- 21553406 TI - Surprise package. HHS delivers its framework for a value-based purchasing system for ambulatory surgery centers, but ASCs are left wondering who will pay. AB - HHS has offered a framework on value-based purchasing for ambulatory surgery centers. And ASCs say they're ready. "We are very serious about getting this up and running as soon as possible. I think the only thing I could (negatively) speak to would be further delay," says Dr. David Shapiro, left, of the Ambulatory Surgery Center Association. But delay could be inevitable as the initiative has to make its way through the charged health policy environment in Washington. PMID- 21553407 TI - FTC fights hospital sale. Ga. case is second antitrust challenge in four months. PMID- 21553409 TI - Deal or no deal? Highmark, West Penn Allegheny rumors continue. PMID- 21553408 TI - Acute-care cuts ahead? CMS proposes $500 million less to hospitals. PMID- 21553410 TI - ICD shakeup. Feds seek info on implantable defibrillators. PMID- 21553411 TI - Another honor for magazine. Modem Healthcare's Carlson wins prestigious NIHCM award for second time. PMID- 21553412 TI - There's an app for that. Number of mobile health tools--and their users- continues to soar. PMID- 21553413 TI - By the numbers. Top business graduate schools for physician-executives. PMID- 21553414 TI - Taking it ot the next level. As reform settles in and economic woes wear on, the Top Women in Healthcare keep moving forward. AB - As the effects of reform start to settle in, the Top 25 Women in Healthcare are helping show how integral changes can be made to the system. "They clearly understand the vision. They asked me to be bold," says Dr. Tracy Gaudet, left, says of the VA. She's leading an effort there to redesign the delivery of healthcare to more than 6 million veterans nationwide. PMID- 21553415 TI - Tenet swings at Community. Fraud complaint opens door for federal probe. PMID- 21553416 TI - On to round two. 2011 budget battle presages tougher fight ahead. PMID- 21553417 TI - Same mission ... but plans for decreasing deficit are very different. PMID- 21553418 TI - FDA under fire. GAO: little progress in medical device approval. PMID- 21553419 TI - By the numbers. Largest hospitals. PMID- 21553420 TI - Access. Commissioners halt soaring referrals. PMID- 21553421 TI - Inequality. Formula change boosts South. PMID- 21553422 TI - Neil Churchill on community action. PMID- 21553423 TI - Time for action is now--or else. PMID- 21553424 TI - Accountability arrives. As providers weigh the regulations for accountable care organizations, many wonder if the risks are worth the possible rewards. AB - As providers peruse the new regulations for accountable care organizations, they're wondering if they want to join in. "Most providers have less comfort with downside risk. ... So your typical hospital or provider CEO will look at this ACO rule and think, 'I'm used to fee-for-service; I'm not used to risk-sharing.' I think that's going to make this voluntary program unattractive to a whole host of provider types," says Chet Speed, left, of the AMGA. PMID- 21553425 TI - FTC scores antitrust win. Federal judge puts ProMedica deal on hold in Ohio. PMID- 21553426 TI - Feds widen probe. 'Most-favored nation' clauses draw more scrutiny. PMID- 21553428 TI - Single-payer path. Vermont bill hinges on federal opt-out proposal. PMID- 21553427 TI - Outside the doc's office. Joblessness, environment impact health: study. PMID- 21553429 TI - Bury the hatchet. Competitors team up to boost workforce. PMID- 21553430 TI - By the numbers. Medicaid expenditures by state. PMID- 21553431 TI - Time-space trends in Swedish divorce behaviour, 1911-1974. AB - This study examines how the divorce rates in Sweden have varied over time and across different geographical areas during the period 1911-1974, and how these variations can be connected to the political, socio-economic and cultural development in Sweden. The analysis provides empirical support for the hypothesis that increased divorce rates have been the result of changes in the structural conditions that determine the degree of economic interdependence between spouses. There is a strong connection between the degree of urbanization and the divorce rate on a regional level for the entire research period. The statistical analysis of the regional data indicates that these patterns are connected to the more diversified economy that has developed in urban settings, in the form of a more qualified labour market and higher wages for females. These characteristics resulted in a faster and more pronounced reduction of economic interdependence between spouses, which made divorce more attainable in these areas as compared with rural settings. PMID- 21553432 TI - Housing shortage and communal politics in European cities around 1900: the cases of Basel 1889 and Belgrade 1906. AB - In the second half of the nineteenth century, European cities faced a problem well known in postindependence India: the population escalated due to immigration from the rural areas causing rapid and considerable housing shortage. This forced large parts of the poorer classes into miserable living conditions. Lack of space, money and hygiene facilitated the epidemic spread of diseases such as tuberculosis and diarrhoea. The town authorities were called upon to stop speculation and to launch state financed housing projects. However, in reality the situation was very different depending on the place, political aims and financial possibilities arising out of the particular crisis. This article discusses the issue in two continental European cities of around 100,000 inhabitants. The Swiss town of Basel was a hub of trade in Central Europe, while Belgrade was the capital of the Southeastern European kingdom of Serbia. PMID- 21553433 TI - Race and health in Guyana: an empirical assessment from survey data. AB - This paper examines racial differences in physical health and mental well-being in Guyana, South America: a country with cultural ties to the Caribbean. It explores the complex relationship among race, socioeconomic status and health outcomes which in developed societies continues to be of significant research interest. Utilizing a random probability sample of over 900 adults, the analyses provide information on the general physical and mental health status of this population and examine the differences by racial groups when other factors are controlled. The results indicate significant age-specific racial differences in physical and mental health in Guyana. Higher rates of diabetes, arthritis or rheumatism, back and breathing problems among Indo-Guyanese when compared to other groups were noted. Racial differences in physical health were attenuated when gender and educational levels were controlled. PMID- 21553434 TI - Health tips. Fingernail care. PMID- 21553435 TI - Mayo invention may improve how doctors diagnose diseases. PMID- 21553436 TI - Psoriasis. Managing this chronic skin disorder. PMID- 21553437 TI - Telomeres and health. Keeping your DNA happy. PMID- 21553438 TI - A while back, my doctor prescribed several new drugs for me. A week later, I broke out in a rash. I stopped taking the drugs, and the rash went away. Since then, my doctor seems to be having a hard time figuring out which drug caused the problem. Isn't there a better way? PMID- 21553439 TI - [Trends of cardiovascular diseases in B&H and Europe]. AB - Cardiovascular diseases (CVD) are the leading cause of death in developed countries and in most developing countries. They represent an important cause of loss of working ability, invalidity, hospitalization and increase of health care costs. Annually, about 20 million people dies from CVDs, and projections says that by the year 2020 25 million people will be casualties from it. Mortality increase from CVDs will be markedly higher in non-developed than in developed countries, which is due to changes in the population structure, prevalence of risk factor and insufficient preventive activity. Last fifty years morbidity and mortality of CVD in B&H are in increasing and follow trends in countries in transition. PMID- 21553440 TI - [Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol in coronary artery disease]. AB - The retrospective study included 250 patients, treated at Clinic for cardiovascular diseases of Tuzla Clinical center, between 30.08.2003. and 15.11.2004. In the coronary disease group there were 145 men, 55 women, with diagnosed coronary artery stenosis of 50% or more. The control group had 150 patients, 35 men and 15 women, medium age of 58.2. The control group had coronary artery stenosis of 50% or less. Coronarography was done using AXIOM ARTIS DFC (SIEMENS). Lipoproteins were determined on the Clinic for biochemistry of Tuzla Clinical Center using automatic analyser DIMENSION LxR (DADE BOEHRING). In the coronary artery disease (CAD) group elevated triglycerides were found in 38.5%, total cholesterol in 88% and LDL 55.5% of patients. The concentration of HDL cholesterol was elevated in 52.5% of patients. In the control group elevated values of triglycerides were found in 28%, total cholesterol 46%, LDL cholesterol 16%, and lower values of HDL in 10% of patients. Statistically significant differences of lipide profile of CAD patients in relation to the control group was defined. Using regresional analysis it was established that decide elevated values of total and LDL cholesterol, low values of HDL were also significant. PMID- 21553441 TI - [Mutations genes in primarly cardiomyopathies]. AB - Diagnosis of primarly cardiomypathies refers to genes discorders in chromosomes. Aim of this paper is to show genetics and molecular knowledges published so far. Familiar form hypertrophic cardiomyopathy is hereditable autosomatically dominantly in any of 10 genes that regulate contractile, structural and regulative function with predomination of mutation in gene for heavy chaire of myocardiac beta myosin localized at 14 chromosome (more than 200 mutation). Sporadic forms appears autosomatically recessively as the result of new mutation or as non-genetic form. Familiar dilated cardiomyopathy is associated with mutation more than 10 genes with frequent mutation of genes (beta myosin of heavy chain, cardiac T throponin, phospholamban and cardiospecific free methavinculin genes) and with clinical features that are mainly uknown (associated with peripheral myopathies). Restrictive cardiomyopathy is considered that the idiopathic restrictice cardiomyopathies has, also, hereditable atiology. A lot of the ries explain genes of this cardiomyopathy with predomination of heredithy with autosomatically dominant type (desmoplacin mutation) with variable expression of genes at 14, 1, 2, 3, 17 and 18 chromosome with programmed myocit death-apoptosis. PMID- 21553442 TI - [Arterial hypertension 2007: Guidelines for the management of arterial hypertension]. AB - Since the publication of "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) in 2003 and "2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension" (ESH/ESC guidelines), no substantial improvement has been made in the control of hypertension. Maybe, publishing of new 2007 Guidelines for the Management of Arterial Hypertension will contribute to a more rational and purposeful management of hypertension. The question whether beta blockers will keep their place as the first-line therapy in the new guidelines has been opened. After 30 years of their use in clinical practice, beta blockers have again become the focus of great discussion and controversy. Namely, according to the National Institute for Health and Clinical Excellence (NICE), beta blockers, which were for more than 30 years the first line therapy for the treatment of high blood pressure, and antihypertensive effects of which were well documented in large randomized placebo controlled studies, have lost the first-line therapy role. Yet the normalization of the blood pressure has been difficult in spite of using the nowadays available drugs. This makes the question of disposal of such drugs even more open and disputable. Taking this into account, the 2007 Guidelines for the Management of Arterial Hypertension have kept beta blockers as the first line therapy. Besides, the separate guidelines for treatment of arterial hypertension and hypercholesterolemia, have been replaced by the new guidelines for management of the integrated cardiovascular risk. According to the Guidelines, the cardiovascular risk score should be applied in the everyday practice. Since cardiovascular risk factors multiply and interact with each other, moderate reduction in several factors will be more beneficial than major reduction in one. Much more than the 2003 ESH/ESC guidelines do, the new 2007 Guidelines emphasize the combined drug therapy using smaller dosages for simultaneous treatment of several cardiovascular risk factors as a replacement for separate management of hypertension alone. Also, there is a new goal of < 130/80 mm Hg for people with established cardiovascular disease including coronary artery disease, diabetes, renal dysfunction, or proteinuria. However, the main benefits of antihypetensive therapy are due to lowering of blood pressure per se. PMID- 21553443 TI - [Pediatric cardiology]. AB - Thanks to embryological knowledge, morphological anatomy and segmental analysis, paediatric cardiology is today an exact science. Modern diagnostically and therapeutical approach in paediatric cardiology allows early application of foetal echocardiography in order of achieving diagnosis of congenital heart anomalies in utero. Diagnostic modalities in paediatric cardiology are represented the application of transthoracic echocardiography, transoesophageal, 3D and in recent years 4D echocardiography with possibilities of heart imaging via magnetic resonance and computerised tomography. Rhythm disturbances id successfully detected by application of 24-72 hrs ECG Holter monitoring. Invasive techniques starting from balloon atrioseptostomy up to diagnostic and therapeutic cardiac catheterisation are the pre condition of lege artist treatment of group of congenital heart anomalies. Establishing foetal echocardiography with transinternet expert supervision, with team work of gynaecologist and paediatric cardiologists in Bosnia and Herzegovina would significantly reduced the number of congenital heart anomalies as well as the costs of cardio surgery and postsurgical care and in the same time would plan needed intervention/surgeries of heart anomalies. Invasive cardiology with foetal and transoesophageal echocardiography as well as widening of spectrum of cardio surgical operations by local team, represents the imperative of strategy in next decade with continuity of research in paediatric cardiology. PMID- 21553444 TI - [The place of the electrophysiology examination and radiofrequent ablation in cardiac arrhythmias]. AB - Intracardial electrophysiology testing is in use to estimate mechanism of heart rate dysfunction, and is the most useful procedure in treatment of arrhythmias and dysfunction in impulse conduction. QRS complex is main electrocardiographically characteristic for supraventricular and ventricular tachycardia, because of that tachycardia can be with narrow QRS complex or with wide QRS complex. Tachycardia with narrow QRS complex is one where the QRS complex last <120 millisecond. Atrioventricular node reentry tachycardia in reentry flow involves atrioventriculare node and surrounding atrial tissue. Wide QRS tachycardia (120 millisecond) can be supraventricular arrhythmias with continuous or frequent dependent aberrant intraventricular conduction and supraventricular arrhythmias with anterograde preexcitacion and ventricular arrhythmia.Safety and cost effectiveness of radiofrekvent ablation, made ablation method of choise in most patients with supraventricular rhythm disorders. PMID- 21553445 TI - [Hypertension treatment in patients on hemodialysis]. AB - Prevalence of arterial hypertension increases with the advancement of chronic renal failure (CRF). In terminal stage of CRF arterial hypertension is present in 80-90% of patients. Cardiovascular and cerebrovascular diseases are the most frequent cause of death in patients on hemodialysis. Cardiovascular mortality rate is three to twenty times higher in patients on hemodialysis compared to general population. In the beginning of the treatment with hemodialysis blood pressure lowers in certain number of patients who had used three, four or more blood pressure lowering medications during the pre-dialysis period. PMID- 21553446 TI - [Off-pump coronary bypass grafting in patient with left main occlusion and 75% stenosis of right coronary artery]. AB - Patients with significant stenosis (>50%) of the left main coronary artery (LM) are considered high risk for coronary artery bypass grafting (CABG). LM disease is mainly considered a relative contraindication for off pump coronary artery bypass grafting (OPCAB) because of the reduced tolerancy of hamodynamic disturbances which occurs during mobilisation and exposition of the heart, necessary for this type of operations. The aim of the study is to show feasibility of OPCAB for patient with occlusion of the LM and 75% stenosis of the right coronary artery. Operation was carried out through median sternotomy, LIMA stitch was used for the exposure, CTS stabilisator was used for local myocardial stabilisation, intracoronary shunt was inserted intraluminary. Three aortocoronary bypasses were created, operation passed without any hamodynamic instability. Main peri and postoperative results: total length of the operation: 265 min; time on respirator: 1 hour; total blood drainage on chest tubes: 532 ml; transfused blood: 0 ml; time in the intensive care unit: 1 day; total hospitalisation time: 7 days. This case review suggest that OPCAB is feasible and safe in the treatment of patients with LM occlusion and significant stenosis of RCA. PMID- 21553447 TI - [Who really first described lesser blood circulation?]. AB - Today, at least 740 years since professor and director of the Al Mansouri Hospital in Cairo Ibn al-Nafis (1210-1288), in his paper about pulse described small (pulmonary) blood circulatory system. At the most popular web search engines very often we can find its name, especially in English language. Majority of quotes about Ibn Nefis are on Arabic or Turkish language, although Ibn Nefis discovery is of world wide importance. Author Masic I. (1993) is among rare ones who in some of the indexed journals emphasized of that event, and on that debated also some authors from Great Britain and USA in the respectable magazine Annals of Internal Medicine. Citations in majority mentioning other two "describers" or "discoverers" of pulmonary blood circulation, Michael Servetus (1511-1553), physician and theologist, and William Harvey (1578-1657), which in his paper "Exercitatio anatomica de motu cordis et sanguinis in animalibus" published in 1628 described blood circulatory system. Ibn Nefis is due to its scientific work called "Second Avicenna". Some of his papers, during centuries were translated into Latin, and some published as a reprint in Arabic language. Professor Fuat Sezgin from Frankfurt published a compendium of Ibn Nefis papers in 1997. Also, Masic I. (1997) has published one monography about Ibn Nefis. Importance of Ibn Nefis epochal discovery is the fact that it is solely based on deductive impressions, because his description of the small circulation is not occurred by observation on corps during section. It is known that he did not pay attention to the Galen's theories about blood circulation. His prophecy sentence say: "If I don't know that my work will not last up to ten thousand years after me, I would not write them". Sapient sat. PMID- 21553448 TI - [Comparative analysis of amniotic fluid lamellar body count and foam stability test as indices of fetal lung maturity]. AB - INTRODUCTION: Respiratory distress syndrome of the newborn caused by the fetal lung immaturity is a very serious clinical problem. Different tests of prenatal analysis of amniotic fluid, such as lamellar body count and Clements' test, are available for predicting the fetal lung maturity. MATERIAL AND METHODS: A prospective clinical study was conducted on amniotic fluid samples from 2005 to 2006. The amniotic fluid samples were obtained at the gestational age of 30 to 42 weeks and collected by vaginal amniotomy, amniotomy during Caesarean section and 72 hours before the delivery by amniocentesis. A haematology analyzer (Nikon - Kohden) was used to determine the lamellar body counts. Clements' test involved adding an equal volume of 96% ethanol to the multiple amniotic fluid volume (1:2, 1:4, 1:16. 1:32), followed by shaking and noting the presence of ring of bubbles. After the delivery, we compared the lamellar body count results and Clements' test and the outcome of pregnancies, primarily the development of respiratory distress syndrome. The most specific lamellar body cutoffs for maturity and immaturity were determined according to receiver operating characteristic curves. RESULTS AND DISCUSSION: Out of 232 amniotic fluid samples which were tested, 112 samples were collected after vaginal amniotomy, 88 during the Caesarean delivery and 32 samples by amniocentesis. The overall incidence of respiratory distress syndrome was 14.6%. Receiver operating characteristic curves were used to identify cutoff points for the test. We found that both tests are good screening tests for predicting the fetal lung maturity with the area under the curve of 0.782 in Clements' test and 0.751 in the lamellar body count. Clements' cutoff 2 with sensitivity of 67.6% and specificity of 72.2%, proved best in the prediction of the fetal lung maturity. The lamellar body count cutoff of 42 x 10(3)/microl had the sensitivity of 82.4% and specificity of 64.6% in predicting the fetal lung maturity. CONCLUSION: Although both tests are good in predicting the fetal lung maturity, the lamellar body count has more advantages, because it is not only more objective, but also inexpensive, easy and fast to do, requires a small sample volume and is universally available. PMID- 21553449 TI - [The effect of applied cytotoxic drugs on biological behaviour of 99mTc radiopharmaceuticals]. AB - INTRODUCTION: This study was aimed at investigating the influence of certain cytotoxic drugs on the organ uptake of the following 9mTc-radiopharmaceuticals: 99mTc-2,3-dicarboxypropane-1, 1-diphosphonic acid, 99mTc-meso-2,3 dimercaptosuccinic acid, 9mTc-tin colloid and 99mTc-macraggregated albumin. Methotrexate sodium and cyclophosphamide were used as models to evaluate these effects. MATERIAL AND METHODS: Two groups of healthy male Wistar rats were treated separately by oral application of the drugs for 7 days. On the eighth day, each of the 99Tc-radiopharmaceuticals was applied in a separate group of treated animals. They were sacrificed at different time intervals and the radioactivity in the organs of interest was measured. The organ uptake of the 99mTc-radiopharmaceuticals in an additional control group of animals was also studied. RESULTS: The results obtained showed an alteration in the organ uptake of 99mTc-radiopharmaceuticals in animals treated with cytotoxic drugs. In the rats treated with methotrexate sodium, there was a higher uptake of 99mTc-meso 2,3-dimercaptosuccinic acid in the bones, stomach and intestine, a higher uptake of 99mTc-2,3-dicarboxypropane-1-,1-diphosphronic acid in the bones, intestine, blood and muscle, a lower uptake of 99mTc-tin colloid in the liver and a lower accumulation of 99mTc-macroaggregated albumin in the lungs. Cyclophosphamide treated animals showed enhanced uptake of 99mTc-meso-2,3-dimercaptosuccinic acid in the kidneys, a twofold enhanced uptake of 99mTc-2,3-dicarboxypropane-1,1 diphosphronic acid in all organs except the stomach, a decreased uptake of 99mTc tin colloid in the lungs, spleen and kidneys and a significantly decreased uptake of 99mTc-macroaggregated albumin in the lungs. CONCLUSION: These results confirm that both methotrexate sodium and cyclophosphamide may alter the organ uptake of 99mTc-radiopharmaceuticals in experimental animals. PMID- 21553450 TI - [Typical errors in pronouncing medical English terminology made by first and second year students of medicine at the Medical School of Novi Sad University]. AB - INTRODUCTION: This paper deals with typical errors on the phonological level made by first and second year medical students at Novi Sad University. It presents the results of a continuous survey conducted over a three-year period of teaching medical English. The aim of this study was to determine the most common pronunciation errors in medical English vocabulary, classify them into distinct types, and propose the teaching methods for overcoming them. MATERIAL AND METHODS: The authors first made a list of the most frequent medical words used at this level of study. They introduced them by means of audiovisual methods and conducted continual oral practice throughout the whole course. RESULTS: The recorded common pronunciation errors were classified into five types on account of the phonological and other factors which cause them. The number of words selected in this paper totals to 67. DISCUSSION: Most of the recorded pronunciation errors are due to the differences between the two phonological systems. The previously acquired knowledge plays an important part as well as the competence level in general English. Other language skills and knowledge of phonological and orthographic rules are important factors as well. CONCLUSION: A teacher of medical English should adjust his/her teaching methods to the needs of English for Specific Purposes. Medical students should practice pronunciation in class and learn the most important rules of English phonetics; they should also be instructed on how to use computer to improve their pronunciation. PMID- 21553451 TI - [Frequency of hospital infections at Department of Urology]. AB - INTRODUCTION: At departments of urology, as well as other hospital departments, hospital infections represent an important problem. The objective of this work was to determine the frequency and the most common localizations of hospital infections at the Department of urology. MATERIAL AND METHODS: All the patients hospitalized for longer than 48 hours at the Department of Urology, General hospital, Sabac were included in a prospective study of incidence in the period of 12 months. The everyday epidemiological surveillance was carried out, as well as the inspection of the existing medical files. The diagnosis of hospital infections was made on the basis of known definitions. RESULTS: Ninety-four out of 554 hospitalized patients included in the research had 122 hospital infections. One hospital infection was recorded in 64 of those included in the research, whereas two and three infections were recorded in 26 and 2 patients, respectively. The incidence rate of the patients with hospital infections was 17.3%, and the rate of the incidence of the infections 22.4%. The incidence rate by 1,000 patients-hospitalization days was 12.4. Out of the total number of infections, 69.7% were urinary tract infections, 27% surgical site infections and 3.3% sepses. The incidence rate of the patients with urinary infections was 14.7% and the incidence rate of urinary infections 15.6%. The rate of urinary infections in the patients with urinary catheter (19.6%) was significantly higher than in those patients without urinary catheter (p < 0.001). The rate of incidence of surgical site infections was 6.1% and the incidence rate of blood infections was 0.7%. CONCLUSION: The most common hospital infections in our work were urinary infections and surgical site infections. The rates recorded in our study are similar to those in the hospitals that have only started the surveillance of hospital infections. PMID- 21553452 TI - [Financial justification of investments into special diet for patients with phenylketonuria]. AB - INTRODUCTION: Phenylketonuria is a genetic disorder of metabolism of amino acid phenylalanine, which results in the absence of phenylalanine hydroxylase, an enzyme that catalyzes the conversion of phenylalanine into tyrosine. It is an autosomal recessive disorder. Screening for phenylketonuria in Voivodina started in 2003. Screening data are shown in this paper. Treatment of phenylketonuria is based on a strict, life long, low protein diet with the controlled phenylalanine intake. Diet must start early, in the first weeks of life. The aim of the diet is to reduce natural protein intake and to cover protein needs by special phenylalanine free protein products. There is a big variety of formulas found available on the market for treatment of phenylketonuria. All of them are free of phenylalanine and very expensive. DISCUSSION: Till May 2005 there was no refunding for these products in our country. According to the decision made by the Provincial Secretariat for Health, providing all children with protein supplement in their first year of life started at the Institute for Child and Youth Healthcare. In September 2007 the Republic Fund for Health Insurance started to refund protein supplement and low protein products for all children up to the age of 18 years. CONCLUSION: Besides all technical and organizational difficulties associated with this work, this paper also shows how, by good prevention of phenylketonuria complications, much more money can be saved than it has been invested, even in countries with low amounts of money allocated for this purpose (in absolute figures). PMID- 21553453 TI - [Quantification of sclerotic renal glomeruli during the aging process in humans]. AB - INTRODUCTION: The aim of our research was to quantify the presence of totally sclerotized glomeruli during the aging process. MATERIAL AND METHODS: The study material were kidney tissue samples taken from fifty-six cadavers, their age ranging from 20 to over 70 years. They were classified in six age groups: I (20 29), II (30-39), III (40-49); IV (50-59); V (60-69) and VI (older than 70). The tissue samples were routinely histologically processed and then cut into the slices 5 mm thick, which were then stained and stereologically analyzed under the microscope with a projection screen (Reichert Visopan) with 10 x lens magnification and multipurpose test system M42 application. The analysis was carried out on 20 fields of vision per one sample. The numerical density of completely sclerotic and other glomeruli was measured, and the resulting percentages were obtained from this parameter. RESULTS: Completely sclerotic glomeruli were not found in the first group. They were observed in the II aging group (5%) for the first time. Their numerical density and percentage increased during the aging process and was 18% in the IV, 25% in the V and maximally 37.5% in the VI aging group. CONCLUSION: Finally, the above cited results pointed to the increase of completely sclerotized and the decreased presence of normal glomeruli during the aging process. PMID- 21553454 TI - [Diagnosis and treatment of esophageal diseases in patients with acquired immunodeficiency syndrome in Serbia]. AB - INTRODUCTION: Gastrointestinal complications are common manifestations of acquired immune deficiency syndrome. The aim of this study was to establish the type and frequency of esophageal disease, the influence of antiretroviral therapy on it and the most adequate approach to this group of patients. MATERIALS AND METHODS: This study included 146 patients with acquired immune deficiency syndrome treated at the Institute of Infectious and Tropical Diseases of Clinical Centre in Serbia from 1991-2001. The statistical data processing was done by the Statistical Package for the Social Sciences for Windows version 10.0. The level of statistical significance was defined to be p < or = 0.05 and p < or = 0.01. The diagnosis was made upon endoscopic exams, pathohistological findings and isolation of causative agents. RESULTS: Esophagitis was found in 78 (53.41%) patients. These patients complained mostly of odynophagia and dysphagia. The most common was Candida esophagitis. It was diagnosed in 59 (40.41%) patients; 5 patients (3.42%) had cytomegalovirus esophagitis; 2 patients (1.37%) had herpes simplex virus esophagitis, and one -patient (0.68%) had a mixed Candida and herpes simplex virus infection of esophagus. Idiopathic esophageal ulcer was diagnosed in one (0.68%) patient. CONCLUSION: Seventy-eight (53.41%) patients with acquired immune deficiency syndrome had esophagitis. Candida (40.41%) was the most common cause of esophagitis. Viral esophagitis was less common: cytomegalovirus in 5 patients (3.42%); herpes simplex virus in 2 patients (1.37%), and idiopathic esophageal ulcer in 1 patient (0.68%)). These patients complained mostly of odynophagia and dysphagia. Modern antiretroviral therapy reduces the frequency of esophagitis and therefore changes symptomatology in patients with acquired immune deficiency syndrome. PMID- 21553455 TI - [Relative length of human kidney as more precise measuring of normal kidney]. AB - INTRODUCTION: Malformations in kidney development and kidney diseases are accompanied with changes in their size. For kidney evaluation in clinical practice, the kidney length is the most widely used measurement, since it provides the most precise results and it is easy to perform. Recently, the measurement of relative renal length has become more preferable as it takes into account the body height. The aim of this study was to measure both the absolute and relative length of normal cadaveric kidneys according to the body height, sex and age. MATERIALS AND METHODS: In this study, we examined 95 adult cadaveric kidneys, without renal and vascular impairment, their age ranging from 23-87 years. To determine the period of the most abundant changes in kidney length, we separated them into a 10-year range. The relative renal length was calculated using the kidney length and body height ratio (kidney/body ratio). RESULTS: The absolute and relative length of left kidney in males was longer than the right one, with a statistically significant correlation. In females, the left kidney length was also longer than the right one, however, without a statistical significance. In contrast to the absolute length, the relative length of both kidneys did not show a significant difference between sexes, and did not manifest a significant decrease with age. There was a significant correlation between the kidney length and the subject's height. CONCLUSION: The relative renal length represents kidney size better than the absolute renal length because it eliminates sex and height differences until the age of 59 year. From the seventh decade of life, there is a significant decrease in both the absolute and relative renal length. PMID- 21553456 TI - [Applicability of Children's Environment and Health Action Plan in Serbia]. AB - The Children's Environment and Health Action Plan for Europe was adopted at the 4th Ministry Conference on Environment (the World Health Organization, 2004). It is focused on children health care against hazards originating from the human environment. In its conclusion, the need is expressed for the development of national plans in the field of Environmental and Children Health for European region by 2007. Mutual activities would be obligatory for each country and their realization should be the responsibility of Ministers of Health Care and Environmental Health. In our country, a draft version of this document was recently adopted, where the following priority regional goals are proposed: safe drinking water and adequate sanitation, injury prevention and adequate physical activity, clean indoor and outdoor air, the human environment without chemicals. Every segment has been explained in details through activities, expected results, indicators, sources of verification and the main participants in the project implementation. The end of the action plan period is proposed to be the year 2019. It is also followed by a defined set of indicators: exposure, activities and health status. The analyses of particular activities or data to be used have pointed to some drawbacks of this draft version, which can be overcome by respecting expert opinions. PMID- 21553457 TI - [Therapeutical approach to dry eye syndrome]. AB - INTRODUCTION: Dry eye disease or dysfunctional tear syndrome is among the most frequently established diagnoses in ophthalmology. It can be defined as a disorder of the tear film resulting in changes in the ocular surface. MECHANISMS IN DEVELOPMENT OF DRY EYE DISEASE: There are many factors causing dry eye and they, can be related to deficiency in any of the components of the tear film. It has been suggested that dry eye is an inflammatory disorder that affects the ocular surface and lacrimal gland. Inflammation is the most important mechanism of corneal and conjunctival cell damage, which is responsible for the symptoms and signs of ocular surface pathology. Hormonal imbalance (particularly androgens), neural dysfunction, increased levels of pro-inflammatory cytokines and loss of immune homeostasis of the lacrimal gland and ocular surface could be possible mechanisms in the pathogenesis of dry eye disease. DISCUSSION: The aim of this paper was to review the advances in the pathogenesis and management of the dry eye disease. The appropriate dry eye treatment presupposes knowledge of all existing pharmacologic and non-pharmacologic therapeutic modalities. The mainstay of therapy is still artificial tears, with anti-inflammatory therapy and punctual occlusion therapy as second and third line therapies. PMID- 21553458 TI - [Convulsive status epilepticus in children]. AB - INTRODUCTION: Convulsive status epilepticus is the most urgent neurological medical emergency in children. Generalized convulsive status epilepticus is the most common and life-threatening type of status epilepticus. It is not a syndrome in the same sense as febrile convulsions, benign rolandic epilepsy, and infantile polymorphic epilepsy. These latter disorders have a tight age frame, seizure semiology, and a reasonably predictable outcome. Episodes of convulsive status epilepticus can occur in each: occasionally in symptomatic and febrile convulsions, and Lennox Gastaut syndrome, rarely in benign rolandic epilepsy, and West syndrome. ETIOLOGY OF CONVULSIVE STATUS EPILEPTICUS: Status epilepticus has many causes, which vary depending on the age and patient population. Convulsive status epileptucus continues to be associated with significant neurological morbidity and mortality, with different hazards and outcome. Although the outcome is dependent on etiology, it is known that appropriate early management may reduce mortality and some of the morbidity associated with convulsive status epilepticus. DISCUSSION: Status epilepticus is a disorder in which the mechanisms attempting at terminating the seizure fail. Continued convulsive activity in convulsive status epilepticus results in decompensation of all organs and systems, thus being life threatening. Seizure activity in convulsive status epilepticus is associated with neuronal damage. The aim should be to halt this activity urgently, using, ideally, a 100% effective drug, administered quickly, without compromising the consciousness level or producing other negative effects on cardiovascular, respiratory function or other unexpected effects. PMID- 21553459 TI - [Drug interactions with grapefruit]. AB - INTRODUCTION: The concentration of many orally given medications may be affected by grapefruit or grapefruit juice consumption. It may result in numerous harmful effects. INTERACTION OF GRAPEFRUIT WITH DRUGS: Taking only one cup of juice may induce interactions with different drugs even during the period of a few days. The effect is induced by suppression of cytochrome P450 isoenzyme CYP3A4 in the intestinal wall. The Latin name of grapefruit, Citrus paradisi, is quite opposite to the effects which could be induced by taking grapefruit and some medications at the same time. It is necessary to avoid taking grapefruit with the drugs whose pharmacokinetics could be altered by the active principles found in that fruit. DISCUSSION: The coloured grapefruit contains less furanocoumarins, but there is no difference in induction and intensity of pharmacokinetic interaction with drugs related to its colour. Other citrus fruits (orange, lemon) do not have such effects, but some other fruits (pomegranate, stella fruit, banpeiyu, hassaku, takaoka-buntan and kinkan) exert inhibitory effects on the activity of cytochrome P450 isoenzyme. PMID- 21553460 TI - [Medical nutrition therapy planning]. AB - INTRODUCTION: Diet has vital, preventive and therapeutic functions. Medical nutrition therapy is a part of the Standardized Nutrition Care Process integrated in health care systems. MATERIAL AND METHODS: An overview of the Nutrition Care Process model and the application of nutrition guidelines based on literature, reports, documents and programmes of international health, food and physical activity authorities was done. RESULTS: The Nutrition Care Process model requires registered dieticians, standardized terminology as well as nutrition diagnosis categorization. It consists of four distinct, but interrelated and connected steps: (a) nutrition assessment, (b) nutrition diagnosis, (c) nutrition intervention, and (d) nutrition monitoring and evaluation. An individual approach is essential for successful medical nutrition therapy. Nutrition guidelines facilitate the process of understanding and application of medical nutrition therapy. CONCLUSION: The Nutrition Care process provides dietetic professionals information on high-quality client nutrition care. The success of medical nutrition therapy rests not only upon the advice of the dietician, but also upon the client's compliance. PMID- 21553461 TI - [Modern pacemaker therapy]. AB - INTRODUCTION: Pacemakers are devices that modern medicine and cardiology cannot be imagined without. The technique of implantation comes to surgical procedure where all principles of asepsis and antisepsis have to be respected. Although some complications do happen, the)y are rather rare. RESULTS: After the implantation of the device, the patient is not handicapped (unless the heart was additionally damaged). On the contrary, the patient returns to his work and functions normally within his family in most of the cases. The first medical appointment is scheduled a month after the implantation and the following are three and six months after. TYPES OF DEVICES: Today there are "new types of electrostimulation"--implantable cardioverter defibrillators and multisite electrostimulators. The former is implanted in patients at high risk of sudden cardiac death and the latter in patients with heart failure and left bundle branch block. Owing to these devices, the sudden cardiac death can be prevented successfully and the quality of a patient's life is improved. PMID- 21553462 TI - [The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis]. AB - INTRODUCTION: Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. ROLE OF OXIDATIVE STRESS IN PARACETAMOL-INDUCED LIVER INJURY: The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol-induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils. Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. ROLE OF MITOCHONDRIA IN PARACETAMOL-INDUCED OXIDATIVE STRESS: The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mitochondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonucleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. ROLE OF KUPFFER CELLS IN PARACETAMOL INDUCED LIVER INJURY: Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. ROLE OF NEUTROPHILS IN PARACETAMOL-INDUCED LIVER INJURY: Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. ROLE OF PEROXYNITRITE IN PARACETAMOL-INDUCED OXIDATIVE STRESS: Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. CONCLUSION: Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species. PMID- 21553463 TI - [Mental health and mental hygiene between two millenniums]. AB - A century has passed since Klifford Beers published his work "A mind that found Itself". This paper has inspired the shift of mental hygiene towards the prevention of mental disorders and health improvements. At the beginning of this millenium, with much improved scientific knowledge, experience and possibilities, but confronted with new challenges we are observing the tempestuous historical features which have influenced the development of mental health care. Mental health is crucial for the welfare of a society and its individuals, since such disorders are not only the cause of emotional suffering, but they also deteriorate the quality of life, cause alienation and discrimination of an individual. At the same time, they are a great economic burden to the society as they require long-term therapy and often result in poor productivity. In order to decrease the burden of mental disorders it is required to stimulate prevention and improvement of mental health of the population within the framework of national policies, legislation and financing. PMID- 21553464 TI - [Lyme borreliosis--diagnostic difficulties in interpreting serological results]. AB - INTRODUCTION: Lyme borreliosis is a multi-systemic disease caused by spirochete Borrelia burgdorferi sensu lato. The specific response is influenced by phenotypic characteristics of Borrelia, different antigen structure, their different geographic distribution, and the patient's capability to react to the infection. The immune response to Borrelia burgdorferi sensu lato develops relatively late, whereas in some patients it never develops. The immune response in the early phase of Lyme borreliosis is very similar to the one of healthy population. DIAGNOSIS OF BORRELIA: Clinical manifestation, detailed anamnesis and epidemiological data are crucial for making the diagnosis. The majority of patients in the late phase of Lyme borreliosis have IgG antibody response, which could be followed by IgM also throughout this period of time. The number of serologically positive findings increases with the duration of the infection. Specific borrelial antigens can be detected by a Western blot test. In patients with neuroborreliosis, antibodies could be synthesized only intrathecally. IgG and IgM antibody response can persist for many years after the treatment. There is no positive serological test, which could be the indicator of the disease activity on its own; even if it demonstrates high antibody titre. If there are no clinical signs of Lyme borreliosis, the diagnosis of Lyme borreliosis should be primarily based on clinical findings, and serological results should be used only to confirm but not to make the diagnosis of Lyme borreliosis. Specific antibodies from the IgM class can be proved in about 50% of patients, 2 to 4 weeks after the onset of primary infection, but an early administration of the antibiotics can postpone or inhibit that response. INTERPRETATION OF SEROLOGICAL RESULTS: When interpreting the serological test results with high level of sensitivity and specificity used for making diagnosis of Lyme borreliosis, it is necessary to take into consideration the seroprevalence in a certain region. In the population with a low prevalence of the disease, the tests will have a low positive predicative value, i.e. the probability of indicating the real disease will be lower. According to the recommendations given by the Centre for Disease Control in North America, all extreme and positive results of EA and IFA are to be confirmed by a Western blot test. DIAGNOSTIC PROBLEMS: The main problem in making diagnosis of Lyme borreliosis is underestimation and overrating of the diagnosis. Not a single positive serologic test is the indicator of the disease activity on its own, regardless of the antibodies titre level, when clear clinical signs are scarce. PMID- 21553465 TI - [Reconstruction of anterior cruciate ligament by using two different techniques]. AB - INTRODUCTION: Modern literature concerning reconstructions of Anterior Cruciate Ligament is mostly focused on the choice of graft (hamstring or bone-tendon bone), its placing, tensioning and fixation. The bone-hamstring-bone graft consists of compressed cancellous bone on its ends and it has been developed to achieve a more rigid fixation of the graft. The aim of this study was to compare the postoperative results in surgically treated patients two years after the reconstruction of anterior cruciate ligament. MATERIAL AND METHODS: The study included 55 patients divided into two groups according to the implanted graft: bone-tendon-bone and bone-hamstring-bone graft. The results were assessed by Tegner and Lysholm scoring systems, arthrometric measurements, functional tests and International Knee Documentation Committee standard. RESULTS: The average postoperative results did not show a statistically significant difference (p < 0.05) between the two groups (94 in the bone-tendon-bone group versus 93 in the bone-hamstring-bone group) according to Lysholm scoring system, nor in the arthrometric measurements obtained by Lachman test (2.0:2.1). According to the International Knee Documentation Committee standard, the bone-hamstring-bone group had more excellent results, but also three unsatisfactory ones; so, the bone-tendon-bone group was found to have uniform and better results (100% of excellent and good results vs. 91% in the bone-hamstring-bone group). Better results were also recorded by Tegner scoring system in the bone-tendon-bone group (8.6 vs. 7.1) due to the fact that there were more active athletes and greater preoperative level of activities in this group (3.1 vs. 7.1 in the bone-hamstring group). CONCLUSIONS: The choice of graft is a less important factor in the reconstruction of anterior cruciate ligament than its placing, tensioning and fixation, because a significant difference between groups was recorded only by the International Knee Documentation Committee standard. PMID- 21553466 TI - [Hospital infections at the Department of Cardiovascular Surgery]. AB - INTRODUCTION: Despite modern surgical techniques, preoperative preventive use of antibiotics and optimal treatment of operative site, patients who underwent surgical procedures are still at a risk of developing hospital infections. The aim of this paper was to estimate the frequency of hospital infections at the Department of Cardiovascular Surgery and their presence according to the anatomic localization as well as to identify the most frequent causes of hospital infections. MATERIAL AND METHODS: During one-year period, all surgically treated patients were prospectively followed at the Department of Cardiovascular Surgery of the Institute of Cardiovascular Diseases, Vojvodina. There were 1302 patients who underwent 1396 surgical procedures during the period observed The descriptive epidemiological method was applied in the study. The following odds ratio and rates were calculated: the incidence rate of patients with hospital infections, the incidence rate of hospital infections and the incidence rate in relation to hospital stay of each patient (incidence density). RESULTS: During that period, 36 hospital infections were recorded in 33 patients. The average incidence rate of patients with hospital infection was 2.53% and hospital infection rate was 2.58% (from 0% to 5.13%). The male-female ratio was 3.1:1. The most frequent hospital infections were surgical site infections (incidence rate 0.86%), then gastroenteritis (incidence rate 0.77%) and bloodstream infections (incidence rate 0.46%). The most common causes of hospital infections were: Staphylococcus aureus (14.8%), Acinetobacter spp (22.2%) and coagulase negative staphylococcus (11.1%). CONCLUSION: The fact is that the incidence rate of hospital infections is relatively low, and such a trend can continue only if the continuous epidemiological control and preventive measures are implemented in the future. PMID- 21553467 TI - [Prevention of spine deformities in adolescents due to inadequate posture]. AB - INTRODUCTION: The spine deformities tend to increase, and in 90% of children they change the quality of life. The aim of this study was to determine the percents of spinal deformity in our population of adolescents, and long bad posture in and out of school as a factor for its increase. MATERIAL AND METHODS: The study included 124 adolescents attending High Musical School in Bitola and Skopje, who underwent four standard spine tests and an interview. RESULTS: According to the test 3, 50% of the examined adolescents in Bitola and 69% in Skopje had the postural spine deformity, the average being 59.5%. The results obtained by the questionnaire showed that 50% of adolescents did not have any physical activity out of school, the longest daily activity, lasting four hours, in 48% of the examinees was practising their musical instruments; 40% of the examinees spent two hours watching TV or using the computer, whereas 18% did not use any of them at all. CONCLUSION: The bad spine posture tends to deteriorate in adolescents and the factor influencing this result should be established by studies aimed at determining the effects of physical activity on reducing such deformities, since the specific type of their education induces the risk of developing pain and early degenerative changes of the spine, which are predominant in the professionals. PMID- 21553468 TI - [Attitudes and behaviour of students related to reproductive health]. AB - INTRODUCTION One of the features of modern societies is the increase of sexual activity among young people. Sexual activity creates new health problems, or to be more exact, it can result in an unplanned pregnancy and disease induced by sexual contact. MATERIAL AND METHODS: The data for the study were obtained from the questionnaires filled in by students of the Faculty of Medicine and Faculty of Economics in Kragujevac in 2008. Out of 615 students of both sexes included in this questionnaire, 222 students were from the Faculty of Medicine and 393 students from the Faculty of Economics. The questionnaire was designed at the Institute for Public Health "Dr Milan Jovanovic Batut" in 2000 for the project "Health condition, health needs and using of health protection by population in Serbia". RESULTS: The research showed that 41.6% of the students included in the questionnaire had sexual relations; 69.1% of female and 30.9% of male students had sexual experience, i.e. one third and two thirds of the interviewed students attending the Faculty of Economics and of Medicine, respectively. The reason for having the first sexual intercourse was love in 50.4%. Almost 80% of the interviewees used a condom during the first sexual contact. According to the answers, 71.9% of the study sample had one sexual partner. More than half (51.6%) of the students having sexual relations did not use contraceptives. Contraceptives were used more frequently by the students of Medical Faculty (54.3%) than those from the Faculty of Economics (45.7%). CONCLUSION: In order to prevent multiple consequences of ignorance and risky behaviour, it is necessary to inform and educate young people about the reproductive health. PMID- 21553469 TI - [Analysis of test anxiety in medical students]. AB - INTRODUCTION: Most students experience some level of anxiety during the exam. However, when anxiety affects the exam performance, it represents a problem. Test anxiety is a special form of anxiety, which is characterised with somatic, cognitive and behavioural symptoms of anxiety in situations of preparing and performing tests and exams. Test anxiety turns into a problem when it becomes so high that it interferes with test preparation and performance. The objective of this study was to ascertain the presence of test anxiety in medical students and to analyze some aspects of test anxiety in medical students of different gender, at different years of studying and possibility of failing a year. MATERIAL AND METHODS: The study sample consisted of 198 students of Belgrade University School of Medicine of all years. Test anxiety was assessed by the Test Anxiety Inventory. RESULTS: The following results have been obtained in the study: 1. Medical students generally present moderate level of test anxiety; 2. female students have statistically significant more intense symptoms of test anxiety than male students. 3. the most intense symptoms are in the 3rd year and the least are in the 4th year of studies; 4. there is no statistically significant difference in the presence of symptoms of test anxiety among the students who have repeated one of the years of studies and regular students. CONCLUSION: There is a considerable number of medical students who have intense symptoms of test anxiety and these students require help and support. PMID- 21553470 TI - [Biphenotypic acute leukaemia: case reports of two paediatric patients]. AB - INTRODUCTION: Biphenotypic acute leukaemia is an uncommon type of leukaemia whose blasts co-express myeloid and B-or T-lymphoid antigens. CASE REPORT: We describe two cases of paediatric patients with biphenotypic acute leukaemia. A four-year old female patient was found to have myeloid and B-lymphoid associated antigens in the same blast cells. Cytogenetic analysis showed a Philadelphia (Ph) positivity t (9;22) (q34;q1l1 with rearrangements of M.bcr-Abl (p210). She was treated with combined acute myeloid leukaemia/acute lymphoblastic leukaemia induction therapy followed by autologous stem cell transplantation. The patient died due to the complications of stem cell transplantation procedure. Another patient was a 20-month-old girl with myeloid and T-lymphoid associated antigens in the blast cells and with normal karyotype. She received acute myeloid leukaemia induction therapy. She has never achieved remission. DISCUSSION: Immunophenotype is essential to establish the diagnosis of biphenotypic acute leukaemia according to the scoring system adopted by the European Group of Immunological Classification of Leukaemia. There is no agreement about uniformity in treatment for the patients with this type of leukaemia. Biphenotypic acute leukaemia is a high risk leukaemia which requires a more intensive treatment. CONCLUSION: Therapy for every patient with biphenotypic acute leukaemia should depend on their immunophenotype and gene rearrangement profiles. PMID- 21553471 TI - [Postpartum intra-abdominal haemorrhage--case report]. AB - INTRODUCTION: The most frequent cause of gynaecological haemoperitoneum is ruptured ectopic pregnancy. Haemoperitoneum after a normal vaginal delivery is rare and it is associated with high maternal mortality. CASE REPORT: A 22-year old primipara had a normal vaginal delivery. She experienced acute abdominal pain and hypovolemic shock ten hours after the delivery and was referred to our hospital twenty one hours after the delivery. An urgent ultrasound profile was done, which revealed free fluid in pelvis and in the whole abdomen. An immediate laparotomy was done and 2 litres of blood were found within the peritoneal cavity. The uterine wall was intact. We found a haematoma on the anterior wall of rectum and livid colours of broad ligament. The peritoneal cavity was cleaned and revised. Any injury of the spleen or liver was excluded. DISCUSSION AND CONCLUSION: Haematoperitoneum after a normal vaginal delivery is rare but life threatening to mothers. It is important to recognize this condition to avoid delay in diagnosis and treatment because of high maternal mortality. Our patient was bleeding from superficial rectal vessels. Only a few cases with undefined aetiologies have been reported in literature. PMID- 21553472 TI - [Study of antibiotic resistance of enterococci strains received in 2009 in the National Reference Centre for Enterococci]. AB - Enterococci are a frequent cause of a variety of human infections, the most common being urinary tract infection followed by bacteraemia, meningitis and endocarditis from hospitalized patients. OBJECTIVE: The study and monitoring of antibiotic resistance of enterococci strains isolated and confirmed in 2009. MATERIALS AND METHODS: Identification of 30 strains received in 2009 was based on phenotypic characteristics (microscopy, culture and biochemical characters); antibiotic susceptibility testing was performed according to CLSI standards 2009 by diffusion test and MIC by agar dilution and E-test. RESULT: The strains belonged to the following species: E. faecalis (18), E. faecium (6), E. gallinarum (5), and E. durans (1), and were isolated from: blood cultures, urine, pus-wound, cerebrospinal fluid (CSF) and catheter. Antibiotic susceptibility testing showed susceptibility to different antibiotics depending on the species and also on the type of clinical samples. CONCLUSIONS: Due to the small number of strains, no resistance phenotypes could be determined. As emergence of antibiotic resistant enterococci is well known, continuous surveillance of antibiotic susceptibility and molecular study of this issue are required. PMID- 21553473 TI - [Antibiotic resistance of Gram-positive cocci isolated in 2008]. AB - OBJECTIVE: Antibiotic resistance evaluation of Gram-positive cocci isolated in 2008. MATERIAL AND METHODS: Antibiotic susceptibility testing was performed for 1044 strains: 610 Staphylococcus aureus (352 from patients, 258 from carriers), 203 Streptococcus pneumoniae (53 from patients, 150 from carriers), 144 Enterococcus faecalis. 57 Enterococcus faecium and 30 Streptococcus spp. using automatic systems Vitek 2 Compact. MicroScan, disc diffusion method and Etest according to 2008 CLSI. A number of 497 Streptococcus pyogenes strains were tested for eritromycin resistance. RESULTS: There were 33.2% MRSA for strains isolated from patients and 30.0% from carriers. From MRSA strains. 35.5% were resistant to gentamicin. 33.6% to ciprofloxacin, 74.3% to erythromycin and 30.5% to rifampin. There were no S. aureus strain resistant to vancomycin and linezolid. S. aureus strains isolated from wounds were more resistant to erythromycin (43.9%) than the strains isolated from systemic infections (12.1%). From 11 S. pneumoniae strains isolated from meningitis, 4 were resistant to penicillin. Neither S. pneumoniae strain isolated from other infections, nor those from carriers had MIC to penicillin more than 4 microg/ml. S. pneumoniae strains isolated from carriers were more resistant to erythromycin. clindamycin and tetracycline than the strains isolated from patients (66.7%, 54.1%, 54.2% vs. 27.4%, 22.6%, 33.9%). E. faecium was 95.9% resistant to penicillin, 90.2% to ampicillin, 64.7% to gentamicin, 72.0% to streptomycin and 78.4% to ciprofloxacin. F. faecalis was less resistant than E. faecium at most of the antibiotics: 32.4% to gentamicin, 59.6% to streptomycin, 28.5% to ciprofloxacin. Viridans group Streptococci, all isolated from blood culture were 92% susceptible to penicillin and ampicillin. To erythromycin, 12% of viridians group Streptococci were resistant. S. pyogenes resistance to eritromycin was 5.8%. CONCLUSIONS: S. aureus strains showed a relatively high level of resistance to oxacillin (33.2%) and resistance in the same time to several antibiotics. S. pneumoniae can not be considered resistant to penicillin administrated parenteral, with exception of the strains isolated from meningitis. E. faecium had a higher resistance rate than E. faecalis. PMID- 21553474 TI - [Study of Streptococcus pneumoniae strains resistant to antibiotics analyzed at "Cantacuzino" NIRDMI during 2006-2008]. AB - OBJECTIVE: The aim of the this study was the analysis of the resistance to antibiotics of Streptococcus pneumoniae isolated in last years. METHODS: 328 S. pneumoniae strains, coming from blood, CSF tracheal aspirate (TA), or sputum, pleural fluid (PL) and other samples (ear and sinus fluid) isolated in 2006-2008, were analyzed at INCDMI "Cantacuzino", National Reference Center for Streptococcus pneumoniae. Strains were tested for susceptibility to by agar diution method (minimal inhibitory concentration-MIC) to the following antibiotics: penicillin (Pc), erythromycin (Em), cephalothin (Kf). cefuroxim (Cxm), cefotaxim (Ctx), trimethoprim/sulfamethoxazol (Sxt), ofloxacin (Ojx), amoxicillin (Amx). tetracycline (Te), cloramphenicol (Cm), vancomycin (Va). RESULTS: The analysis of the results was done according to CLSI 2009. Pneumococci strains isolated from blood, CSF, TA or sputum and PL showed lower resistance level to antibiotics (38.8% Pc, 9.3% Cxm. 4.1% Ctx, 2.7% Amx. 24% Em, 2.4% Ofx, 68% Sxt) against those isolated from ear ans sinus fluid which revealed high levels of resistance (70% Pc, 11.2 % Cxm, 5.9 % Ctx, 3.4% Amx, 58.4 % Em. 3.8% Ofx, 73% Sxt). Strains resistant to penicillin, isolated from blood and CSF revealed the following aspects: 17% low level of resistance and 11 % high level of resistance. CONCLUSIONS. The most efficient antibiotics were Ctx, Amx and Oft. A continuous surveillance of pneumococci strains resistant to antibiotics is needed, as well as the use of an pneumococcal efficient vaccine. PMID- 21553475 TI - [Comparative study and sensitivity tests of Mycobacterium tuberculosis strains using nitrate reductase and absolute concentrations methods]. AB - INTRODUCTION: The alarming increase of cases of tuberculosis with resistant germs renders compulsory the orientation towards rapid and cheap methods that would allow large-scale testing of mycobacterial strains. AIM: Evaluation of the performances of two phenotypic methods for mycobacteria sensitivity testing. nitrate reductase and absolute concentrations. MATERIAL AND METHOD: In two different laboratories we tested the same set of 20 mycobacterial strains from the 2008/2009 international panel and an additional 10 strains isolated in the second laboratory, using the absolute concentration method as standard and the nitrate reductase method, both using Lowenstein Jensen medium with rifampicine and isoniaside incorporated The results obtained in both laboratories are concordant for both methods and show sensitivity and specificity of 100% for nitrate reductase method compared to absolute concentration method The results obtained using the two methods in the two laboratories also showed a 100% reproducibility. CONCLUSIONS: Nitrate reductase method is easy to perform and to acknowledge. It does not require special equipment, besides what is usually found in the laboratory. It showed a 100% sensitivity and specificity. The 100% reproducibility and repetability of results can represent arguments for a possible use of the methods in all the laboratories belonging to the national network of mycobacteriology laboratories, in order to screen for multiresistant strains. PMID- 21553476 TI - [Bacterial enteric pathogens' resistance to fluoroquinolones and last generation cephalosporines]. AB - The increase of incidence of resistance to the antibiotics became the most worrisome subject within the clinical and research communities in the medical fields. Intrinsic resistance genetic mutations, horizontal transfer of mobile structures carrying genes coding for resistance to the antibiotics within the pan microbial genome are representing the bacterial resistome which is bearing the genetic information regarding the defensive mechanisms developed by micro organisms to protect themselves against antibiotics. Rice in the resistance of enteric bacteria, pathogens involved in a large number of human infections, to the cephalosporin of last generation and to the fluoroquinolones is a very actual subject in the medical area. Production of beta-lactamases with extended spectrum is the most important enzymatic defence system, developed by micro-organisms, consisting in the inactivation of beta-lactam antibiotics by destroying the beta lactam ring. Enterobacteria are able to produce beta-lactamases of type TEM, SHV and/or CTX-M. Punctual mutations in nucleotide structure of bla genes, coding for beta-lactamases synthesis, are leading on production of a large diversity of enzymes with enlarged spectrum of activity (ESBL). At the beginning of 90's the first beta-lactamases resistance to clavulanic acid were detected and in our days more then 170 TEM, 120 SVH and 90 CTX-MESBLs are known. Escherichia coli strains are producing, firstly, TEM ESBLs, Klebsiella pneumoniae SHV ESBLs. and both are producing CTX-M type ESBLs, are resistant to the fluoroquinolones due to punctual mutations in nucleotide structure of gyr gene coding for gyrases production, enzymes involved in nucleic acids replication. Resistance to the antibiotics with extended activity is a public health threat due to their capacity of large spreading within bacterial population, when the coding structures are located on mobile genetic structures. The menace increase when genes coding for fluoroquinolones resistance (qnr) are identified on such of structures. PMID- 21553477 TI - [Macrolides, lincosamides, streptogramines (MLS): mechanisms of action and resistance]. AB - Macrolides, lincosamides and streptogramines are distinct antibiotic (AB) families, with different chemical structure, but with similar antibacterial spectre and mechanisms. Macrolides are natural products of secondary metabolism of several species of actynomyces; they represent a group of compounds with a lactonic ring of variable dimensions (12-22 atoms of C) that can bind, by means of glycosidic bonds, sacharridic and/or amino-sacharridic structures. Most of the MLS antibiotics are bacteriostatic. Their mechanisms consist in inhibiting protein synthesis. the target being 50 S subunit of the bacterial ribosome, the binding sites being different for the different MLS classes. Erythromycin (E) was introduced in therapy in 1952; quickly, several bacterial genera started developing resistance to E. Strains resistant to E were as well resistant to all macrolides and other antibiotics with different structures--lincosamides and streptogramines B--resistance phenotype called MLSB. The main molecular mechanisms for bacterial resistance to MLS are: (1) Target modification, coded by erm genes (>12 classes). In Gram-positive cocii MLSB resistance, regardless of erm gene, can be: inducible (i MLSB)--when the presence of the inductor AB is necessary for methylation enzyme production; constitutive (c MLSB)--when the methylation enzyme is continuously produced Distinction between iMLSB and cMLSB can be easily appreciated based on the phenotypic expression of bacteria. In streptococci--all MLSB antibiotics can act as methylase inductors. (2) The decrease of AB intracellular concentration by active efflux, coded by mef genes- also called M resistance phenotype, low level resistance (LLR). (3) AB inactivation (enzymatic modification of AB); there are different resistance phenotypes: MLSB +SA and L phenotype (in staphyilococci) or SA4 phenotype and L phenotype (in enterococci). PMID- 21553478 TI - [Nosocomial Clostridium difficile diarrhea--adverse effect of antibiotic therapy]. AB - C. difficile is recognised as the main cause for colitis in hospitalised patients which are treated with antibiotics, chemotherapics or other drugs that disturb intestinal microbiota. Thus, a rapid and correct diagnostic of Clostridium difficile infections is essential for preventing nosocomial infection spread. Empiric therapy, regardless of the laboratory investigation results, is inadequate, especially in epidemic situations, as not all the cases of diarrhoea are due to C. difficile infection. Other risk factors for CDAD (Clostridiumn difficile Associated Diseases might be: prolonged hospitalization or residency in an asylum, age, existence of a severe chronic disease in the background nasogastric intubation, anti-ulcer drugs, at less extent gastrointestinal surgery, other immunosuppresive compounds etc. In our country, C. difficile infection is rather frequent in adults, though it is not always reported by clinicians. The circulation of endemic rybotype 027 in Romania is not well documented, the rybotype being extremely virulent and spread in other European countries. Hence the importance of extending the diagnostic capacity of C. difficile infection in order to allow detection of this rybotype among the strains isolated in our country. PMID- 21553479 TI - [Antimicrobial resistance surveillance: from the bottle plunged into the ocean to a critical evaluation of the methods]. AB - According to the resolution adopted by the Member States in the "Microbial threat" Conference, Copenhaga, 1988. antimicrobial resistance surveillance is one of the four pillars of the control strategy of this increasingly serious public health problem, coming together with the antimicrobial consumption surveillance, intersectoral actions and antibiotics prudent use promotion. Seventeen years ago, O'Brien and col. were describing the current degree of the antimicrobial resistance surveillance as follow: "There are no reliable data in this area- simply fragments of information and anecdotes that we use to draw an overall picture" (Diagnostic Microbiology and Infectious Diseases, 1992, 15.53S-60S). Ten years later, Morris and Masterton were showing that there were reports underlying the big volume of activity delivered in the field of antimicrobial resistance surveillance during that time, but there were no major changes in respect of the data quality (JAC,. 2002, 49, 7-10). According to the WHO definition, surveillance, as continuous and systematic process of data collection, data analysis and data reporting, is reaching it's scope only if it is able to provide information valuable for action. Though it is by excellence a type of surveillance based on the microbiology laboratory activity, antimicrobial resistance surveillance is not coming to be useful according to the WHO and EUCAST (European Committee for Antimicrobial Susceptibility Testing) acception without using the epidemiology methods in order to make possible the adoption of a clear strategy, starting from the definition of the type of information that we want to obtain. Pending on the scope and taking into account the preexisting premises for setting up a surveillance network, we need to select the appropriate surveillance methods, in respect of data and strains collection and storage, data reporting, appropriate denominators (population categories. admission days, patient days etc.), data stratifying etc. In Romania there are few data on antimicrobial resistance surveillance which could resist to a critical evaluation of representativity, reporting to adequate denominators, stratifying methodologies which would allow to follow trends, comparing data by wards, hospitals, counties, intercomparing data with other countries etc. Contacting the European Antimicrobial Resistance Surveillance System in 2001 was an initial modality to decrease the huge gap existing by that time, but could not remain the unique solution to develop in this direction. On the other hand, participating in the European Antimicrobial Resistance Surveillance System is enforcing the involvement of all implicated professional categories, improving logistic and interdisciplinary collaboration, in order to set up a systematic surveillance. We are supporting the initiative of a critical evaluation of the existing situation, as of setting up a surveillance strategy in accordance with the targetted goals, starting from the recent recommendations of WHO and ESCMID Antimicrobial Resistance Surveillance Study Group. This initiative could contribute, together with the participation in the European antimicrobial resistance surveillance program, to the efficient turning account of the resources and uncoordinated and sometimes redundant efforts of different working groups including prestigious microbiology, infectious diseases and epidemiology specialists. PMID- 21553480 TI - [Trends of antimicrobial resistance in microbial strains isolated from invasive infections in Romania. Experience of participation in EARSS (European Antimicrobial Resistance Surveillance System), 2002-2008]. AB - EARSS (European Antimicrobial Resistance Surveillance System) is the biggest antimicrobial resistance surveillance project in the world financed from public finds, aiming to provide validated and comparable official data on antimicrobial resistance of invasive microbial strains (isolated from blood and CSF), belonging to 6 indicator bacterial species, i.e.: S. aureus, E. coli, E. faecium/faecalis, Str. pneumoniae, Ps. aeruginosa, K. pneumoniae. Romania reported data to EARSS since 2002 so far. Though the number of participating laboratories increased progressively from 12 to 35, the number of hospitals which reported for EARSS. as the number of strains included in the data base remained steady and relatively low. This issue is related to the particular position of Romania in the European context, in respect of the very low number of blood cultures performed in hospitals. Our paper is presenting the trends of antimicrobial resistance in the indicator strains in the 2002-2008 interval. During the 2002-2008 interval, Romania reported to EARSS a total number of 1276 bacterial strains, distributed by species as follows: 513 S aureus, 369 E. coli, 128 Streptococcus pneumoniae, 127 Enterococcus spp.. 71 Klebsiella pneumoniae, 68 Pseudomonas aeruginosa. Klebsiella pneumoniae and Pseudomonas aeruginosa were reported, according to the EARSS protocol, only for the 2005-2008 interval. It is difficult to describe trends, specially in Enterococcus, Streptococcus pneumonaie and the 2 species collected only since 2005, because of the low number of isolates, but there are several results that are supporting us to claim that antimicrobial resistance in invasive isolates is a real problem in Romanian hospitals, like in other Central, Southern and South Eastern European countries: more than 25% of S. aureus strains resistant to methicilline, with more than 50% in some years, high aminoglycozides resistance in more than 70-80% of Enterococcus faecium invasive strains, more than 80% of strains resistant to 3rd generation cephalosporines etc. PMID- 21553481 TI - [Bacterial strains isolated from systemic infections and reported for evaluation and antibiotic resistance surveillance by the "Dr. Victor Babes" Clinical Hospital for Infectious and Tropical Diseases, Bucharest]. AB - AIM: Testing antibiotic resistance of bacterial strains (compulsor, reported for EARSS surveillance) isolated from patients hospitalised for systemic infection in the "Dr. V. Babe" Hospital for Infectious and Tropical Diseases during 01.01.2005 11.11.2009, for a dynamic evaluation and for the surveillance of resistance emergence for certain classes of antibiotics. MATERIAL AND METHODS: Bacterial isolation: BacT/ALERT system; strain identification in classic and automated system (ATB Expression. VITEK 2C): antibioresistance: disk-difussion method (NCCLS 2005--CLSI 2009), MIC (E-Test, ATB/ Expression, VITEK 2C). Screening of ESBL-producing strains performed with double disk-difussion method (DDD). Reference strains used: S. aureus ATCC 25923, S. pneumoniae ATCC 49619, E. coli A TCC 25922, Enterococcus fiecalis ATCC 29212. RESULTS: During the studied period, 245 bacterial strains have been isolated, identified and tested (Staphylococcus aureus / 70, Streptococcus pneumoniae / 61, Enterococcus faecalis / 18, Enterococcus faecium / 5, Neisseria meningitidis / 18, E. coli / 73). out of 166 hemocultures and 79 cerebrospinal fluids / CSF. The average incidence of MRSA strains in systemic infections was 34.28%. 44.28% of the S. aureus strains were resistant to erythromycin, 17.14% to cyprofloxacyne, 15.71% to rifampicine, 14.49% to gentamycine. No strain resistant to vancomycine and linezolide. Streptococcus pneumoniae presented an average high resistance to penicillin G of 11.47%. and a 1.63% resistance to third generation cephalosporines. 0% resistance to vancomycine and rifampicine. 7/ 18 Enterococcus faecalis strains and 4/5 Enterococcus faecium strains presented high level resistance to gentamycine (CN 120 microg/disk) and no strain was resistant to vancomycine, teicoplanin or linezolid. The 18 Neisseria meningitidis strains were all sensitive to beta lactams, macrolides, fluoroquinolones and cloramphenicol. For the 73 Escherichia coli strains, the average incidence of ESBL-producing isolates was 10.95%, the average resistance to ampicillin was 58.90%, to gentamycine--13.88% and to cyprofloxacin--20.83%. No strain resistant to carbapenemes and amikacine. CONCLUSIONS: For the systematic surveillance of antibiotic resistance there is a need for a harmonised protocol of data gathering and strain selection and the rigurous implementation of correct evaluating methods for antibiotic resistance in the microbiology laboratory. Carbapenemes. glycopeptides and oxazolidinones still present a major effectiveness in the first intention treatment of systemic infections. PMID- 21553482 TI - [Evaluation of antibiotic resistance in the frame of the surveillance system for nosocomial infections. Strong and weak points]. AB - Since 2005 a sentinel system for surveillance of nosocomial diseases has been introduced in Romania which had, among other objectives, the evaluation of antibiotic resistance. The surveillance methodology was shared annually, the number of participants varying between 12 and 40 hospitals. During 2005-2008 the Reference Laboratory for Nosocomial Infections and Antibiotic Resistance in the "Cantacusino" NIRDMI received 1481 bacterial strains, comprising 531 S. aureus, 486 Pseudomonas aeruginosa, 439 enterobacteria and 25 enterococci strains. The resistance percents widely differred for some species, especially regarding the type of hospital unit that sent the strains (ex., Pseudomonas aeruginosa isolated form patients with burns). A great variability was noted concerning the manner in which nominalized hospitals responded to the solicitations in the methodology that was shared. especially regarding participation to a national bank for bacterial strains. Only for 5 out of the 40 hospitals that participated along the 4 years in the sentinel programme the annual comparative evaluations of antibiotic resistance were achieved. for a small number of microorganisms that underwent surveillance (S. aureus, E. coli). Among the strong points of the system we can point out: unity in methodology; working protocols for microbiological investigation given to all the participants; special forms for reporting. Among the weak points, we consider: modification in the number of participant hospitals during the program: unequal participation of hospitals, with unwanted effects on the sample representativity of analysed microbial strains; difficulties in stocking and processing laboratory data. In order to increase the quality of data provided, we consider the following as useful: harmonization of the objectives regarding integrated surveillance of nosocomial infections and antibiotic resistance in hospital environment, correlated with the ECDC demands and recommendations; inclusion in the system of sanitary units that fit the needs of the program fir microbiological identification and investigation of nosocomial infections; intensification of the training activities of persons involved in the program, regardless of the level of responsibility and the acknowledgement of each person's responsibilities in nosocomial infection monitoring; external and internal control implementation in the laboratories: selection of aspects concerning the emergence and spread of antibiotic resistance that come out during surveillance in order to be studied using molecular methods for the emphasizing of mechanisms and causes, in view of implementing measures for prevention and control; evaluation of the necessity for molecular investigation in view of identifying resistant bacterial clones in the hospitals in Romania etc. PMID- 21553483 TI - [Antimicrobial use and its correlations with the frequency of carbapenem resistant Pseudomonas aeruginosa strains in a hospital setting]. AB - One of the major causes leading to increased antibiotic resistance is excess antimicrobial consumption. We have analysed the correlation between antibiotic use and frequency of carbapenem-resistant Pseudomonas aeruginosa (CRPA) strains in the general intensive care unit of a university hospital Antibiotic use was expressed as number DDD (daily defined doses)/100 occupied hospital bed-days (BD). CRPA incidence rates were determined by number of unique isolates reported to 100,000 BD. The average use of antibiotics between January and August 2008 was 174 DDD/100 BD. The first four most frequently prescribed antibiotics were as follows: first and second generation cephalosporins (47 DDD/100 BD), carbapenemns (29 DDD/100 BD), fluoroquinolones (26 DDD/100 BD) and glycopeptids (20 DDD/100 BD). Average monthly incidence rate of CRPA was 546/100,000 BD (319-773/100,000 BD. CI 95%). There was a correlation between CRPA incidence rate and carbapenem plus fluoroquinolone use (Pearson coefficient of correlation r = 0.7, p < 0.05). Our data showed that the evolution of CRPA incidence rates was related to carbapenem and fluoroquinolone use. PMID- 21553485 TI - [Effects of physical environments on nucleation of protein crystals: a review]. AB - This paper reviews the effects of physical environments (including light, electric field, ultrasound, magnetic field, microgravity, temperature, mechanical vibration, and heterogeneous nucleation interface) on protein crystal nucleation. The research results are summarized and the possible mechanisms of the effects are discussed. In the end of this review, the application prospects of these physical environments (including coupled environments) in protein crystallization are presented. PMID- 21553484 TI - [Effect of sequential biocatalyst addition on Anammox process]. AB - Anaerobic ammonium oxidation (Anammox) process is a high-rate nitrogen removal technology that has been applied in sludge dewatering effluents treatment with nitrogen removal rate as high as 9.5 kg/(m x d). However, due to the slow growth rate of the autotrophic Anammox bacteria and the susceptivity to environmental conditions, the start-up of Anammox process is very long; the operation is unstable; and the nitrogen removal from organic-containing and/or toxicant containing ammonium-rich wastewaters using Anammox process becomes difficult. Thus, the application of this high-rate process is significantly limited. In this paper, a newly-developed Anammox process with sequential biocatalyst (Anammox biomass) addition was established based on the procedure in fermentation engineering. We introduced the Anammox process with sequential biocatalyst addition on start-up, stable operation and the treatment of organic-containing and toxicant-containing ammonium-rich wastewaters. Results show that supplementing high-activity Anammox biomass into reactors will increase the amount of as well as the ratio of Anammox bacteria. Thus, the innovative Anammox process with sequential biocatalyst addition not only accelerates the start-up course, but also enhances the stability of Anammox process. Furthermore, it overcomes the drawbacks of wastewaters containing high organic content and toxic substances. Therefore, the application of Anammox process may be further enlarged. PMID- 21553486 TI - [Role of estrogen-related receptor alpha in adipocyes lipolysis]. AB - Estrogen-related receptor a (ERRalpha) is a key regulator for energy metabolism and adipogenesis. However, its role in lipolysis is unknown. To study the function of ERRalpha in lipolysis, primary cultured differentiated porcine adipocytes were treated by a specific inverse agonist XCT790 or infected with adenoviral vector expressed ERRalpha for 48 h, in the absence and/or presence of specific protein kinase A (PKA) inhibitor or extracellular signal-related kinase (ERK) inhibitor. Then, we measured the triglyceride (TG) content and the glycerol release into the culture media to analysis the effect of ERRalpha on lipolysis; Further, we analyzed the expression of PPARgamma, perilipin A, p-perilipin A, HSL and ATGL with Western blotting. Here, we found that ERRalpha significantly increased adipocytes differentiation, TG accumulation and glycerol release. Separately or simultaneously block the PKA and ERK pathway do not significantly altered the effect of ERRalpha on glycerol release. ERRalpha significantly up regulated the proteins expression of PPARgamma, perilipin A, HSL and ATGL, while the p-perilipin A protein level was not significantly changed. These findings imply that ERRalpha could increase lipolysis via up-regulating HSL and ATGL, thereby to supply more FFA as substrate for a larger turnover of cellular triglyceride pool during adipocytes differentiation. PMID- 21553487 TI - [Prokaryotic expression, purification and preparation of polyclonal antibody for wheat grain peroxidase WP1 gene]. AB - Wheat peroxidases 1 (WP1) is the major cationic peroxidase of wheat (Triticum aestivum) grain, which is involved in the development of seeds and an important factor to affect the final processing quality of flour. We constructed a prokaryotic expression vector pET28a-WP1, and transformed it into E. coli host strain T7 Expression. His-tag fused WP1 existed as inclusion body, and the recombinant protein was purified by Ni-NTA resin affinity chromatography under denatured condition. The purity of target protein reached 98%. The recombinant WP1 was refolded by gradient urea dialysis, then used as antigen to immune rabbit to prepare polyclonal antibody. The result of ELISA showed that the titer of rabbit anti-WP1 antiserum was higher than 1:625 000. The result of Western blotting demonstrated that the prepared WP1 polyclonal antibody could be used to detect WP1 with high specificity. PMID- 21553488 TI - [Elimination of succinate and acetate synthesis in recombinant Escherichia coli for D-lactate production]. AB - When Escherichia coli CICIM B0013-030 (B0013, ack-pta, pps, pflB) was used for D lactate production, succinate and acetate were the main byproducts (as much as 11.9 and 7.1% the amount of lactate respectively). In order to decrease the byproduct levels, we inactivated succinate and acetate synthesis in B0013-030. Two recombinant plasmids containing mutation cassettes of frdA::difGm and tdcDE::difGm respectively were constructed first. The mutation cassettes were used to delete the target genes on the chromosomal by Red recombination. Subsequently, the antibiotic resistance gene was excised from the chromosomal by Xer recombination. Thereby, mutants B0013-040B (B0013-030, frdA) and B0013-050B (B0013-040B, tdcDE) were produced. D-lactate producing abilities of the engineered strains were tested both in shake flasks and in bioreactors using two phase fermentation (aerobic growth and anaerobic fermentation) with glucose as the sole carbon source. When fermentation was carried out in shake flasks, inactivation of frdA in B0013-030 to produce B0013-040B reduced succinate accumulation by 80.8%. When tested in a 7-liter bioreactor, B0013-040B accumulated 114.5 g/L D-lactate of over 99.9% optical purity. However, 1.0 g/L succinate and 5.4 g/L acetate still remained in the broth. Further inactivation of tdcD and tdcE genes in B0013-040B to produce B0013-050B decreased acetate and succinate accumulation to 0.4 g/L and 0.4 g/L respectively, and lactate titer was as much as 111.9 g/L (tested in the 7-liter bioreactor). In lightof the lower byproduct levels and high lactate production, strain B00 13-050B may prove useful for D-lactate production. PMID- 21553489 TI - [Diversity analysis of archaeal and fungal communities in adjacent cucumber root soil samples in greenhouse by small-subunit rRNA gene cloning]. AB - Soil archaea and fungi play important roles in the greenhouse soil ecosystem. To develop and apply rich microbial resources in greenhouse ecological environment, and to understand the interaction between microbes and plants, we constructed archaeal 16S rRNA and fungal 18S rRNA gene libraries to analyze the compositions of archaeal and fungal communities. Total greenhouse soil DNA was directly extracted and purified by skiving-thawing-lysozyme-proteinase K-SDS hot treatment and treatment of cetyltriethylammnonium bromide (CTAB). After PCR amplification, retrieving, ligating, transforming, screening of white clones, archaeal 16S rRNA and fungal 18S rRNA gene libraries were constructed. The sequences of archaea and fungi were defined into operational taxonomic units (OTUs) when 97% similarity threshold for OTU assignment was performed by using the software DOTUR. Phylogenetic analysis showed that crenarchaeota and unidentified-archaea were the two major sub-groups and only a few of euryarchaeota existed in the archaeal clone library, total 45 OTUs. All the crenarchaeota belonged to thermoprotei; except for Basidiomycotina, the other four sub-group fungi were discovered in the fungal library, total 24 OTUs. The diversities of archaea were very abundant and a few euryarchaeota (methanebacteria) existed in the archaeal clone library, it might be directly related to the long-term high temperature, high humidity, and high content of organic matter. The limitation of oxygen was the other reason for causing this phenomenon; Ascomycotina (over 80%) was the dominant sub-groups in fungal library. It was because most of the plant fungal diseases belonged to soil borne diseases which gone through the winter by the ways of scierotium or perithecium and became the sources of primary infection. PMID- 21553490 TI - [Mechanism of Cr(VI) biosorption by flocculating yeast]. AB - The flocculating yeast strain SPSC01 is a fusant strain of Saccharomyces cerevisiae and Schizosaccharomyces pombe. The use of SPSC01 to absorb Cr(VI) from Cr(VI) containing aqueous solution would greatly reduce the cost of post adsorption separation, since the superior flocculating property of SPSC01 would allow easy separation of the Cr(VI)-biomass from the solution. In order to investigate the effects of flocculating proteins on Cr(VI) reduction and absorption by SPSC01, the absorption behaviors of SPSC01 and its parental strains were compared. The results showed that Cr(VI) removal rate of SPSC01 was almost the same as that of S. pombe, which also has flocculating ability, but was faster than that of S. cerevisiae, which has no flocculating ability. When the system reached equilibrium, the amount of total Cr adsorbed by S. pombe, SPSC01 and S. cerevisiae were 68.8%, 48.6% and 37.5%, respectively. This showed that flocculation was beneficial to Cr(VI) reduction and adsorption, and suggested that focculating proteins may play a role in enhancing the Cr(VI) adsorption capacity of SPSC01 and S. pombe. We investigated the mechanism of Cr(VI) adsorption by SPSC01 using chemical modification and FTIR. The results indicated that the major functional groups (amino, carboxyl and amide) of surface proteins may contribute to the absorption of Cr(VI). PMID- 21553491 TI - [Cloning and sequence analysis of a new cathepsin L-like cysteine proteinase gene from Ditylenchus destructor]. AB - The Cathepsin L-like cysteine proteinase genes (cpls) are multifunction genes related to the parasitic abilities of plant parasitic nematodes. A new cathepsin L-like cysteine proteinase gene (Dd-cpl-1) (GenBank Accession GQ 180107) was cloned from Ditylenchus destructor by RT-PCR and RACE. The cDNA sequence consisted of a 1 131 bp open reading frame (ORF) encoding 376 amino acid residues that were franked by a 29 bp 5'-untranslated region (UTR) and a 159 bp 3'-UTR. Genomic sequence analysis showed that Dd-cpl-1 contained 7 introns, obeyed the GT/AG rule in the splice-site junctions. Homology analysis showed that the identity was 77% between Dd-cpl-1 deduced protein Dd-CPL-1 and cathepsin L-like cysteine proteinase of Bursaphelenchus xylophilus. Multi-sequence alignment indicated that there were the catalytic triad (Cys183, His322 and Asn343) and two motifs ERFNIN motif and GNFD motif in deduced protein Dd-CPL-1. Cysteine proteinases phylogenetic analysis showed that Dd-cpl-1 belonged to the sub-clade of cathepsin L-like cysteine proteinases. PMID- 21553492 TI - [Effects of phytohormones on plant regeneration and production of flavonoids in transgenic Saussurea involucrata hairy roots]. AB - We investigated the plant regeneration and production of flavonoids in three high yield flavonoids transgenic Saussurea involucrata hairy roots C17, C27 and C46 by quantification of two phytohormones GA3 and IAA. The results showed that GA3 concentration at more than 1.0 mg/L could induce adventitious shoots in the hairy root lines. The highest shoot regeneration rate, about 82%, was obtained when the hairy roots C17 were cultured with 2.0 mg/L GA3. The results on HPLC and UV spectrophotometry showed that exogenous application of both GA3 and IAA increased the content of flavonoids in the hairy roots. The contents of flavonoids and apigenin in the hormone-treated hairy roots and regenerates were higher comparing with those in the untreated hairy roots and the regenerates. However, the content of flavonoids was not related to tissue weight, and was negatively related to the regeneration efficiency. PMID- 21553493 TI - [Molecular characterizations of two dehydroascorbate reductases from Selaginella moellendorffii]. AB - Plant dehydroascorbate reductase (DHAR) is a physiologically important reducing enzyme in the ascorbate-glutathione recycling reaction. In this study, two DHARs genes (SmDHAR1 and SmDHAR2) were isolated from Selaginella moellendorffii. The SmDHAR1 and SmDHAR2 genes encode two proteins of 218 and 241 amino acid residues, with a calculated molecular mass of 23.97 kDa and 27.33 kDa, respectively. The genomic sequence analysis showed SmDHAR1 and SmDHAR2 contained five and six introns, respectively. Reverse transcription PCR revealed that the SmDHAR1 and SmDHAR2 were constitutive expression genes in S. moellendorffii. The recombinant SmDHAR1 and SmDHAR2 proteins were overexpressed in E. coli, and were purified by Ni-affinity chromatography. The recombinant SmDHAR1 showed 116-fold higher enzymatic activity towards the substrate dehydroascorbate than recombinant SmDHAR2. The recombinant SmDHAR1 showed higher thermal stability than recombinant SmDHAR2. These results indicated obvious functional divergence between the duplicate genes SmDHAR1 and SmDHAR2. PMID- 21553494 TI - [Effect of adenovirus-mediated ING4 and IL-24 co-expression on chemosensitivity to human lung adenocarcinoma in vitro and in vivo]. AB - To study the chemosensitivity and the mechanisms of recombinant adenovirus vector expressing ING4 and IL-24 (Ad-ING4-IL-24) on lung adenocarcinoma in vitro and in vivo, the expression of ING4 and IL-24 in A549 cells was detected by RT-PCR and Western blotting. The growth inhibition, apoptosis rate and apoptosis body were measured by MTT, flow cytometry and Hoechst staining respectively. For in vivo study, we first established the A549 tumor model by grafting A549 cells in athymic nude mice; and then injected Ad-ING4-IL-24 into the tumors. Two weeks after injection, we killed the mice, removed the tumors, weighted and calculated the ratios of tumor-suppression. We also detected the expressions of ING4, IL-24, bax, bcl-2, VEGF with immunohistochemistry. The results indicated that ING4 and IL-24 were proved successfully transcription and expression in A549 cells. More interestingly, the joint group inhibited the growth of A549 cells and induced apoptosis. The in vivo data showed that the joint group suppressed the tumor growth conspicuously through up-regulating the expression of bax, and down regulating the expression of bcl-2, VEGF. The study proved that Ad-ING4-IL-24 significantly enhanced the chemosensitivity to anticancer drug DDP in lung adenocarcinoma, which may related with cell apoptosis and antiangiogenesis. PMID- 21553495 TI - [Boosting with HBV subunit particle vaccine enhance immune response of novel DNA vaccine consisting of S-PreS1 fusion gene in mice]. AB - To develop novel and effective HBV therapeutic vaccine, we constructed an expression vector, pVRC-HBSS1, in which PreS1 (21-47aa) coding gene fused to the C-terminal of the S (1-223 aa) coding gene of HBV, and prepared the protein particle vaccine HBSS1 that consist of S and PreS1 fusion antigen derived from CHO system. We immunized mice by priming three times with DNA vaccine via different methods (i.e., intramuscular injection, intradermal injection with electroporation), then boosting once with protein particle vaccine. We analyzed the immune response among various vaccination groups. The higher level of S or PreS1 specific antibodies was detected in the group via intradermal injection with electroporation, compared with that of direct intramuscular injection. We further found that the specific cellular immune responses (IFN-gamma ELISpot analysis) in the group priming with DNA vaccines and boosting with protein subunit vaccine particles, was significantly higher than that of the DNA or protein particle subunit alone. Moreover, combination vaccination priming with intradermal injection DNA via electroporation and boosting with protein particle induced the strongest cellular immune response. These results provide a basis for rational design and application of the novel HBV therapeutic vaccine. PMID- 21553496 TI - [Construction of yeast Pichia pastoris to produce Man5GlcNAc2 mammalian mannose type glycoprotein]. AB - Glycosylation is vital for activity, higher structure and function of protein. Glycoproteins derived from yeast contain N-glycan of high mannose type and are usually hyperglycosylated, while those from mammalian cells contain N-glycan of hybrid or complex type. We introduced the alpha-1,2-mannosidase I (MDSI) into yeast cells, which catalyzed an essential proceeding of N-glycan structures from Man8GlcNAc2 to Man5GlcNAc2. The plasmids contained MDSI genes from Homo sapiens [HMDSI(delta185)] or Arabidopsis thaliana [ATMDSI(delta48)], and three ER-signals were used to be transformed a mutant Pichia pastoris GJK01, respectively. The reporter protein HSA/GM-CSF (human serum albumin and granulocyte-macrophage colony stimulating factor fusion protein) was expressed and its N-glycans were analyzed by DSA-FACE (DNA sequencer assisted fluorophore-assisted carbohydrate electrophoresis). The plasmid contained ER-ScMnsI-ATMDSI(delta48) was expressed in Pichia pastoris, the Man5GlcNAc2 N-glycan on secreted glycoprotein HSA/GM-CSF was observed. The research reported here provided basic substrate to obtain the hybrid- and complex-type glycans in mammalian cell. PMID- 21553497 TI - [Expression of porcine interleukin-18 in baculovirus/insect cells]. AB - IL-18, as a polyphonic cytokine, is important in immune response and physiologic function. We designed one pair of primers, amplified the porcine IL-18 gene fused with a C-terminal 6xHistidine tag, and then subcloned into the pFastBacDual of Baculovirus transfer vector and transformed into DH10Bac containing a shuttle vector of Bacmid. After co-transfecting the recombinant plasmid into insect cells, the 18 kDa expressed protein of porcine IL-18 was detected by SDS-PAGE; the specificity of expressed protein was confirmed by Western blotting. The purified porcine IL-18 protein induced obvious proliferation of porcine T lymphocytes in vitro, which indicated that the expression of IL-18 had high biological activity. PMID- 21553498 TI - [Analysis of porcine preadipocytes differentiation by atomic force microscope]. AB - Abnormal changes during fat formation are closely related to the prevalence of many diseases. In order to understand the formation mechanism of fat, we used atomic force microscopy (AFM) to characterize the morphology and mechanical properties of porcine preadipocytes during the differentiation. Preadipocytes and adipocytes were different morphologically. The surface roughness of adipocytes was less than preadipocytes by detection of the ultrastructure. The mechanical properties of preadipocytes were changed during differentiation with AFM-based force spectroscopy. Preadipocytes were 20% higher than adipocytes in the adhesion force, stiffness and Young's modulus. Therefore, AFM analysis of membrane changes related to adipocytes formation provided quantitative data in the nanometer level for further studying the formation mechanism of the adipocytes. PMID- 21553499 TI - [Distribution and force spectroscopy of CD20 antigen-antibody binding on the B cell surface]. AB - The lower expression of CD20 antigen molecules on the B cell membrane is the primary characteristic of B-chronic lymphocytic leukemia (B-CLL). In this paper, we combined laser scanning confocal microscopy (LSCM) and quantum dots labeling to detect the expression and distribution of CD20 molecules on CD20+B lymphocyte surface. Simultaneously, we investigated the morphology and ultrastructure of the B lymphocytes that belonged to the normal persons and B-CLL patients through utilizing the atomic force microscope (AFM). In addition, we measured the force spectroscopy of CD20 antigen-antibody binding using the AFM tips modified with CD20 antibody. The fluorescent images indicated that the density of CD20 of normal CD20+B lymphocytes was much higher than that of B-CLL CD20+B cells. The AFM data show that ultrastructure of B-CLL CD20+B lymphocytes became more complicated. Moreover, the single molecular force spectroscopy data show that the special force of CD20 antigen-antibody was four times bigger than the nonspecific force between the naked AFM tip and cell surface. The force map showed that CD20 molecules distributed homogeneously on the normal CD20+B lymphocytes, whereas, the CD20 molecules distributed heterogenous on B-CLL CD20+B lymphocytes. Our data provide visualized evidence for the phenomenon of low-response to rituximab therapy on clinical. Meanwhile, AFM is possible to be a powerful tool for development and screening of drugs for pharmacology use. PMID- 21553500 TI - [How to treat children and adolescents with type 1 diabetes mellitus?]. AB - Internationally, long-term therapeutic objectives for type 1 diabetes (e.g. HbA1c value) have been strengthened. At the same time, achievement of these objectives have become more realistic than before. Treatment of juvenile diabetes is still complicated by fear of hypoglycemia, fluctuating blood glucose levels and feeling of being different. Regular monitoring of blood glucose levels, optimization of insulin therapy, regular physical exercise and adhering to a healthy diet and regular rhythm of meals still constitute the cornerstones of diabetes therapy. For the goals to be realized, it is important that a multiprofessional team and the family commit themselves to good treatment. PMID- 21553501 TI - [Assessment and treatment of cannabis use disorders in primary health care]. AB - In Finland every fourth young adult (25 to 34 years of age) has experience with the use of cannabis and in younger people (15 to 24 years) about 10% have used it during the previous year. The majority (about 90%) neither becomes addicted nor develops significant psychiatric symptoms, but in some individuals regular cannabis-use can cause a variety of problems (health, emotional, behavioural, social, legal). If problems have not yet developed or are still minor, patient's cannabis-use may be addressed by brief intervention in a primary care setting. Also, treatment of uncomplicated cannabis withdrawal as well as of minor symptoms from smoking (bronchitis, sleep disturbances), can be treated in community health centres. Children and adolescents, pregnant individuals or those with psychiatric symptoms should be treated by services with expertise in addiction medicine. PMID- 21553502 TI - [Neuromodulation in urology and proctology]. AB - Electrical stimulation of sacral nerve roots is called neuromodulation. In urology, neuromodulation has been used for the treatment of frequency syndrome, urinary incontinence and urinary retention. Faecal incontinence and constipation are the most significant indications for the use of neuromodulation in gastroenterology. Carefully selected patients should be evaluated by trial test during which the symptom diary will be filled before implantation. Permanent generator implantation can be done for patients with significant objective relief of symptoms. Generator setting can be adjusted by a remote control. Clinical trials have shown the benefit of neuromodulation in long-term. Implanted patients have to stay under routine follow-up in order to detect device malfunctions. PMID- 21553503 TI - [Internet-based cognitive-behavioral therapy in the treatment of psychiatric disorders]. AB - Recent years have seen the development of Internet-based cognitive-behavioral therapy, i.e. psychological self-help program mediated via the Internet, the patient being in contact via e-mail with the support person directing the therapy. Internet-based cognitive-behavioral therapy usually consists of psychoeducation, exercises and prevention of the recurrence of symptoms. Modules of the network program are thus the cornerstones of "live" cognitive-behavioral therapy. Self-help provided by Internet-based cognitive-behavioral therapy therapy has been found to be effective especially in the treatment of panic disorder, social phobia and depression, providing an opportunity to extend therapeutic services also to persons beyond the reach of traditional therapy. PMID- 21553504 TI - [Whey protein and creatine as nutritional supplements]. AB - Nutritional supplements are very popular especially among athletes although some studies show either controversial or even negative results. However, whey protein and creatine seem to have positive effects on muscle size, strength and athletic performance without major adverse effects and high costs. Most studies have shown that supplementation of whey protein can enhance muscle growth in response to resistance training. Some studies also suggest that whey may enhance recovery from heavy exercise and possibly decrease muscle damage and soreness. Creatine supplementation increases the intracellular pool of phosphocreatine in skeletal muscle. Phosphocreatine provides a reserve of energy to rapidly regenerate ATP, which is consumed as a result of muscle contraction. Creatine has been studied in hundreds of clinical trials and has shown benefits including increased muscle strength, power and size. PMID- 21553505 TI - [Multiple chemical sensitivity is for real]. AB - Diagnosis of multiple chemical sensitivity is based on symptoms described by the patient. Sometimes the symptom is manifested as flushing of the face and as watering of the eyes and nose. Patients with multiple chemical sensitivity do not sense lower concentrations of scents and smells than do healthy persons, but their olfaction does not adapt to the smell. Because the mechanism of the sensitivity is not properly known, a good treatment does not exist. Some patients are alleviated by antihistamines or nasally sprayed corticosteroids or dilute local anesthetics. The best way is to avoid intense smells. PMID- 21553506 TI - [Elevation of hepatic enzyme values in hyperthyroidism]. AB - Serum or plasma alanine aminotransferase (ALAT) activity may sometimes exhibit even considerable increases in connection with hyperthyroidism and present a diagnostic as well as a therapeutic problem. Open questions include whether the hepatic change is related to a primary disease, and how to select treatment. We report two patients, in whom carbimazole medication initiated for Graves' disease normalized elevated ALAT values. PMID- 21553507 TI - [Pediatric septic shoulder arthritis. Is routine arthrotomy still necessary?]. AB - BACKGROUND: Arthrotomy is recommended as a routine treatment for childhood septic arthritis of the shoulder, although scientific evidence is lacking. Suggested alternatives are arthroscopic lavage, serial aspirations and a mere diagnostic aspiration. MATERIAL AND METHODS: 9 patients with septic arthritis of the shoulder aged 3 months to 12 years underwent a diagnostic aspiration after which large dose antimicrobials were given qid (clindamycin or 1st generation cephalosporin). RESULTS: One child underwent arthrotomy, otherwise all patients recovered normally. There were no sequelae. CONCLUSIONS: Routine arthrotomy for all patients is of questionable value in the emergency treatment of septic shoulder arthritis in children. PMID- 21553508 TI - [Update on current care guidelines: management of adult obesity]. AB - Diagnosis is based on body mass index and waist circumference. The aim of treatment is to prevent and alleviate obesity comorbidities (e.g. type 2 diabetes, cardiovascular diseases, sleep apnoea and osteoarthritis) through a permanent weight reduction of at least 5%. The core element in management is lifestyle counselling on eating and exercise behaviours. This should be organised in primary care. Modalities supporting lifestyle changes include very-low-energy diets and orlistat drug therapy. Obesity surgery is indicated in cases of morbid obesity, if the appropriate conservative therapies do not lead to substantial weight loss. A flowchart presenting treatment options at different levels of health care is introduced. PMID- 21553509 TI - [Volunteering in the health system]. PMID- 21553510 TI - [New intravenous infusion: another step forward in patient safety]. AB - We describe a new intravenous infusion (Intrafix SafeSet) with a number of improvements over conventional equipment designed to increase patient safety and simplify the work of nursing. Its design incorporates a special filter in the drip chamber that prevents air entry into the computer and into the bloodstream after exhaustion of fluid infusion. As a result, reduces the risk of air embolism, limiting the manipulations on the circuit and reduces the risk of contamination and infection. The presence of another filter at the distal part prevents fluid leakage during the priming process, enabling the automatic execution of it. PMID- 21553511 TI - [Historical aspects of the use of physical restraint: from antiquity to the era of moral treatment]. AB - The implementation of harsh methods of restriction has been seen since ancient times as an acceptable solution to the problems caused by mental illness. This practice was hardly questioned and only a few professionals struggled to improve the hard living conditions of the patients. Amongst these can be mentioned some physicians of ancient Greece and Rome: such as, Caelius Aurelianus, Asclepiades or Soranus of Ephesus, who objected to this procedure. During the Middle Ages, Arabic culture also helped to humanize care in the first hospitals for the insane, Avicenna being one of the most important figures. By contrast, in Medieval Europe madness was seen as a form of sin, and punishment was the way to treat it. Already by the fifteenth century asylums in Valencia and Zaragoza were pioneering the removal of chains and more humane treatment. Although, undoubtedly the most notable advances in the care of mental patients occurred during the eighteenth century through moral treatment, Philippe Pinel being its most well known practioner. Also at this time, the benevolent efforts of the Quakers stood out. As an alternative to shackles, they introduced occupational programmes to stimulate patients; in fact, this type of therapy had already been applied centuries before. To put this phenomenon in perspective, it can be said that discussions about physical restraint have been taking place since ancient times, causing debate amongst professionals for many centuries, when considering its advisability. PMID- 21553512 TI - [Physical restraint of patients: historical notes relating to the nineteenth and twentieth century]. AB - Physical restraint has been historically considered a necessary procedure to control the behaviour of the mentally ill. In the late eighteenth century moral treatment would pave the way for new initiatives against restraint, such as those instituted by British psychiatrists. They stressed the importance of training and supervision, as well as a minimum staff ratio, as being determining factors in reducing the use of restraint. This philosophy of treatment, despite its benefits, was introduced later and to a lesser extent in the rest of Europe, although, in other countries care was also made more humane through new therapeutic procedures. By contrast, in the United States most psychiatrists disagreed with those who advocated non-restraint, and continued using controversial methods to control the behaviour of patients. In Spain many difficulties hindered the improvement of conditions in institutions, many of which were in a sorry state. The initiatives of a few professionals and some cautious legal advances tried to alleviate the harshness of the treatment methods used. In the early twentieth century professional manuals were already available, which included the care to be given during the application of physical restraints. However it was not until the 1950, when the emergence of new psychotropic drugs and the distribution of important guidelines on the protection of the rights of patients that the widespread use of this procedure would be successfully reduced. PMID- 21553514 TI - [The art of positive relations. Interview by Maria Jesus Nadal Nadal]. PMID- 21553513 TI - [Nursing care in the patient with an artificial airway in the intensive care unit]. AB - INTRODUCTION: Complications related to the artificial airway (endotracheal tube and tracheotomy) in intensive care units are a major health problem that depends largely on the management and care applied to these devices. The daily challenge of nursing professionals is to minimize the incidence of these complications (among which highlights the pneumonia associated with mechanical ventilation). INTERVENTIONS: We analyzed 21 measures related to management of these devices in order to reflect the recommendations based on scientific evidence and provide quality care applied to the patient that need these devices. CONCLUSIONS: Compliance with the standards for care and management of patients with an artificial airways is vital in reducing the incidence of complications associated with these devices. Not all management rules are standardized. PMID- 21553515 TI - [Systems of measurement of body temperature]. AB - Measuring body temperature is a common practice in the area of care. There are various measuring instruments, ranging from simple glass thermometers to sophisticated electronics that allow measurement in different body sites. This article presents the advantages and disadvantages of different thermometers are currently on the market. PMID- 21553516 TI - [Safety patient in medication use and administration]. AB - We face two realities of great importance in health today: first patient safety as a basic and essential component of quality of care, and secondly the complexity of drug management. Ensure appropriate use and administration medication is essential to guarantee patient safety and necessary condition to ensure optimal levels of quality of clinical practice. We made an analysis of both realities to see what are the implications to health professionals in this area. PMID- 21553517 TI - [Clinical analysis on 15 cases with cystic lymphangiomas located in head and neck in children]. AB - OBJECTIVE: To discuss the diagnosis and effective treatment of cystic lymphangiomas located in head and neck in children. METHOD: Fifteen cystic lymphangiomas,diagnosed with pathological evidence, located in head and neck in children were retrospectively analyzed including clinical characteristics, diagnosis, treatment and follow-up data. RESULT: CT and ultrasonography were used to evaluate the size, shape and extent of lymphangiomas in all patients. All patients were treated with surgery. Complete resection was performed in 14 cases, and subtotal resection in one case. Two post-operative complications were found,one was paralyses of mandibular branch of facial nerve, another was Horners syndrome. Tracheotomy operation was done in one case,and the tracheal cannula was taken away before discharged from hospital. Fourteen patients were followed up. There was no recurrence during the follow-up from 6 months to 8 years, while one case who suffered from Horner's syndrome after operation was not cured. CONCLUSION: CT and ultrasonography are effective to diagnose cystic lymphangiomas and evaluate the security of clinical treatment. Total or subtotal resection is effective to treat cystic lymphangiomas. PMID- 21553518 TI - [Follicular dendritic cell sarcoma: a case report and review of literature]. AB - OBJECTIVE: To report a case of follicular dendritic cell sarcoma (FDCS) of tonsil,analyze its clinical and pathological features, as well as the diagnosis and differential diagnosis. METHOD: Tonsillectomy of low temperature coblation were done with general anesthesia. Histopathology, immunohistochemistry, electron microscope were used to analyzed the features of FDCS. The clinical character and treatment were reported. RESULT: There was no evidence of recurrence in two years. CONCLUSION: A correct diagnosis of FDCS was difficult to make , and immunohistochemical and ultrastructural studies are useful to FDCS's diagnosis. Low temperature coblation used in FDCS need more experience. PMID- 21553519 TI - [Clinical analysis of plasma cell granuloma occurred in head and neck]. AB - OBJECTIVE: To discuss the diagnosis and treatment of plasma cell granuloma in the head and neck region. METHOD: Retrospective analysis of 3 cases of plasma cell granuloma occurred in head and neck. One case treated with endoscopic surgery and nasal and oral steroids after operation. Two cases treated with Caldwell-Luc style resection, followed by oral steroids and radiotherapy, one of the two cases combined with chemotherapy simultaneously. RESULT: The patient done with endoscopic surgery followed up for 5 years, there was no tumor recurrence in the nasal cavity and maxillary sinus openings and sinus lining. Paranasal sinus CT was examed on the patient done with partial resection and radiotherapy 2 years after operation, no residual tumor proliferation. The third patient underwent paranasal sinus CT examination 3 years after operation, and no limitation of mouth opening was found. CONCLUSION: The incidence rate of Plasma cell granuloma occured in head and neck is low. It is an inflammatory disease, but its physical signs and imaging findings are similar to malignant tumors. Because of the invasion feature, surgical resection should be the first choice, and if combined with radiotherapy and chemotherapy, the prognosis could be better. PMID- 21553520 TI - [The changes of memory and their correlations to S100beta protein as well as neuron-specific enolase in patients with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To explore the possible mechanism of brain damage and memory impairment in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) by detecting the memory, serum S100beta protein, neuron specific enolase( NSE) and analyzing the relationship among them. METHOD: Thirty patients with moderate or severe OSAHS (AHI > 20/h) and twenty normal controls were included in this study. All subjects were detected by polysomnography in the sleep laboratory and the memory of them were evaluated before PSG examination. Memory tests including point memory, association learning, picture free recall, meaningless picture recognition, face characters associated memory have been conducted. The serum S100beta protein was detected by ELISA and the serum NSE was detected by immunoradiometric assay. The relationship between memory and serum S100beta as well as NSE were analyzed in both experiment group and control group. RESULT: The score of point memory, association learning, meaningless picture recognition, face characters associated memory and memory quotient in patients with OSAHS was significantly lower than control group (P < 0.05). The serum S100beta and NSE level was significantly higher than control group (P < 0.05); and correlated positively with AHI as well as ODI; and correlated negatively with MSaO2. Memory quotient correlated negatively with AHI, ODI, serum S100beta and NSE level; and correlated positively with LSaO2, MSaO2. CONCLUSION: Memory impairment were present in patients with OSAHS. The increased level of serum S100Beta and NSE may be one of the mechanisms of brain damage and memory impairment in with, OSAHS. And nocturnal hypoxia may contribute to the increased level of serum S100beta and NSE. PMID- 21553521 TI - [Research on the serum levels of matrix metalloproteinase-9 and free fatty acids in OSAHS cases]. AB - OBJECTIVE: To study the expression of matrix metalloproteinase-9 (MMP-9) and free fatty acids (FFA) in obstructive sleep apnea-hypopnea syndrome(OSAHS) patients. And the relativity among the serum level of MMP-9, FFA, four factors of blood lipids,hypopnea index (AHI), minimum oxygen saturation, body mass index (BMI) in OSAHS patients. METHOD: Fifty cases diagnosed of OSAHS,with integral clinical data in our department, were enrolled in the research. Fifty cases were selected as control group by the sleepiness scale score and the exclusion of the physical examination OSAHS. There was no significant difference (P > 0.05) of the body mass index (BMI) and age in the two groups. Two fasting venous blood samples of 3 ml were taken from every object in the morning wake from sleep monitoring and kept at room temperature for 30 min. The samples were sent to the laboratory to test the four factors of blood lipid and the FFA by colorimetric determination. Another fasting venous blood samples of 3 ml was preserved in refrigerator at -75 degrees C, used for serum MMP-9 test with Enzyme-linked immunoadsorbent assay (ELISA). SPSS 13.0 statistical software was used for all relevant data processing and analysis. RESULT: Serum levels of MMP-9 and FFA in severe OSAHS cases were significantly higher than those in control group (P < 0.01). Serum four factors of blood lipids level of severe OSAHS was a little higher(P < 0.05) than those in control group. There were a close relationship among serum FFA and TG, LSaO2 , BMI and AHI in severe O()SAHS patients. Serum FFA level was positively related with TG, BMI and AHI and negatively related with LSaO2. There were also a close relationship among serum MMP-9 and FFA, LSaO2 and AHI. The serum MMP-9 was positively related with FFA and AHI and negatively related with LSaO2. There was a positive linear correlation between serum FFA concentration and MMP-9 concentration in severe OSAHS cases. CONCLUSION: The higher risk of endocrinopathy and cardiovascular diseases were happened in OSAHS patients. The higher expression of both MMP-9 and FFA in OSAHS cases suggested a higher risk than that of the single high expression of them. PMID- 21553522 TI - [Coblation treatment of partial tonsillectomy in children with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To investigate the efficacy and feasibility of coblation treatment of partial tonsillectomy in children with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHOD: The clinical datum of 91 children with OSAHS were retrospective analysis during the period from January 2009 to November 2009. All subjects, the main obstructive lesions were hypertrophy of tonsils and adenoids ,and which without recurrent pharyngodynia and tonsillitis, were applied with coblation treatment of partial tonsillectomy and adenoid ablation. RESULT: Intraoperative blood loss was about 1-2 ml in all subjects,no primary and delayed hemorrhage happened and postoperative pain happened. All subjects were followed-up for 12 months to 22 months, symptoms of snoring and mouth breathing disappeared. No tonsil regeneration and repeated inflammatory episode was found. CONCLUSION: Coblation treatment of partial tonsillectomy in children with OSAHS is micro invasive, safe and effective, which is suitable for children of different age groups with hypertrophy of tonsils. PMID- 21553523 TI - [Primary clinical outcome of the tongue mobility via deep cervical nerve or accessory nerve-restored sublingual nerve]. AB - OBJECTIVE: To explore the clinical prognosis of sublingual nerve anastomosis with a branch of the deep cervical nerves or accessory nerve. METHOD: To retrospectively analyze 2 cases of paraganglion tumor,in which the sublingual nerve were disconnected because of overdrawing of surrounding tissue and tumor invasion. One branch of deep cervical nerve or accessory nerve was dissected and anastomosed to the distal end of sublingual nerve. Steroids and nerve nutritional chemicals were given after operation, and early functional physical exercise was recommended for the two patients. RESULT: The lingual mobility of the two patients was restored partially 1 to 2 months after operation, while the tongue of lesion side suffered from slight atrophy especially in the posterior 1/2 part. The patients experienced better and better mobility of the tongue. CONCLUSION: Sublingual nerve anastomosis with a branch of the deep cervical nerves or accessory nerve is viable. It could be a reconstructive modality for patients suffered from sublingual nerve disconnected. PMID- 21553524 TI - [CT scan of frontal recess]. AB - OBJECTIVE: To make 3-D reconstruction of frontal recess by high speed spiral CT, which can be helpful to nasal endoscopic frontal sinus operation. METHOD: Fifty one cases (102 laterals) of frontal recess 3-D reconstruction by 16 line high speed spiral CT were enrolled in the research, which included 58 laterals with chronic frontal sinusitis and 44 laterals of normal nasal sinus. The structure of frontal recess, the agger nasi and the adhere style of uncinate process were recognized. The parameter of frontal recess was measured. Finally the data of two groups were compared and analyzed. RESULT: CT 3-D reconstruction of frontal recess could display the frontal sinus, frontal endosome and frontal recess. The shape of frontal recess varied greatly in different cases, which depended on the near structure especially agger nasi and uncinate process. The difference of average Y axes inner diameter between agger nasi and frontal endosome was significant. The difference of average Y axes inner diameter between frontal endosome and anterior nasal spine, between the line of frontal endosome to anterior nasal spine and the line of Aeby's plane and between bhullar cell and anterior nasal spine were not significant in two groups. CONCLUSION: The drainage flow of frontal recess depends on the near structures especially on the agger nasi and uncinate process. The prevalence of agger nasi is high, and the position of it is constancy, as far agger nasi can be an anatomic landmark of frontal sinus operation. The position of frontal endosome is constancy. The scalloped area from anterior nasal spine 50-60 degrees to the line of Aeby's plane and within 100 mm radius is safety section to nasal endoscopic frontal sinus operation. CT 3-D reconstruction of this area is helpful to avoid insult. PMID- 21553525 TI - [The expression and relationship of CXCR4 and microvessel density in laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the expression of chemokine receptor 4 (CXCR4) in laryngeal squamous carcinoma and its correlation with clinicopathology character and the building of microvessel density (MVD). To evaluate its role in the carcinogenesis and progression in laryngeal squamous carcinoma. METHOD: The expression of CXCR4 in fresh laryngeal squamous carcinoma tissues and adjacent normal tissues from 42 patients were examined by RT-PCR, immunohistochemical staining and Image-pro-plus software. The numbers of regeneration blood vessels in the laryngeal squamous carcinoma was counted by antibody against factor V associated antigen and immunohistochemical analysis. RESULT: The positive expression rate of CXCR4 in tumor samples was significantly higher than that in normal ones (P < 0.01). In tumor samples, the expression of CXCR4 were not associated with age, sex, tumor site and T stage (P > 0.05), while it were higher in tumors of grade III, IV than in grade I, II of pathology classification (P < 0. 01). The expression of CXCR4 were significantly higher in tumors with cervical lymph node metastasis than that in tumor without cervical lymph node metastasis (P < 0.01). The expression of CXCR4 protein and CXCR4 mRNA were at the same level. The expression level of CXCR4 in the laryngeal squamous carcinoma tissue was positively correlated with vascularization. CONCLUSION: The higher expression of CXCR4 may play a key role in the invasion and metastasis of laryngeal squamous carcinoma, and were correlated with micro-vascularization. PMID- 21553526 TI - [Apoptosis inducing effect by TRAIL on human laryngeal squamous carcinoma Hep-2 cells]. AB - OBJECTIVE: To study the apoptosis inducing effect of tumor necrosis factor related apoptosis-ligand (TRAIL) on human laryngeal squamous carcinoma Hep-2 cells and its effect mechanism. METHOD: The human laryngeal squamous carcinoma Hep-2 cell line was treated with different concentration of TRAIL in vitro. The inhibition ratio of tumor cells was determined by MTT colorimetric assay, the incidence of cell apoptosis was determined by flow cytometry method. The morphologic changes of laryngeal squamous carcinoma Hep-2 cell were observed with transmission electron microscope. RESULT: In vitro, all the different concentrations of TRAIL inhibited laryngeal squamous carcinoma cell's growth. The inhibited growth ratio showed significant concentration-dependence. The concentrations for inducing apoptosis-ratio(TRAIL 1, 10, 100 microg/L) determined by flow cytometry was (11.49 +/- 0.36)%, (22.31 +/- 0. 82)%, (59.64 +/- 1.10)% respectively in the study group, and (3.13 +/- 0.12)% in the control group, which was significantly different between these two groups (P < 0. 01). CONCLUSION: In vitro, TRAIL inhibited the growth of human laryngeal squamous carcinoma Hep-2 cells. The induced apoptosis of TRAIL shows significant concentration- independence. TRAIL inhibits the growth of human laryngeal squamous carcinoma Hep 2 cells trough inducing apoptosis. PMID- 21553527 TI - [Remote surveillance system of artificial ventricular assist device]. AB - Performances of reliability and portability are important for artificial ventricular assist devices. This paper presents a remote surveillance system that can observe the condition of the patients and the driving condition of artificial heart online. The system is mainly based on the embedded Compact RIO platform and Ethernet technology. Combined with the driver module of the assist device, this remote system has been tested. PMID- 21553528 TI - [Cuffless blood pressure acquisition system based on a novel calibration method]. AB - Based on Moens-Korteweg model & hydrostatic principle, a simple calibration method by changing vertical distance between heart and radial artery is proposed in this paper. Using hydrostatic pressure to change arterial pressure and pulse wave transmit time, consequently obtain several sets of cardiovascular parameters and finally build up relationship between blood pressure and pulse wave transmit time. Clinical tests have been carried with different age and gender for long and short time monitoring. The comparison results with Sphygmomanometer OMRON EW3152 show its promising accuracy and coincidence feature in blood pressure measurement. PMID- 21553529 TI - [Study on mobile phone based wireless ECG monitoring technology system typical demonstration applications]. AB - Based on the mobile phone platform with wireless real-time ECG monitoring system developed in our lab, this article is dedicated to evaluate its practical value in people test. A series of new conceptual experiments were designed and performed. Particularly, ECG characteristics under different age, gender, health and motion conditions are evaluated. Effects of living habits such as drinking wine, coffee including various psychological conditions such as excitation, anxiety etc. to the ECG response are investigated. The human ECG under different time in a day such as morning, afternoon and late-night was evaluated. These conceptual experiments, which are hard to conduct otherwise using conventional devices, demonstrate the pervasive merits of the new system for fundamental study of heart disease as well as daily healthcare. PMID- 21553530 TI - [Application of the mixed programming with Labview and Matlab in biomedical signal analysis]. AB - This paper introduces the method of mixed programming with Labview and Matlab, and applies this method in a pulse wave pre-processing and feature detecting system. The method has been proved suitable, efficient and accurate, which has provided a new kind of approach for biomedical signal analysis. PMID- 21553531 TI - [The research in a foot pressure measuring system based on LabVIEW]. AB - This paper presents a system of foot pressure measuring system based on LabVIEW. The designs of hardware and software system are figured out. LabVIEW is used to design the application interface for displaying plantar pressure. The system can realize the plantar pressure data acquisition, data storage, waveform display, and waveform playback. It was also shown that the testing results of the system were in line with the changing trend of normal gait, which conformed to human system engineering theory. It leads to the demonstration of system reliability. The system gives vivid and visual results, and provides a new method of how to measure foot-pressure and some references for the design of Insole System. PMID- 21553532 TI - [Development and application of a fundus transverse microscopic imaging system]. AB - A human fundus transverse microscopic imaging system based on a MEMS deformable membrane mirror was developed. A 37 element small MEMS deformable membrane mirror was used as wave front corrector in this system. Wavefront errors were measured by a Hartman-Shack wave front sensor which contains 127 micro lens lets. After the wavefront error of human eye had been corrected by the deformable membrane mirror under the control of a computer, the imaging illumination light was triggered by a electronic shutter to illuminate the retina, the images were captured by a CCD camera. It has been showed in model eye's test that the system could measure and correct the eye's wavefront aberration efficiently. The fundus image achieved the diffraction limit after aberration correction. It was showed in clinic that except a few patients with turbid eye, most patients could finish the process of measuring and correcting wavefront aberration and then taking fundus image. The examination process could be finished safely, quickly and reliably. PMID- 21553533 TI - [Research of working condition monitoring and analyzing system for rotating anode X-ray tube based on the vibration measurement]. AB - A non-invasive detecting and analyzing method which used to monitor the working condition of rotating anode X-ray was proposed. Based on the NI development environment, accelerometer, 24-bit high resolution data acquisition card and personal computer were connected to construct the system for collecting the vibration signal of X-ray tube. Results demonstrate that the system could acquire and store the vibration data of X-ray tube quickly and efficiently. The characteristics of vibration, were extracted and processed, which proposed a new approach to detect the malfunction of rotating anode X-ray early and effectively. PMID- 21553534 TI - [Failure analysis of orthopedic implants]. AB - The clinical failure factors of Orthopedic implants which happened recent years have been summarized. The main failure factors are quality of orthopedic implants itself, iatrogenic and patient-derived. The ways to preventive measures have been suggested. PMID- 21553535 TI - [Information extraction methodology used in electronic medical records]. AB - We try to use information extraction technology in some parts of the medical records and extract disease information to accumulate experience for extracting complete information from medical records. This paper attempts to use dictionary and rules to achieve the named entity recognition. Information extraction is based on shallow parsing and use pattern sentence matching method with the help of a 3 levels finite state automaton. PMID- 21553536 TI - [Study of the radiation sterilization of narcosis gas adsorber]. AB - This paper describes the radiation sterilization of narcosis gas-adsorber for single use. We researched into the sterilization process, obtained the best radiation dose, tested and verified the sterilization process and confirmed the sterilization process. PMID- 21553537 TI - [Embedded system design of color-blind image processing]. AB - An ARM-based embedded system design schemes is proposed for the color-blind image processing system. The hardware and software of the embedded color-blind image processing system are designed using ARM core processor. Besides, a simple and convenient interface is implemented. This system supplies a general hardware platform for the applications of color-blind image processing algorithms, so that it may bring convenience for the test and rectification of color blindness. PMID- 21553538 TI - [A design of simple ventilator control system based on LabVIEW]. AB - This paper designed a ventilator control system to control proportional valves and motors. It used LabVIEW to control the object mentioned above and design ,validate, evaluate arithmetic, and establish hardware in loop platform. There are two system' s hierarchies. The high layer was used to run non-real time program and the low layer was used to run real time program. The two layers communicated through TCP/IP net. The program can be divided into several modules, which can be expanded and maintained easily. And the harvest in the prototype designing can be seamlessly used to embedded products. From all above, this system was useful in employing OEM products. PMID- 21553539 TI - [An overview of PET/CT image reconstruction techniques]. AB - This paper introduced the imaging principle, data acquisition method and image characteristics of PET/CT; Then reviewed several image reconstruction methods widely used in PET/CT at present in detail, such as FBP, ML-EM, 3DRP and so on. Finally, the advantages and disadvantages of these methods were summarized and compared. PMID- 21553540 TI - [Research status and trend of heart modeling]. AB - It is significant to research the heart modeling for the diagnosis and treatment of heart disease. With the development of biomedical technology, material and computer science, there are new requirements for heart modeling and simulation in terms of heart data acquisition, modeling approach, clinical application and so on. The research status of heart geometric/anatomical model, heart electrophysiological model and mechanical dynamic model has been summarized in this paper, and the problems and trends of heart modeling have been analyzed synthetically. PMID- 21553541 TI - [Essential principles of safety and performance of medical devices and regulations of medical devices in China]. PMID- 21553542 TI - [Study on the supervision of in-vitro diagnostic reagents]. AB - The regulatory history and status of in vitro diagnostic reagents (IVD) at home and abroad are introduced. Suggestions are also provided on the administration of IVD. PMID- 21553543 TI - [Revelation of purchase system of developed nation to large medical equipment group purchase in our country]. AB - There were some features of purchase system in developed nation, such as clear purchase objectives flexible methods, standard programming, emphasis on competition and open process. The measures suggested include playing the role of competition purchasing; establishing the e-business modern purchasing information system; establishing legislation system; and completing business purchasing. PMID- 21553544 TI - [The establishment of three methods to improve the management of implantable medical device]. AB - Based on the managerial deficiencies of Implantable medical device, using the RFID technology, the automatically comparison of data, Intelligent logistics, this article has established three conceptional methods of the original system of increment and iterative development. And details are included in aspect of principle, framework and etc. Meanwhile, advices have been given in the scientific and effective management of the medical instrument. PMID- 21553545 TI - Frontline--on the evolution of psychodynamic practice. PMID- 21553546 TI - [OCCAM: a tool for the workpractice of the units of occupational health, safety and prevention]. PMID- 21553547 TI - [Major-Accident Hazards. Has anything changed?]. PMID- 21553548 TI - Epilogue: Conversations between a psychoanalyst and a psychiatry resident. AB - The authors discuss the importance of psychoanalytic training from the perspectives of a psychiatry resident about to begin psychoanalytic training and a psychiatrist who is a training and supervising psychoanalyst. Drs. Hyun and Alfonso discuss psychoanalytic motivations and engage in a dialogue reflecting on the relevance of psychoanalytic training in current psychiatric practice and the profession's need for more dynamically trained psychiatrists. In doing so this article provides further insight from their firsthand experiences as to why young psychiatrists today still choose to engage in psychoanalytic training and its positive impact on their clinical practices. PMID- 21553549 TI - [Trial for improvements of calendar type clinical pathway of transcatheter arterial chemoembolization (TACE) for patients with hepatocellular carcinoma]. PMID- 21553550 TI - [Melanoma and non-melanoma skin cancer]. PMID- 21553551 TI - [Melanoma: new neoplasm staging system by AJCC (2009) and current status of treatment]. PMID- 21553552 TI - [Squamous cell carcinoma: new neoplasm staging system by UICC and AJCC (2009)]. PMID- 21553553 TI - [Paget disease extramammary: necessities of understanding by doctors other than dermatologist to prevent differential diagnosis]. PMID- 21553554 TI - [Primary cutaneous B cell lymphoma: classification and current status of treatment]. PMID- 21553555 TI - Adverse events and placebo effects: African scientists, HIV, and ethics in the 'global health sciences'. AB - This paper builds on the growing literature in 'postcolonial technoscience' by examining how science and ethics travel in transnational HIV research. I use examples of two controversial US-funded studies of mother-to-child transmission in Africa as case studies through which to explore quandaries of difference and inequality in global health research. My aim is not to adjudicate the debates over these studies, but rather to raise some questions about transnational research, science, and ethics that often get lost in public controversies over the moral status of such trials. Using interviews conducted with American and Ugandan HIV researchers as well as relevant material published in the popular and medical press, I argue that debates over research practice and the conditions under which practices are deemed ethically legitimate or questionable reflect the challenges faced by African researchers seeking to participate in global health science. In doing so, I show how questions of scientific legitimacy and authority are played out in debates over who decides what constitutes 'the normal' in human biological research and who can legitimately 'speak for Africa' regarding the ethics of research design and practice. I conclude that researchers from'resource poor settings' must often walk a tightrope between claims of difference from the global North and assertions of sameness, in which a claim too forceful in either direction can undermine the ethical--and thus scientific--legitimacy of their research. PMID- 21553556 TI - Epidural and spinal anesthesia use during labor: 27-state reporting area, 2008. AB - OBJECTIVES: This report presents 2008 data on receipt of epidural and spinal anesthesia as collected on the 2003 U.S. Standard Certificate of Live Birth. The purpose of this report is to describe the characteristics of women giving birth and the circumstances of births in which epidural or spinal anesthesia is used to relieve the pain of labor for vaginal deliveries. METHODS: Descriptive statistics are presented on births occurring in 2008 to residents of 27 states that had implemented the 2003 U.S. Standard Certificate of Live Birth as of January 1, 2008. Analyses are limited to singleton births in vaginal deliveries that occurred in the 27-state reporting area only and are not generalizable to the United States as a whole. RESULTS: Overall, 61 percent of women who had a singleton birth in a vaginal delivery in the 27 states in 2008 received epidural or spinal anesthesia; non-Hispanic white women received epidural or spinal anesthesia more often (69 percent) than other racial groups. Among Hispanic origin groups, Puerto Rican women were most likely to receive epidural or spinal anesthesia (68 percent). Levels of treatment with epidural or spinal anesthesia decreased by advancing age of mother. Levels increased with increasing maternal educational attainment. Early initiation of prenatal care increased the likelihood of epidural or spinal anesthesia receipt, as did attendance at birth by a physician. Use of epidural or spinal anesthesia was more common in vaginal deliveries assisted by forceps (84 percent) or vacuum extraction (77 percent) than in spontaneous vaginal deliveries (60 percent). Use of epidural or spinal anesthesia was less likely when infants were born prior to 34 weeks of gestation or weighed less than 1,500 grams. Women with chronic and gestational diabetes were more likely to receive an epidural or spinal anesthesia than women with no pregnancy risk factors. Precipitous labor (less than 3 hours) was associated with decreased epidural or spinal anesthesia receipt. longer second stage of labor, and fetal distress (compared with women who receive opiates intravenously or by injection) (1,5,6). Severe headache, maternal hypotension, maternal fever, and urinary retention have also been associated with epidural/spinal anesthesia receipt (5). This report examines the relationship between epidural/spinal anesthesia receipt and selected characteristics of the mother and of labor among vaginal deliveries in the 27-state reporting area as reported on the 2003 U.S. Standard Certificate of Live Birth. PMID- 21553557 TI - Environmental monitoring programme in the cell therapy facility of a research centre: preliminary investigation. AB - INTRODUCTION: Recent discoveries in cell therapy research present new opportunities for cellular products to be used to treat severe, and as yet incurable, diseases. It is therefore essential to implement a quality control programme in order to ensure that safe cells and tissues are provided. METHODS: In a preliminary phase of the setting up of a the cellfactory, monitoring was carried out monthly over a 6-month period in one out of three cell therapy laboratories and filter rooms in order to evaluate the microbial contamination of air and surfaces and the presence of airborne particulates. RESULTS: The mean total bacterial and fungal loads measured in the air in the centre of the filter room were 20.7 +/1 28.9 colony-forming units (cfu)/m3 and 9.2 +/- 15.4 cfu/m3, respectively, and 5.2 +/- 4.1 cfu/m3 and 6.8 +/- 13.4 cfu/m3, respectively, in the laboratory. The mean fungal load values recorded on the surfaces sampled in the laboratory were in 6 out of 18 cases higher than the reference values (5 cfu/plate). As to the results of particulate monitoring, with regard to the 0.5 microm particles, about 83% of the samples revealed values below the limit of 350.000 particles per cubic metre. CONCLUSIONS: In this set-up phase, monitoring was able to pick out structural and organisational flaws acceptable in a laboratory compliant with Good Manufacturing Practices class C (Annex 1), but not in a class B facility. Thanks to this preliminary monitoring phase, and by correcting these flaws, the clean room facility could achieve compliance to class B. PMID- 21553558 TI - Frequency of human papillomavirus infection and genotype distribution among women with known cytological diagnosis in a Southern Italian region. AB - INTRODUCTION: In the Puglia region (South Italy) about 200 new hospitalizations for cervical cancer are registered every year. The study investigated the frequency of Human Papillomavirus (HPV) infection and the genotype distribution of HPV in a sample of women with known cytology attending the outpatient clinics of four Gynecological Departments of the University of Bari over a four-year period (2005-2008). METHODS: Cervical samples from 1,168 women were analyzed for the presence of HPV-DNA through Polymerase Chain Reaction (PCR) in L1 region and reverse hybridization. The cytological results were associated with HPV positivity and type-specific prevalence. RESULTS: Overall, HPV infection was found in 355 (30.4%) women. HPV-DNA was found in 34.4% of women with a cytological diagnosis of ASCUS, in 46.8% of women with Low-grade Squamous Intraepithelial Lesion (LSIL) and in 87.0% of women with High-grade Squamous Intraepithelial Lesion (HSIL)/carcinoma. Also 16.0% of women with normal Pap smear were found to be HPV-DNA positive. The most common HPVgenotype was type 16 found in 27.3% of positives, followed by type 53 (11.5%), type 66 (9.2%) and type 31 (9.0%). HPV genotype 18 was found in 6.4% of positives. Types 16 or 18 were detected in about 34% (120/355) of all infected women, in about 33% of LSIL and in 60% of HSIL/ carcinoma HPV-positive women. Among low risk (LR) genotypes, type 61 was found in 10.7% of HPV positive women, type 62 in 8.4%, type 42 in 8.1% and type CP6108 in 7.8%. DISCUSSION AND CONCLUSIONS: The findings of the study give evidence that HPV infection is frequent in the studied cohort of women. The most widespread genotypes found were 16 and 53. These data may represent a benchmark for future evaluation after the recent introduction of vaccination against HPV in 12-year-old girls. PMID- 21553559 TI - Community awareness of bird flu and the practice of backyard poultry in a North Central state of Nigeria. AB - INTRODUCTION: The practice of backyard poultry is a very common practice in many homes in Nigeria. Birds raised at home are usually free ranged, which increases close contact between man and birds, thus increasing the risk of transmission of avian influenza virus to man. This study investigated the awareness of bird flu infection and identifies risk factors associated with the practice of backyard/free ranged poultry among the residents of a state in Northern Nigeria. METHODS: This cross-sectional study was carried out in Kwara State using 130 wards selected through cluster sampling technique. Households in each ward were sampled through systematic random sampling technique using the primary health care house numbering register. Semi-structured questionnaire was used to generate relevant information through interview and 650 participants consented and were used for the study. RESULTS: Most of the respondents 604 (92.9%) kept birds in their homes and one-third 204 (33.8%) of this group knew that infection from birds can be transmitted to man. However, less than a third 186 (30.8%) of those who keep birds were aware of avian influenza (AI) infection. Out of the 186 respondents, 78 (41.9%) had experienced massive bird deaths in the preceding year prior to the interview. Less than half 81 (43.5%) were willing to report AI or massive deaths occurring in flocks of their birds to designated officers /authority. During outbreaks with massive deaths in birds some of the respondents sold infected live birds 45 (57. 7%), few slaughtered and dressed the birds before sale 11 (14.1%), while some slaughtered and consumed the birds in their families 19 (24.4%). CONCLUSION: The practice of backyard poultry is very high with little knowledge and awareness of mechanism and risk of infection associated with it. This was also reflected in their attitude towards reporting of outbreaks in birds. Public awareness campaign and home visit by environmental and veterinary officers are important strategies that can prevent AI infection transmission among domestic birds and man. PMID- 21553560 TI - Hospitalization rate as a proxy for the quality of life evaluation: the case of dilated cardiomiopathy. AB - RATIONALE, AIMS AND OBJECTIVES: Some objective indicators like symptoms, toxicity, performance status, rate of hospitalization or re-employment have been already employed in scientific literature as proxies of Quality of Life assessment, and, in spite of the intrinsic limitations of such a measurement, they represent a valuable source of information in all the situations where a formal assessment is impossible, due to budget, time or human resources constrains. We concentrate here on some models for the analysis of frequency of hospitalization data and we discuss an application to the Hearth Muscle Disease Study Group data. METHODS: A sample of 235 patients with dilated cardiomyopathy (DCM) prospectively treated at the Department of Cardiology (Trieste, Italy) have been observed during a period of 18 years, from 1978 to 1992 and data regarding hospitalization history were collected. The hospitalization process depends on the time since the last event, and usually is a function of a set of explanatory variables, such as the current state of the patient, treatments he has been receiving and the severity of disease. We propose here a semi-Markov representation of the hospitalization process, and we analyze data regarding DCM, implementing Exponential, Weibull, and Cox models; in Cox models we take care also of the stratification according to the duration or to the levels of the state factor. RESULTS: The probability of experiencing a second hospitalization within one year after the first one is estimated about 0.50, and within two years about 0.30. After this point the probability remains constant at a 0.10 level. The same pattern is observed for the second hospitalization, while things are getting worse after the third hospitalization, when the probability of not having a subsequent hospitalization is about 0.10 within one year. Betablockers have a strong influence in enlarging the time interval spent between an hospitalization and the other. CONCLUSIONS: The hospitalization process can be viewed only as a rough approximation of the good standing of the patient. However, for diseases like DCM can be reasonable, because of the relatively fast increment in the worsening conditions of the patients and the consequently high chances of observing new hospitalizations up to the absorbing state (the death). Moreover a very detailed modeling of the process leads to extract as much information as possible from the data. PMID- 21553561 TI - Cost analysis of emergency department. AB - This paper is intended to examine both clinical and economic data concerning the activity of an emergency department of an Italian primary Hospital. Real data referring to arrivals, waiting times, service times, severity (according to triage classification) of patients' condition collected along the whole 2009 are matched up with the relevant accounting and economic information concerning the costs faced. A new methodological approach is implemented in order to identify a "standard production cost" and its variability. We believe that this kind of analysis well fits the federalizing process that Italy is experiencing. In fact the federal reform is driving our Country toward a decentralized provision and funding of local public services. The health care services are "fundamental" under the provisions of the law that in turn implies that a standard cost has to be defined for its funding. The standard cost (as it is defined by the law) relies on the concepts of appropriateness and efficiency in the production of the health care service, assuming a standard quality level as target. The identification and measurement of health care costs is therefore a crucial task propaedeutic to health services economic evaluation. Various guidelines with different amount of details have been set up for costing methods which, however, are defined in simplified frameworks and using fictious data. This study is a first attempt to proceed in the direction of a precise definition of the costs inherent to the emergency department activity. PMID- 21553562 TI - Perception of HIV/AIDS among preclinical dental students. AB - OBJECTIVE: To determine the knowledge, attitude and willingness of preclinical dental students to treat HIV/AIDS patients in the future. METHOD: The sample comprised 150 students of both genders drawn from the third and fourth year dental students of the University of Benin, Benin City. One hundred and fifty questionnaires were self-administered, with 139 (92.6%) retrieval. The parameters measured were knowledge, status, immunization against hepatitis B virus, willingness to treat, knowledge of post exposure prophylaxis (PEP) and its protocol in the of University of Benin Teaching hospital (UBTH). RESULTS: Data analysis showed that 100 (71.9%) students rated their knowledge of HIV/AIDS as high and very high. Sixty-three (45.3%) students thought that HIV was a contagious disease while 46 (33.1%) felt HIV was more infectious than tuberculosis or any of the strains of hepatitis virus. Only 59 (42.4%) students knew their HIV status. One hundred and twenty seven (91.4%) students felt that professional oral health care will be beneficial to HIV/AIDS patients; while fifty-one students (36.7%) are not prepared to administer dental care to HIV/AIDS patients in future. Majority of respondents adjudged health workers to be more at risk than sex workers. Forty students comprising 28.8% of the study population had been immunized against Hepatitis B. Ninety- four (67.7%) students had no knowledge of PEP while 122 (87.8%) students did not know the PEP protocol in UBTH. CONCLUSION: Although a large number of these students claim to be knowledgeable about HIV/AIDS. It is obvious that a true understanding is lacking. Concerted effort should be made to change their perception by implementing a curriculum designed to enhance the knowledge of dental students; if we hope to save HIV/AIDS patients from the discrimination of future healthcare givers. PMID- 21553563 TI - Reverse transcriptase loop-mediated isothermal amplification assay for infectious hematopoietic necrosis virus in Oncorhynchus keta. AB - A reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) assay was developed for detecting infectious hematopoietic necrosis virus (IHNV) from chum salmon Oncorhynchus keta in South Korea with high specificity, sensitivity and rapidity. A set of 6 IHNV-specific primers was designed, based on the G protein sequence of IHNV (PRT strain), recognizing 8 distinct sequences of the target RNA. The assay was optimized to detect IHNV at 63 degrees C for 30 min. The limit of detection was 0.01 fg of RNA extracted from IHNV-infected CHSE-214 cells, compared with 1.0 fg for nested RT-PCR. The applicability of this RT-LAMP assay was further tested by comparison with nested RT-PCR using field samples. Of 473 samples tested, 191 samples (40.38%) were IHNV-positive by RT-LAMP, whereas 162 samples (34.25%) were IHNV-positive by nested RT-PCR. These results indicate that, because of its high sensitivity and rapidity, the RT-LAMP assay is useful for early diagnosis of IHN. PMID- 21553564 TI - Identification of a 27.8 kDa protein from flounder gill cells involved in lymphocystis disease virus binding and infection. AB - In vitro, lymphocystis disease virus (LCDV) infection of flounder gill (FG) cell cultures causes obvious cytopathic effect (CPE). We describe attempts to isolate and characterize the LCDV-binding molecule(s) on the plasma membrane of FG cells that were responsible for virus entry. The results showed that the co immunoprecipitation assay detected a 27.8 kDa molecule from FG cells that bound to LCDV. In a blocking ELISA, pre-incubation of FG cell membrane proteins with the specific antiserum developed against the 27.8 kDa protein could block LCDV binding. Similarly, antiserum against 27.8 kDa protein could also inhibit LCDV infection of FG cells in vitro. Mass spectrometric analysis established that the 27.8 kDa protein and beta-actin had a strong association. These results strongly supported the possibility that the 27.8 kDa protein was the putative receptor specific for LCDV infection of FG cells. PMID- 21553565 TI - Pathogenicity and oxidative stress in Nile tilapia caused by Aphanomyces laevis and Phoma herbarum isolated from farmed fish. AB - Identified (n = 17) and unidentified (n = 1) fish-pathogenic fungal species from 10 genera of Oomycetes and soil fungi were isolated from 40 infected freshwater fish samples of the species Oreochromis niloticus niloticus (Nile tilapia) and Clarias gariepinus (African catfish). Samples were collected from various fish farms in the Nile Delta, Egypt. Nile tilapia were tested in aquaria for their susceptibility to the commonest Oomycetes species, Aphanomyces laevis and Achlya klebsiana, and also against the 2 most prevalent pathogenic soil fungi, Paecilomyces lilacinus and Phoma herbarum. Two techniques were used: water bath exposure and intramuscular (subcutaneous) injection. Water bath exposure to the 2 species of Oomycetes caused greater mortalities of O. niloticus niloticus than intramuscular injection, but the reverse was true of the soil fungal species. Regardless of the infection method, the 2 Oomycetes species were more potent pathogens than the soil fungal species. In both gills and mytomal muscles of fish infected by A. laevis and P. herbarum, we measured and compared with controls the oxidative stress parameters total peroxide (TP), lipid peroxidation (LPO) and nitric oxide (NO), as well as levels of the antioxidants vitamin E and glutathione (GSH), and superoxide dismutase (SOD) and catalase (CAT) activities. Infection by these 2 fungal species through either spore suspension or spore injection significantly increased oxidative damage in gills and induced marked decrease in most studied antioxidants. In addition, both routes showed similar effects and A. laevis depressed the antioxidants CAT, vitamin E and GSH more than P. herbarum. PMID- 21553566 TI - Isolation and characterization of virulent Aeromonas veronii from ascitic fluid of oscar Astronotus ocellatus showing signs of infectious dropsy. AB - The cichlid oscar Astronotus ocellatus has worldwide commercial value in the pet fish industry because of its early maturation, relatively high fecundity, ability to identify its caretaker and also to alter colouration amongst conspecifics. Pathogenic strains of Aeromonas veronii resistant to multiple antibiotics were isolated from A. ocellatus individuals showing signs of infectious abdominal dropsy. The moribund fish showed haemorrhage in all internal organs, and pure cultures could be obtained from the abdominal fluid. The isolates recovered were biochemically identified as A. veronii biovar sobria and genetically confirmed as A. veronii based on 16S rRNA gene sequence analysis (GenBank accession no. FJ573179). The RAPD profile using 3 primers (OPA-3, OPA-4 and OPD-20) generated similar banding patterns for all isolates. They displayed cytotoxic and haemolytic activity and produced several exoenzymes which were responsible for the pathogenic potential of the isolates. In the representative isolate MCCB 137, virulence genes such as enterotoxin act, haemolytic toxin aerA, type 3 secretion genes such as aexT, ascVand ascF-ascG, and gcat (glycerophospholipid-cholesterol acyltransferase) could be amplified. MCCB 137 exhibited a 50% lethal dose (LD50) of 10(5.071) colony-forming units ml(-1) in goldfish and could be subsequently recovered from lesions as well as from the internal organs. This is the first description of a virulent A. veronii from oscar. PMID- 21553567 TI - Diseases of farmed Atlantic salmon Salmo salar associated with infections by the microsporidian Paranucleospora theridion. AB - The microsporidian Paranucleospora theridion was discovered in Atlantic salmon Salmo salar suffering from proliferative gill disease in a marine farm in western Norway in 2008. The parasite develops in cells of the reticuloendothelial system, cells important for normal immune function. The aim of this study was to see if P. theridion could play a part in some of the diseases with unclear causes in salmon production in Norway, i.e. proliferative gill disease (PGI), pancreas disease (PD), heart and skeletal muscle inflammation (HSMI) and cardiomyopathy syndrome (CMS). P. theridion was present in all areas with salmon farming in Norway, but high prevalence and densities of the parasite in salmon and salmon lice were only seen in southern Norway. This region is also the main area for PGI and PD in Norway. Quantification of pathogens associated with PGI, PD, HSMI and CMS diagnoses showed that P. theridion levels are high in southern Norway, and may therefore play a role in susceptibility and disease development. However, among the different diagnoses, fish with PGI are particularly heavily infected with P. theridion. Therefore, P. theridion appears as a possible primary agent in cases with high mortality in connection with PGI in western Norway. PMID- 21553568 TI - In vitro effect of seven antiparasitics on Acolpenteron ureteroecetes (Dactylogyridae) from largemouth bass Micropterus salmoides (Centrarchidae). AB - Few drugs are approved by the United States Food and Drug Administration for treating parasite infections in minor species such as fish, due in part to the high cost of developing such drugs and to a relatively small market share for drug sponsors. Because in vivo effectiveness trials for antiparasitic drugs are costly, time consuming, and use many animals, a systematic in vitro screening approach to describe parasite motility could help find promising drug candidates. We evaluated the effects of 7 antiparasitics on the activity and survival of the endoparasitic monogenean Acolpenteron ureteroecetes (Dactylogyridae) collected from the posterior kidneys of juvenile largemouth bass Micropterus salmoides (Lacepede, 1802) (Centrarchidae) held in the laboratory. Tests were conducted in 12 well tissue culture plates; each well had 3 parasites, and we tested 3 concentrations and 1 control for each of the 7 antiparasitics. The parasites were observed immediately after adding the drug, at 1 to 3 h, and 17 to 26 h, and video recordings were made. Drug effects were recorded by documenting morbidity (reduced movement, tremors, contracted body, abnormal morphology) and mortality. A. ureteroecetes was strongly affected by the quinoline praziquantel, the imidazothiazide levamisole, and the organophosphates dichlorvos and trichlorfon. The parasites were moderately affected by the macrocyclic lactones ivermectin and emamectin, and generally unaffected by the benzimidazole mebendazole. Our study demonstrates the utility of characterizing in vitro responses with video microscopy to document responses of fish parasites for initial screens of drug effects on a fish monogenean. PMID- 21553569 TI - Specific primers for the detection of the black-yeast fungus associated with lethargic crab disease (LCD). AB - Lethargic crab disease (LCD) is an emerging infirmity that has been causing extensive mortalities in populations of the mangrove land crab Ucides cordatus (Ocypodidae) along the Atlantic coast of Brazil. Previous studies have indicated that LCD is associated with a dematiaceous fungus, Exophiala cancerae de Hoog et al. In the present study, we sequenced the internal transcribed spacer (ITS) of the rDNA region of this black yeast species and developed species-specific PCR primers. Sensitivity tests indicated that the developed protocol is capable of detecting very small amounts of target DNA. Also, the application of the protocol to a variety of other dematiaceous fungi did not generate any false positives. The specific primers provided in the present study represent an important tool for rapidly surveying a large number of crab individuals, as well as environmental samples. Such knowledge will be instrumental in understanding the epidemiological dynamics of LCD. PMID- 21553570 TI - Occurrence of the oribatid mite Trhypochthoniellus longisetus longisetus (Acari: Trhypochthoniidae) on tilapia Oreochromis niloticus. AB - Mites as parasites infesting fish have been described in a few case reports involving Histiostoma anguillarum, H. papillata, and Schwiebea estradai. We describe the unexpected occurrence of oribatid mites of the genus Trhypochthoniellus on farmed tilapia Oreochromis niloticus. The fish had mites on the skin, fins, and gills, as well as in the mouth. The morphological characteristics of the mites, observed by optical and scanning electron microscopy, were consistent with those described for T. longisetus longisetus. All stages of development were observed, suggesting that the mites were able to actively reproduce on fish. PMID- 21553571 TI - Antemortem diagnosis of a ventricular septal defect in a California sea lion Zalophus californianus. AB - A yearling California sea lion Zalophus californianus stranded in poor body condition, and on physical examination a heart murmur was audible bilaterally. The sea lion was diagnosed with a left-to-right shunting membranous ventricular septal defect (VSD) using B-mode, color-flow Doppler and continuous-wave Doppler echocardiography. A left-to-right intracardiac shunting lesion was confirmed during cardiac angiographic computed tomography. The VSD defect was verified during the necropsy examination. On histologic examination concurrent mild multifocal myocarditis with focal mild ventricular free-wall myocardial necrosis were identified. A specific cause for the myocarditis and myocardial necrosis was not found, and association with the VSD and resultant myocardial dysfunction was presumed. This is the first report of the antemortem diagnosis of a VSD in a marine mammal and the first report of a VSD in a California sea lion. PMID- 21553572 TI - Eugenics, environment, and acclimatizing to Manchukuo: psychiatric studies of Japanese colonists. AB - Both the advocates and critics of what has been called "the new imperial history," which may be characterized by its focus on how colonies were not simply influenced by but also exercised an influence on a dominating foreign state, have inspired this article. The article addresses the production and dissemination of medical knowledge in its examination of psychiatric research conducted in the 1930s in Japan's unofficial colony of Manchukuo. It highlights the political dimension of studies of psychosomatic disorders, syphilis, and alcoholism among colonists by placing it in the context of contending theories of racial improvement and growing official support for mass migration, especially to northeast China. Moreover, it inquires into restrictions on the flow of ideas from the colonies by examining how these studies were received in Japan. While interest in the colonies ensured that psychiatrists in Manchukuo were able to publish their research in leading Japanese medical journals, their findings jeopardized too many political and professional interests to become more public. In much-publicized debates stimulated by the impeding establishment of eugenic sterilization legislation, their colleagues in Japan in the late 1930s who championed the argument of environment over heredity were conspicuously silent about conditions among Japanese colonists, using instead examples of European and North American colonists to make their case. PMID- 21553573 TI - On grief and loss. PMID- 21553574 TI - Adapting the transtheoretical model of change to the bereavement process. AB - Theorists currently believe that bereaved people undergo some transformation of self rather than returning to their original state. To advance our understanding of this process, this article presents an adaptation of Prochaska and DiClemente's transtheoretical model of change as it could be applied to the journey that bereaved individuals experience. This theory is unique because it addresses attitudes, intentions, and behavioral processes at each stage; it allows for a focus on a broader range of emotions than just anger and depression; it allows for the recognition of two periods of regression during the bereavement process; and it adds a maintenance stage, which other theories lack. This theory can benefit bereaved individuals directly and through the increased awareness among counselors, family, friends, employers, and society at large. This theory may also be used as a tool for bereavement programs to consider whether they are meeting clients' needs throughout the transformation change bereavement process rather than only focusing on the initial stages characterized by intense emotion. PMID- 21553575 TI - Self-determination, the right to die, and culture: a literature review. AB - Self-determination is a primary ethical principle underlying social work practice in health care settings. Since the 1970s, a right-to-die movement that shares the social work commitment to self-determination has grown and influences end-of-life care decisions. However, the role of culture is notably absent in discussions of the right to die. A literature review was conducted to explore self-determination and the role of culture in the context of the history of the right-to-die movement. A total of 54 articles met the criteria for inclusion in the review. Of the total, 21 related to self-determination, and 12 related to ethnicity and culture at the end of life. A history based on the review of the right-to-die movement is presented. The review found that social workers support passively hastening death and that views of self-determination are affected by both law and culture. In response, social workers will face three tasks: (1) becoming more public in their support for client self-determination as an important standard in end-of-life care, (2) being more explicit in support of diverse cultural traditions in end-of-life decision making, and (3) expanding their traditional educational and bridging roles between families and medical personnel. PMID- 21553576 TI - A quest for meaning: hospice social workers and patients with end-stage dementia. AB - Research shows that few social workers are interested in working with cognitively impaired older adults, such as those with Alzheimer's disease or a related dementia. As the number of individuals with dementia grows, the demand for social workers to provide services to patients with dementia will increase. Although much attention has been given to the needs of individuals with early- and middle stage dementia, little attention has been directed toward patients at the end stages of the disease. Even less is known about how professionals, particularly hospice social workers, form therapeutic relationships with these patients given their severe cognitive impairment. This qualitative study, based on a focus group methodology, examined how hospice social workers find meaning in their therapeutic relationships with patients with end-stage dementia. Two primary themes emerged, each containing three subthemes, that captured the barriers to and strategies for forming meaningful relationships with patients with end-stage dementia. The results of this study have implications for hospice social workers and social workers in other health care settings and the types of training they need to strengthen their practice with cognitively impaired populations. PMID- 21553577 TI - Importance of empathy for social work practice: integrating new science. AB - Empathy is more important than ever to a national population worried about difficult political and socioeconomic situations. During the last 10 years, an enormous amount of research has been carried out to elucidate the nature, mechanism, and function of empathy. New research from social-cognitive neuroscience and related fields indicates that, like language or eye-hand coordination, empathy is an innate human capability that can be greatly enhanced by purposeful and informed guidance. Empathy is particularly important to social work practice. Clients experiencing empathy through treatment have improved outcomes. Empathic social work practitioners are more effective and can balance their roles better. Social work practitioners can and should learn about emerging research on empathy and use that information to better serve their client populations. This article, emphasizing research of the past decade, focuses on empathy and its benefits as an asset to social work practitioners. PMID- 21553578 TI - Using spiritual interventions in practice: developing some guidelines from evidence-based practice. AB - Research indicates that many social work practitioners are interested in using spiritual interventions in clinical settings. Unfortunately, studies also indicate that practitioners have frequently received minimal training on the topic during their graduate education. Drawing from the evidence-based practice movement, this article develops some guidelines to assist practitioners in using spiritual interventions in an ethical, professional manner that fosters client well-being. These guidelines can be summarized under the following four rubrics: (1) client preference, (2) evaluation of relevant research, (3) clinical expertise, and (4) cultural competency. The article concludes by emphasizing that these overlapping guidelines should be considered concurrently, in a manner that privileges clients' needs and desires in the decision-making process. PMID- 21553579 TI - Correlates of depression among older Kurdish refugees. AB - Little is known about the psychological status of older refugees who have immigrated from war-torn areas in the Middle East. This study examined the nature and predictors of depression among older Kurds living in one city in the United States. Older Kurds (N = 70) were recruited and surveyed by trained Kurdish interviewers in their native dialect. The majority of participants had very low incomes; had no education; were illiterate in their own language; and had little to no ability to speak, read, or write English. Elevated levels of depression were found, with 67.1 percent scoring above the clinical cutoff for depression and 25.7 percent scoring in the severe depression range. Depression was associated with demographic (age), stressor (migratory grief, death of spouse, number of medical conditions, functional disability, and income), and coping (English proficiency and social support) variables. Health conditions exerted the greatest effect. Migratory grief and social support were also significant predictors of depression. Results suggest substantial psychological distress among this understudied population of older refugees. Implications for research and practice with older members of newly established refugee populations are discussed. PMID- 21553580 TI - An exploration of lesbian maternal bereavement. AB - Research on parental bereavement has focused historically on single or partnered cross-gendered (heterosexual) bereaved parents. No previous studies have examined the unique experiences of same-gendered bereaved parents. This multiple-case study focused on child death in same-gendered-parent families. The goal of this study was to yield information that will expand the existing body of knowledge regarding parental bereavement and add to the scant literature on lesbian parenthood and the challenges that lesbians may face as a marginalized group. The study used in-depth interviews with six self-identified lesbian mothers who had experienced the death of a child at various ages and from various causes. Results suggest that lesbian bereaved mothers experience a type of double disenfranchisement after their losses and that social support is often insufficient to meet their psychological needs. Because previous research has not been published on this specific population, the findings may be worthwhile for the lesbian and gay parenting community, community advocacy groups, and the clinicians who serve them. PMID- 21553581 TI - Moving beyond a systematic review of sexual reorientation therapy. PMID- 21553582 TI - Lessons from Nebraska. PMID- 21553583 TI - Collaborative digital techniques and urban neighborhood revitalization. PMID- 21553584 TI - A response to activism or to terrorism? PMID- 21553585 TI - Is phycovolatilization of heavy metals a probable (or possible) physiological phenomenon? An in situ pilot-scale study at a leather-processing chemical industry. AB - Using algae to treat industrial effluents containing heavy metals presents an alternative to the current practice of using other biosorbents and physical and chemical methods. In this study, effluent from a leather-processing chemical industry in Ranipet, Tamil Nadu, India, was treated for the removal of heavy metals using the microalga, Chlorella vulgaris, which was isolated from the effluent itself. The objectives of this study were to (1) assess the mass balance of a model parameter, lead, in laboratory conditions and estimate the lead adsorption capabilities of the microalga and (2) conduct pilot-scale studies for the removal of heavy metals, using the microalga, from the effluent and the solid waste accumulated over the years generated by conventional treatment methods. The results of the study show that after 8 hours, Chlorella vulgaris exhibited a better adsorption capacity under sunlight compared to laboratory conditions (i.e., 30.6 mg/g dry weight vs 10.5 mg/g dry weight, respectively). Similarly, reduction of heavy metals and mass balance in pilot-scale field studies conducted in a high-rate algal pond showed that the microalga, apart from adsorption, complexation, and entrapment mechanisms, is likely to possess phycovolatilization capability probably via biotransformation processes. PMID- 21553586 TI - Pre-treatment of industrial wastewater polluted with lead using adsorbents and ultrafiltration or microfiltration membranes. AB - This work investigated the use of ultrafiltration (UF) or microfiltration (MF) membranes combined with natural minerals for the pre-treatment of wastewater containing high amounts of lead. The effects of initial lead concentration, solution pH, membrane pore size, mineral type and concentration and mineral - metal contact time were investigated. Lead removal accomplished by the UF system was higher in wastewater compared to that obtained in aqueous solutions and this was attributed to the formation of insoluble metal precipitates/complexes, which were effectively retained by the membranes. At pH = 6 the dominant removal mechanism was precipitation/complexation, while mineral adsorption enhanced lead removal. The combined use of minerals and UF/MF membranes can effectively remove lead from wastewater resulting in a final effluent that can be further treated biologically with no biomass inhibition problems or can be safely discharged into municipal sewers. Kinetics investigation revealed a two-stage diffusion process for all minerals employed. The Langmuir isotherm exhibited the best fit to the experimental data. PMID- 21553587 TI - Modeling the inactivation of microorganisms occluded in effluent wastewater particles to enhance operation of filtration and disinfection systems. AB - In disinfection systems, incomplete penetration of chlorine into effluent wastewater particles can result in a residual population of viable microorganisms. In this work, a combined experimental and numerical approach was used to quantify inactivation of microorganisms in effluent particles and identify combinations of particle removal and chlorine dose that would result in a reduction of occluded microorganisms for six full-scale facilities in the United States with different nitrification levels. The results reveal that combined chlorine is more effective for inactivating occluded microorganisms than free chlorine; model calibration results suggest that free chlorine is less effective because it is more reactive. However, nitrified effluents appear to have lower effluent particle concentrations, and decreases in particle concentrations significantly reduce the chlorine required. Additionally, in disinfection systems that are designed and operated based on inactivation of indicator organisms, the chlorine dose may be insufficient to inactivate occluded pathogens to levels consistent with current regulations. PMID- 21553588 TI - Production of biodiesel and biogas from algae: a review of process train options. AB - Algae are an attractive biofuel feedstock because of their fast growth rates and improved land use efficiency when compared with terrestrial crops. Process train components needed to produce algal biofuels include (1) cultivation, (2) harvesting, and (3) conversion into usable fuel. This paper compares various process train options and identifies knowledge gaps presently restricting the production of algal biodiesel and algae-derived biogas. This analysis identified energy-intensive processing and the inability to cultivate large quantities of lipid-rich algal biomass as major obstacles inhibiting algal biodiesel production. Anaerobic digestion of algal biomass requires fewer process train components and occurs regardless of lipid content. In either scenario, the use of wastewater effluent as a cultivation medium seems necessary to reduce greenhouse gas emissions and maximize water use efficiency. Furthermore, anaerobically digesting algal biomass generated from low-technology wastewater treatment processes represents an appropriate technology approach to algal biofuels that is poorly investigated. Coupling these processes can improve global health by improving sanitation, while providing a cleaner burning biogas alternative to indoor biomass cooking systems typical of less-developed areas. PMID- 21553589 TI - Minimum requirements for trace metals (iron, nickel, cobalt, and zinc) in thermophilic and mesophilic methane fermentation from glucose. AB - The minimum requirements for four essential trace metals were examined in both thermophilic and mesophilic methane fermentation of glucose. The minimum requirement here was defined as the amount that supports the effluent soluble chemical oxygen demand (COD) of 1000 mg/ L or less for the duration of several times the hydraulic retention time (HRT). For this purpose, completely mixed reactors were run semi-continuously at 5 days HRT, with 10 g/L substrate COD. The minimum requirements determined as milligrams per gram COD removed were 0.45, 0.049, 0.054, and 0.24 in the thermophilic system and 0.20, 0.0063, 0.017, and 0.049 in the mesophilic system for iron, nickel, cobalt, and zinc, respectively. The thermophilic system required larger amounts (2.2 to 7.8 times) of the trace metals than the mesophilic system, indicating greater assimilation by biomass and/or less bioavailability under thermophilic conditions. The results can give quantitative information on trace metal nutrition for successful methane fermentation. PMID- 21553590 TI - Development of a depth-integrated sample arm to reduce solids stratification bias in stormwater sampling. AB - A new depth-integrated sample arm (DISA) was developed to improve the representation of solids in stormwater, both organic and inorganic, by collecting a water quality sample from multiple points in the water column. Data from this study demonstrate the idea of vertical stratification of solids in storm sewer runoff. Concentrations of suspended sediment in runoff were statistically greater using a fixed rather than multipoint collection system. Median suspended sediment concentrations measured at the fixed location (near the pipe invert) were approximately double those collected using the DISA. In general, concentrations and size distributions of suspended sediment decreased with increasing vertical distance from the storm sewer invert. Coarser particles tended to dominate the distribution of solids near the storm sewer invert as discharge increased. In contrast to concentration and particle size, organic material, to some extent, was distributed homogenously throughout the water column, likely the result of its low specific density, which allows for thorough mixing in less turbulent water. PMID- 21553591 TI - Effect of pipe sags on wastewater collection system performance. AB - Sagging of pipelines is a common problem in centralized wastewater collection systems. Wastewater flowing through sags experiences several changes of slope, and the flow through flat and negative slope sections is prone to a significant reduction in mean velocity. The objective of this study is to determine when pipe sags would result in significant velocities below design conditions, which also would increase the risk of a sewer backup. A sagged pipe configuration that could be encountered in sanitary sewer systems was depicted; thereby, analyses on uniform and gradually varied flows were conducted to determine velocity profiles through different segments of the sagged pipeline setup used for the study. The results indicate that there are significant occurrences when either the velocity in the pipe sags goes below minimum, as recommended in the Ten States Standards (Health Research, Inc., 2004) (0.61 m/s [2.0 ft/ sec]), or flow depth rises to pipe diameter (full section flow). Additionally, velocities along a sagged pipe were calculated for temporal flow rates to account for daily and seasonal flow rate changes in a typical wastewater collection system. Results of the temporal flow rate analysis suggest that, for a 200-mm (8-in.) diameter sagged pipe segment with full-section (wet weather) flow, 75% of the mean velocities would be below the minimum velocity recommended as a Ten States Standard. PMID- 21553592 TI - Ammonia-nitrogen sorptional properties of banana peels. AB - Using modified banana peel as a biosorbent to treat water containing ammonia nitrogen (NH4(+)-N) was studied. Related parameters in the sorptional process, such as chemical modification, pH, and contact time were investigated. The experimental results showed that banana peel modified by 30% sodium hydroxide (NaOH) and mesothermal microwaves (NMBPs) can greatly improve the sorption removal for NH4(+)-N. The kinetics study revealed that the sorption behavior better fit the pseudo-second-order equation than the Lagergren first-order equation. Fourier transform infrared absorption spectrum analysis of banana peels and NMBPs before and after NH4(+)-N sorption revealed that the activity of hydroxyl groups at the surface of the banana peels was strengthened after modification, and nitrogenous groups appeared after biosorpting the NH4(+)-N. In the end, metallurgical wastewater containing a low concentration of NH4(+)-N was treated by NMBPs. The initial NH4(+)-N concentration of 138 mg/L was reduced to 13 mg/L in 25 minutes by 4 g/L NMBPs at pH 10. PMID- 21553593 TI - Chabazite biofilter for enhanced stormwater nitrogen removal. AB - Enhanced nitrogen removal from stormwater using chabazite, a natural cation exchanger, was evaluated in a pilot-plant biofilter operated for 216 days. A parallel sand filter served as the control. The biofilters were subject to various operating modes including baseline periods of steady flowrate and loading, simulated high flowrate (storm) events following steady flowrates, high flowrates following extended no-flow periods, and with limited influent dissolved oxygen. Under steady-flow operation, chabazite removed 93% of ammonium and sand removed 87%; total inorganic nitrogen was reduced 35% by chabazite versus 15% by sand. In a simulated storm event following steady-flow operation, 97% of cumulative ammonia mass was retained by the chabazite biofilter versus 70% for sand. Following a 40 day no-flow period, the chabazite biofilter retained 98% of influent ammonium in a storm event while sand exhibited high effluent ammonium. Chabazite ammonium retention was high under limited influent dissolved oxygen, verses significant breakthrough by the sand biofilter. Chabazite media provided superior performance resiliency under dynamic conditions that typify stormwater treatment. PMID- 21553594 TI - Understanding global climate change: paleoclimate perspective from the world's highest mountains. AB - Glaciers are among the world's best recorders of, and first responders to, natural and anthropogenic climate change and provide a time perspective for current climatic and environmental variations. Over the last 50 years such records have been recovered from the polar regions as well as low-latitude, high elevation ice fields. Analyses of these ice cores and of the glaciers from which they have been drilled have yielded three lines of evidence for past and present abrupt climate change: (1) the temperature and precipitation histories recorded in the glaciers as revealed by the climate records extracted from the ice cores; (2) the accelerating loss of the glaciers themselves; and (3) the uncovering of ancient fauna and flora from the margins of the glaciers as a result of their recent melting, thus illustrating the significance of the current ice loss. The current melting of high-altitude, low-latitude ice fields is consistent with model predictions for a vertical amplification of temperature in the tropics. The ongoing rapid retreat of the world's mountain glaciers, as well as the margins of the Greenland and Antarctic ice sheets, is not only contributing to global sea level rise, but also threatening fresh-water supplies in many of the most populous regions. More recently, strong evidence has appeared for the acceleration of the rate of ice loss in the tropics, which especially presents a clear and present danger to water supplies for at-risk populations in South America and Asia. The human response to this issue, however, is not so clear, for although the evidence from both data and models becomes more compelling, the rate of global CO2 emissions continues to accelerate. Climatologically, we are in unfamiliar territory, and the world's ice cover is responding dramatically. The loss of glaciers, which can be viewed as the world's water towers, threatens water resources that are essential for hydroelectric power, crop irrigation, municipal water supplies, and even tourism. As these glaciers are disappearing, we are also losing very valuable paleoclimate archives. PMID- 21553595 TI - Population and climate change. AB - To review, the four broad dimensions of any complex human problem, including climate change, are the human population, economics, culture, and environment. These dimensions interact with one another in all directions and on many time scales. From 2010 to 2050, the human population is likely to grow bigger, more slowly, older, and more urban. It is projected that by 2050 more than 2.6 billion people (almost 94% of global urban growth) will be added to the urban population in today's developing countries. That works out to 1.26 million additional urban people in today's developing countries every week from 2010 to 2050. Humans alter the climate by emitting greenhouse gases, by altering planetary albedo, and by altering atmospheric components. Between 1900 and 2000, humans' emissions of carbon into the atmosphere increased fifteenfold, while the numbers of people increased less than fourfold. Population growth alone, with constant rates of emissions per person, could not account for the increase in the carbon emissions to the atmosphere. The world economy grew sixteenfold in the twentieth century, accompanied by enormous increases in the burning of gas, oil, and coal. In the last quarter of the twentieth century, population grew much faster in developing countries than in high-income countries, and, compared with population growth, the growth of carbon emissions to the atmosphere was even faster in developing countries than in high-income countries. The ratio of emissions-to-population growth rates was 2.8 in developing countries compared with 1.6 in high-income countries. Emissions of CO2 and other greenhouse gases are influenced by the sizes and density of settlements, the sizes of households, and the ages of householders. Between 2010 and 2050, these demographic factors are anticipated to change substantially. Therefore demography will play a substantial role in the dynamics of climate changes. Climate changes affect many aspects of the living environment, including human settlements, food production, and diseases. These changes will affect poor people more severely than rich, and poor nations more severely than rich. Yet not enough is known to predict quantitatively many details that will matter enormously to future people and other species. Three kinds of responses are related to demographic issues that affect climate changes: universal secondary education, voluntary contraception and maternal health services, and smarter urban design and construction. These responses may prevent, reduce, or ameliorate the impacts of climate changes. They are as relevant to rich countries as to poor, though in ways that are as different as are rich countries and poor. They are desirable in their own right because they improve the lives of the people they affect directly; and they are desirable for their beneficial effects on the larger society and globe. They are effective responses to the twin challenges of reducing poverty and reducing greenhouse gas emissions. PMID- 21553596 TI - The immediate challenge of climate change: reducing impacts on the poorest communities in the poorest countries. PMID- 21553597 TI - Redefining what's possible. PMID- 21553598 TI - The public's trust in scientific claims regarding offshore oil drilling. AB - Our study examines how individuals decide which scientific claims and experts to believe when faced with competing claims regarding a policy issue. Using an experiment in a public opinion survey, we test the source content and credibility hypotheses to assess how much confidence people have in reports about scientific studies of the safety of offshore oil drilling along the California coast. The results show that message content has a substantial impact. People tend to accept reports of scientific studies that support their values and prior beliefs, but not studies that contradict them. Previous studies have shown that core values influence message acceptance. We find that core values and prior beliefs have independent effects on message acceptance. We also find that the sources of the claims make little difference. Finally, the public leans toward believing reports that oil drilling is riskier than previously believed. PMID- 21553599 TI - Activist trust: the diffusion of green expertise in a Brazilian landscape. AB - MST (Movimento Sem Terra/Landless People's Movement) is the largest rural movement of Latin America. Since the late 1990s, it has taken part in the diffusion of expertise about biodiversity conservation. Using an ethnographic approach, this paper investigates sources and roles of trust within this process. How does trust work when experts and laypeople belong to the same movement? The paper uses and critically discusses the works of Brian Wynne and the Actor Network Theory. It describes the particular ways in which the building of trust takes place within the intimate networks of MST. As ecological expertise becomes a central element within MST's project of liberation, the sources of trust are both affective and effective. Interests, social recognition and identity are intertwined. In the conclusion, I propose the concept of activist trust. PMID- 21553600 TI - Implicit media frames: automated analysis of public debate on artificial sweeteners. AB - The framing of issues in the mass media plays a crucial role in the public understanding of science and technology. This article contributes to research concerned with the analysis of media frames over time by making an analytical distinction between implicit and explicit media frames, and by introducing an automated method for the analysis of implicit frames. In particular, we apply a semantic maps method to a case study on the newspaper debate about artificial sweeteners, published in the New York Times between 1980 and 2006. Our results show that the analysis of semantic changes enables us to filter out the dynamics of implicit frames, and to detect emerging metaphors in public debates. Theoretically, we discuss the relation between implicit frames in public debates and the codification of meaning and information in scientific discourses, and suggest further avenues for research interested in the automated analysis of frame changes and trends in public debates. PMID- 21553601 TI - Bimbo or boffin? Women in science: an analysis of media representations and how female scientists negotiate cultural contradictions. AB - This paper examines the gendered representations of scientists in the UK media. Our analysis reveals the asymmetrical ways in which men and women working in science, engineering and technology are portrayed, in particular through the emphasis on women's appearance and a focus on their exceptional status. It also highlights the way female scientists may be used to "sex up" the discipline in the context of increasing concern about the (un)popularity of science. This media analysis is contextualized by drawing on data from 86 scientists examining how women themselves experience press and television coverage and address the cultural contradictions surrounding their role. The research highlights the challenges facing women working in these fields and the dilemmas for those seeking to develop a "human" face for science and promote a positive image for women. PMID- 21553602 TI - Does the public communication of science influence scientific vocation? Results of a national survey. AB - The purpose of this work was to determine if public communication of science and technology (PCST) has any influence on people's decision to become dedicated to scientific research. For this reason, a national survey involving 852 researchers from all disciplines was conducted in Argentina. The results showed that the factors affecting scientific vocation are many, and that, regardless of differences in gender, age or discipline, the greatest influence on the decision to go into scientific research is exerted by teachers. The analysis also demonstrated that different manifestations of PCST (science books, press articles, audiovisual material, and activities such as visits to science museums) play a significant role in awakening the vocation for science. From these results it may be stated that PCST--in addition to its function of informing and forming citizens--exerts a significant influence in fostering scientific vocation. PMID- 21553603 TI - Helping with inquiries or helping with profits? The trials and tribulations of a technology of forensic reasoning. AB - The commercialization of forensic scientific provision in the UK over the last two decades has had a major role in shaping a changing epistemic identity for forensic scientists working within this jurisdiction. Efforts to match the presumed epistemological standards of the 'pure' sciences have been brought together with concerns about value for money in a new approach to the interpretation of evidence, an activity that lies at the heart of criminal investigative practice. A study of the Case Assessment and Interpretation method developed by members of the UK Forensic Science Service is used to show how a technical innovation in the delivery of forensic science services to the police has instantiated these two recent social processes. PMID- 21553604 TI - Envisioning cyclopropane: scientific product or medical technology? AB - In the late 1920s, V.E. Henderson and his team at the University of Toronto discovered the anaesthetic properties of cyclopropane. For a number of reasons, Henderson did not envision cyclopropane as a useful technology: to him it was simply a gas that possessed anaesthetic properties, rather than a potential clinical product, and this explains why cyclopropane was not first introduced into Toronto hospitals. In contrast, the practicing anaesthesiologist Ralph M. Waters envisioned cyclopropane as a medical technology, partly because it could assist his effort to professionalize anaesthesiology in the 1930s. This paper argues that it is useful to make a historically-informed distinction between cyclopropane the experimental laboratory gas and cyclopropane the medical anaesthetic because such a distinction highlights the social dimensions of the process of scientific discovery and helps illuminate the relationship between scientific production and medical technology. PMID- 21553605 TI - 'Professional techs': machines, technical skills and professional aspirations in hearing prosthetics and respiratory care in Quebec, 1950-1990. AB - In the sociology of professions, working with machines is often seen as an obstacle to professional aspirations. This is especially true in healthcare, where a sharp distinction between professionals and technicians has prevailed since the early 20th century. However, only a few studies have documented the meaning of machines and technical skills for healthcare technicians. The purpose of this article is to show how and why two groups of such technicians, hearing prosthetists and respiratory technicians, actually tried to reconcile the use of machines with professionalization projects. It concludes with considerations about what these stories tell us about the history of technical work, about the transformations of the healthcare work environment in the second half of 20th century, and about the place of technical skills in the system of professions. PMID- 21553606 TI - Cave men: stone tools, Victorian science, and the 'primitive mind' of deep time. AB - Palaeoanthropology, the study of the evolution of humanity, arose in the nineteenth century. Excavations in Europe uncovered a series of archaeological sediments which provided proof that the antiquity of human life on Earth was far longer than the biblical six thousand years, and by the 1880s authors had constructed a basic paradigm of what 'primitive' human life was like. Here we examine the development of Victorian palaeoanthropology for what it reveals of the development of notions of cognitive evolution. It seems that Victorian specialists rarely addressed cognitive evolution explicitly, although several assumptions were generally made that arose from preconceptions derived from contemporary 'primitive' peoples. We identify three main phases of development of notions of the primitive mind in the period. PMID- 21553607 TI - Human tools of the European tertiary? Artefacts, brains and minds in evolutionist reasoning, 1870-1920. AB - This essay explores evolutionary reasoning and notions of progress at the turn of the twentieth century by focusing on the various interpretations used to understand eoliths. These 'dawn' (Greek eos) 'stones' (Greek lithos) were contested objects and I focus on three geographic episodes in which they were used to support scientific, and sometimes socially inspired, accounts of human origins. Particular attention is paid to the work of Gabriel de Mortillet (1821 98), James Reid Moir (1879-1944) and Henry Fairfield Osborn (1857-1935). PMID- 21553608 TI - 'Hurrah for the missing link!': a history of apes, ancestors and a crucial piece of evidence. AB - In the nineteenth century the idea of a 'missing link' connecting humans with the rest of the animal kingdom was eagerly embraced by professional scientists and popularizers. After the publication of Charles Darwin's Origin of Species in 1859, many tied the idea and subsequent search for a crucial piece of evidence to Darwin and his formulation of the theory of evolution by natural selection. This article demonstrates that the expression was widely used and that the framework for discussions about human's relation to the apes and gaps in the fossil record were well in place and widely debated long before Origin of Species became the standard reference for discussing human evolution. In the second half of the century the missing link gradually became the ultimate prize in palaeoanthropology and grew into one of the most powerful, celebrated and criticized icons of human evolution. PMID- 21553609 TI - Comparison of definitions of metabolic syndrome in relation to risk for coronary artery disease and stroke. AB - OBJECTIVES: To compare definitions of metabolic syndrome (MS) in relation to their association with coronary artery disease (CAD) and stroke. METHODS: We performed a cross-sectional study in a primary care setting, involving 719 general practitioners and based on stratified distribution proportional to the population density. The first two adult patients scheduled for an appointment on a given day were invited to participate, irrespective of the reason for the consultation. A questionnaire was applied to record sociodemographic, clinical and laboratory data. A diagnosis of MS was defined according to NCEP-ATP III 2001, NCEP-ATP III 2004, IDF and AHA/NHLBI criteria. Multivariate logistic regression analysis was used to assess the risk of CAD and stroke according to gender, age, body mass index, waist circumference, HDL cholesterol, triglycerides, hypertension, diabetes and MS according to each definition. RESULTS: The study included 16,856 individuals (age 58.1 +/- 15.1 years). The prevalence of MS adjusted for gender, age and region size according to the 2001 and 2004 NCEP-ATP III, IDF and AHA/NHLBI definitions was 28.4%, 32.8%, 65.5% and 69.4%, respectively. The degree of agreement according to k statistics was modest and only 60.3% simultaneously fulfilled the criteria of all definitions. Hypertension was the treatable risk factor most strongly associated with CAD and stroke. Only the IDF and AHA/NHLBI definitions of MS were independently associated with CAD (OR: 1.74 and 2.26, respectively). Regarding stroke, only the AHA/NHLBI criteria showed a statistically significant association (OR: 1.85). CONCLUSIONS: MS as defined according to the AHA/NHLBI criteria appears to be the best predictor of CAD and stroke in the Portuguese population, and remains an independent risk factor for CAD and stroke after adjustment for its individual components. PMID- 21553610 TI - Atrial fibrillation and thromboembolic risk: what is the extent of adherence to guidelines in clinical practice? AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac rhythm disorder in clinical practice, with a growing prevalence in recent decades. Through the use of thromboembolic risk scores it is possible to adjust thromboprophylaxis to individual risk. The aim of this study was to evaluate the conformity of antithrombotic therapy prescribed at hospital discharge with the guidelines in patients with AF and its influence on long-term morbidity and mortality. METHODS: We performed a retrospective analysis, based on medical records and phone interview, of consecutive patients admitted to an internal medicine department over a one-year period with a diagnosis of AF or atrial flutter--ICD-9-CM 427.31/32. We determined individual thromboembolic risk in accordance with the ACC/AHA/ESC risk categories, and assessed conformity of antithrombotic therapy with the guidelines. Independent predictors of long-term (378 +/- 241 days) mortality and mortality or readmission were identified by multivariate analysis. RESULTS: The study population consisted of 174 patients with a diagnosis of AF, 59.8% (104) female, mean age 77 +/- 10 years. Hypertension (65.7%) and heart failure (61.3%) were the most prevalent comorbidities. Most patients (82.7%) were stratified as high thromboembolic risk and the remainder as moderate risk. The antithrombotic therapy prescribed at hospital discharge was documented in 155 patients, 126 (81.3%) with high thromboembolic risk. Of the latter group of patients, oral anticoagulation (OAC) was prescribed in 65 (51.6%) and proposed but contraindicated in 24 (19.0%). In patients with moderate thromboembolic risk, therapeutic options were divided between OAC (69.0%), antiplatelet therapy (17.2%) and no thromboprophylaxis (13.8%). Overall there was discordance between the therapy instituted and the guidelines in 25.8% of patients. Age 85 years or over was the only independent predictor of death (HR 1.92; 95% CI 0.94-3.91), while OAC (HR 0.43; 95% CI 0.27-0.70) and male gender (HR 0.58; 95% CI 0.36-0.94) were independent protective factors against death or hospital readmission. CONCLUSIONS: In this study, patients admitted with AF were mainly elderly, women and with high thromboembolic risk. The prescription rate of OAC in patients at high risk was lower than recommended in the guidelines, which were not followed in a quarter of patients. The main therapeutic option in cases of moderate risk was OAC. OAC use was the only modifiable factor able to improve prognosis of patients with AF, and it is thus crucial to ensure adherence to the guidelines in daily clinical practice. PMID- 21553611 TI - Ischemic versus non-ischemic cardiomyopathy--are there differences in prognosis? Experience of an advanced heart failure center. AB - INTRODUCTION: Previous studies have associated heart failure (HF) of ischemic etiology with worse prognosis compared to HF from non-ischemic cardiomyopathy. HF treatment has evolved significantly in recent years. Has this evolution had an impact on this prognostic gap? OBJECTIVE: The aim of our study was to compare patients with advanced HF--nonischemic versus ischemic etiology--in terms of baseline characteristics, treatment, and in-hospital and long-term prognosis (including death, heart transplantation and hospital readmission). METHODS: We performed a retrospective study including 286 consecutive patients with systolic HF admitted to an HF unit between January 2003 and June 2006. We compared two groups according to HF etiology: Group A--ischemic cardiomyopathy (n = 109); Group B--non-ischemic cardiomyopathy (n = 177). Mean follow-up was 41 months. RESULTS: Group A were older (62.2 +/- 10.4 vs. 55.9 +/- 15.2 years, p < 0.001), with a higher proportion of males (80.7 vs. 67.8%, p = 0.017), diabetes, anemia, dyslipidemia and smokers; they required more prolonged treatment with inotropic drugs and more frequent treatment with statins, antiplatelet agents and nitrates. On admission, Group B patients presented with lower serum sodium and higher aminotransferase levels. There were no differences in the occurrence of cardiogenic shock or dysrhythmias, baseline ECG rhythm, frequency of left bundle branch block, renal function, BNP, left ventricular ejection fraction, heart rate or implantation of intracardiac devices. Group A had higher in-hospital mortality (11.0 vs. 4.0%, p = 0.020). Multivariate analysis showed that the only predictor of in-hospital mortality was serum sodium < 133 mmol/l and also showed that HF etiology was not a predictor of this endpoint; previous medication with angiotensin-converting enzyme inhibitors was a protective factor. On Kaplan-Meier analysis, it was observed that, in the long-term, there were no significant differences in either survival rates (70.0 vs. 76.8%, p = 0.258), or the combined endpoints of survival free of death or heart transplantation (55.7 vs. 54.5%, p = 0.899) and survival free of death, heart transplantation or hospital readmission (38.0 vs. 32.8%, p = 0.386). CONCLUSIONS: Although in-hospital mortality was higher in ischemic cardiomyopathy, this variable was not an independent predictor of mortality and the difference appears to fade in the long-term, in contrast to what had been reported in older studies, but in agreement with more recent data. PMID- 21553612 TI - Resting heart rate is a powerful predictor of arrhythmic events in patients with dilated cardiomyopathy and implantable cardioverter-defibrillator. AB - Patients with dilated cardiomyopathy and implantable cardioverter-defibrillator (ICD) are a high-risk group for arrhythmias. They regularly undergo cardiopulmonary exercise testing (CPET) to assess cardiac reserve and to guide clinical decisions or therapeutic adjustments. Data from previous studies demonstrate that prognosis in patients with heart failure (HF) worsens with the presence of appropriate shocks. OBJECTIVE: The purpose of this study was to evaluate the value of CPET parameters to predict shocks and other arrhythmic events in HF patients with ICD, in order to identify a high-risk group for arrhythmias. METHODS: This was a prospective single-center registry of 61 consecutive patients (mean age 55 +/- 15 years, 18% female), with dilated cardiomyopathy (ischemic etiology in 57%) and ICD, who underwent symptom-limited maximal CPET six months or less before device implantation. Minimum follow-up was 180 days. The primary endpoint was appropriate shock and the composite endpoint was appropriate shock and/or ventricular fibrillation (VF) and/or sustained ventricular tachycardia (VT), which were then correlated with hemodynamic variables (heart rate and blood pressure) and CPET parameters. RESULTS: During a mean follow-up of 27 months, eight patients died (13%), two of them from arrhythmic cause (3.3%), and 16 (26%) patients received at least one appropriate ICD shock, eight (13%) due to VF. Sustained VT was recorded in 23 patients (38%) and nonsustained VT in 42 patients (69%). CPET showed that the group with the primary end point had lower peak VO2, anaerobic threshold and chronotropic reserve. On multivariate analysis, resting heart rate was the only independent predictor of appropriate shock (HR 1.06; 95% CI 1.01-1.10; p = 0.025). Univariate analysis identified peak VO2, anaerobic threshold, VE/VCO2 slope, resting heart rate and heart rate decrease during the first minute of recovery, and systolic blood pressure during exercise as predictive of the composite endpoint (shock/VF/sustained VT). Multivariate analysis identified resting heart rate and peak VO2 as independent predictors, with HR 1.04; 95% CI 1.00-1.09 (p = 0.050) and HR 0.88; 95% CI 0.78-0.98 (p = 0.026), respectively. The best cut-off for resting heart rate to predict the composite and primary endpoints was > 76 bpm (area under the ROC curve: 0.67; 95% CI 0.53-0.78 and 0.65; 95% CI 0.51-0.76, respectively). CONCLUSION: Resting heart rate and peak VO2 were identified in multivariate analysis as good predictors of arrhythmic events and resting heart rate was the only independent predictor of appropriate shock in HF patients with ICD. Both advanced stage heart failure and sympathetic overdrive may be associated with the development of malignant arrhythmias. PMID- 21553613 TI - Stent fracture: case report and literature review. AB - We report the case of a man presenting with acute myocardial infarction and a history of percutaneous coronary intervention with implantation of a drug-eluting stent, which was now fractured. This case highlights the growing recognition of stent fracture as a potential mechanism for late stent thrombosis in the drug eluting stent era. Following the case report, we review the literature on the incidence, contributing factors and clinical impact of stent fracture. PMID- 21553614 TI - Ventricular tachycardia in acromegaly. AB - Cases of sudden cardiac death have been reported in patients with acromegaly. Malignant ventricular arrhythmias may play an important role in this fatal complication, but the exact mechanisms are not well understood. We report on an acromegalic patient presenting with documented recurrent syncopal ventricular tachycardia. PMID- 21553615 TI - Combined percutaneous treatment of severe aortic stenosis and left main disease in a high surgical risk patient. AB - We report the case of a 77-year-old man with heart failure (NYHA class IV), angina (CCS class III) and multiple comorbidities. The evaluation showed severe aortic sten osis and left main coronary disease. Due to the very high perioperative risk, conventional surgery was denied. It was therefore decided to perform a combined percutaneous intervention. First, left main PCI was successfully performed. A few days later, a percutaneous aortic valve prosthesis was implanted via a femoral approach using the CoreValve ReValving system. Immediately after prosthesis implantation, the control angiogram showed severe paravalvular aortic regurgitation, which was corrected by implanting another percutaneous aortic prosthesis inside the first one (valve-in-valve procedure). During follow-up the patient experienced a remarkable improvement in hemodynamic and clinical status. We demonstrate that the combination of two different percutaneous interventions in severe aortic and coronary disease is feasible and can be a suitable alternative approach in high surgical risk patients. PMID- 21553616 TI - Bias in clinical studies. AB - Clinical studies are designed fundamentally to obtain data to support practice, whether diagnostic, therapeutic or prognostic. No matter how well a study was designed, implemented or analyzed, it is never possible to guarantee the truth of its results with absolute certainty. This is due to two factors that can change the study's results: random error and systematic error (also called bias). The first appears without warning and cannot be modulated, while the second--defined as the systematic introduction of error into a study--can be removed (if not completely, at least partially). In this paper we present the most common types of bias found in clinical studies, whether therapeutic (clinical trials), or with other experimental or observational designs. PMID- 21553617 TI - Descending necrotizing mediastinitis presenting as cardiac tamponade. PMID- 21553618 TI - Optical coherence tomography findings in ST-elevation acute myocardial infarction in a young woman. PMID- 21553619 TI - How do we get to meaningful use? PMID- 21553620 TI - An end in sight for nurse staffing nightmares. More hospitals are equipping staff with the right tools to simplify scheduling, improve morale and provide better patient care. PMID- 21553621 TI - Making decisions for 2011 and beyond. Provider organizations should plan not only for immediate requirements, but also in anticipation of continued industry changes. PMID- 21553622 TI - The accountable care delivery model. Using technology to change provider and patient behaviors. PMID- 21553623 TI - Streamline your front-end processes. Opportunities abound for improvement when a hospital looks at building a super-efficient patient access production system. PMID- 21553624 TI - The digital juggle. Meeting the information demands of business executives, regulators and counsel in the pharmaceutical industry. PMID- 21553625 TI - When it matters most. Rugged computing devices and mobile health technologies enable safe and responsive care. PMID- 21553626 TI - Circulating smallpox knowledge: Guatemalan doctors, Maya Indians and designing Spain's smallpox vaccination expedition, 1780-1803. AB - Drawing on the rich but mostly overlooked history of Guatemala's anti-smallpox campaigns in the 1780s and 1790s, this paper interweaves an analysis of the contribution of colonial medical knowledges and practical experiences with the construction and implementation of imperial science. The history of the anti smallpox campaigns is traced from the introduction of inoculation in Guatemala in 1780 to the eve of the Spanish Crown-sponsored Royal Maritime Vaccination Expedition in 1803. The paper first analyses the development of what Guatemalan medical physician Jose Flores called his 'local method' of inoculation, tailored to material and cultural conditions of highland Maya communities, and based on his more than twenty years of experience in anti-smallpox campaigns among multiethnic populations in Guatemala. Then the paper probes the accompanying transformations in discourses about health through the anti-smallpox campaigns as they became explicitly linked to new discourses of moral responsibility towards indigenous peoples. With the launch of the Spanish Vaccination Expedition in 1803, anti-smallpox efforts bridged the New World, Europe and Asia, and circulated on a global scale via the enactment of imperial Spanish health policy informed, in no small part, by New World and specifically colonial Guatemalan experiences with inoculation in multiethnic cities and highland Maya towns. PMID- 21553627 TI - Locating the sciences in eighteenth-century Egypt. AB - In the last years of the eighteenth century, Egypt famously witnessed the practice of European sciences as embodied in the members of Bonaparte's Commission des sciences et des arts and the newly founded Institut d'Egypte. Less well known are the activities of local eighteenth-century Cairene religious scholars and military elites who were both patrons and practitioners of scientific expertise and producers of hundreds upon hundreds of manuscripts. Through the writings of the French naturalist Etienne Geoffroy Saint-Hilaire (1772-1844) and those of the Cairene scholar and chronicler Abd al-Rahman al Jabarti (1753-1825), I explore Egypt as a site for the practice of the sciences in the late eighteenth century, the palatial urban houses which the French made home to the Institut d'Egypte and their role before the French invasion, and the conception of the relationship between the sciences and social politics that each man sought. Ultimately, I argue that Geoffroy's struggle to create scientific neutrality in the midst of intensely tumultuous political realities came to a surprising head with his fixation on Paris as the site for the practice of natural history, while al-Jabarti's embrace of this entanglement of knowledge and power led to a vision of scientific expertise that was specifically located in his Cairene society, but which--as Geoffroy himself demonstrated--could be readily adapted almost anywhere. PMID- 21553628 TI - Following insects around: tools and techniques of eighteenth-century natural history. AB - This paper examines the movement of the materials, ideas and practices that went into the construction of natural-historical observations in Paris and the French provinces--in particular, observations of insects. The paired notions of circulation and locality expose the complex dynamic at play in the production of knowledge about these mundane creatures. I show how the movement of things and people problematizes the notion of a single 'centre of calculation', even where a dominant figure like Reaumur was managing collections and producing authoritative texts. Reaumur was indeed managing the flow of observations, letters and specimens from his privileged vantage point in Paris, but he was not the only one doing the processing, and the objects and knowledge flowed in all directions. The paper uses correspondence among eighteenth-century naturalists of various sorts to get at the dynamics of circulation, tracing the movements of insects, bits of text or narrative, drawings, letters, questions, apparatus, books and people. My title refers to the activities of naturalists, who had to follow insects around in order to observe them, and to my own activity in following the insects in their movement through letters, conversations, specimen jars, drawings and texts. My research depends on the accumulation of details about experimental and observational practice, culled from the masses of letters that moved continually around Europe, much as the science of insects depended on the accumulation of details about insects--their physiology, habits, metamorphosis and place in the human economy and the economy of nature. PMID- 21553629 TI - Locality and circulation in the Habsburg empire: disputing the Carlsbad medical salt, 1763-1784. AB - By looking at the fierce debates in the city of Carlsbad in Bohemia around the fabrication of medical salt by a local doctor, David Becher, from 1763 to 1784, the paper examines the interactions between different spheres or levels of circulation of knowledge in the Habsburg Empire. The dispute crystallized around the definition of the product, about its medical qualities and its relation with the water of the local mineral spring. The city's inhabitants contested the vision of the medical experts, fearing that the extraction of the medical salt from the spring water and its sale outside the town would have a negative effect on the number of visitors to the spa. Their vision implied a more or less 'popularized' form of alchemical thinking as it identified the mineral water with the extracted 'salt', conceived as the 'essence' of the water, produced by evaporation. The Carlsbad salt dispute highlights the complex interactions among the different networks in which knowledge circulated through the Habsburg Empire in the eighteenth century. The different actors relied on specific networks with different logics of discourse and different modes of circulation. In each case the relation between the local, the regional and the imperial had to be negotiated. The paper thus sketches out the different geographies of knowledge in the Habsburg Empire but also its localization in and around Carlsbad. PMID- 21553630 TI - Birth-baptism intervals in 68 Lancashire parishes, 1646-1917. AB - This article examines the birth/baptism interval in 68 Anglican parishes. It provides a continuous annual record from 1646 to 1917 thereby augmenting previous studies in which periods such as the 1640s, the mid-eighteenth and late nineteenth centuries have been sparsely represented. During the seventeenth century intervals remained stable, but afterwards they increased with many parishes experiencing late baptism. Evidence is also presented to support the view that serious epidemic illness could result in shortening of the interval while population increase or a change of incumbent could lead to a lengthening of the interval. PMID- 21553631 TI - Yet another inquiry into the trustworthiness of eighteenth-century London's Bills of Mortality. AB - This is an enquiry into how eighteenth-century London's Bills of Mortality were compiled. It concludes that while they remain tolerably accurate in aggregate, particularly when considered over a number of years, they are liable to be very misleading if particular localities or parishes are considered. They are a record of registered burials-not deaths-of most of those who had been baptised as Anglicans, so they omit some burial grounds within London, and some dissenters. Crucially, they are most misleading guides to those who had died in one parish but whose family chose to have them buried in another. Several London parishes deliberately undercut their neighbours by charging lower burial fees to attract custom; others opened extra-parochial burial grounds. St Martin-in-the-Fields offers an example of the latter from 1806, but the scale of the new burial ground was not large and it was mainly confined to those who had died in the workhouse. Much more significant was the neighbouring parish of St Anne Soho, which at its peak period in the 1760s to the 1790s was alone handling the equivalent of between 2 and 5 per cent of all Anglican burials within the total area of London's Bills of Mortality. This was only one, though perhaps a particularly egregious, London parish, while the export of corpses to one's erstwhile 'home' parish demonstrates why the Bills cannot be trusted in their detailed geography, as well as providing a warning to all English population historians confronted with a sudden fall or rise in their burial totals. PMID- 21553632 TI - The eighteenth-century vagrant contractor. AB - This article traces the salient developments in poor law and vagrancy law that led to the counties of England and Wales being obliged to shoulder the financial burden of the mobile poor throughout the eighteenth century. It shows that despite the lack of statutory authority many, probably most, counties contracted with a new type of official to implement the conveyance of vagrants under vagrancy legislation in an attempt to counter suspected negligence and profiteering by constables. It shows, with particular reference to Middlesex and the West Riding, that the terms and conditions of these contracts varied considerably, and describes arrangements for the vagrants. The article also suggests reasons why the mobile poor formed an increasing segment of the population well into the nineteenth century and finds that by then the contractors were suspected of the same faults as the constables before them, leading to the abandonment of the contractor system. PMID- 21553633 TI - Reflexive modernization at the source: local media coverage of bovine spongiform encephalopathy in rural Alberta. AB - The potential for reflexive modernization is defined by multiple factors, but the acknowledgment of risk is crucial, particularly among social groups that play a key role in risk minimization. This study offers an examination of the role of local media in response to the outbreak of bovine spongiform encephalopathy (BSE) in beef-producing communities in rural Alberta. BSE is one of several global risk issues that reflexive modernization theorists argue have the potential to trigger a transformation toward a critically reflexive society in which such risks are minimized. Content analysis of newspapers in beef-producing regions in Alberta, however, shows how local media framed BSE in a manner that maximized community cohesion and protection of local culture. This selective coverage of BSE in rural Alberta is quite likely to have contributed to, or at least reinforced, support for the current institutional structure of Canadian agriculture in beef-producing regions, through the constriction of discourse. PMID- 21553634 TI - Socioeconomic status and body mass index in Canada: exploring measures and mechanisms. AB - We examine the relationship between socioeconomic status (SES), sociodemographic characteristics, lifestyle behaviors (fruit and vegetable intake, exercise, smoking, and alcohol consumption), and body mass index (BMI) using the Canadian Community Health Survey 2.1. We explore two different measures of SES, education and income, to elucidate material and cultural explanations of the SES-BMI relationship. Results vary significantly by gender, highlighting the complexity of the relationship between SES, sociodemographic and lifestyle factors, and BMI. We suggest that body weight is still a gendered status symbol, and that cultural and psychosocial factors may be more important than material factors in perpetuating this health inequality. PMID- 21553635 TI - The many lives of Charles Darwin: early biographies and the definitive evolutionist. AB - This article focuses on the early book-length biographies of Darwin published from his death in 1882 up to 1900. By making 1900 the cutoff point I can examine the biographies produced when the iconic figure was not yet set in stone, and before the rediscovery of Mendel's work in the early twentieth century and the anniversary celebrations of 1909 changed the way in which Darwin was regarded. Darwin's biographers dealt with three major themes. First, several biographers emphasized his scientific abilities, in particular his powers of observation and his prowess in conducting experiments. Second, many biographers discussed his character, a key issue in determining whether or not he could be trusted as a scientific guide. Finally, his scientific theories and religious beliefs, and how they related to the evolutionary controversy, formed a topic taken up by most biographers. By focusing on these three themes, the biographies published before 1900 were important in shaping the image of Darwin that was forming in American and British culture. PMID- 21553636 TI - Selling eugenics: the case of Sweden. AB - This paper traces the early (1910s to 1920s) development of Swedish eugenics through a study of the social network that promoted it. The eugenics network consisted mainly of academics from a variety of disciplines, but with medicine and biology dominating; connections with German scientists who would later shape Nazi biopolitics were strong. The paper shows how the network used political lobbying (for example, using contacts with academically accomplished MPs) and various media strategies to gain scientific and political support for their cause, where a major goal was the creation of a eugenics institute (which opened in 1922). It also outlines the eugenic vision of the institute's first director, Herman Lundborg. In effect the network, and in particular Lundborg, promoted the view that politics should be guided by eugenics and by a genetically superior elite. The selling of eugenics in Sweden is an example of the co-production of science and social order. PMID- 21553637 TI - Sir John Tomes FRS, Fellows of the Royal Society, and dental reform in the nineteenth century. AB - In this paper Sir John Tomes HonFRCS LDS FRS (1815-95), surgeon-dentist, is presented as the agent through whose membership of the Royal Society the previously disorganized profession of dentistry shared in the process of reform and scientific progress that engaged the medical profession in the second half of the nineteenth century. The study identifies 70 of the Fellows of the Royal Society who were involved in medical and dental research and/or who gave structure and effect to the governance of the medical and dental professions. In recording the education of Tomes as a scientist, his election to the Society and his place in the process of reform, the paper identifies the Royal Society as a superculture, enabling him to act at a functional remove from the cultures of the surgeons and the dentists of the day. PMID- 21553638 TI - Different differences: the use of 'genetic ancestry' versus race in biomedical human genetic research. AB - This article presents findings from our ethnographic research on biomedical scientists' studies of human genetic variation and common complex disease. We examine the socio-material work involved in genome-wide association studies (GWAS) and discuss whether, how, and when notions of race and ethnicity are or are not used. We analyze how researchers produce simultaneously different kinds of populations and population differences. Although many geneticists use race in their analyses, we find some who have invented a statistical genetics method and associated software that they use specifically to avoid using categories of race in their genetic analysis. Their method allows them to operationalize their concept of 'genetic ancestry' without resorting to notions of race and ethnicity. We focus on the construction and implementation of the software's algorithms, and discuss the consequences and implications of the software technology for debates and policies around the use of race in genetics research. We also demonstrate that the production and use of their method involves a dynamic and fluid assemblage of actors in various disciplines responding to disciplinary and sociopolitical contexts and concerns. This assemblage also includes particular discourses on human history and geography as they become entangled with research on genetic markers and disease.We introduce the concept of'genome geography' to analyze how some researchers studying human genetic variation'locate' stretches of DNA in different places and times. The concept of genetic ancestry and the practice of genome geography rely on old discourses, but they also incorporate new technologies, infrastructures, and political and scientific commitments. Some of these new technologies provide opportunities to change some of our institutional and cultural forms and frames around notions of difference and similarity. Nevertheless, we also highlight the slipperiness of genome geography and the tenacity of race and race concepts. PMID- 21553639 TI - Generating sociability to drive science: patient advocacy organizations and genetics research. AB - This paper examines how patient advocacy organizations (PAOs) representing those with rare genetic disorders drive research to their concerns. The rarity of the diseases produces a basic condition of marginalization: small numbers of widely distributed disease sufferers. The lack of promise of an eventual market makes it difficult to attract the economic and biological resources necessary for sustained research. My analysis relies mainly on 21 interviews with leaders from nine PAOs and scientists involved with them, and seeks to understand how PAOs try to attract and influence scientific research. Using a comparative framework, I find that the five main mechanisms emphasized in the literature--economic resources, social movement-style mobilization, moving early, lay expertise, and organizational controls--cannot fully explain the differences in strategies and relationships among members of my PAO sample. I propose instead to show how 'sociability'--forging close relationships with scientists and orchestrating relationships among them--enables PAOs to drive research to their concerns. I show how the strategic manipulation of sociability can give PAOs substantial influence over the research process. However, the forms of sociability that yield the greatest effects are difficult to achieve, and most forms of relationship building offer PAOs much less influence on research. PMID- 21553640 TI - Imagination and technoscientific innovations: governance of transgenic cows in New Zealand. AB - This paper examines a controversial research programme aimed at the production of transgenic cows in New Zealand. It emphasizes the contested representation of the research, in its promotion, in its governance, and in the opposition sparked amongst environmentallanti-genetic modification groups and within the Maori community. The paper contends that the case of New Zealand's genetically modified cows certainly reveals some unique features of the prevailing economic, geographical and cultural context, but nonetheless has salience for the broader understanding of the promotion, public reception and governance of genetic modification. PMID- 21553641 TI - Matters of care in technoscience: assembling neglected things. . AB - This paper aims to encourage an ethos of care in the study of science and technology. It starts with a reading of Bruno Latour's notion of'matters of concern' as favouring an awareness of the ethico-political effects of constructivist accounts in STS. Introducing attention to concern brings us closer to a notion of care. However, there is a'critical' edge to care that Latour's politics of things tends to disregard. Drawing upon feminist knowledge politics, I propose to treat matters of fact and sociotechnical assemblages as 'matters of care' and argue that engaging with care requires a speculative commitment to neglected things. PMID- 21553642 TI - Soluble epoxide hydrolase: a promising therapeutic target for cardiovascular diseases. AB - Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP450) products of arachidonic acid and EETs are endogenous lipid mediators synthesized by the vascular endothelium which perform important biological functions, including vasodilation, anti-inflammation, antimigratory, and cellular signaling regulations. However, EETs are rapidly degraded by soluble epoxide hydrolase (sEH) to the corresponding diols: dihydroxyeicosatrienoic acids (DHETs), which have little active in causing vasorelaxation. A number of studies have supported that the inhibition of sEH (sEHIs) had cardiovascular protective effects in hypertension, cardiac hypertrophy, atherosclerosis, ischemia-reperfusion injury, and ischemic stroke. Moreover, sEHIs could slow the progression of inflammation, protect end-organ damage and prevent ischemic events, also, attenuate endothelial dysfunction, suggesting that the pharmacological blockade of sEH might provide a broad and novel avenue for the treatment of many cardiovascular diseases. PMID- 21553643 TI - Cationic liposomes as gene delivery system: transfection efficiency and new application. AB - As it has been generally reported that oppositely charged cationic liposomes (CLs) are superior to either neutral or anionic liposomes as gene delivery carrier, interest in the properties, structures, transfection mechanism of CLs and so forth arises unprecedentedly. However, our understanding about the mechanism of CLs-gene complexes (lipoplex)-cell interaction and factors influencing the transfection efficiency (TE) of CLs remains poor. In this article, we describe some new results aimed at elucidating the relationship between the chemical-physical properties of lipoplex with TE and introducing recent applications of CLs in gene therapy. PMID- 21553644 TI - Biopharmaceutical characterization of some new papaverine decomposition products. AB - 2,3,9,10-Tetramethoxy-12-oxo-12-H-indolo[2,1-a]isoquinolinium chloride 1 (compound X) and 13-(3,4-dimethoxyphenyl)-2,3,8,9-tetramethoxy-6a, 12a diazadibenzo[a,g] fluorenylium chloride 2 (compound NF) are new papaverine oxidation products. A solution of compound 1 bleaches on addition of sodium hydroxide solution. A new entity, 2-(2-carboxy-4,5-dimethoxyphenyl)-6,7 dimethoxyisoquinolinium inner salt 3 (compound WP), is formed. The physico chemical properties of compounds 1-3, such as solubility in water and lipophilicity, have been measured. The IC50 for compounds 1 and 3 was also assessed. PMID- 21553645 TI - Olanzapine degradation kinetics in aqueous solution. AB - The degradation kinetics of olanzapine as a function of pH and temperature has been studied by a spectrophotometric method. The degradation reaction rates were observed to follow first-order kinetics with respect to olanzapine. The hydrolytic reaction was shown to be hydrogen and hydroxide ion-catalyzed and the Arrhenius plots showed the temperature dependence of olanzapine degradation. PMID- 21553646 TI - Development, characterization and in vitro assessement of stearylamine-based lipid nanoparticles of paclitaxel. AB - The objective of the study was to design and evaluate a solid lipid nanoparticle (SLN) drug delivery system for delivery of paclitaxel. Components of the SLN were lipid (stearylamine) and surfactants (Pluronic F68 and Soya lecithin). The paclitaxel loaded nanoparticles were prepared by a modified solvent injection method. Experiments were carried out with excipients, where surfactants, lipid and drug molar ratios were varied to optimize the formulation characteristics. The in vitro drug release profile from the nanoparticles followed a diffusion controlled mechanism. The modified solvent injection method ensured high entrapment efficiency (approximately 75%), produced smaller, stable nanoparticles with a narrow size distribution and proved to be a reproducible and fast production method. The present study describes the feasibility and suitability of stearylamine based SLN produced using a mixture of surfactants to develop a clinically useful system with targeting potential for poorly soluble antineoplastic drugs. PMID- 21553647 TI - Preparation and characterization of nitrendipine solid lipid nanoparticles. AB - Nitrendipine, a dihydropyridine calcium channel blocker, has very poor oral bioavailability (10-20%) due to first pass effect. Solid lipid nanoparticle (SLN) delivery systems of nitrendipine have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers stearylamine and dicetyl phosphate. SLNs were prepared by hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperatures above the melting point of lipids. Optimization studies of process and formulation variables were carried out. Particle size and zeta potential were measured by photon correlation spectroscopy (PCS) using Malvern zetasizer. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies were performed to characterize state of drug and lipid modification. In vitro release studies were performed in phosphate buffer pH 6.8 using modified Franz diffusion cell. Stable nitrendipine SLNs of mean size range 79 to 213 nm and zeta potential -38.2 to +34.6 mV were developed. About 99% nitrendipine was entrapped in SLNs and were stable on storage at 4 and 25 degrees C. DSC and PXRD analyses revealed that nitrendipine is dispersed in SLNs in an amorphous state. The release pattern of drug is analyzed and found to follow Weibull distribution rather than first order and Higuchi equation. PMID- 21553648 TI - Preservative system development for argan oil-loaded nanostructured lipid carriers. AB - Nanostructured lipid carriers (NLC) are used in many dermal cosmetic formulations. To prevent microbiological spoilage of NLC suspensions preservative systems must be used. Preservatives can impair the physical stability of NLC suspensions. Therefore, a systematic screening of preservative systems should be performed and the compatibility of these preservative systems with each NLC formulation has to be investigated. In this study three Argan oil-loaded NLC formulations were developed. Ethanol, propylene glycol and pentylene glycol were admixed to these formulations as preservative systems. The physical stability of the non-preserved and preserved formulations has been investigated. Upon admixing 20% w/w ethanol to the selected formulations, immediate particle aggregation could be detected using laser diffractometry and after 24 hours gelling occurred. This was accompanied with a lowering of Zeta potential value. Samples preserved with 10% w/w propylene glycol did not show any change in particle size or in Zeta potential, in comparison to the non-preserved formulation, when measured after one day and 120 days. Samples preserved with 5% pentylene glycol proved also to be stable after 120 days and did not show any change in particle size or Zeta potential. PMID- 21553649 TI - Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin. AB - The effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin was investigated at room temperature. The surfactants used in the study were anionic sodium lauryl sulfate (SLS) and nonionic polysorbate 80 (Tween 80). Sodium lauryl sulfate showed very significant increase in solubility Tween 80 at the highest concentration studied. The intrinsic dissolution rates were determined compared to at the same surfactant concentrations used in the solubility study by rotating disk method. Diffusion coefficient (D) of sparfloxacin was evaluated to be 7.19 x 10(-6) cm2S(-1) and the apparent mean diffusion coefficient for sparfloxacin-loaded micelle was estimated to 3.98 x 10( 6) and 2.21 x 10(-6) cm2S(-1) in Tween 80 and SLS respectively. PMID- 21553650 TI - Beta-glycerophosphate accelerates RANKL-induced osteoclast formation in the presence of ascorbic acid. AB - Despite numerous reports of the synergistic effects of beta-glycerophosphate and ascorbic acid in inducing the differentiation of osteoblasts, little is known about their roles in osteoclastic differentiation. Therefore, we investigated the effect of beta-glycerophosphate on osteoclastogenesis in the presence of ascorbic acid using primary mouse bone marrow cultures treated with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL). Beta-Glycerophosphate dose-dependently increased RANKL-induced osteoclast formation in the presence of ascorbic acid. This stimulatory effect was apparent when beta-glycerophosphate and ascorbic acid were only added during the late stages of the culture period, indicating that they influence later events in osteoclastic differentiation. While the combination of beta glycerophosphate and ascorbic acid inhibited RANKL-stimulated activation of ERK and p38, and degradation of IkappaB, it increased the induction of c-Fos and NFATc1. In addition, beta-glycerophosphate and ascorbic acid together enhanced the induction of COX-2 following RANKL stimulation. Taken together, our data suggest that beta-glycerophosphate and ascorbic acid have synergistic effects on osteoclast formation, increasing RANKL-mediated induction of c-Fos, NFATc1 and COX-2 in osteoclast precursors. PMID- 21553651 TI - PDE4 inhibitor suppresses PGE2-induced osteoclast formation via COX-2-mediated p27(KIP1) expression in RAW264.7 cells. AB - We investigated the effects of phosphodiesterase 3 (PDE3) and PDE4 inhibitors, which are cAMP degrading enzymes, on prostaglandin E2 (PGE2)-induced osteoclast formation. A PDE4 inhibitor decreased PGE2-induced osteoclast formation, whereas a PDE3 inhibitor did not, possibly due to the lack of PDE3 expression in RAW 264.7 cells. Cell cycle analysis revealed that the PDE4 inhibitor stimulated PGE2 induced p27(KIP1) expression, which leads to increased growth arrest at G0/G1 phase. The PDE4 inhibitor increased cyclooxygenase 2 (COX-2) expression in the presence of PGE2. COX-2 overexpression was associated with growth suppression via p27(KIP1) expression in RAW 264.7 cells. Taken together, our data demonstrate that the PDE4 inhibitor enhances PGE2-induced growth arrest of osteoclast precursors via COX-2-mediated p27(KIP1) expression, which in turn negatively regulates osteoclast formation. PMID- 21553652 TI - Modulation in concentrative nucleoside transporters-mediated intestinal absorption of mizoribine, an immunosuppressive agent, in lipopolysaccharide treated rats. AB - The characteristics of intestinal absorption of mizoribine and cephalexin, that are mediated by concentrative nucleoside transporters (CNTs) and PEPT1, respectively, was examined in lipopolysaccharide (LPS)-treated rats. LPS treatment is known to modify the expression of some transporters and induce cholestasis. At 24 h after the LPS treatment, averaged concentrations of IL-6 and total bile acids in plasma were 15-fold and 2-fold that in untreated control rats, respectively, and bile flow rate decreased by 40% of control, indicating the induction of inflammatory and cholestatic states. The oral bioavailability, estimated by urinary excretion percentage of unchanged form, of mizoribine in LPS treated rats was 1.5-fold higher than that in control rats, whereas the bioavailability of cephalexin remained unchanged. When mizoribine and cephalexin were administered into in-situ jejunum loops, there were no differences in the absorption rates between control and LPS-treated rats. These results indicated that the functional expression of CNT1, CNT2, and PEPT1 were not modulated by LPS treatment. When mizoribine (a CNT1/CNT2 substrate) and gemcitabin (a CNT1 substrate) were administered as a solution dissolved in bile into the intestinal loop, their absorption rates decreased significantly. In contrast, the absorption rate of ribavirin (a CNT2 substrate) remained unchanged. In conclusion, LPS treatment exerted no significant effect on the expression of CNT1 and CNT2 in the intestine. Bile was found to suppress the CNT1-mediated intestinal absorption of mizoribine and gemcitabin. The increased oral bioavailability of mizoribine in LPS-treated rats could be ascribed to the less amount of bile or bile acids in the intestine under cholestatic state of rats. PMID- 21553653 TI - Inhibitory potential of chlormadinone acetate (CMA) on five important UDP glucuronosyltransferases in human liver. AB - Chlormadinone acetate (CMA), a derivative of 17-a-hydroxyprogesterone, has been widely used as an orally effective progestogen in hormone replacement therapy (HRT). Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the major steps responsible for the metabolism of many drugs, environmental chemicals and endogenous compounds. Pharmacokinetic behaviours of drugs could be altered by inhibition of these UGT isoforms, and the search for drugs that potentially inhibit these UGT isoforms is very significant from a clinical point of view. In the present study, inhibition of five important UGT isoforms in human liver (UGT1A1, 1A3, 1A6, 1A9 and 2B7) by CMA was investigated using 4-MU as nonspecific substrate and recombinant UGT isoforms as enzyme sources. The results showed that CMA exhibited inhibitory effects on UGT1A3 (IC50 = 8.6 +/- 1.4 microM) and UGT2B7 (IC50 = 14.2 +/- 3.8 microM), with other UGT isoforms negligibly influenced. Lineweaver-Burk and Dixon plots showed that CMA noncompetitively inhibited UGT1A3 and UGT2B7. The Ki value was calculated to be 36.9 microM and 4.1 microM for UGT1A3 and UGT2B7, respectively. Considering that UGT1A3 and UGT2B7 are involved in the metabolism of many drugs, special attentions should be paid when CMA was co-administered with the drugs which mainly underwent UGT1A3, 2B7-mediated metabolism. PMID- 21553654 TI - Reversible inhibition of four important human liver cytochrome P450 enzymes by diethylstilbestrol. AB - Diethylstilbestrol (DES), a synthetic estrogen clinically used to treat threatened abortion between the 1940s and the 1970s, has been restricted to treat certain cases of prostatic and breast cancer due to its adverse drug responses such as teratogenicity and carcinogenicity. Some reports have demonstrated that the addition of DES to docetaxel could modify tubulin composition and improve response of prostate cancer to chemotherapy. Given that DES might be co administered with other drugs such as docetaxel, the present study focused on CYP based drug-drug interaction (DDI). In vitro inhibitory effects of DES on CYP isoforms were investigated, and the results showed that DES could competitively inhibit CYP3A4, CYP2C8, CYP2C9 and CYP2E1. The inhibition constants (Ki) were calculated to be 4.4 microM, 3.0 microM, 5.0 microM and 8.0 microM for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, respectively. Based on peak serum DES level after drip influsion of 500 mg of fosfestrol (DES diphosphate) in patients, [I]/Ki was calculated to be 4.3, 6.2, 3.7 and 2.3 for CYP3A4, CYP2C9, CYP2E1 and CYP2C8, which suggested that DES was likely to induce in vivo DDI through inhibition of these four major CYP isoforms. These results collectively demonstrate that adverse drug responses might exist when DES is co-administered with other drugs. PMID- 21553655 TI - Influence of CYP2C9 and vitamin k oxide reductase complex (VKORC)1 polymorphisms on time to determine the warfarin maintenance dose. AB - Polymorphisms in cytochrome P450 (CYP) 2C9 and the vitamin K oxide reductase complex subunit 1 (VKORC1) greatly affect the maintenance dose of warfarin. To prevent adverse events, immediate dose adjustment is required. The purpose of this study was to investigate the influence of these polymorphisms on the time taken to determine the warfarin maintenance dose for individual patients, and to assess the advantages of genotype-based dosing on initial anticoagulant therapy. We analyzed the genotypes of CYP2C9 and VKORC1 from 72 patients. The number of days taken to determine the maintenance dose was compared with the genotypes. The time taken to determine the maintenance dose of warfarin in group A (CYP2C9*1/*1, VKORC1 -1639AA), B (*1/*1, - 1639GA), C (*1/*3, - 1639AA), and D (*1/*3, - 1639GA) patients was 19 +/- 19, 28 +/- 28, 27 +/- 20 and 7 days, respectively. We analyzed the relationship between the initial dose of warfarin and the number of days required to determine the maintenance dose based on the VKORC1 genotypes. Patients with the VKORC1 - 1639AA genotype and who were initially treated with more than 3mg warfarin, required approximately 2 weeks for the maintenance dose to be determined. Patients with the VKORC1 - 1639GA genotype and the same initial warfarin dosage required approximately a month; however, patients initially treated with 5 mg of warfarin only required 9.5 +/- 5.3 days. We found a tendency that the time taken to determine the warfarin maintenance dose depends on the genotypes. Genotype-based dosing may improve initial anticoagulant therapy. PMID- 21553656 TI - A survey on diarrhea and convenience of intake associated with a single-dose extended release formulation of azithromycin. AB - The development of a single-dose extended release formulation of azithromycin (AZ SR) improves the adherence. However, gastrointestinal side effects such as diarrhea are frequent adverse drug reactions. The aim of the present study was to investigate the incidence of patient-reported in a diarrhea and the convenience of intake of AZ-SR in an Asian population. To assess the incidence of diarrhea and convenience of intake, patient-reported in a questionnaire about the incidence, onset, duration and severity of diarrhea, shape of stool, and patients' impression on taste. The drug was prepared and used in common with the hospital pharmacy and the community pharmacy. AZ-SR was prescribed in 96 outpatients, among whom 81 patients received the medicine and the questionnaire at the hospital pharmacy or one of five neighboring community pharmacies. The recovery of the questionnaire was 40.7%. Diarrhea occurred in 18 of 33 patients (54.5%), which was more frequent than in earlier reports, although the symptom was mild (grade 1-2) and occurred in most cases within 2 days. Approximately one third of patients reported inconvenience in taking the formulation in respect of the ease (36.4%), amount (42.4%), and unpleasant bitter taste (36.4%). We report here the importance of collaboration between hospital pharmacists and community pharmacists in providing accurate drug information, including the incidence of diarrhea, to patients receiving AZ-SR. PMID- 21553657 TI - Dietary guidelines for Americans, 2010: the cornerstone of nutrition policy. PMID- 21553658 TI - Emergency department visits for antiviral adverse events during the 2009 H1N1 influenza pandemic. AB - The 2009 pandemic influenza A (H1N1) outbreak was associated with an increased use of antiviral agents and highlighted the role of population-based monitoring for related adverse drug events (ADEs). An ongoing, nationally representative emergency department-based surveillance system was used to identify and characterize ADEs during the pandemic. Active surveillance for ADEs successfully provided timely, population-based data during the pandemic. Increases in antiviral ADEs paralleled increases in prescribing. Type and severity of ADEs were similar across all seasons. PMID- 21553659 TI - Cancer-related disparities and opportunities for intervention in Northern Plains American Indian communities. AB - OBJECTIVES: We examined behavioral trends associated with cancer risk and cancer screening use from 1997 through 2006 among American Indians/Alaska Natives (AI/ANs) in the Northern Plains region (North Dakota, South Dakota, Nebraska, and Iowa) of the United States. We also examined disparities between that population and non-Hispanic white (NHW) people in the Northern Plains and AI/ANs in other regions. METHODS: We analyzed Behavioral Risk Factor Surveillance System data from the Centers for Disease Control and Prevention for 1997-2000 and 2003-2006. We used age-adjusted Wald Chi-square tests to test the difference between these two periods for AI/ANs and the difference between AI/ANs and NHW people during 2003-2006. RESULTS: There was no statistically significant improvement among AI/ANs in the Northern Plains region for behaviors associated with cancer risk or cancer screening use, and there was a significant increase in the obesity rate. The prevalence of binge drinking, obesity, and smoking among AI/ANs in the Northern Plains was significantly higher than among NHW people in the same region and among AI/AN populations in other regions. Although the percentage of cancer screening use was similar for all three groups, the use of sigmoidoscopy/colonoscopy was significantly lower among the Northern Plains AI/ANs than among NHW people. CONCLUSION: These results indicate a need for increased efforts to close the gaps in cancer health disparities between AI/ANs and the general population. Future efforts should focus not only on individual level changes, but also on system-level changes to build infrastructure to promote healthy living and to increase access to cancer screening. PMID- 21553660 TI - Prevalence of high-risk HPV types and abnormal cervical cytology in American Indian/Alaska Native women, 2003-2005. AB - OBJECTIVES; We described prevalence estimates of high-risk human papillomavirus (HR-HPV), HPV types 16 and 18, and abnormal Papanicolaou (Pap) smear tests among American Indian/Alaska Native (AI/AN) women compared with women of other races/ethnicities. METHODS: A total of 9,706 women presenting for cervical screening in a sentinel network of 26 clinics (sexually transmitted disease, family planning, and primary care) received Pap smears and HR-HPV type-specific testing. We compared characteristics of 291 women self-identified as AI/AN with other racial/ethnic minority groups. RESULTS: In our population, AI/AN and non Hispanic white (NHW) women had similar age- and clinic-adjusted prevalences of HR HPV (29.1%, 95% confidence interval [CI] 23.9, 34.3 for AI/AN women vs. 25.8%, 95% CI 24.4, 27.2 for NHW women), HPV 16 and 18 (6.7%, 95% CI 3.9, 9.6 for AI/AN women vs. 8.8%, 95% CI 7.9, 9.7 for NHW women), and abnormal Pap smear test results (16%, 95% CI 11.7, 20.3 for AI/AN women vs. 14.9%, 95% CI 13.7, 16.0 for NHW women). AI/AN women had a higher prevalence of HR-HPV than Hispanic women, and a similar prevalence of HPV 16 and 18 as compared with Hispanic and African American women. CONCLUSIONS: We could not demonstrate differences in the prevalence of HR-HPV, HPV 16 and 18, or abnormal Pap smear test results between AI/AN and NHW women. This finding should improve confidence in the benefit of HPV vaccine and Pap smear screening in the AI/AN population as an effective strategy to reduce rates of cervical cancer. PMID- 21553661 TI - Who are California's late HIV testers? An analysis of state AIDS surveillance data, 2000-2006. AB - OBJECTIVES: Late HIV testing leads to preventable, severe clinical and public health outcomes. California, lacking a mature HIV surveillance system, has been excluded from documented analyses of late HIV testers in the United States. We identified factors associated with late HIV testing in the California AIDS surveillance data to inform programs of HIV testing and access to treatment. METHODS: We analyzed data from California AIDS cases diagnosed between 2000 and 2006 and reported through November 1, 2007. Late testers were people diagnosed with HIV within 12 months before their AIDS diagnosis. We identified factors significantly associated with late HIV testing using multivariable logistic regression. RESULTS: Among 28,382 AIDS cases, 61.2% were late HIV testers. Late testing was significantly associated with those > or = 35 years of age, heterosexual contact or unknown/other reported transmission risk, and being born outside of the U.S. When further classified by country of birth, people born in Mexico were most likely to be HIV late testers who progressed to AIDS. CONCLUSIONS: Our findings support wider implementation of opt-out HIV testing and HIV testing based in emergency departments. Services for HIV testing and treatment should be inclusive of all populations, but especially targeted to populations that may have more limited access. PMID- 21553662 TI - Electronic matching of HIV/AIDS and hepatitis C surveillance registries in three states. AB - OBJECTIVES: Both HIV and hepatitis C virus (HCV) can be transmitted through percutaneous exposure to blood in similar high-risk populations. HCV and HIV/AIDS surveillance databases were matched in Colorado, Connecticut, and Oregon to measure the frequency of co-infection and to characterize coinfected people. METHODS: We defined a case of HCV infection as a person with a reactive antibody for hepatitis C, medical diagnosis, positive viral-load test result, or positive genotype reported to any of three state health departments from the start of each state's hepatitis C registry through June 30, 2008. We defined a case of HIV/AIDS as a person diagnosed and living with HIV/AIDS at the start of each state's respective hepatitis C registry through June 30, 2008. HIV/AIDS and hepatitis C datasets were matched using Link King, public domain record linkage and consolidation software, and all potential matches were manually reviewed before acceptance as a match. RESULTS: The proportion of reported hepatitis C cases co infected with HIV/ AIDS was 1.8% in Oregon, 1.9% in Colorado, and 4.9% in Connecticut. Conversely, the proportion of HIV/AIDS cases co-infected with hepatitis C was consistently higher in the three states: 4.4% in Oregon, 9.7% in Colorado, and 23.6% in Connecticut. CONCLUSIONS: Electronic matching of registries is a potentially useful and efficient way to transfer information from one registry to another. In addition, it can provide a measure of the public health burden of HIV/AIDS and hepatitis C co-infection and provide insight into prevention and medical care needs for respective states. PMID- 21553663 TI - Age as an independent risk factor for intensive care unit admission or death due to 2009 pandemic influenza A (H1N1) virus infection. AB - OBJECTIVE: This study evaluated risk factors for intensive care unit (ICU) admission or death among people hospitalized with 2009 pandemic influenza A (pH1N1) virus infection. METHODS: We based analyses on data collected in Washington State from April 27 to September 18, 2009, on deceased or hospitalized people with laboratory-confirmed pH1N1 infection reported by health-care providers and hospitals as part of enhanced public health surveillance. We used bivariate analyses and multivariable logistic regression to identify risk factors associated with ICU admission or death due to pH1N1. RESULTS: We identified 123 patients admitted to the hospital but not an ICU and 61 patients who were admitted to an ICU or died. Independent of high-risk medical conditions, both older age and delayed time to hospital admission were identified as risk factors for ICU admission or death due to pH1N1. Specifically, the odds of ICU admission or death were 4.44 times greater among adults aged 18-49 years (95% confidence interval [CI] 1.97, 10.02) and 5.93 times greater among adults aged 50-64 years (95% CI 2.24, 15.65) compared with pediatric patients < 18 years of age. Likewise, hospitalized cases admitted more than two days after illness onset had 2.17 times higher odds of ICU admission or death than those admitted within two days of illness onset (95% CI 1.10, 4.25). CONCLUSION: Although certain medical conditions clearly influence the need for hospitalization among people infected with pH1N1 virus, older age and delayed time to admission each played an independent role in the progression to ICU admission or death among hospitalized patients. PMID- 21553664 TI - Trends in hospitalizations with antibiotic-resistant infections: U.S., 1997-2006. AB - OBJECTIVES: Antibiotic resistance is a significant global problem, but the trends in prevalence and impact of antibiotic resistance in hospitalizations in the United States are unclear. We evaluated the trends in hospitalizations associated with antibiotic-resistant infections in U.S. hospitals from 1997 to 2006. METHODS: We analyzed the National Hospital Discharge Survey (NHDS) during 1997 2006 (unweighted n = 3.3 million hospitalizations; weighted n = 370.3 million hospitalizations) and examined trends in prevalence of hospitalizations with antibiotic-resistant infections, length of stay, and discharge status. RESULTS: The number of infection-related hospitalizations with antibiotic resistance increased 359% during the 10-year period, from 37,005 in 1997 to 169,985 in 2006. The steepest rise was seen among individuals < 18 years of age. The mean age of individuals with infection-related hospitalizations that had antibiotic-resistant infections decreased substantially, from 65.7 years (standard error [SE] = 2.01) in 1997 to 44.2 years (SE = 1.47) in 2006. As the proportion of patients with antibiotic-resistant infections who did not have insurance increased, the length of stay for those hospitalizations had a corresponding decrease (r = 0.91, p < 0.01). CONCLUSIONS: Antibiotic-resistant infections are becoming increasingly commonplace in hospitalizations in the U.S., with a steady upward trend between 1997 and 2006. Antibiotic-resistant infections are increasingly being seen in younger patients and those without health insurance. PMID- 21553665 TI - Health selection among migrants from Mexico to the U.S.: childhood predictors of adult physical and mental health. AB - OBJECTIVES: We tested whether positive selection on childhood predictors of adult mental and physical health contributed to health advantages of Mexican-born immigrants to the United States relative to U.S.-born Mexican Americans. METHODS: We combined data from surveys conducted during 2000-2003 in Mexico and the U.S. with the same structured interview. We examined retrospective reports of childhood (i.e., < 16 years of age) predictors of adult health--education, height, childhood physical illness, childhood mental health, early substance use, and childhood adversities--as predictors of migration from Mexico to the U.S. at > or = 16 years of age. We estimated overall selection by comparing migrants to all non-migrants. We also examined selection at the family (members of families of migrants vs. members of families without a migrant) and individual (migrants vs. non-migrants within families of migrants) levels. RESULTS: Distinguishing between family and individual selection revealed evidence of positive health selection that is obscured in the overall selection model. In particular, respondents in families with migrants were more likely to have > or = 12 years of education (odds ratio [OR] = 1.60) and be in the tallest height quartile (OR = 1.72) than respondents in families without migrants. At both the family and individual levels, migrants are disadvantaged on mental health profiles, including a higher prevalence of conduct problems, phobic fears, and early substance use. CONCLUSIONS: Positive health selection may contribute to physical health advantages among Mexican immigrants in the U.S. relative to their U.S. born descendants. Mental health advantages likely reflect a lower prevalence of psychiatric disorders in Mexico, rather than protective factors that distinguish migrants. PMID- 21553666 TI - Prospectively assessed posttraumatic stress disorder and associated physical activity. AB - OBJECTIVES: We examined the association of physical activity with prospectively assessed posttraumatic stress disorder (PTSD) symptoms in a military cohort. METHODS: Using baseline and follow-up questionnaire data from a large prospective study of U.S. service members, we applied multivariable logistic regression to examine the adjusted odds of new-onset and persistent PTSD symptoms associated with light/moderate physical activity, vigorous physical activity, and strength training at follow-up. RESULTS: Of the 38,883 participants, 89.4% reported engaging in at least 30 minutes of physical activity per week. At follow-up, those who reported proportionately less physical activity were more likely to screen positive for PTSD. Vigorous physical activity had the most consistent relationship with PTSD. Those who reported at least 20 minutes of vigorous physical activity twice weekly had significantly decreased odds for new-onset (odds ratio [OR] = 0.58, 95% confidence interval [CI] 0.49, 0.70) and persistent (OR = 0.59, 95% CI 0.42, 0.83) PTSD symptoms. CONCLUSIONS: Engagement in physical activity, especially vigorous activity, is significantly associated with decreased odds of PTSD symptoms among U.S. service members. While further longitudinal research is necessary, a physical activity component may be valuable to PTSD treatment and prevention programs. PMID- 21553667 TI - Health impact in New York City during the Northeastern blackout of 2003. AB - OBJECTIVE: This study assessed the health effects of the 2003 Northeastern blackout, the largest one in history, on mortality and hospital admissions due to respiratory, cardiovascular, and renal diseases in New York City (NYC), and compared the disease patterns and sociodemographic profiles of cases during the blackout with those on control days. METHOD: We investigated the effects of the blackout on health using incidence rate ratios to compare the disease on blackout days (August 14 and 15, 2003) with those on normal and comparably hot days (controls). Normal days were defined as summer days (June-August) between the 25th and 75th percentiles of maximum temperature during 1991-2004. Comparably hot days were days with maximum temperatures in the same range as that of the blackout days. We evaluated the interactive effects of demographics and the blackout using a case-only design. RESULTS: We found that mortality and respiratory hospital admissions in NYC increased significantly (two- to eightfold) during the blackout, but cardiovascular and renal hospitalizations did not. The most striking increases occurred among elderly, female, and chronic bronchitis admissions. We identified stronger effects during the blackout than on comparably hot days. In contrast to the pattern observed for comparably hot days, higher socioeconomic status groups were more likely to be hospitalized during the blackout. CONCLUSIONS: This study suggests that power outages may have important health impacts, even stronger than the effects of heat alone. The findings provide some direction for future emergency planning and public health preparedness. PMID- 21553668 TI - Policy implications of first-dollar coverage: a qualitative examination from the payer perspective. AB - OBJECTIVES: Immunization against potentially life-threatening illnesses for children and adults has proved to be one of the great public health successes of the 20th century and is extremely cost-effective. The Patient Protection and Affordable Care Act includes a number of provisions to increase coverage and access to immunizations for the consumer, including a provision for health plans to cover all Advisory Committee on Immunization Practices-recommended vaccines at first dollar, or without cost sharing. In this study, we examined payers' perspectives on first-dollar coverage of vaccines and strategies to improve vaccination rates. METHODS: This was a qualitative study, using a literature review and semistructured expert interviews with payers. RESULTS: Four key themes emerged, including (1) the cost implications of the first-dollar change; (2) the importance of examining barriers to children, adolescents, and adults separately to focus interventions more strategically; (3) the importance of provider knowledge and education in increasing immunization; and (4) the effect of first dollar coverage on those who decline vaccination for personal reasons. CONCLUSIONS: We determined that, while reducing financial barriers through first dollar coverage is an important first step to increasing immunization rates, there are structural and cultural barriers that also will require collaborative, strategic work among all vaccine stakeholders. PMID- 21553669 TI - Hurricane Katrina: addictive behavior trends and predictors. AB - OBJECTIVES: Post-disaster trends in alcohol consumption and cigarette smoking, as well as their predictors, were identified. Methods. Data from cross-sectional and panel surveys of African American adults in New Orleans, Louisiana, were used from before (2004: n = 1,867; 2005: n = 879) and after (2006a: n = 500; 2006b: n = 500) Hurricane Katrina. RESULTS: Alcohol consumption increased significantly from pre- to post-Hurricane Katrina, while cigarette smoking remained constant. In 2006, posttraumatic stress disorder (PTSD) was associated with cigarette smoking, whereas "news attention" and "provided social support" were inversely associated with cigarette smoking. "News attention" was also inversely associated with cigarette smoking frequency, while "neighborliness" was associated with alcohol consumption. In addition, the effects of PTSD on alcohol consumption were moderated by "neighborliness." CONCLUSIONS: In the wake of Hurricane Katrina, there were complex predictive processes of addictive behaviors involving PTSD, news information, and social capital-related measures. PMID- 21553670 TI - Describing local boards of health: insights from the 2008 National Association of Local Boards of Health Survey. AB - OBJECTIVES: We examined findings from the 2008 National Association of Local Boards of Health Survey to provide information about this understudied entity to the public health community. METHODS: The survey instrument consisted of 196 items covering five parts: (1) demographics; (2) composition and organizational structure; (3) roles, responsibilities, and authorities; (4) telecommunications infrastructure; and (5) concerns and needs. The survey was sent to chairs of local boards of health (LBHs) in 2008 (n = 3,276). After six months of follow-ups and reminders, and a month of data cleaning and screening, the final sample consisted of 870 respondents, for a return rate of 27%. RESULTS: LBHs tend to represent smaller communities and are primarily appointed. Governing and policy making boards are more prevalent than advisory boards. Most boards do not have official websites or e-mail addresses of board members available to the public; however, most report the capability to receive training via webcasts. Boards express concerns and needs in a variety of areas, particularly public health law, strategic planning, and accreditation. CONCLUSIONS: Little is known about the more than 3,000 LBHs across the United States that are often charged with making and enforcing public health law. This article is a first step toward providing the public health community with information about LBHs based on survey data. PMID- 21553671 TI - Multilevel analysis of the determinants of pre-hypertension and hypertension in rural southwest China. PMID- 21553672 TI - The Freedom of Information Act: implications for public health policy and practice. PMID- 21553673 TI - Community-based participatory research and the Escuela de Salud Publica in Mexico. PMID- 21553674 TI - An innovative public health preparedness training program for graduate students. PMID- 21553675 TI - Evaluation of deer-targeted interventions on Lyme disease incidence in Connecticut. PMID- 21553676 TI - Economy and psychology: a marriage in trouble. PMID- 21553677 TI - The psychohistorical roots of the American "Tea Party" Movement. AB - Extreme resistance to governmental taxation and authority is derived, according to Freud's theory of anal characterology, from premature and harshly coercive toilet training, in which a child is forced unfairly and against its will to surrender the products of his eliminations (which represent money, among other things, in the unconscious) to parental authority. Among these individuals anal eroticism plays a significant role in the psychogenesis of paranoia and conspiracy theorizing, which may represent a defense mechanism erected against repressed fears of passive submission. PMID- 21553678 TI - U.S. annihilation anxieties and the search for enemies. PMID- 21553679 TI - Putin and Medvedev: double leadership in Russia. PMID- 21553680 TI - Single-payer proposition gets close second look. PMID- 21553681 TI - Lipitor kicks off onslaught of drug patent conversions. PMID- 21553682 TI - Excessive profits--where? PMID- 21553683 TI - Poor transitions of care can be corrected now. PMID- 21553684 TI - Geisinger's embedded nurses improve transitions. PMID- 21553685 TI - His program reduces bloodstream infections across the country. What's next? PMID- 21553686 TI - Health plans struggle to manage rheumatoid arthritis. PMID- 21553687 TI - Retail clinics expand in numbers, services. PMID- 21553688 TI - Effects of a pregnancy management program on birth outcomes in managed Medicaid. AB - OBJECTIVE: Examine the effect of a prenatal program on birth outcomes, specifically birth weight, in a managed Medicaid pregnant population, and identify the potential barriers to obtaining the risk screening information required for successful interventions. DESIGN: Retrospective propensity-adjusted cohort comparison. METHODS: Retrospective propensity-adjusted comparison of pregnant women in a managed Medicaid plan enrolled in a prenatal program and pregnant women who were not enrolled. Program enrollment was initiated by receipt of a Notification of Pregnancy (NOP) risk screening assessment. RESULTS: We demonstrate a statistically significant improvement in delivery outcomes in the women who participate in the pregnancy management program (NOP group) compared with those who do not (non-NOP group). The incidence of low-birth-weight infants was lower in the NOP group compared to the non-NOP group. Odds ratio estimates indicate that the NOP participants are likely to have 7.9% lower adverse event frequency for delivery weights <2500 g; 20% lower adverse event frequency for delivery weights <1500 g; and 31.2% lower adverse event frequency for delivery weights <1000 g. All p values are statistically significant. CONCLUSION: Participation in a pregnancy management program improves birth outcomes in women who are at risk of low-birth-weight deliveries. Early identification of pregnant women and their risk factors for the purpose of enrollment in a managed Medicaid prenatal program is an important factor in improving birth outcomes, specifically birth weight. Our results indicate that this is an important area for investment if birth outcomes are to be improved. PMID- 21553689 TI - Prescription prices rise faster after recession. PMID- 21553690 TI - Replacing gleaming steel with copper's aged patina. PMID- 21553691 TI - Increasing lupus cases coincide with Benlysta approval. PMID- 21553692 TI - Isolated cases? The history and historiography of Australian medical research. AB - For over two hundred years, Australia has been portrayed as a terminus rather than a hub for scientific exchange. Alongside narratives valorising the struggle for a distinct national identity, the motif of isolation abounds in the historiography of Australian medical research. Yet these orthodoxies are ripe for rescripting, as illustrated by a symposium held in Sydney in 2010: Isolated Cases? 100 Years of Australian Medical Research. Weaving together several historical themes from this conference with wider historiographic threads, this article questions many prevailing representations. In particular the authors argue that rather than isolation or dependency, Australian medical science has been characterised by a profound interdependence across two centuries of antipodean endeavour. PMID- 21553693 TI - Prisoners' bodies: methods and advances in convict medicine in the transportation era. AB - Recent historical research looks upon the plight of Australian convicts not as victims of a harsh penal system, but as workers whose health had to be judiciously maintained. What then can be said for the medical treatments provided for convict patients during this chapter in Australia's past? Did convicts receive medical treatments with the same measure of importance and urgency as the free populace, or were prisoners' bodies considered with such a measure of insignificance that they provided veritable opportunities for advances in medicine? This article will provide general insight into prison medicine in Australia during the transportation era and how some convicts were subjected to experimental medical practices. It will also place these techniques into a wider global context by considering experimental practices involving convict patients in establishments in other places, such as Wakefield and Bermuda. PMID- 21553694 TI - Public health in an industrial community: Port Kembla, 1907-2007. AB - This paper considers how various health agencies in New South Wales have responded to the issue of air pollution, particularly in Port Kembla since the end of World War II when levels rose dramatically and residents began calling for something to be done. Several shortcomings surrounding the production of the report of the NSW government-appointed Smoke Abatement Committee in the 1950s created the foundation for a tradition of inadequate research into the effects of industrial contamination on public health, and of legislation which sought to address environmental amenity rather than risks to public health. The reopening of a copper smelter in Port Kembla in 1997 demonstrated a continued policy to relegate the impacts on public health to a low priority consideration and is a damning reflection on more than fifty years of inquiry. PMID- 21553695 TI - Science and survival in paradise. AB - Nineteenth-century European colonialists of Papua New Guinea brought western ideas and government, along with diseases that decimated the population. They received in exchange the killing endemic diseases of the country and all nineteenth-century settlers suffered severely. As doctors were few, and medicines did little, and as sick children could not attend school, sixty years of prewar medical services and education had little impact. However over those same years there was an expansion of medical science and the challenge in 1946 was to use these advances to reduce the high morbidity and mortality and ensure healthy children for educators to prepare for eventual national self sufficiency. Epidemiological research within the Public Health Department was an essential component in generating management and prevention strategies for all the significant diseases. The principal outcomes by 1975 were a raised life expectancy from 34 years to 56 years, a doubled population, many university graduates, and nationhood. PMID- 21553696 TI - 'Watch out for these KILLERS!': newspaper coverage of the Sydney funnel web spider and its impact on antivenom research. AB - Based on a content analysis of treatments of the funnel web spider in the Sydney Morning Herald between 1955 and 1985, this paper argues that negative attitudes towards the funnel web were encouraged throughout this period in news stories, commentary, and advertisements and were demonstrated in the reported words and actions of members of the general public. Despite this opprobrium, research into a funnel web antivenom was able to proceed because of the willingness of individuals to collect the spiders and forward them to researchers. Negative attitudes towards the funnel web were able to be directed to a positive action which eventually helped to bring about the development of an antivenom, lessening the real threat posed by the spider. PMID- 21553697 TI - Iatrogenic concerns of the twentieth century: post-vaccinal encephalitis and spongiform encephalopathy. AB - Throughout the twentieth century, iatrogenic disease constituted an enduring problem in western medical discourse and practice. A survey of the medical literature, investigative reports, and archival material indicates that iatrogenic concerns persisted throughout the century. Two groups of case studies are presented: one associated with post-vaccinal encephalitis; the other, with the iatrogenically transmitted spongiform encephalopathies, scrapie and Creutzfeldt-Jakob disease. Kuru, a similar disease investigated in New Guinea- but which is thought to be neither iatrogenically caused nor transmitted--is also discussed to speculate on whether an iatrogenic lens might be a valuable tool with which to re-view its mode of transmission. PMID- 21553698 TI - International travel as medical research: architecture and the modern hospital. AB - The design and development of the modern hospital in Australia had a profound impact on medical practice and research at a variety of levels. Between the late 1920s and the 1950s hospital architects, administrators, and politicians travelled widely in order to review the latest international developments in the hospital field They were motivated by Australia's geographic isolation and a growing concern with how to govern the population at the level of physical health. While not 'medical research' in the conventional sense of the term, this travel was a powerful generator of medical thinking in Australia and has left a rich archival legacy. This paper draws on that archive to demonstrate the ways in which architectural research and international networks of hospital specialists profoundly shaped the provision of medical infrastructure in Australia. PMID- 21553699 TI - Disaster preparedness for nurses: a teaching guide. AB - As one of the largest groups of health care providers in the United States, nurses are trained to attend to the physical, psychological, and spiritual needs of their patients, making them highly qualified to influence the outcomes of victims of an emergency situation. Unfortunately, nursing programs offer limited content on delivering care under extreme conditions, and few continuing education programs are available to practicing nurses. This article provides a brief educational presentation that can be used without an extensive time commitment or in-depth instructor knowledge of the subject. The course content has been presented to nurses at the American Red Cross, at local chapter meetings of professional nursing organizations, and to both graduate and undergraduate nursing students. This presentation is not designed to be a comprehensive study of disaster nursing, but serves as a starting point that might lead to further study and encourage active participation in preparedness education and planning. PMID- 21553700 TI - Preparing nurse educators to use simulation technology: a consortium model for practice and education. AB - BACKGROUND: As nurses seek to advance their education through online courses, considering best practices in feedback is especially important. Rich and rapid feedback has long been considered a best teaching practice, but how to provide this feedback in an online course environment is not always clear. This study was conducted to identify how experienced faculty provide feedback to online students. METHODS: This descriptive exploratory study surveyed faculty about their approach to feedback with broad exploratory questions and a validation survey. The sample included faculty in four different states who benchmark online educational best practices. RESULTS: Content analysis was used to evaluate data, with 15 themes emerging. These themes were organized into three categories: using best available tools; having a system; and creating a feedback-rich environment. CONCLUSION: The findings support and extend the guidelines for best practices in online education, including a focus on multisource feedback opportunities during course design. PMID- 21553701 TI - Fixating dislocated intraocular lens by 25-gauge vitrectomy. AB - BACKGROUND AND OBJECTIVES: To describe a technique for suturing a dislocated intraocular lens (IOL) with 25-gauge (G) instruments. PATIENTS AND METHODS: Non comparative interventional case series performed at a single center. Five patients with a dislocated IOL underwent 25-G transconjunctival sutureless vitrectomy (25G-TSV) with a temporary externalization of the haptics to fixate the IOL. Three IOLs enclosed in the lens capsule were dislocated into the vitreous and removed from the capsule with 25G-TSV using perfluorocarbon liquid. The best-corrected visual acuity and surgical complications resulting from this technique were recorded. RESULTS: In all cases, the IOL was fixed stably and remained well positioned. The visual acuity was improved or maintained in all cases. There were no intraoperative or postoperative complications except for one eye with a postoperative iris capture of the sutured IOL. CONCLUSION: Findings indicate that 25G-TSV is a practical and safe method for fixating a dislocated IOL. PMID- 21553702 TI - Ultra-wide-field green-light (532-nm) autofluorescence imaging in chronic Vogt Koyanagi-Harada disease. AB - BACKGROUND AND OBJECTIVE: To assess the prevalence of peripheral fundus autofluorescence (FAF) abnormalities in chronic Vogt-Koyanagi-Harada disease (VKH). PATIENTS AND METHODS: A retrospective review of cases at the Doheny Eye Institute between December 2009 and April 2010. Patients with chronic VKH who had ultra-wide-field FAF and pseudo-color imaging performed were included. All images were reviewed independently by two reading center certified retina specialists. RESULTS: Twenty eyes of 10 patients were included in this analysis. Fourteen eyes of 7 patients (70%) showed peripheral changes on FAF images outside the posterior pole. Three different patterns were observed: multifocal hypofluorescent spots (n = 11 eyes), hyperfluorescent spots (n = 8 eyes), and a unique lattice-like pattern in both eyes of one patient. There were noticeable disparities between FAF and color images. CONCLUSION: Peripheral FAF abnormalities are frequent in chronic VKH and are readily revealed by wide-field FAF imaging and manifesting with distinct patterns. Further investigation in prospective studies is warranted. PMID- 21553703 TI - Alternative drug therapies for dementia. AB - Drugs currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease include acetylcholinesterase inhibitor (i.e., tacrine, donepezil, rivastigmine, and galantamine) and glutamate-modulating (i.e., memantine) drugs. Because these drugs have modest benefits, various alternative drug therapies have been of interest. Drugs with vasodilator activity were originally tried in dementia when it was hypothesized that the condition was due to cerebrovascular insufficiency. Isoxsuprine and ergoloid mesylates are FDA approved for the treatment of dementia, although they have limited evidence of benefit and are rarely used. The hypothesis that free radicals may initiate and maintain mechanisms responsible for neurodegeneration in dementia has stimulated interest in investigating various antioxidant and anti-inflammatory drugs. There is no evidence that other drug therapies, including vitamin E, selegiline, nonsteroidal anti-inflammatory drugs, statin drugs, omega-3 fatty acids, estrogen or combined estrogen plus progestin therapy, or B vitamins, are sufficiently effective and safe to justify their clinical use for the treatment of dementing disorders. PMID- 21553704 TI - A comparison of methionine, histidine and cysteine in copper(I)-binding peptides reveals differences relevant to copper uptake by organisms in diverse environments. AB - The N-terminal, extracellular regions of eukaryotic high affinity copper transport (Ctr) proteins vary in composition of the Cu(i) binding amino acids: methionine, histidine, and cysteine. To examine why certain amino acids are exploited over others in Ctrs from different organisms, the relative Cu(i) binding affinity and the dependence of binding on pH were examined for 3 peptides of the sequence MG(2)XG(2)MK, where X is either Met, His, or Cys. Cu(i) affinity was examined using an ascorbic acid oxidation assay, an electrospray ionization mass spectrometry technique, and spectrophotometric titration with a competitive Cu(i) chelator. The relative affinities of the peptides with Cu(i) reveal a trend whereby Cys > His > Met at pH 7.4 and Cys > Met > His at pH 4.5. Ligand geometry and metric parameters were determined with X-ray absorption spectroscopy. Susceptibility of the peptides to oxidation by hydrogen peroxide and copper catalyzed oxidative conditions was evaluated by mass spectrometry. These results support hypotheses as to why certain Cu(i) binding amino acids are preferred over others in proteins expressed at different pH and exposed to oxidative environments. The results also have implications for interpreting site-directed mutagenesis studies aimed at identifying copper binding amino acids in copper trafficking proteins. PMID- 21553705 TI - Peptic ulcers. Stopping them for good. PMID- 21553706 TI - Multiple myeloma. Progress is being made. PMID- 21553707 TI - I've heard that skin cancer is slow to develop. I'm 78 years old. At my age, do I really need to wear sunscreen and otherwise protect myself from the sun? PMID- 21553708 TI - Mucosal immunology: Steps for keeping calm. PMID- 21553709 TI - Vaccines: Dual TLR hit for vaccine success. PMID- 21553710 TI - Antibody responses: FcRn-not just for the kids. PMID- 21553711 TI - Tumour immunology: TSLP drives human tumour progression. PMID- 21553713 TI - Antiviral immunity: IL-21 comes with age. PMID- 21553712 TI - Tumour immunology: Pro-metastatic T(Reg) cells get RANKed. PMID- 21553714 TI - T cells: A little help from mTOR's friends. PMID- 21553715 TI - China progresses with health reform but challenges remain. PMID- 21553716 TI - Burning issues: tackling indoor air pollution. PMID- 21553717 TI - Gone to earth-the burial grounds of the Royal London Hospital. PMID- 21553718 TI - Arrhythmias: apixaban triumphs over aspirin for stroke prevention in patients with atrial fibrillation. PMID- 21553719 TI - Prevention: CV risk assessment and education in community pharmacies work! PMID- 21553720 TI - Pharmacotherapy: NSTE ACS--benefit of concomitant eptifibatide and clopidogrel use before angiography? PMID- 21553721 TI - Hypertension: white-coat hypertension in the primary-care setting reduced with automated BP measures. PMID- 21553722 TI - Device therapy: CRT-D--why women benefit more. PMID- 21553723 TI - Interventional cardiology: percutaneous pulmonary valve implantation: 1-year safety and efficacy reported in German study. PMID- 21553724 TI - Obesity: long-term benefits of gastric bypass on cardiac structure and function. PMID- 21553725 TI - Hypertension: AT1 autoantibodies and response to therapy. PMID- 21553726 TI - Acute coronary syndromes: worse prognosis of cocaine users with ACS--a call for routine urine tests? PMID- 21553727 TI - Surgery: CABG-associated stroke explored. PMID- 21553728 TI - Prevention: could flu vaccine join the secondary prevention armamentarium for ACS? PMID- 21553729 TI - Retraction notice to "Immobilization of 5-amino-1,3,4-thiadiazole-thiolonto kanemite for thorium (IV) removal: thermodynamic and equilibrium study" [J. Colloid Interface Sci. 338 (2009) 30-39]. PMID- 21553730 TI - Retraction notice to "Designed pendant chain covalently bonded to analogue of heulandite for removal of divalent toxic metals from aqueous solution: thermodynamic and equilibrium study" [JCIS 337/1 (2009) 122-130]. PMID- 21553731 TI - Distinguishing "government" and "politics". PMID- 21553732 TI - Simulation in psychiatric nursing education. PMID- 21553737 TI - Radiologic case study. Calcific tendinitis of the rectus femoris with intraosseous extension of calcification. PMID- 21553738 TI - Notice of Duplicate Publication: "Treatment of Epiphyseal Injury of the Distal Ulna Without Associated Radial Fracture" (Orthopedics. 2006; 29[2]:157-159. http://www.orthosupersite.com/view.aspx?rid=5441). PMID- 21553739 TI - Scrub suits: revisited. PMID- 21553740 TI - Novel angle measurements for assessment of shoulder location using the scapular y radiograph. AB - Shoulder dislocation is an injury with potential long-term consequences that requires prompt diagnosis and treatment. Patient positioning and imperfect radiographic views may result in discomfort, added examination time, and problematic diagnosis. The scapular Y radiograph has been shown to be useful in diagnosing shoulder dislocation but is not considered sufficient in isolation. Using a synthetic bone shoulder model, we propose a novel technique wherein osseous landmarks are used to form angles that significantly improved diagnostic accuracy for shoulder dislocation, even in significantly rotated and otherwise indeterminate scapular Y radiographs. PMID- 21553741 TI - Osteoporosis and fracture risk. PMID- 21553742 TI - Intraoperative navigation for minimally invasive resection of periarticular and pelvic tumors. AB - The surgical approach to benign, metastatic, and some low-grade malignant tumors is often difficult due to their typically precarious locations. This article presents a series of cases where intraoperative stealth navigation was used to treat periarticular tumors. The use of paired point imaging with image fusion has made approaching tumors through an accurate and minimally invasive technique a viable option for the treatment of a subset of musculoskeletal tumors. PMID- 21553743 TI - Strategies for the management of postoperative atrial fibrillation. AB - Atrial fibrillation is an important complication of non-cardiothoracic surgery and is associated with higher hospital costs and increased morbidity. Strategies of rate versus rhythm control have been compared in several studies and patient populations and generally result in equivalent patient outcomes. Hemodynamically unstable patients should be electrically cardioverted for immediate restoration of sinus rhythm. However, in stable patients, a variety of pharmacologic agents can be selected for either rate or rhythm control. Selection of a particular agent should be based on a patient's comorbidities and preferences, as well as specific characteristics of each agent. PMID- 21553744 TI - Treatment of ankle fractures in patients with diabetes. AB - Patients with diabetes mellitus have a higher risk of complications after sustaining an ankle fracture, including fracture displacement, superficial and deep infection, hardware failure, and neuropathic arthropathy. With the increased incidence of diabetes among the aged, the increased incidence of complications due to diabetes mellitus and its sequelae are important to keep in mind when treating ankle fractures. PMID- 21553745 TI - Prevention of VTE Following total hip and knee arthroplasty in Hemophilia patients. AB - The often debilitating condition of hemophilic arthropathy is treated with elective total joint arthroplasty. Little has been published addressing the role of thromboembolic prophylaxis in the hemophilic patient population following total hip arthroplasty (THA) and total knee arthroplasty (TKA). Although the American College of Chest Physicians and the American Academy of Orthopaedic Surgeons have set guidelines for thromboembolic prophylaxis in the general population, no such standard of care is in place for hemophilic patients. While the risk of thrombosis in hemophilic patients following THA and TKA is thought to be lower, cases have been reported of pulmonary embolism and deep vein thrombosis (DVT) in hemophilic patients. PMID- 21553747 TI - Assessing pain in older adults. PMID- 21553752 TI - It's all about leadership. PMID- 21553753 TI - Speed sims: an innovative approach to nursing education. PMID- 21553754 TI - Using YouTube to bridge the gap between Baby Boomers and Millennials. PMID- 21553755 TI - Ectasia after LASIK: new treatments, new hope. PMID- 21553756 TI - Clonic orbscans and tropicamide. PMID- 21553757 TI - Essentials of disaster management: the role of the orthopaedic surgeon. AB - Disaster preparedness and management education is essential for allowing orthopaedic surgeons to play a valuable, constructive role in responding to disasters. The National Incident Management System, as part of the National Response Framework, provides coordination between all levels of government and uses the Incident Command System as its unified command structure. An "all hazards" approach to disasters, whether natural, man-made, intentional, or unintentional, is fundamental to disaster planning. To respond to any disaster, command and control must be established, and emergency management must be integrated with public health and medical care. In the face of increasing acts of terrorism, an understanding of blast injury pathophysiology allows for improved diagnostic and treatment strategies. A practical understanding of potential biologic, chemical, and nuclear agents and their attendant clinical symptoms is also prerequisite. Credentialing and coordination between designated organizations and the federal government are essential to allow civilian orthopaedic surgeons to access systems capable of disaster response. PMID- 21553758 TI - Soft-tissue management after trauma: initial management and wound coverage. AB - Before proceeding with treatment, it is necessary to recognize that bony injuries are always associated with soft-tissue disruption and damage. A good soft-tissue envelope is essential to fracture healing and overall extremity function. Injury management begins by recognizing and classifying the injury. Wound debridement with irrigation fluid at low pressure and the administration of antibiotics are essential aspects of treatment. Wound treatment starts with applying dressing material using negative suction and can be guided by the tenets of an algorithm modeled on the reconstructive ladder. PMID- 21553759 TI - The mangled limb: salvage versus amputation. AB - A mangled extremity is defined as a limb with injury to three of four systems in the extremity. The decision to salvage or amputate the injured limb has generated much controversy in the literature, with studies to support advantages of each approach. Various scoring systems have proved unreliable in predicting the need for amputation or salvage; however, a recurring theme in the literature is that the key to limb viability seems to be the severity of the soft-tissue injury. Factors such as associated injuries, patient age, and comorbidities (such as diabetes) also should be considered. Attempted limb salvage should be considered only if a patient is hemodynamically stable enough to tolerate the necessary surgical procedures and blood loss associated with limb salvage. For persistently hemodynamically unstable patients and those in extremis, life comes before limb. Recently, the Lower Extremity Assessment Project study attempted to answer the question of whether amputation or limb salvage achieves a better outcome. The study also evaluated other factors, including return-to-work status, impact of the level of and bilaterality of the amputation, and economic cost. There appears to be no significant difference in return to work, functional outcomes, or the cost of treatment (including the prosthesis) between the two groups. A team approach with different specialties, including orthopaedics, plastic surgery, vascular surgery and trauma general surgery, is recommended for treating patients with a mangled extremity. PMID- 21553760 TI - Review of treatment and diagnosis of acute compartment syndrome of the calf: current evidence and best practices. AB - Compartment syndrome of the calf has received a great deal of attention in the literature. A MEDLINE search was conducted to identify English-language publications pertaining to compartment syndrome of the leg and calf so that principles, recent evidence, and best practices for the diagnosis and treatment of this syndrome could be reviewed. Clinical series that reported outcomes and diagnostic criteria were reviewed and summarized. The currently available evidence is limited to level IV and V studies. Early diagnosis and treatment of compartment syndromes is associated with better results; however, many patients have chronic symptoms after treatment, even when the diagnosis is made promptly and fasciotomy is performed early. Although compartment syndrome of the leg and calf often has been described in the literature, prospective clinical series are lacking, and meaningful outcomes data are scarce. There is a need for further study on functional outcomes of acute compartment syndrome of the calf, with particular attention to diagnosis and treatment. PMID- 21553761 TI - Diagnosis and treatment of less common compartment syndromes of the upper and lower extremities: current evidence and best practices. AB - Compartment syndromes of the forearm, gluteal region, thigh, and foot have not been extensively studied. To provide best-practice recommendations, the available evidence from four systematic reviews of English-language reports with two or more patients with compartment syndromes of the forearm, gluteal region, thigh, and foot were reviewed and compared. For each case of compartment syndrome, the cause, method of diagnosis, treatment options, and outcomes were determined. Most compartment syndromes were caused by trauma, with the exception of gluteal compartment syndrome, which usually resulted from prolonged immobilization and postarthroplasty analgesia. The diagnosis was often based on clinical findings, with compartment pressure measurements performed in approximately 50% of the patients. Compartment pressure measurements of the foot were more commonly obtained (in 64% of the patients). Compartment syndrome of the forearm and thigh were treated surgically in 73% and 100% of patients, respectively. Complications occurred with all four compartment syndromes, with nerve deficits and stiffness being the most common problems. Reports on functional outcomes lacked uniformity and did not allow for meaningful comparisons. Management principles for the less common compartment syndromes are the same as those used in treating compartment syndrome of the calf. Gluteal compartment syndrome usually has a nontraumatic etiology and is less likely to be surgically treated, probably because of major systemic complications and late presentation. Complications are common after these four types of compartment syndrome, but outcomes data are lacking. PMID- 21553762 TI - Clavicle and scapula fracture problems: functional assessment and current treatment strategies. AB - Historically, nonsurgical treatment was recommended for both clavicle and scapula fractures. Good functional outcomes were reported with nonsurgical treatment, whereas surgical treatment had a high complication rate. Recent studies have shown that the functional outcomes of nonsurgically treated fractures may not be as acceptable as had been previously believed. These studies also support the surgical treatment of clavicle and scapula fractures in certain circumstances. Relative indications for surgical treatment of clavicle fractures include skin compromise, neurologic or vascular injury, open fractures, high-energy closed fractures with greater than 15 to 20 mm of shortening, fractures with 100% displacement, and fractures with comminution. Relative indications for the surgical treatment of scapula fractures include displaced acromion or coracoid process fractures (> 10 mm), displaced intra-articular glenoid fractures (> 5 mm), and those associated with humeral subluxation. PMID- 21553763 TI - The "not so simple" ankle fracture: avoiding problems and pitfalls to improve patient outcomes. AB - Ankle fractures are among the most common injuries managed by orthopaedic surgeons. Many ankle fractures are simple, with straightforward management leading to successful outcomes. Some fractures, however, are challenging, and debate arises regarding the best treatment to achieve an optimal outcome. Some patients have medical comorbidities that increase the risk for complications or may require modifications to standard surgical techniques and fixation methods. Several recent investigations have highlighted the pitfalls in accurately reducing syndesmotic injuries. Controversy remains regarding the number and diameter of screws, the duration of weight-bearing limitations, and the need or timing of screw removal. Open reduction may allow more accurate reduction than standard closed methods. Direct fixation of associated posterior malleolus fractures may provide improved syndesmotic stability. Posterior malleolus fractures vary in size and can be classified based on the orientation of the fracture line. As the size of the posterior malleolus fracture fragment increases, the load pattern in the ankle is altered. Direct or indirect reduction and surgical fixation may be required to prevent posterior talar subluxation and restore articular congruency. The supination-adduction fracture pattern is also important to recognize. Articular depression of the medial tibial plafond may require reduction and bone grafting. Optimal fixation requires directing screws parallel to the ankle joint or using a buttress plate. Identifying ankle fractures that may present additional treatment challenges is essential to achieving a successful outcome. A careful review of radiographs and CT scans, a thorough patient assessment, and detailed preoperative planning are needed to improve patient outcomes. PMID- 21553764 TI - Surgical approach and techniques for total shoulder arthroplasty: tips and tricks. AB - In patients treated with total shoulder arthroplasty, it is beneficial to be aware of several tips and tricks to optimize patient outcomes. Prior to surgery, appropriate preoperative planning is essential to ensure a smooth procedure with no unexpected intraoperative findings. The procedure begins with appropriate patient positioning to allow for safety and ease of shoulder manipulation. The approach using the deltopectoral interval is described, with emphasis on the proper use of retractors and adequate soft-tissue releases. Appropriate handling of the subscapularis and lesser tuberosity during both exposure and closure is imperative for a good surgical outcome. Other portions of the procedure also can be less problematic if the surgeon is familiar with certain techniques. PMID- 21553765 TI - Shoulder arthroplasty for the young, active patient. AB - Patients younger than 55 years with degenerative conditions of the glenohumeral joint represent a unique population that can be treated with shoulder arthroplasty. Certain challenges related to this cohort may include greater patient expectations, higher functional demands, soft-tissue contracture from previous surgery, and glenoid bone loss. Surgical treatment options include unconstrained total shoulder arthroplasty; hemiarthroplasty; humeral head resurfacing alone; hemiarthroplasty with concentric reaming of the glenoid; and hemiarthroplasty with adjunctive biologic glenoid resurfacing with autogenous fascia lata, Achilles tendon allograft, or meniscal allograft. PMID- 21553766 TI - Arthroplasty for fractures of the proximal part of the humerus. AB - Proximal humeral fractures account for 4% to 5% of all fractures. Most of these fractures are nondisplaced or minimally displaced and amenable to nonsurgical treatment or open reduction and internal fixation. Complex proximal humeral fractures with displaced three- and four-part fragments, fracture-dislocations, and humeral head splits are more difficult to treat. In older patients, hemiarthroplasty or reverse shoulder arthroplasty is often the indicated treatment. Arthroplasty in this patient cohort is very technique-dependent and relies on preserving deltoid function, proper component placement and fixation, and tuberosity healing. Complications include tuberosity nonunion, instability, heterotopic ossification, and infection. Although pain relief is predictable, it is often difficult to achieve functional improvement. Results depend on the patient's age, timing of the surgery, tuberosity healing, and adequate rehabilitation. Recently, successful outcomes for reverse total shoulder arthroplasty have been reported in older, low-demand patients with cuff deficiency, deficient bone in the tuberosity, or compromised healing of the tuberosity. PMID- 21553767 TI - Shoulder arthroplasty for the treatment of rotator cuff insufficiency. AB - Irreparable rotator cuff tendon tears result from chronic tears, failed cuff repairs, and fracture sequelae and occur in patients with rheumatoid arthritis. The management of patients with cuff tear arthropathy can be challenging. When pain is severe and function is poor, surgical options include hemiarthroplasty, bipolar arthroplasty, extended head arthroplasty, arthroplasty with tendon transfer, reverse shoulder arthroplasty, and fusion. A review of the literature shows good pain relief with hemiarthroplasty in carefully selected patients; however, the reverse prosthesis has been found to better restore motion in patients with pseudoparalysis, failed fracture treatment, or a failed prosthesis. PMID- 21553768 TI - Evolution of rotator cuff repair techniques: are our patients really benefiting? AB - The repair integrity of rotator cuff tears, which are a common disorder, is influenced by many biologic, environmental, and surgical factors. Surgery for rotator cuff repairs has evolved significantly over the past decade. The technical goals of rotator cuff repair include achieving high initial fixation strength, minimizing gap formation, and maintaining mechanical stability until biologic healing occurs. A variety of surgical techniques have been established to capitalize on certain aspects of these tenets and have been shown to provide biomechanical and biologic benefits; however, overall clinical outcomes may be dependent on certain tear characteristics. It is important for orthopaedic surgeons to be familiar with the natural history of rotator cuff disease to understand the various repair strategies and techniques and the outcomes associated with these procedures. PMID- 21553769 TI - Glenohumeral arthritis in the young adult. AB - Treating glenohumeral arthritis in the young adult remains a significant challenge. There are a variety of etiologies that can lead to this condition, and the diagnosis is often not straightforward. With advances in both surgical techniques and biologic options, the treatment algorithm for patients with glenohumeral arthritis is constantly evolving. When nonsurgical treatment fails, there are a variety of possible surgical options, each with potential benefits. It is helpful to review the diagnostic challenges presented by these patients and understand the palliative, reparative, restorative, and reconstructive surgical options and their associated clinical outcomes, which provide a framework for clinical and surgical decision making. PMID- 21553770 TI - Elbow arthroplasty: lessons learned from the past and directions for the future. AB - Joint arthroplasty in general has experienced tremendous advances over the past few decades. Numerous improvements in implant design, instrumentation, anesthesia, surgical techniques, intraoperative navigation, and materials have occurred in hip and knee arthroplasty. Although elbow arthroplasty also has seen continual improvements, much remains to be accomplished before elbow arthroplasty can be recommended to patients with the same level of confidence as hip or knee arthroplasty. PMID- 21553771 TI - Elbow arthroscopy: setup, portal placement, and simple procedures. AB - Elbow arthroscopy has become an accepted treatment for numerous elbow conditions, including loose bodies, lateral epicondylitis, contractures, painful osteophytes, synovitis, osteochondritis dissecans, synovial plica, and osteoarthritis. It is absolutely necessary that the treating surgeon have complete knowledge of elbow anatomy. Three options exist for patient positioning: supine, prone, and lateral decubitus. Standard arthroscopic probes, grasping forceps, punches, and motorized shavers and burrs are used in the procedure. Retractors are essential for visualizing, exposing, and protecting nerves. Specially designed capsular biters can be used to develop a plane between the capsule and the surrounding soft tissues to facilitate capsulotomy and capsulectomy. Among elbow arthroscopists, the sequence of portal placement varies; however, there is little variation in the exact location of portal placement because of neurovascular constraints. Loose body removal and extensor carpi radialis brevis release for lateral epicondylitis are common procedures suitable for the beginning arthroscopist. For beginning and advanced procedures, the surgeon's skill and competence must be at a level consistent with the procedure to avoid complications. PMID- 21553772 TI - Elbow arthroscopy: capitellar osteochondritis dissecans and radiocapitellar plica. AB - The combination of excessive radiocapitellar compressive forces and the limited vascularity of the capitellum are responsible for the development of osteochondritis dissecans. Repetitive compressive forces are generated by throwing or racket swinging motions or from constant axial compressive loads on the elbow, which are common in athletes such as gymnasts. Symptoms include activity-associated pain and stiffness. Physical examination findings show tenderness over the radiocapitellar joint and, commonly, loss of extension. Plain radiographs may show flattening and sclerosis of the capitellum, lucencies, and possibly intra-articular loose bodies. MRI can detect bone edema early in the disease process and further delineate the extent of the injury. The management of osteochondritis dissecans lesions is primarily based on the demands of the patient, the size and location of the lesion, and the status and stability of the overlying cartilage. Possible treatments include transarticular drilling; removing detached fragments or loose bodies, followed by drilling; and mosaicplasty. Radiocapitellar plica can cause chondromalacic changes on the radial head and capitellum, with symptoms including painful clicking and effusions. Arthroscopic plica resection is indicated when nonsurgical treatment fails. PMID- 21553773 TI - Elbow arthroscopy: valgus extension overload. AB - Valgus torque combined with deceleration produces high compression and shear forces acting on the posteromedial olecranon and the posteromedial trochlea. This valgus extension overload process may cause posteromedial trochlea chondromalacia, chondral flap formation, osteochondrosis, subchondral erosion, a subchondral insufficiency fracture, and marginal exostosis formation. Olecranon pathologies include proximal stress reaction, a posteromedial tip stress fracture, a transverse proximal process stress fracture, exostosis formation, exostosis fragmentation, and intra-articular loose bodies. Symptoms include posteromedial elbow pain during the deceleration phase of the throwing motion. The extension impingement test reproduces posterior or posteromedial pain similar to that experienced while throwing. Special radiographic techniques and CT scans can show loose bodies and osteophyte fragmentation. Surgical treatment is indicated when symptoms persist despite nonsurgical management. Based on clinical and basic science research, all patients with valgus extension overload should be comprehensively evaluated for medial ulnar collateral ligament insufficiency. Surgical treatment is limited to the resection of osteophytes only; normal olecranon should not be resected. PMID- 21553774 TI - Fractures and dislocations of the elbow: a return to the basics. AB - Elbow instability is classified as simple or complex. Complex elbow instability, an elbow dislocation with associated fractures, had historically poor outcomes. Most complex elbow dislocations render the elbow unstable, necessitating surgical treatment. The primary goal of surgery is to restore sufficient stability to the critical anatomy to initiate early range of motion, which has been shown to be a key factor for a successful outcome. Recent literature has improved the understanding of elbow anatomy, biomechanics, and the pathoanatomy of complex instability, thereby allowing the development of systematic approaches for treatment and rehabilitation. These advances in knowledge combined with improved implants and surgical techniques have translated into better outcomes for patients with simple and complex elbow instability. PMID- 21553775 TI - The recurrent unstable elbow: diagnosis and treatment. AB - The elbow is a difficult joint to treat because of the subtle nuances involved in pathology, examination, and treatment. Patients experiencing the sequelae of recurrent elbow instability can lose substantial function in the affected upper extremity. Elbow instability comprises a wide spectrum of diseases, ranging from valgus instability in the throwing athlete to traumatic recurrent rotatory instability to iatrogenic damage. For the orthopaedic surgeon to develop a systematic algorithm for treating elbow instability disorders, it is necessary to understand the basic elbow biomechanics and the alterations that occur in the unstable elbow. A thorough knowledge of the history, physical examination techniques, and imaging studies necessary to diagnose these injury patterns is also needed. Cutting-edge advances in the surgical reconstruction of the unstable elbow will allow those caring for patients with these difficult injuries to make the proper management decisions. PMID- 21553776 TI - Achieving stability and lower limb length in total hip arthroplasty. AB - Total hip arthroplasty is an exceptionally cost-effective and successful surgical procedure. Dislocation, infection, osteolysis, and limb-length inequality are among the most common complications affecting the long-term success of total hip arthroplasty. Instability is a challenging complication to treat. The surgeon frequently must try to achieve a stable hip at the cost of increasing the length of the operated extremity. It is important to understand the factors associated with stability and limb length; the surgical options available; the effect and role of the various surgical approaches; and methods to manage instability, with and without limb-length inequality. PMID- 21553777 TI - The evolution and modern use of metal-on-metal bearings in total hip arthroplasty. AB - Metal-on-metal bearings have been used in total hip arthroplasty for decades. Because younger patients with higher physical demands are now being treated with hip arthroplasty, the popularity and use of metal-on-metal bearings has increased over the past 10 years. New concerns, however, have emerged regarding the percentage of patients with a hypersensitivity reaction or pseudotumor formation after arthroplasty with these bearings. These concerns have raised questions concerning long-term outcomes for patients treated with metal-on-metal bearings. It is important for orthopaedic surgeons to review these issues so that better educated decisions can be made in treating their patients. PMID- 21553778 TI - Alternative bearing surface options for revision total hip arthroplasty. AB - Despite the overall success of total hip arthroplasty (THA), there has been an increase in the rate of revision hip surgeries performed each year in the United States. These revision surgeries result in several billion dollars in health care costs. Bearing surface wear can result in the need for revision surgery through a variety of mechanisms. Many implant failures necessitating the need for revision surgeries occur secondary to dislocations, which are often related to prothesis wear and eventual loosening of the components. Wear also can lead to osteolysis and may play a role in aseptic loosening. Specific concerns regarding the wear rates of metal-on-polyethylene (the most common bearing surface) have encouraged the manufacture of newer polyethylene implants with improved wear properties, as well as alternative bearing surfaces. The goal is to improve the durability of revision implants and/or reduce the incidence of revision THAs. Revision arthroplasty involves using alternative surfaces, such as replacing the metal femoral head with a ceramic component or changing the entire prosthesis to a metal-on-metal or ceramic-on-ceramic articulation. It is important to review the characteristics of these alternative bearing surface options and their contributions to improved THA tribology and prolonged prosthesis longevity. The choice of a bearing surface for a revision THA should consider factors such as the patient's age and activity level, the cost of the implant, and both the surgeons' and patients' preferences. Although laboratory studies and small clinical trials have generated optimistic results for these alternative implants in vitro and in vivo, much still needs to be learned about the long-term performance of these materials in patients after total hip revision surgery. PMID- 21553779 TI - Revision total knee arthroplasty: what the practicing orthopaedic surgeon needs to know. AB - The number of revision total knee arthroplasties (TKAs) continues to steadily increase. The evaluation of painful and revision TKAs may be challenging for the general orthopaedic surgeon, but a standardized, systematic approach to each patient will allow predictable surgical outcomes. This approach begins with a consistent and thorough preoperative patient evaluation. Revision surgery should not be performed until the etiology of failure of the index arthroplasty is known. The possibility of infection in the revision setting also must be considered because this complication will drastically alter the treatment algorithm. Adjunctive techniques, including the quadriceps snip, the medial collateral ligament slide, and the tibial tubercle osteotomy, can greatly enhance surgical exposure and the efficient removal of components in revision TKAs. A thorough knowledge of the reconstructive options for replacing bone loss is crucial, and the availability of appropriate revision instrumentation is required for surgical efficiency. A concise diagnostic algorithm coupled with clear reconstructive principles will allow more efficient and confident management of a patient with a failed TKA. PMID- 21553780 TI - What is the state of the art in orthopaedic thromboprophylaxis in lower extremity reconstruction? AB - Venous thromboembolic events, including deep venous thromboses and pulmonary embolisms, have a high risk of occurrence in patients treated with lower extremity arthroplasty and hip fracture surgery. Although the prevalence of these complications has been lowered with the use of venous thromboembolic prophylaxis, the current rate is still troublesome because of the possibility of death or the need for lifetime treatment of postthrombotic syndrome and/or pulmonary hypertension. Prophylactic methods currently include mechanical devices and pharmacologic agents. Mechanical devices are difficult to compare because they are not standardized, the devices are often used in multimodal prophylactic regimens, and the devices cannot be used when the patient is ambulating or at home. A new portable compression device allows use during ambulation and can be used by the patient at home. A recent study of this portable device in patients treated with total hip arthroplasty showed an efficacy similar to that of low molecular-weight heparin, with fewer major bleeding complications. Pharmacologic prophylaxis includes low-molecular-weight heparin, synthetic pentasaccharide, warfarin, and aspirin. All of these agents have different degrees of efficacy and safety. New oral agents for thromboprophylaxis are on the horizon but are not yet approved by the Food and Drug Administration. PMID- 21553781 TI - New oral anticoagulants for venous thromboembolism prophylaxis in orthopaedic surgery. AB - Anticoagulant drugs reduce the risk of venous thromboembolic events after total hip and knee arthroplasty. However, the use of current drugs, such as low molecular-weight heparins, is hampered by their subcutaneous administration. The use of a vitamin K antagonist, such as warfarin, is hampered by the required routine coagulation monitoring and dose titration to provide effective anticoagulation without an increased risk of bleeding. Numerous possible food and drug interactions must also be considered. New classes of oral anticoagulant agents have been developed that have a fixed dose, do not require coagulation monitoring, do not have food and drug interactions, and demonstrate similar or better efficacy and safety profiles when compared with current agents. PMID- 21553782 TI - Comparing and contrasting current guidelines for venous thromboembolism prophylaxis after total hip and total knee arthroplasty. AB - Orthopaedic surgeons may be impacted by three different clinical venous thromboembolism guidelines: the American College of Chest Physicians guidelines, the Surgical Care Improvement Project guidelines, and, most recently, the American Academy of Orthopaedic Surgeons (AAOS) guideline. The American College of Chest Physicians guidelines use deep venous thrombosis detected by venography or ultrasonography as their primary outcome measure. High-grade recommendations are based on prospective randomized studies only, usually comparing one pharmacologic agent to another. The Surgical Care Improvement Project guidelines are essentially based on the 2004 American College of Chest Physicians guidelines and seek to determine if surgeons prescribe venous thromboembolism prophylaxis within 24 hours of admission. Compliance with these guidelines may affect the quality rating of a particular hospital. The AAOS guideline was designed with the clinical outcome measures of symptomatic pulmonary embolism, fatal pulmonary embolism, major bleeding, and all-cause mortality. This guideline recommends that surgeons preoperatively evaluate the patient's risks (standard or elevated) for pulmonary embolism and serious bleeding and individualize pharmacologic prophylaxis based on a risk-benefit ratio. The three guidelines all have advantages and disadvantages. PMID- 21553783 TI - The use of arthrodesis to correct rigid flatfoot deformity. AB - Rigid adult flatfoot deformity ranges in severity and is caused by a variety of conditions. Treatment is based on the etiology, the severity of symptoms, the stage of the deformity, and patient goals. Posterior tibial tendon pathology, osteoarthritis, posttraumatic arthritis/deformity, inflammatory arthropathy, and neuropathic arthropathy are all known causes of adult flatfoot deformity. Regardless of the cause, treatment goals are the same-restore a plantigrade foot, decrease symptoms, and increase function. When nonsurgical modalities have failed, many surgical reconstructive options are available to restore anatomy and function. PMID- 21553784 TI - The management of complications following the treatment of flatfoot deformity. AB - Adult acquired flatfoot deformity encompasses a wide spectrum of clinical conditions. Current management approaches have emerged from a growing understanding of its manifestations, which have been learned from decades of clinical trial and error. Although surgical trends continue to evolve, many basic principles and practices have endured. Adult flatfoot deformity can arise from multiple causes, the most common of which remains posterior tibial tendon rupture with subsequent elongation of secondary supportive structures. Regardless of the cause, the fundamental goals of surgical management include correcting peritalar subluxation, restoring hindfoot-midfoot-forefoot relationships and muscle balance, attaining a plantigrade foot, and preserving motion when possible. Surgical correction may be associated with a variety of potential problems, including errors in decision making, undertreatment, overcorrection, and technical mistakes. These complications can lead to adjacent joint arthritis, recurrent deformity, rigidity, nonunion, and persistent pain. PMID- 21553785 TI - Diagnosis and treatment of chronic ankle pain. AB - The differential diagnosis for chronic ankle pain is quite broad. Ankle pain can be caused by intra-articular or extra-articular pathology and may be a result of a traumatic or nontraumatic event. A detailed patient history and physical examination, coupled with judicious selection of the appropriate imaging modalities, are vital in making an accurate diagnosis and providing effective treatment. Chronic ankle pain can affect all age groups, ranging from young athletes to elderly patients with degenerative joint and soft-tissue disorders. It has been estimated that 23,000 ankle sprains occur each day in the United States, representing approximately 1 sprain per 10,000 people per day. Because nearly one in five ankle injuries result in chronic symptoms, orthopaedic surgeons are likely to see patients with chronic ankle pain. Many patients with chronic ankle pain do not recall any history of trauma. Reviewing the management of the various disorders that can cause chronic ankle pain will help orthopaedic surgeons provide the best treatment for their patients. PMID- 21553786 TI - The current state of minimally invasive spine surgery. AB - Minimally invasive surgery for spinal disorders is predicated on the following basic principles: (1) avoid muscle crush injury by self-retaining retractors; (2) do not disrupt tendon attachment sites of key muscles, particularly the origin of the multifidus muscle at the spinous process; (3) use known anatomic neurovascular and muscle compartment planes; and (4) minimize collateral soft tissue injury by limiting the width of the surgical corridor. The traditional midline posterior approach for lumbar decompression and fusion violates these key principles of minimally invasive surgery. The tendon origin of the multifidus muscle is detached, the surgical corridor is exceedingly wide, and significant muscle crush injury occurs with the use of powerful self-retaining retractors. The combination of these factors leads to well-described changes in muscle physiology and function. Minimally invasive posterior lumbar surgery is performed with table-mounted tubular retractors that focus the surgical dissection to a narrow corridor directly over the surgical target site. The path of the surgical corridor is chosen based on anatomic planes, specifically avoiding injury to the musculotendinous complex and the neurovascular bundle. With these relatively simple modifications in the minimally invasive surgical technique, significant improvements have been achieved in intraoperative blood loss, postoperative pain, and surgical morbidity. However, minimally invasive surgical techniques remains technically demanding, and a significant complication rate has been reported during a surgeon's initial learning curve for the procedures. Improvements in surgeon training along with long-term prospective studies will be needed for advancements in this area of spine surgery. PMID- 21553787 TI - Top 10 pediatric orthopaedic surgical emergencies: a case-based approach for the surgeon on call. AB - Pediatric patients who require orthopaedic surgical emergency care are often treated by orthopaedic surgeons who primarily treat adult patients. Essential information is needed to safely evaluate and treat the most common surgical emergencies in pediatric patients, including hip fractures; supracondylar humeral, femoral, and tibial conditions of the hip (such as slipped capital femoral epiphysis and septic arthritis); and limb- and life-threatening pathologies, including compartment syndrome, the dysvascular limb, cervical spine trauma, and the polytraumatized child. To provide optimal care to pediatric patients, it is important to be aware of the key points in patient evaluation and surgical care as well as expected complications. PMID- 21553788 TI - Management of fractures in adolescents. AB - There are well-established treatment standards for adults who sustain fractures; however, these treatment standards are not always applicable when treating adolescents with similar fractures because of the presence of physes. Fractures in adolescents are treated by pediatric orthopaedic surgeons, adult orthopaedic traumatologists, or general orthopaedic surgeons. It is imperative that the principles of fracture management are well defined and discussed in both the pediatric and adult orthopaedic community. Controversial topics include the youngest age at which an adolescent can be treated as an adult and acceptable fracture reduction criteria. The general principles of managing fractures in adolescents regarding classification, treatment options, complications, and estimating skeletal age should be understood by the treating physician. PMID- 21553789 TI - Repair of complex and avascular meniscal tears and meniscal transplantation. AB - A functional meniscus is critical to the long-term health of the knee joint. The repair of meniscal tears that extend into the central avascular region requires understanding the appropriate indications, contraindications, surgical techniques, and postoperative rehabilitation protocols. An inside-out repair technique using multiple vertical divergent sutures with an accessory posteromedial or posterolateral incision is recommended for optimal stability. In young, active patients, the risk of repair failure and the need for revision are outweighed by the benefit of meniscal preservation. Although many meniscal tears are repairable, not all are salvageable, especially if considerable tissue damage has occurred. The goals of transplantation of human menisci are to restore partial load-bearing meniscal function, decrease patient symptoms, and provide chondroprotective effects. Clinical studies have shown that meniscal transplantation decreases tibiofemoral joint pain in the short term. The procedure remains in an evolving state with an unpredictable long-term outcome; however, most meniscal transplants gradually deteriorate, tear, or shrink in size over time, thereby losing the ability to provide function. The current goal is to provide short-term benefits to the patient until a superior meniscal transplant is clinically available. PMID- 21553790 TI - All-arthroscopic meniscus repair of avascular and biologically at-risk meniscal tears. AB - Meniscal repair strategies have evolved over time from a more invasive open method to less invasive, all-arthroscopic approaches. Novel devices and surgical techniques currently enable the successful arthroscopic placement of biomechanically optimal sutures that provide compression across the tear site with less potential surgical morbidity. Current techniques do not require accessory posteromedial or posterolateral incisions and significantly reduce the incidence of complications and pain associated with more invasive surgery. Along with these improved methods, the indications for meniscal repair are expanding to include tear patterns previously considered biologically at risk for poor healing. More recently, with the addition of biologic augmentation methods, such as the introduction of platelet- rich plasma as well as reported tissue engineering advances, it may be possible to continue to broaden the indications and success of meniscal preservation through repair and replacement. PMID- 21553791 TI - Enhancing meniscal repair through biology: platelet-rich plasma as an alternative strategy. AB - Meniscal tears are common orthopaedic injuries that can manifest with significant pain and mechanical symptoms. The treatment of meniscal tears has evolved from total meniscectomy to partial meniscectomy and meniscal repair. Preserving the meniscus is ideal because the loss of any portion of the meniscus can lead to significantly increased articular cartilage contact stresses compared with the intact state. However, most of the meniscus has a limited ability to heal because of poor vascularity. This has prompted a search for a better understanding of the biology of meniscal healing and methods to enhance the process. Growth factors have been shown to positively affect meniscal cell function, including platelet derived growth factor, fibroblast growth factor, basic fibroblast growth factor, transforming growth factor-beta, insulin-like growth factor, bone morphogenetic protein, hepatocyte growth factor, and vascular endothelial growth factor. In vitro studies have shown that other cytokines, including interleukin-1, tumor necrosis factor-alpha, and the matrix metalloproteinases, negatively affect meniscal healing. Identification of these growth factors has led to strategies to deliver serum-derived factors to the meniscus to improve healing. Platelet-rich plasma is the latest technique to be evaluated for augmenting meniscal healing. Activation of the platelets leads to the local release of growth factors from the alpha and dense granules located in the platelet cytoplasm. These growth factors have been associated with the initiation of a healing cascade leading to cellular chemotaxis, angiogenesis, collagen matrix synthesis, and cell proliferation. PMID- 21553792 TI - Surgical management of articular cartilage defects of the knee. AB - Articular cartilage defects of the knee present diagnostic and treatment challenges for orthopaedic surgeons. As new data and technologies become available, treatment algorithms are continually being refined. It is important to examine treatment recommendations from the current literature and understand surgical techniques for articular cartilage repair. PMID- 21553793 TI - Technical aspects of anterior cruciate ligament reconstruction for the general orthopaedic surgeon. AB - Anterior cruciate ligament reconstruction is the sixth most common procedure performed by orthopaedic surgeons. The goals of the procedure are to restore knee stability and patient function. These goals are dependent on proper graft positioning and incorporation. Anterior cruciate ligament reconstruction involves a technically complicated series of steps, all of which affect graft healing and clinical outcome. A wide variety of graft choices and surgical techniques are currently available for use. It is important for orthopaedic surgeons performing anterior cruciate ligament reconstructions to be aware of the indications for graft selection, techniques for correct graft placement, and the biologic implications related to these factors. PMID- 21553794 TI - Anterior cruciate ligament graft placement recommendations and bone-patellar tendon-bone graft indications to restore knee stability. AB - The anterior cruciate ligament (ACL) resists the combined abnormal motions of anterior tibial translation and internal tibial rotation that occur in the pivot shift phenomenon. The placement of a single ACL graft high and proximal at the femoral attachment and posterior at the tibial attachment results in a vertical graft orientation. This graft position has a limited ability to provide rotational stability. A more oblique ACL graft orientation in the sagittal and coronal planes achieved from a central anatomic femoral and tibial location provides an orientation that is better in resisting the pivot-shift phenomenon. Tibial and femoral tunnels are drilled independently; transtibial drilling of the femoral tunnel is not recommended. The meticulous surgical technique for ACL reconstruction includes identifying the appropriate landmarks to achieve correct graft placement. There are insufficient experimental and clinical data to recommend the more complex double-bundle ACL graft technique over a central anatomic single graft in terms of restoring knee rotational stability. Allografts are used only in select knees for which autograft tissue is not available. The postoperative rehabilitation program takes into account the condition of the menisci and articular cartilage and associated reconstructive procedures. PMID- 21553795 TI - Management of complex knee ligament injuries. AB - The ideal management of the dislocated knee remains controversial. These injuries often can be elusive; a significant number of dislocated knees spontaneously reduce and appear relatively benign on routine radiographs. A high index of suspicion, based on the mechanism of injury, soft-tissue assessment of the limb, and the level of knee instability should alert the physician to the possibility of a dislocated knee. Early recognition and appropriate neurovascular assessment is paramount to the successful treatment of these complex injuries. Controversies exist regarding surgical versus nonsurgical management, early versus delayed surgery, the use of allograft versus autograft tissue, the decision to repair versus reconstruct torn ligamentous structures, and the type of reconstruction technique and postoperative rehabilitation program. To achieve optimal patient care, it is important to be aware of the current evaluation and treatment strategies for complex knee ligament injuries, including modern anatomic reconstruction techniques. Current recommendations include measurement of the ankle-brachial indices in each patient, early surgical management, the use of autograft or allograft tissue, reconstruction as opposed to repair alone of the fibular collateral ligament/posterolateral corner structures, reconstruction of the anterior and posterior cruciate ligaments, and repair and/or reconstruction of the medial collateral ligament/posteromedial corner depending on the injury pattern and the quality of tissue. PMID- 21553796 TI - Surgical site infection prevention and control: an emerging paradigm. AB - Examining the current state of infection in orthopaedic surgery provides tools and techniques to reduce the risks of nosocomial infections and prevent and treat infections from drug-resistant organisms. It is important for surgeons to recognize modifiable surgical risk factors and be aware of the importance of preoperative patient screening in reducing surgical site infections. The latest evidence-based data from scientific exhibits, instructional course lectures, and the Orthopaedic Knowledge Online continuing medical education module gathered during the past 5 years by the American Academy of Orthopaedic Surgeons Patient Safety Committee are useful in understanding and controlling the increasing and vital problem of surgical site infection. PMID- 21553797 TI - Prophylactic antibiotics in orthopaedic surgery. AB - The use of prophylactic antibiotics in orthopaedic surgery has been proven effective in reducing surgical site infections after hip and knee arthroplasty, spine procedures, and open reduction and internal fixation of fractures. To maximize the beneficial effect of prophylactic antibiotics, while minimizing any adverse effects, the correct antimicrobial agent must be selected, the drug must be administered just before incision, and the duration of administration should not exceed 24 hours. PMID- 21553798 TI - Modifiable risk factors for surgical site infection. AB - Multiple risk factors for orthopaedic surgical site infection have been identified. Some of these factors directly affect the wound-healing process, whereas others can lead to blood-borne sepsis or relative immunosuppression. Modifying a patient's medications; screening for comorbidities, such as HIV or diabetes mellitus; and advising the patient on options to diminish or eliminate adverse behaviors, such as smoking, should lower the risk for surgical site infections. PMID- 21553799 TI - Surgical site infection prevention: the operating room environment. AB - Surgical site infections can complicate orthopaedic procedures and contribute to morbidity, mortality, and health care costs. Extensive literature has been published on this topic; however, the quality of data using standards of evidence based medicine is variable with a lack of well-controlled studies. A review of the literature concerning measures to prevent surgical site infections in the operating room environment may be helpful in preventing such infections. PMID- 21553800 TI - Principles of biomechanics and biomaterials in orthopaedic surgery. AB - There are few surgical procedures within the field of orthopaedic surgery that do not entail the basis or need for understanding basic biomechanical principles. Every subspecialty field requires some aspect of biomechanics to properly understand and perform surgical procedures, patient examinations, and clinical treatment. A proper review of these principles will allow surgeons to better approach all treatment modalities used for patient care. PMID- 21553801 TI - Applied biomechanics in articular injuries: perspectives in the basic investigation of articular injuries and clinical application. AB - Joint injury is an important cause of arthritis. Although the treatment of injury, in general, has been widely studied, the contribution of injury to the development of posttraumatic arthritis is still a relatively understudied area. One of the most perplexing aspects of investigating articular injuries is the complex nature of the injury itself and the multiple facets of the injury mechanism that can potentially lead to the development of arthritis. A symposium by the Orthopaedic Research Society and the American Academy of Orthopaedic Surgeons was designed to examine the spectrum of basic science to clinical investigation in the role of biomechanics in the study of joint injury and subsequent posttraumatic arthritis. Four perspectives in the clinical aspects of managing articular injuries were investigated, including the clinical applications of basic science findings, the challenges and advancements in measuring and modeling articular fractures, the relationship of articular cartilage mechanical injuries and osteoarthritis, and the controlled creation of an intra-articular fracture to permit observations of the natural history of posttraumatic arthritis. PMID- 21553802 TI - Orthopaedic expert opinion, testimony, and the physician as a defendant. AB - Medicolegal issues continue to challenge orthopaedic surgeons. Although health reform legislation has passed Congress, the first phase has not incorporated any significant changes regarding liability reform for practicing orthopaedic surgeons. Medical malpractice, personal injury, and workers' compensation litigation remains an issue for patients and physicians. Although orthopaedic surgeons can be defendants, it is more likely that they will be retained as treating physicians or experts as part of the litigation process. The involvement of a qualified physician as an expert witness is essential to the outcome of any litigation involving medical issues. As triers of the facts, the judge and jury members rely on quality medical testimony. Expert witness testimony can be a time consuming process. A physician who assumes the role must be able to spend the time necessary to do a good job. A prepared expert witness can have a profound effect on litigation. A poorly prepared physician expert witness can be harmful to a case and risks the loss of prestige, honor among colleagues, and future work. Sanctions may be imposed by professional organizations. Most importantly, a physician working within the legal system must remain honest and tell nothing but the truth. PMID- 21553803 TI - Using PubMed effectively to access the orthopaedic literature. AB - PubMed is the free public Internet interface to the US National Library of Medicine's MEDLINE database of citations to medical scientific articles. Many orthopaedic surgeons use PubMed on a regular basis, but most orthopaedic surgeons have received little or no training in how to use PubMed effectively and express frustration with the experience. Typical problems encountered are data overload with very large numbers of returns to look through, failure to find a specific article, and a concern that a search has missed important papers. It is helpful to understand the system used to enter journal articles into the database and the classification of the common types of searches and to review suggestions for the best ways to use the PubMed interface and find sources for search teaching and assistance. PMID- 21553804 TI - Resiliency and medicine: how to create a positive energy balance. AB - A career in orthopaedics is a race-a marathon. Many outside forces converge to increase stressors to high levels. Resiliency, or the ability to bounce back from difficulty, can be learned and nurtured. The management of energy, rather than time, holds the key to avoiding burnout. Orthopaedic surgeons must minimize "energy drain" by first recognizing their ability to become proactive and control their lives. Surgeons must learn how to say "no" and delegate work and responsibilities. A positive energy balance can be attained when relationships, not things, are given priority. A focus on passions and inspiration helps to maintain energy, while a connection to a "source" and living a morally just, service-oriented life will yield endless energy. PMID- 21553805 TI - Stress management and balance for the orthopaedic surgeon: mindfulness. AB - Orthopaedic surgeons work in an environment in which decisions must be made in the moment, day-to-day, often with insufficient information and sometimes with immense uncertainty. Surgeons must discern patterns within the unfolding events of patient interviews or in the course of surgery. These patterns must be related to past experience, intuition, weighing the odds, and weighing the benefits and risks. To make these judgment calls, orthopaedic surgeons need ever-present awareness and integrity; they need the ability to embrace mindfulness, or to live in the moment. By tending to the moments of their lives, surgeons can be "in" the moment rather than carelessly letting it drift by. The practice of mindfulness dramatically reduces stress, worry, and regret and replaces these negative reactions with a vibrant awareness, joy, and enthusiasm, which are medicinal and spiritual. PMID- 21553806 TI - Plants as biofactories: physiological role of reactive oxygen species on the accumulation of phenolic antioxidants in carrot tissue under wounding and hyperoxia stress. AB - Plants subjected to postharvest abiotic stresses synthesize secondary metabolites with health-promoting properties. Here, we report the potential use of carrots (Daucus carota) as biofactories of caffeoylquinic acids when subjected to wounding and hyperoxia stresses. Wounding stress induced an increase of ~287% in total phenolic content (PC) in carrots stored for 48 h at 20 degrees C. This increase was higher (~349%) in the wounded tissue treated with hyperoxia stress. To further understand the physiological role of reactive oxygen species (ROS) as a signaling molecule for the stress-induced accumulation of phenolics in carrots, the respiration rate as well as the enzymatic activities of NADPH oxidase, superoxide dismutase, ascorbate peroxidase, and catalase were evaluated. Likewise, shredded carrots were treated with diphenyleneiodonium chloride solution to block NADPH oxidase ROS productions, and the phenylalanine ammonia lyase activity and total PC were evaluated. Results demonstrated that ROS play a key role as a signaling molecule for the stress-induced accumulation of PC in carrots. PMID- 21553807 TI - K(NpO2)3(H2O)Cl4: a channel structure assembled by two- and three-center cation cation interactions of neptunyl cations. AB - A Np(V) compound containing three-center cation-cation interations, K(NpO(2))(3)(H(2)O)Cl(4), has been prepared by reacting Np(V) with KCl in molten boric acid. This compound forms a three-dimensional channel structure that is constructed from both two- and three-center cation-cation interactions. Three new bonding modes for cation-cation interactions are added to the summary of all known Np(V) compounds. PMID- 21553808 TI - Lipoprotein-associated phospholipase A(2) interacts with phospholipid vesicles via a surface-disposed hydrophobic alpha-helix. AB - Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) plays important roles in both the inhibition and promotion of inflammation in human disease. It catalyzes the hydrolytic inactivation of plasma platelet activating factor (PAF) and is also known as PAF acetylhydrolase. High levels of PAF are implicated in a variety of inflammatory diseases such as asthma, necrotizing enterocolitis, and sepsis. Lp-PLA(2) also associates with lipoproteins in human plasma where it hydrolyzes oxidized phospholipids to produce pro-inflammatory lipid mediators that can promote inflammation and the development of atherosclerosis. Lp-PLA(2) plasma levels have recently been identified as a biomarker of vascular inflammation, atherosclerotic vulnerability, and future cardiovascular events. The enzyme is thus a prominent target for the development of inflammation and atherosclerosis modulating therapeutics. While the crystallographically determined structure of the enzyme is known, the enzyme's mechanism of interaction with PAF and the function-modulating lipids in lipoproteins is unknown. We have employed peptide amide hydrogen-deuterium exchange mass spectrometry (DXMS) to characterize the association of Lp-PLA(2) with dimyristoylphosphatidylcholine (DMPC) vesicles and found that specific residues 113-120 in one of the enzyme's surface-disposed hydrophobic alpha-helices likely mediate liposome binding. PMID- 21553809 TI - Distance-dependent metal-enhanced quantum dots fluorescence analysis in solution by capillary electrophoresis and its application to DNA detection. AB - Here the distance dependence of metal-enhanced quantum dots (QDs) fluorescence in solution is studied systematically by capillary electrophoresis (CE). Complementary DNA oligonucleotides-modified CdSe/ZnS QDs and gold nanoparticles (Au NPs) were connected together in solution by the hybridization of complementary oligonucleotides, and a model system (QD-Au) for the study of metal enhanced QDs fluorescence was constructed, in which the distance between the QDs and Au NPs was controlled by adjusting the base number of the oligonucleotide. In our CE experiments, the metal-enhanced fluorescence of the QDs solution was only observed when the distance between the QDs and Au NPs ranged from 6.8 to 18.7 nm, and the maximum enhancement by a factor of 2.3 was achieved at 11.9 nm. Furthermore, a minimum of 19.6 pg of target DNA was identified in CE based on its specific competition with the QD-DNA in the QD-Au system. This work provides an important reference for future study of metal-enhanced QDs fluorescence in solution and exhibits potential capability in nucleic acid hybridization analysis and high-sensitivity DNA detection. PMID- 21553810 TI - Selenium bioavailability from naturally produced high-selenium peas and oats in selenium-deficient rats. AB - This study determined the bioavailability of selenium (Se) from yellow peas and oats harvested from the high-Se soil of South Dakota, United States. The Se concentrations were 13.5 +/- 0.2 and 2.5 +/- 0.1 mg/kg (dry weight) for peas and oats, respectively. Male weanling Sprague-Dawley rats were depleted of Se by feeding them a 30% Torula yeast-based diet (4.1 MUg Se/kg) for 56 days, and then they were replenished with Se for an additional 50 days by feeding them the same diet supplemented with 20, 30, or 40 MUg Se/kg from peas or oats, respectively. Selenium bioavailability was determined on the basis of the restoration of Se dependent enzyme activities and tissue Se concentrations in Se-depleted rats, comparing those responses for yellow peas and oats to those for l selenomethionine (SeMet; used as a reference) by using a slope-ratio method. Dietary supplementation with peas or oats resulted in linear or log-linear, dose dependent increases in glutathione peroxidase activities in blood and liver and in thioredoxin reductase activity in liver. Supplementation with peas or oats resulted in linear or log-linear, dose-dependent increases in Se concentrations of plasma, liver, gastrocnemius muscle, and kidneys. The overall bioavailability was approximately 88% for Se from yellow peas and 92% from oats, compared to SeMet. It was concluded that Se from naturally produced high-Se yellow peas or oats is highly bioavailable in this model and that these high-Se foods may be a good dietary source of Se. PMID- 21553811 TI - A direct, efficient method for the preparation of siRNAs containing ribo-like North bicyclo[3.1.0]hexane pseudosugars. AB - An efficient method for the preparation of siRNAs modified with ribo-like North bicyclo[3.1.0]hexane pseudosugars is described. The combined use of 2'-O-(2 cyanoethoxymethyl) (CEM) and 2'-O-TBDMS protection was successfully employed for RNA synthesis with the added advantage that both groups were efficiently removed in a single step. The resulting North ribo-methanocarba-modified siRNAs are compatible with the intracellular RNAi machinery and can mediate specific degradation of target mRNA. PMID- 21553812 TI - Thiazolides as novel antiviral agents. 1. Inhibition of hepatitis B virus replication. AB - We report the syntheses and activities of a wide range of thiazolides [viz., 2 hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2 hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 MUm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results. PMID- 21553813 TI - Chaxamycins A-D, bioactive ansamycins from a hyper-arid desert Streptomyces sp. AB - Streptomyces sp. strain C34, isolated from soil collected in the Chilean hyper arid Atacama Desert, was cultured on different media, resulting in the isolation and identification of four new ansamycin-type polyketides. The organism was selected for chemical investigation on the basis of a genome-mining PCR-based experiment targeting the gene encoding rifamycin-specific 3-amino-5 hydroxybenzoic acid synthetase (AHBA). The isolated compounds were structurally characterized using NMR and MS techniques and named chaxamycins A-D (1-4). Compounds 1-4 were tested for their antibacterial activity against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 and for their ability to inhibit the intrinsic ATPase activity of the heat shock protein 90 (Hsp90). Chaxamycin D (4), which showed a selective antibacterial activity against S. aureus ATCC 25923, was tested further against a panel of MRSA clinical isolates. In a virtual screening experiment, chaxamycins A-D (1-4) have also been docked into the ATP-binding pocket in the N-terminal domain of the Hsp90, and the observed interactions are discussed. PMID- 21553814 TI - Synthesis of benzocycloheptanones through coupling of delta,epsilon-unsaturated chromium carbene complexes and 2-alkynylbenzoyl derivatives. AB - The coupling of pentenylcarbene complexes and 2-alkynylbenzoyl derivatives affords naphthocycloheptanones in a single step involving simultaneous construction of both the seven-membered ring and one of the aromatic rings. Aryl tethered systems undergo intramolecular cyclopropanation. PMID- 21553815 TI - Comment on "Sustainability metrics: life cycle assessment and green design in polymers". PMID- 21553817 TI - Comment on "Sustainability metrics: life cycle assessment and green design in polymers". PMID- 21553818 TI - Comment on "Sustainability metrics: life cycle assessment and green design in polymers". PMID- 21553819 TI - On resin side-chain cyclization of complex peptides using CuAAC. AB - Triazole tethers have been explored for stabilization of secondary structures in peptides. Despite the utility of this approach, cyclization efficiency in complex peptides remains a significant challenge. A robust, on-resin protocol for side chain to side chain macrocyclization by CuAAC is described. This protocol was applied to the synthesis of a series of 21 amino acid helical peptides presenting a binding dipeptide motif from the membrane proximal external region (MPER) of HIV-1 gp41. PMID- 21553820 TI - Rhenium-catalyzed regio- and stereoselective addition of two carbon units to terminal alkynes via carbon-carbon bond cleavage of beta-keto sulfones. AB - Treatment of beta-keto sulfones with terminal alkynes gave unsaturated delta-keto sulfones in good to excellent yields under rhenium catalysis. In this reaction, the insertion of the alkynes into the nonstrained carbon-carbon single bond between the alpha- and beta-positions of the beta-keto sulfones proceeded smoothly, and (Z)-isomers were produced with high regio- and stereoselectivities. PMID- 21553821 TI - Interference prevention in size-exclusion chromatographic analysis of debranched starch glucans by aqueous system. AB - Branch chain-length distribution of amylopectin plays an important role on the characteristics of starch. One of the adapted protocols for determining the chain length distribution and mass proportion of starch molecules is that starch is debranched with isoamylase and then analyzed by using high-performance size exclusion chromatography coupled with multiangle laser-light scattering and refractive index detection (HPSEC-MALS-RI). However, ammonium sulfate in commercial isoamylase and acetate in debranching buffer give significant interferences on the chromatograms because of their undesirable ionic interactions with column sorbent materials. This study deals with development for correcting those interferences. A weak anion-exchange resin or selective precipitation with barium acetate was employed to remove sulfate prior to HPSEC determination. The interference of acetate was overcome by means of high ionic strength eluent, 0.3 M sodium nitrate. The specific refractive index increment (dn/dc) of amylodextrin was determined to be 0.147 using the modified conditions and was applied to calculate the molecular weight distribution of debranched starch molecules. PMID- 21553822 TI - Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents. AB - Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ~700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition. PMID- 21553823 TI - Conjugated ligands modulated sandwich structures and luminescence properties of lanthanide metal-organic frameworks. AB - A conjugated ligand, 2-(carboxylic acid)-6-(2-benzimidazolyl) pyridine (Hcbmp), and a series of Lanthanide metal-organic frameworks (MOFs) [Ln(2)(cbmp)(ox)(3)(H(2)O)(2)](2).2H(3)O(+).7H(2)O (Ln = Sm (3), Eu (4), and Gd (5), H(2)ox = oxalic acid) have been designed and assembled. To elucidate how the conjugated ligands modulate the structures and luminescence properties, we carried out the structural characterizations and luminescence studies of complexes 3 and 4, and their corresponding oxalate complexes [Ln(ox)(1.5)(H(2)O)(3)].2H(2)O (Ln = Sm (1) and Eu (2)) were also investigated for comparison. The changes of luminescence behaviors upon dehydration and D(2)O rehydration processes are presented and discussed in detail. The results indicated that, the cbmp(-) ligands distribute on both sides of the ox(-)-Ln bilayer network to construct a sandwich structure. Moreover, the lowest triplet state of cbmp(-) ligands can match well the energy levels of the Sm(3+) and Eu(3+) cations which allow the preparation of new Ln-MOF materials with enhanced luminescence properties. Meanwhile, the crystallinity of solid states produces more substantial change in the luminescence behaviors than removal or replacement of effective nonradiative relaxers. PMID- 21553824 TI - Soft secondary building unit: dynamic bond rearrangement on multinuclear core of porous coordination polymers in gas media. AB - A new synthetic approach to prepare flexible porous coordination polymers (PCPs) by the use of soft secondary building units (SBUs) which can undergo multiple reversible metal-ligand bonds breaking is reported. We have prepared a zinc paddle-wheel-based two-fold interpenetrated PCP, {[Zn(2)(tp)(2)(L(2))].2.5DMF.0.5water}(n) (2a, H(2)tp = terephthanlic acid; L(2) = 2,3-difluoro-1,4-bis(4-pyridyl)benzene), showing dynamic structural transformations upon the removal and rebinding of guest molecules. The X-ray structures at different degrees of desolvation indicate the highly flexible nature of the framework. The framework deformations involve slippage of the layers and movement of the two interpenetrated frameworks with respect to each other. Interestingly, the coordination geometry of a zinc paddle-wheel unit (one of the popular SBUs) is considerably changed by bond breaking between zinc and oxygen atoms during the drying process. Two zinc atoms in the dried form 2d reside in a distorted tetrahedral geometry. Compound 2d has no void volume and favors the uptake of O(2) over Ar and N(2) at 77 K. The O(2) and Ar adsorption isotherms of 2d show gate-opening-type adsorption behaviors corroborating the structure determination. The CO(2) adsorption isotherm at 195 K exhibits multiple steps originating from the flexibility of the framework. The structural transformations of the zinc clusters in the framework upon sorption of guest molecules are also characterized by Raman spectroscopy in which the characteristic bands corresponding to nu(sym)(COO(-)) vibration were used. PMID- 21553825 TI - Activation energies for the rate-limiting step in water photooxidation by nanostructured alpha-Fe2O3 and TiO2. AB - Competition between charge recombination and the forward reactions required for water splitting limits the efficiency of metal-oxide photocatalysts. A key requirement for the photochemical oxidation of water on both nanostructured alpha Fe(2)O(3) and TiO(2) is the generation of photoholes with lifetimes on the order of milliseconds to seconds. Here we use transient absorption spectroscopy to directly probe the long-lived holes on both nc-TiO(2) and alpha-Fe(2)O(3) in complete PEC cells, and we investigate the factors controlling this slow hole decay, which can be described as the rate-limiting step in water oxidation. In both cases this rate-limiting step is tentatively assigned to the hole transfer from the metal oxide to a surface-bound water species. We demonstrate that one reason for the slow hole transfer on alpha-Fe(2)O(3) is the presence of a significant thermal barrier, the magnitude of which is found to be independent of the applied bias at the potentials examined. This is in contrast to nanocrystalline nc-TiO(2), where no distinct thermal barrier to hole transfer is observed. PMID- 21553826 TI - Photodeposition of Ag2S quantum dots and application to photoelectrochemical cells for hydrogen production under simulated sunlight. AB - UV light irradiation of TiO(2) (lambda > 320 nm) in a mixed solution of AgNO(3) and S(8) has led to the formation of Ag(2)S quantum dots (QDs) on TiO(2), while Ag nanoparticles (NPs) are photodeposited without S(8). Photoelectrochemical measurements indicated that the Ag(2)S photodeposition proceeds via the preferential reduction of Ag(+) ions to Ag(0), followed by the chemical reaction with S(8). The application of this in situ photodeposition technique to mesoporous (mp) TiO(2) nanocrystalline films coated on fluorine-doped SnO(2) (FTO) electrodes enables formation of Ag(2)S QDs (Ag(2)S/mp-TiO(2)/FTO). Ag(2)S/mp-TiO(2)/FTO has the interband transition absorption in the whole visible region, while in the spectrum of Ag/mp-TiO(2)/FTO, a localized surface plasmon resonance absorption of Ag NPs is present centered at 490 nm. Ag(2)S QD sensitized photoelectrochemical cells using the Ag(2)S/mp-TiO(2)/FTO and Ag/mp TiO(2)/FTO photoanodes were fabricated. Under illumination of one sun, the Ag(2)S photoanode cell yielded H(2) at a rate of 0.8 mL.h(-1) with a total conversion efficiency of 0.29%, whereas the Ag/mp-TiO(2)/FTO photoanode is inactive. PMID- 21553827 TI - Hydrothermal synthesis of hollow silica spheres under acidic conditions. AB - It is well-known that silica can be etched in alkaline media or in a unique hydrofluoric acid (HF) solution, which is widely used to prepare various kinds of hollow nanostructures (including silica hollow structures) via silica-templating methods. In our experiments, we found that stober silica spheres could be etched in generic acidic media in a well-controlled way under hydrothermal conditions, forming well-defined hollow/rattle-type silica spheres. Furthermore, some salts such as NaCl and Na(2)SO(4) were found to be favorable for the formation of hollow/rattle-type silica spheres. PMID- 21553828 TI - Evidence of a mobile precursor state in nonspecific protein adsorption. AB - We study the dynamics of nonspecific protein adsorption using nanometer micrometer-scale patterns involving hydrophobic domains in hydrophilic matrices. We report the discovery of a critical requirement for the sizes of the hydrophobic/adhesive pads for protein adsorption: the area of each adhesive pad must be more than 2 orders of magnitude larger than the footprint of a protein molecule before irreversible adsorption occurs. We attribute this to the minimal surface area sampled by a mobile protein molecule in a precursor state before irreversible adsorption occurs. Kinetic analysis based on the precursor model quantitatively accounts for the experimental observation and reveals that the distance sampled by the mobile precursor state before irreversible adsorption increases with the size of the protein molecule. PMID- 21553829 TI - Design, synthesis, and cytotoxic evaluation of acyl derivatives of 3 aminonaphtho[2,3-b]thiophene-4,9-dione, a quinone-based system. AB - A series of 3-acyl derivatives of the dihydronaphtho[2,3-b]thiophen-4,9-dione system were studied with respect to cytotoxicity and topoisomerase II inhibitory activity. These analogues were designed as electron-deficient anthraquinone analogues with potential intercalation ability. Derivatives 3-(diethylamino)-N (4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3-yl)propanamide (11m) and 3-(2 (dimethylamino)ethylamino)-N-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]thiophen-3 yl)propanamide (11p) showed a high efficacy in cell lines that were highly resistant to treatment with doxorubicin, such as MDA-MB435 (melanoma), IGROV (ovarian), and SF-295 (glioblastoma) human cell lines. Both compounds inhibit topoisomerase II mediated relaxation of DNA, while only 11p incites arrest at the S phase in Caco-2 cells, inducing a delay of cell cycle progression and an increase of cell differentiation. The ability of these derivatives to modulate small heat shock proteins and cardiotoxicy effects was also explored. In addition, the DNA-binding properties of these compounds were investigated and discussed. PMID- 21553830 TI - Internal dynamics of the tryptophan repressor (TrpR) and two functionally distinct TrpR variants, L75F-TrpR and A77V-TrpR, in their l-Trp-bound forms. AB - Backbone amide dynamics of the Escherichia coli tryptophan repressor protein (WT TrpR) and two functionally distinct variants, L75F-TrpR and A77V-TrpR, in their holo (l-tryptophan corepressor-bound) form have been characterized using (15)N nuclear magnetic resonance (NMR) relaxation. The three proteins possess very similar structures, ruling out major conformational differences as the source of their functional differences, and suggest that changes in protein flexibility are at the origin of their distinct functional properties. Comparison of site specific (15)N-T(1), (15)N-T(2), (15)N-{(1)H} nuclear Overhauser effect, reduced spectral density, and generalized order (S(2)) parameters indicates that backbone dynamics in the three holo-repressors are overall very similar with a few notable and significant exceptions for backbone atoms residing within the proteins' DNA binding domain. We find that flexibility is highly restricted for amides in core alpha-helices (i.e., helices A-C and F), and a comparable "stiffening" is observed for residues in the DNA recognition helix (helix E) of the helix D-turn helix E (HTH) DNA-binding domain of the three holo-repressors. Unexpectedly, amides located in helix D and in adjacent turn regions remain flexible. These data support the concept that residual flexibility in TrpR is essential for repressor function, DNA binding, and molecular recognition of target operators. Comparison of the (15)N NMR relaxation parameters of the holo-TrpRs with those of the apo-TrpRs indicates that the single-point amino acid substitutions, L75F and A77V, perturb the flexibility of backbone amides of TrpR in very different ways and are most pronounced in the apo forms of the three repressors. Finally, we present these findings in the context of other DNA-binding proteins and the role of protein flexibility in molecular recognition. PMID- 21553831 TI - Investigation of the mechanism of nickel electroless deposition on functionalized self-assembled monolayers. AB - We have investigated the seedless electroless deposition (ELD) of Ni on functionalized self-assembled monolayers (SAMs) using scanning electron and optical microscopies, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry. For all SAMs studied, the Ni deposition rate is dependent on the bath pH, deposition temperature, and complexing agent. In contrast to the physical vapor deposition of Ni on SAMs, electrolessly deposited Ni does not penetrate through the SAM. This behavior indicates that ELD is a suitable technique for the deposition of low-to-moderate reactivity on organic thin films. We demonstrate that Ni can be selectively deposited on SAMs using two different methods. First, selectivity can be imparted by the formation of Ni(II) surface complexes. As a demonstration, we selectively deposited Ni on the -COOH terminated SAM areas of patterned -COOH/-CH(3) or -COOH/-OH terminated SAMs. Here, Ni(2+) ions form Ni(2+)-carboxylate complexes with the -COOH terminal group, which comprise the nucleation sites for subsequent metal deposition. Second, we demonstrate that nickel is selectively deposited on the -CH(3) terminated SAM areas of a patterned -OH/-CH(3) terminated SAM. In this case, the Ni(2+) ion does not specifically interact with the -CH(3) terminal group. Rather, selectivity is imparted by the interaction of the reductant, dimethylamine borane (DMAB), with the -OH and -CH(3) terminal groups. PMID- 21553832 TI - Fast excited-state deactivation in N(5)-ethyl-4a-hydroxyflavin pseudobase. AB - We present a study of the excited-state behavior of N(5)-ethyl-4a-hydroxyflavin (Et-FlOH), a model compound for bacterial bioluminescence. Using femtosecond pump probe spectroscopy, we found that the Et-FlOH excited state exhibits multiexponential dynamics, with the dominant decay component having a 0.5 ps lifetime. Several possible mechanisms for fast excited-state decay in Et-FlOH were considered: (i) excited-state deprotonation of the -OH proton, (ii) thermal deactivation via (1)n,pi* -> (1)pi,pi* conical intersection, and (iii) excited state release of OH(-) ion. These mechanisms were excluded based on transient absorption studies of two model compounds (N(5)-ethyl-4a-methoxyflavin, Et-FlOMe, and N(5)-ethyl-flavinium ion, Et-Fl(+)) and based on the results of time dependent density functional theory (TD-DFT) calculations of Et-FlOH excited states. Instead, we propose that the fast decay in Et-FlOH is caused by S(1) -> S(0) internal conversion, initiated by the excited-state nitrogen planarization (sp(3) -> sp(2) hybridization change at the N(5)-atom of Et-FlOH S(1) state) coupled with out-of-plane distortion of the pyrimidine moiety of flavin. PMID- 21553833 TI - Combination of Markov state models and kinetic networks for the analysis of molecular dynamics simulations of peptide folding. AB - Atomistic molecular dynamics simulations of the TZ1 beta-hairpin peptide have been carried out using an implicit model for the solvent. The trajectories have been analyzed using a Markov state model defined on the projections along two significant observables and a kinetic network approach. The Markov state model allowed for an unbiased identification of the metastable states of the system, and provided the basis for commitment probability calculations performed on the kinetic network. The kinetic network analysis served to extract the main transition state for folding of the peptide and to validate the results from the Markov state analysis. The combination of the two techniques allowed for a consistent and concise characterization of the dynamics of the peptide. The slowest relaxation process identified is the exchange between variably folded and denatured species, and the second slowest process is the exchange between two different subsets of the denatured state which could not be otherwise identified by simple inspection of the projected trajectory. The third slowest process is the exchange between a fully native and a partially folded intermediate state characterized by a native turn with a proximal backbone H-bond, and frayed side chain packing and termini. The transition state for the main folding reaction is similar to the intermediate state, although a more native like side-chain packing is observed. PMID- 21553834 TI - Conformational and photophysical changes in conjugated polymers exposed to Couette shear. AB - Conjugated polymers in solution exhibit interesting photophysical behavior, which is dictated by their molecular conformation. The conformations and resulting photophysics can be altered by deformational flows such as simple shear. Solutions of poly[2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH PPV) in dimethylformamide (DMF) show large decreases in fluorescence intensity as a function of shear rate, combined with significant spectral shifts upon exposure to shear. The excitation and emission spectra shift toward shorter wavelengths, indicating a change in conformation with shortened conjugated segment lengths attributed to compressive hydrodynamic forces in flow. Addition of poly(methyl methacrylate) to the solutions is shown to alter the fluorescence emission spectral behavior, which we ascribe to energy transfer from the higher energy, short segments to a small population of lower energy conjugated segments. The measured fluorescence changes were not reversible upon cessation of shear, demonstrating that permanent conformational changes are induced by flow. PMID- 21553835 TI - Glass formation and thermodynamics of supercooled monatomic liquids. AB - Atomic mechanism of glass formation of a supercooled simple monatomic liquid with Lennard-Jones-Gauss (LJG) interatomic potential is studied by molecular dynamics (MD) simulation. Supercooled and glassy states are obtained by cooling from the melt. Glassy state obtained at low temperatures is annealed for very long time, on the order of microsecond, and we find that glassy state remains unchanged and that the long-lived glassy state of a simple monatomic system in three dimensions is realized. We analyze the spatiotemporal properties of solid-like and liquid like atoms that are defined by the Lindemann-like freezing criterion. The number of solid-like atoms, distributed throughout the liquid, increases with decreasing temperature toward glass transition and they form clusters. In the deeply supercooled region, almost all solid-like atoms form a single percolation cluster and its characteristic size increases sharply on further cooling. Glass formation in supercooled liquid occurs when a single percolation cluster of solid-like atoms involves a majority of atoms to form a relatively rigid solid phase. We also obtain several physical quantities of the system, including temperature dependence of mass density, Lindemann ratio, incoherent intermediate scattering function, alpha-relaxation time, evolution of radial distribution function, and local bond-pair orders detected by Honeycutt-Andersen analysis. We identify three characteristic temperatures related to the vitrification: a temperature at which crossover from liquid-like to solid-like dynamics occurs on cooling, the glass transition temperature, and the Vogel-Fulcher-Tammann temperature. Behavior of liquid-like atoms in glassy state has been analyzed and discussed. PMID- 21553836 TI - Structural studies and electrical properties of Cs/Al/Te/O phases with the pyrochlore structure. AB - A series of polycrystalline and single crystal cesium aluminum tellurates with the pyrochlore structure have been prepared and characterized. The variations in cell edge for the Cs/Al/Te/O phases range from 10.06 A for the Al rich limit to 10.14 A for the Te rich limit. Rietveld structural analyses based on both X-ray and neutron diffraction data were performed on 5 different compositions. Single crystals of 3 compositions were prepared and studied by X-ray diffraction. The anharmonic component of the thermal motion for Cs was small but became significant on replacing Cs with Rb. A maximum in the electrical conductivity of about 0.1 S/cm is found in the middle of this range close to the ideal composition of CsAl(1/3)Te(5/3)O(6). The conductivity is attributed to filled Te 5s states associated with Te(4+) lying just below the conduction band based on empty Te 5s states associated with Te(6+). The relatively large Te(4+) ion is compressed by the lattice, and as this compression increases the filled 5s states approach the conduction band and thereby increases conductivity. PMID- 21553837 TI - Solvent effect and time-dependent behavior of C-terminus-cysteine-modified cecropin P1 chemically immobilized on a polymer surface. AB - Sum frequency generation (SFG) vibrational spectroscopy has been applied to the investigation of peptide immobilization on a polymer surface as a function of time and peptide conformation. Surface immobilization of biological molecules is important in many applications such as biosensors, antimicrobial materials, biobased fuel cells, nanofabrication, and multifunctional materials. Using C terminus-cysteine-modified cecropin P1 (CP1c) as a model, we investigated the time-dependent immobilization behavior in situ in real time. In addition, potassium phosphate buffer (PB) and mixtures of PB and trifluoroethanol were utilized to examine the effect of peptide secondary structure on CP1c immobilization to polystyrene maleimide (PS-MA). The orientation of immobilized CP1c on PS-MA was determined using polarized SFG spectra. It was found that the peptide solution concentration, solvent composition, and assembly state (monomer vs dimer) prior to immobilization all influence the orientation of CP1c on a PS MA surface. The detailed relationship between the interfacial peptide orientation and these immobilization conditions is discussed. PMID- 21553838 TI - On the mechanism of the palladium-catalyzed tert-butylhydroperoxide-mediated Wacker-type oxidation of alkenes using quinoline-2-oxazoline ligands. AB - The mechanism of the tert-butylhydroperoxide-mediated, Pd(Quinox)-catalyzed Wacker-type oxidation was investigated to evaluate the hypothesis that a selective catalyst-controlled oxidation could be achieved by rendering the palladium coordinatively saturated using a bidentate amine ligand. The unique role of the Quinox ligand framework was probed via systematic ligand modifications. The modified ligands were evaluated through quantitative Hammett analysis, which supports a "push-pull" relationship between the electronically asymmetric quinoline and oxazoline ligand modules. PMID- 21553839 TI - Infrared emission following photolysis of methylisothiocyanate and methylthiocyanate. AB - Methylisothiocyanate (CH(3)NCS) was photolyzed at 193 and 248 nm, and the resulting time-resolved infrared emission was observed. Similar experiments were performed on methylthiocyanate (CH(3)SCN) photolyzed at 193 nm. Previous work suggested that these isomers undergo excited-state isomerization prior to dissociation, but other experiments have contradicted this claim. In the infrared emission experiments, we observed the same products from both starting materials, supporting the theory of excited-state isomerization prior to dissociation. Methylisothiocyanate is the active ingredient in a widely used pesticide and has been observed to form highly toxic methyl isocyanate (CH(3)NCO) under environmental conditions. The mechanism for this formation has been unclear, but must involve some oxygen-containing species. At 248 nm, methylisothiocyanate was photolyzed alone and with three atmospheric oxidizers: O(2), NO, and NO(2). No chemical reaction was observed with O(2), whereas secondary reactions were observed with NO and NO(2). When methylisothiocyanate was photolyzed with NO(2), methyl isocyanate (CH(3)NCO) was observed, suggesting a likely environmental mechanism for methyl isocyanate formation. PMID- 21553840 TI - Completely monodisperse, highly repetitive proteins for bioconjugate capillary electrophoresis: development and characterization. AB - Protein-based polymers are increasingly being used in biomaterial applications because of their ease of customization and potential monodispersity. These advantages make protein polymers excellent candidates for bioanalytical applications. Here we describe improved methods for producing drag-tags for free solution conjugate electrophoresis (FSCE). FSCE utilizes a pure, monodisperse recombinant protein, tethered end-on to a ssDNA molecule, to enable DNA size separation in aqueous buffer. FSCE also provides a highly sensitive method to evaluate the polydispersity of a protein drag-tag and thus its suitability for bioanalytical uses. This method is able to detect slight differences in drag-tag charge or mass. We have devised an improved cloning, expression, and purification strategy that enables us to generate, for the first time, a truly monodisperse 20 kDa protein polymer and a nearly monodisperse 38 kDa protein. These newly produced proteins can be used as drag-tags to enable longer read DNA sequencing by free-solution microchannel electrophoresis. PMID- 21553841 TI - Lung surfactant protein A (SP-A) interactions with model lung surfactant lipids and an SP-B fragment. AB - Surfactant protein A (SP-A) is the most abundant protein component of lung surfactant, a complex mixture of proteins and lipids. SP-A performs host defense activities and modulates the biophysical properties of surfactant in concerted action with surfactant protein B (SP-B). Current models of lung surfactant mechanism generally assume SP-A functions in its octadecameric form. However, one of the findings of this study is that when SP-A is bound to detergent and lipid micelles that mimic lung surfactant phospholipids, it exists predominantly as smaller oligomers, in sharp contrast to the much larger forms observed when alone in water. These investigations were carried out in sodium dodecyl sulfate (SDS), dodecylphosphocholine (DPC), lysomyristoylphosphatidylcholine (LMPC), lysomyristoylphosphatidylglycerol (LMPG), and mixed LMPC + LMPG micelles, using solution and diffusion nuclear magnetic resonance (NMR) spectroscopy. We have also probed SP-A's interaction with Mini-B, a biologically active synthetic fragment of SP-B, in the presence of micelles. Despite variations in Mini-B's own interactions with micelles of different compositions, SP-A is found to interact with Mini-B in all micelle systems and perhaps to undergo a further structural rearrangement upon interacting with Mini-B. The degree of SP-A-Mini-B interaction appears to be dependent on the type of lipid headgroup and is likely mediated through the micelles, rather than direct binding. PMID- 21553842 TI - Seeding atomic layer deposition of high-k dielectrics on epitaxial graphene with organic self-assembled monolayers. AB - The development of high-performance graphene-based nanoelectronics requires the integration of ultrathin and pinhole-free high-k dielectric films with graphene at the wafer scale. Here, we demonstrate that self-assembled monolayers of perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) act as effective organic seeding layers for atomic layer deposition (ALD) of HfO(2) and Al(2)O(3) on epitaxial graphene on SiC(0001). The PTCDA is deposited via sublimation in ultrahigh vacuum and shown to be highly ordered with low defect density by molecular-resolution scanning tunneling microscopy. Whereas identical ALD conditions lead to incomplete and rough dielectric deposition on bare graphene, the chemical functionality provided by the PTCDA seeding layer yields highly uniform and conformal films. The morphology and chemistry of the dielectric films are characterized by atomic force microscopy, ellipsometry, cross-sectional scanning electron microscopy, and X-ray photoelectron spectroscopy, while high resolution X-ray reflectivity measurements indicate that the underlying graphene remains intact following ALD. Using the PTCDA seeding layer, metal-oxide-graphene capacitors fabricated with a 3 nm Al(2)O(3) and 10 nm HfO(2) dielectric stack show high capacitance values of ~700 nF/cm(2) and low leakage currents of ~5 * 10(-9) A/cm(2) at 1 V applied bias. These results demonstrate the viability of sublimated organic self-assembled monolayers as seeding layers for high-k dielectric films in graphene-based nanoelectronics. PMID- 21553843 TI - Opening the gate: framework flexibility in ZIF-8 explored by experiments and simulations. AB - ZIF-8 is a zeolitic imidazole-based metal-organic framework with large cavities interconnected by narrow windows. Because the small size of the windows, it allows in principle for molecular sieving of gases such as H(2) and CH(4). However, the unexpected adsorption of large molecules on ZIF-8 suggests the existence of structural flexibility. ZIF-8 flexibility is explored in this work combining different experimental techniques with molecular simulation. We show that the ZIF-8 structure is modified by gas adsorption uptake in the same way as it is at a very high pressure (i.e., 14,700 bar) due to a swing effect in the imidazolate linkers, giving access to the porosity. Tuning the flexibility, and so the opening of the small windows, has a further impact on the design of advanced molecular sieving membrane materials for gas separation, adjusting the access of fluids to the porous network. PMID- 21553844 TI - Encapsulation of metal cations by the PhePhe ligand: a cation-pi ion cage. AB - Structures and binding thermochemistry are investigated for protonated PhePhe and for complexes of PhePhe with the alkaline-earth ions Ba(2+) and Ca(2+), the alkali-metal ions Li(+), Na(+), K(+), and Cs(+), and the transition-metal ion Ag(+). The two neighboring aromatic side chains open the possibility of a novel encapsulation motif of the metal ion in a double cation-pi configuration, which is found to be realized for the alkaline-earth complexes and, in a variant form, for the Ag(+) complex. Experimentally, complexes are formed by electrospray ionization, trapped in an FT-ICR mass spectrometer, and characterized by infrared multiple photon dissociation (IRMPD) spectroscopy using the free electron laser FELIX. Interpretation is assisted by thermochemical and IR spectral calculations using density functional theory (DFT). The IRMPD spectrum of protonated PhePhe is reproduced with good fidelity by the calculated spectrum of the most stable conformation, although the additional presence of the secondmost stable conformation is not excluded. All metal-ion complexes have charge-solvated binding modes, with zwitterion (salt bridge) forms being much less stable. The amide oxygen always coordinates to the metal ion, as well as at least one phenyl ring (cation-pi interaction). At least one additional chelation site is always occupied, which may be either the amino nitrogen or the carboxy carbonyl oxygen. The alkaline-earth complexes prefer a highly compact caged structure with both phenyl rings providing cation-pi stabilization in a "sandwich" configuration (OORR chelation). The alkali-metal complexes prefer open-cage structures with only one cation-pi interaction, except perhaps Cs(+). The Ag(+) complex shows a unique preference for the closed-cage amino-bound NORR structure. Ligand-driven perturbations of normal-mode frequencies are generally found to correlate linearly with metal-ion binding energy. PMID- 21553845 TI - Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation. AB - Galactooligosaccharides (GOS), prebiotic nondigestible oligosaccharides derived from lactose, have the potential for improving mineral balance and bone properties. This study examined the dose-response effect of GOS supplementation on calcium and magnesium absorption, mineral retention, bone properties, and gut microbiota in growing rats. Seventy-five 4-week-old male Sprague-Dawley rats were randomized into one of five treatment groups (n = 15/group) and fed a diet containing 0, 2, 4, 6, or 8% GOS by weight for 8 weeks. Dietary GOS significantly decreased cecal pH and increased cecal wall weight and content weight in a dose dependent manner (p < 0.0001). Fingerprint patterns of the 16S rRNA gene PCR-DGGE from fecal DNA indicated the variance of bacterial community structure, which was primarily explained by GOS treatments (p = 0.0001). Quantitative PCR of the samples revealed an increase in the relative proportion of bifidobacteria with GOS (p = 0.0001). Net calcium absorption was increased in a dose-response manner (p < 0.01) with GOS supplementation. Dietary GOS also increased (p < 0.02) net magnesium absorption, femur 45Ca uptake, calcium and magnesium retention, and femur and tibia breaking strength. Distal femur total and trabecular volumetric bone mineral density (vBMD) and area and proximal tibia vBMD increased (p < 0.02) with GOS supplementation. Trabecular-rich bones, that is, those that rapidly turn over, were most benefited. Regression modeling showed that GOS benefited calcium and magnesium utilization and vBMD through decreased cecal pH, increased cecal wall and content weight, and increased proportion of bifidobacteria. PMID- 21553846 TI - Shedding light on axial stress effect on resonance frequencies of nanocantilevers. AB - The detection back-action phenomenon has received little attention in physical, chemical, and biological sensors based on nanomechanical systems. We show that this effect is very significant in ultrathin bimetallic cantilevers, in which the laser beam that probes the picometer scale vibration largely modifies the resonant frequencies of the system. The light back-action effect is nonlinear, and some resonant frequencies can even be reduced to a half with laser power intensities of 2 mW. We demonstrate that this effect arises from the stress and strain generated by the laser heating. The experiments are explained by two dimensional nonlinear elasticity theory and supported by finite element simulations. The found phenomenology is intimately connected to the old unsolved problem about the effect of surface stress on the resonance frequency of singly clamped beams. The results indicate that to achieve the ultimate detection limits with nanomechanical resonators one must consider the uncertainty due to the detection back-action. PMID- 21553847 TI - Size- and shape-selective isostructural microporous metal-organic frameworks with different effective aperture sizes. AB - Two isostructural metal-organic frameworks (MOFs) having micropores of the same "static aperture size" but different "effective aperture size" have been prepared using 5-(pyridin-3-ylethynyl)isophthalic acid as a ligand having two different types of functional units, an isophthalate (iph) unit and a pyridyl unit, simultaneously in a single ligand. The combination of iph unit and Cu (or Zn) ion led to two-dimensional layers of Kagome (kgm) net topology, the layers being further pillared by the internal auxiliary pyridyl unit to form a three dimensional microporous framework having two different types of cage-like pores, cage A and cage B, with different aperture sizes and shapes. (1) The MOFs can distinguish the adsorbates (N(2)/Ar) not based on the widely used kinetic diameters of the adsorbates but based on the minimum diameters of the adsorbates, which are more shape dependent. While cage A with a sufficiently large aperture size compared with the size of the adsorbates does not show any size selectivity, cage B with an approximate size match between the adsorbates and the pore apertures shows shape selectivity for the adsorbates. The smaller but spherically shaped Ar atom is not allowed into the pore with the oval-shaped aperture; however, the larger linear N(2) molecule is allowed into the pore with the oval shaped aperture. (2) Even though the two isostructural MOFs have the same static aperture size of cage B, they show different size selectivity for the adsorbates based on the effective aperture size, which reflects the different extents of the framework flexibility. PMID- 21553848 TI - Modulating the photophysical properties of azamacrocyclic europium complexes with charge-transfer antenna chromophores. AB - Two europium complexes with bis(bipyridine) azamacrocyclic ligands featuring pendant arms with or without pi-conjugated donor groups are synthesized and fully characterized by theoretical calculations and NMR spectroscopy. Their photophysical properties, including two-photon absorption, are investigated in water and in various organic solvents. The nonfunctionalized ligand gives highly water-stable europium complexes featuring bright luminescence properties but poor two-photon absorption cross sections. On the other hand, the europium complex with an extended conjugated antenna ligand presents a two-photon absorption cross section of 45 GM at 720 nm but is poorly luminescent in water. A detailed solvent dependent photophysical study indicates that this luminescence quenching is not due to the direct coordination of O-H vibrators to the metal center but to the increase of nonradiative processes in a protic solvent induced by an internal isomerization equilibrium. PMID- 21553849 TI - Infrared and Raman spectroscopic studies of the antimicrobial effects of garlic concentrates and diallyl constituents on foodborne pathogens. AB - The antimicrobial effects of garlic (Allium sativum) extract (25, 50, 75, 100, and 200 MUL/ml) and diallyl sulfide (5, 10, and 20 MUM) on Listeria monocytogenes and Escherichia coli O157:H7 cultivated in tryptic soy broth at 4, 22, and 35 degrees C for up to 7 days were investigated. L. monocytogenes was more resistant to garlic extract and diallyl compounds treatment than E. coli O157:H7. Fourier transform infrared (FT-IR) spectroscopy indicated that diallyl constituents contributed more to the antimicrobial effect than phenolic compounds. This effect was verified by Raman spectroscopy and Raman mapping on single bacteria. Scanning electron microscope (SEM) and transmission electron microscope (TEM) showed cell membrane damage consistent with spectroscopic observation. The degree of bacterial cell injury could be quantified using chemometric methods. PMID- 21553850 TI - Activity of psoralen-functionalized nanoscintillators against cancer cells upon X ray excitation. AB - We report development of a nanoparticle-based, X-ray-activated anticancer "nanodrug" composed of yttrium oxide (Y(2)O(3)) nanoscintillators, a fragment of the HIV-1 TAT peptide, and psoralen. In this formulation, X-ray radiation is absorbed by the Y(2)O(3) nanoscintillators, which then emit UVA light. Absorption of UVA photons by nanoparticle-tethered psoralen has the potential to cross-link adenine and thymine residues in DNA. UVA-induced cross-linking by free psoralen upon activation with UVA light has previously been shown to cause apoptosis in vitro and an immunogenic response in vivo. Studies using the PC-3 human prostate cancer cell line demonstrate that X-ray excitation of these psoralen functionalized Y(2)O(3) nanoscintillators yields concentration-dependent reductions in cell number when compared to control cultures containing psoralen free Y(2)O(3) nanoscintillators. PMID- 21553851 TI - Bovine serum albumin-poly(methyl methacrylate) nanoparticles: an example of frustrated phase separation. AB - A new protein-polymer conjugate made of denatured bovine serum albumin (BSA) covalently bonded to poly(methyl methacrylate) (PMMA) is synthesized by attaching PMMA to acryloylated BSA followed by nanoparticle precipitation. Depending on the BSA to PMMA ratio, these conjugates self-assemble into uniform spherical nanoparticles which show "island" growth on the surface of the nanoparticles. This growth is promoted or retarded by exposing the nanoparticles to different solvents, causing the two components to undergo incipient phase separation. Incipient phase separation of the BSA-PMMA conjugate two-component system was observed in single nanoparticles, resulting in "island" growth on the surface of the nanoparticles. Incipient phase separation of the BSA-PMMA conjugate two component system was observed in single nanoparticles, resulting in "island" growth on the surface of the nanoparticles. PMID- 21553852 TI - Fluoride-rich, hydrofluorothermal routes to functional transition metal (Mn, Fe, Co, Cu) fluorophosphates. AB - Hydrofluorothermal methods are shown to offer a facile route to a very large family of mid-late first row, transition metal fluorophosphates with 50 new compounds identified to date for manganese(III), iron(III), cobalt(II), and copper(II). Reactions of a transition metal fluoride with a phosphate source in a very low-water, high-fluoride content system and in the presence of framework charge balancing metal cations or template molecular cations, lead to materials with structures formed from linked M(O,F)(n) and P(O,F)(n) polyhedra. The structures of these materials, which contain a variety of 1, 2, and 3-dimensional motifs with a level of framework termination dependent upon their fluoride content, show numerous useful characteristics for functionality and applications. The new and unusual features of these fluorophosphate materials include interlayer spaces or channels lined with fluoride ions, metal polyhedra, M(O,F)(n), linked through vertex, edge, or face-sharing, and MU(2), MU(3), and MU(4) bridging fluoride ions. Preliminary characterization of the properties of some of these metal fluorophosphates is reported, including reductive lithium ion insertion, of interest for Li-ion battery positive electrodes, ion exchange reactions, the formation of nanoporous material derivatives through template destruction, and magnetic susceptibility behaviors. PMID- 21553853 TI - Local electronic properties of graphene on a BN substrate via scanning tunneling microscopy. AB - The use of boron nitride (BN) as a substrate for graphene nanodevices has attracted much interest since the recent report that BN greatly improves the mobility of charge carriers in graphene compared to standard SiO(2) substrates. We have explored the local microscopic properties of graphene on a BN substrate using scanning tunneling microscopy. We find that BN substrates result in extraordinarily flat graphene layers that display microscopic Moire patterns arising from the relative orientation of the graphene and BN lattices. Gate dependent dI/dV spectra of graphene on BN exhibit spectroscopic features that are sharper than those obtained for graphene on SiO(2). We observe a significant reduction in local microscopic charge inhomogeneity for graphene on BN compared to graphene on SiO(2). PMID- 21553854 TI - Self-assembly versus directed assembly of nanoparticles via pulsed laser induced dewetting of patterned metal films. AB - A nanoscale, synthetic perturbation was all that was required to nudge a natural, self-assembly process toward significantly higher order. Metallic thin film strips were transformed into nanoparticle arrays by nanosecond, liquid-phase dewetting. Arrays formed according to an evolving Rayleigh-Plateau instability, yet nanoparticle diameter and pitch were poorly controlled. However, by patterning a nanoscale sinusoid onto the original strip edge, a precise nanoparticle diameter and pitch emerged superseding the naturally evolving Rayleigh-Plateau instability. PMID- 21553855 TI - Wildtype and engineered monomeric triosephosphate isomerase from Trypanosoma brucei: partitioning of reaction intermediates in D2O and activation by phosphite dianion. AB - Product yields for the reactions of (R)-glyceraldehyde 3-phosphate (GAP) in D2O at pD 7.9 catalyzed by wildtype triosephosphate isomerase from Trypanosoma brucei brucei (Tbb TIM) and a monomeric variant (monoTIM) of this wildtype enzyme were determined by (1)H NMR spectroscopy and were compared with the yields determined in earlier work for the reactions catalyzed by TIM from rabbit and chicken muscle [O'Donoghue, A. C., Amyes, T. L., and Richard, J. P. (2005), Biochemistry 44, 2610 - 2621]. Three products were observed from the reactions catalyzed by TIM: dihydroxyacetone phosphate (DHAP) from isomerization with intramolecular transfer of hydrogen, d-DHAP from isomerization with incorporation of deuterium from D2O into C-1 of DHAP, and d-GAP from incorporation of deuterium from D2O into C-2 of GAP. The yield of DHAP formed by intramolecular transfer of hydrogen decreases from 49% for the muscle enzymes to 40% for wildtype Tbb TIM to 34% for monoTIM. There is no significant difference in the ratio of the yields of d-DHAP and d-GAP for wildtype TIM from muscle sources and Trypanosoma brucei brucei, but partitioning of the enediolate intermediate of the monoTIM reaction to form d DHAP is less favorable ((k(C1))(D)/(k(C2))(D) = 1.1) than for the wildtype enzyme ((k(C1))(D)/(k(C2))(D) = 1.7). Product yields for the wildtype Tbb TIM and monoTIM-catalyzed reactions of glycolaldehyde labeled with carbon-13 at the carbonyl carbon ([1-(13)C]-GA) at pD 7.0 in the presence of phosphite dianion and in its absence were determined by (1)H NMR spectroscopy [Go, M. K., Amyes, T. L., and Richard, J. P. (2009) Biochemistry 48, 5769-5778]. There is no detectable difference in the yields of the products of wildtype muscle and Tbb TIM-catalyzed reactions of [1-(13)C]-GA in D2O. The kinetic parameters for phosphite dianion activation of the reactions of [1-(13)C]-GA catalyzed by wildtype Tbb TIM are similar to those reported for the enzyme from rabbit muscle [Amyes, T. L. and Richard, J. P. (2007) Biochemistry 46, 5841-5854], but there is no detectable dianion activation of the reaction catalyzed by monoTIM. The engineered disruption of subunit contacts at monoTIM causes movement of the essential side chains of Lys-13 and His-95 away from the catalytic active positions. We suggest that this places an increased demand that the intrinsic binding energy of phosphite dianion be utilized to drive the change in the conformation of monoTIM back to the active structure for wildtype TIM. PMID- 21553856 TI - Thermal conductivity of nanocrystalline silicon: importance of grain size and frequency-dependent mean free paths. AB - The thermal conductivity reduction due to grain boundary scattering is widely interpreted using a scattering length assumed equal to the grain size and independent of the phonon frequency (gray). To assess these assumptions and decouple the contributions of porosity and grain size, five samples of undoped nanocrystalline silicon have been measured with average grain sizes ranging from 550 to 64 nm and porosities from 17% to less than 1%, at temperatures from 310 to 16 K. The samples were prepared using current activated, pressure assisted densification (CAPAD). At low temperature the thermal conductivities of all samples show a T(2) dependence which cannot be explained by any traditional gray model. The measurements are explained over the entire temperature range by a new frequency-dependent model in which the mean free path for grain boundary scattering is inversely proportional to the phonon frequency, which is shown to be consistent with asymptotic analysis of atomistic simulations from the literature. In all cases the recommended boundary scattering length is smaller than the average grain size. These results should prove useful for the integration of nanocrystalline materials in devices such as advanced thermoelectrics. PMID- 21553857 TI - Impact of molecular flexibility on binding strength and self-sorting of chiral pi surfaces. AB - In this work, we have explored for the first time the influence of conformational flexibility of pi-core on chiral self-sorting properties of perylene bisimides (PBIs) that are currently one of the most prominent classes of functional dyes. For this purpose, two series of chiral macrocyclic PBIs 3a-c and 4a-c comprising oligoethylene glycol bridges of different lengths at the 1,7 bay positions were synthesized and their atropo-enantiomers (P and M enantiomers) were resolved. Single crystal analysis of atropo-enantiomerically pure (P)-3a not only confirmed the structural integrity of the ethylene glycol bridged macrocycle but also illustrated the formation of pi-stacked dimers with left-handed supramolecular helicity. Our detailed studies with the series of highly soluble chiral PBIs 4a-c by 1- and 2-D (1)H NMR techniques, and temperature- and concentration-dependent UV/vis absorption and circular dichroism (CD) spectroscopy revealed that in pi-pi stacking dimerization of these PBIs chiral self-recognition (i.e., PP and MM homodimer formation) prevails over self-discrimination (i.e., PM heterodimer formation). Our studies clearly showed that with increasing conformational flexibility of PBI cores imparted by longer bridging units, the binding strength for the dimerization process increases, however, the efficiency for chiral self recognition decreases. These results are rationalized in terms of an induced-fit mechanism facilitating more planarized pi-scaffolds of PBIs containing longer bridging units upon pi-pi-stacking. PMID- 21553858 TI - Comprehensive NO-dependent study of the products of the oxidation of atmospherically relevant aromatic compounds. AB - A comprehensive product study, performed via the turbulent flow chemical ionization mass spectrometry (TF-CIMS) technique, of the primary OH-initiated oxidation of many of the atmospherically abundant aromatic compounds was performed. The bicyclic peroxy radical intermediate, a key proposed intermediate species in the Master Chemical Mechanism (MCM) for the atmospheric oxidation of aromatics, was detected in all cases, as were stable bicyclic species. The NO product yield dependences suggest a potential role for bicyclic peroxy radical + HO(2) reactions at high HO(2)/NO ratios, which are postulated to be a possible source of the inconsistencies between previous environmental chamber results and predictions from the MCM for ozone production and OH reactivity. The TF-CIMS product yield results are also compared to previous environment chamber results and to the latest MCM parametrization. PMID- 21553859 TI - Photoelectron imaging of Ag(-)(H2O)x and AgOH(-)(H2O)y (x=1,2, y=0-4). AB - The photoelectron images of Ag(-)(H(2)O)(x) (x=1,2) and AgOH(-)(H(2)O)(y) (y=0-4) are reported. The Ag(-)(H(2)O)(1,2) anionic complexes have similar characteristics to the other two coinage metal-water complexes that can be characterized as metal atomic anion solvated by water molecules with the electron mainly localized on the metal. The vibrationally well-resolved photoelectron spectrum allows the adiabatic detachment energy (ADE) and vertical detachment energy (VDE) of AgOH(-) to be determined as 1.18(2) and 1.24(2) eV, respectively. The AgOH(-) anion interacts more strongly with water molecules than the Ag(-) anion. The photoelectron spectra of Ag(-)(H(2)O)(x) and AgOH(-)(H(2)O)(y) show a gradual increase in ADE and VDE with increasing x and y due to the solvent stabilization. PMID- 21553860 TI - Total synthesis of (+/-)-aspidophylline A. AB - We report the total synthesis of (+/-)-aspidophylline A, one of many complex furoindoline-containing alkaloids that has not been synthesized previously. Our route features a number of key transformations, including a Heck cyclization to assemble the [3.3.1]-bicyclic scaffold as well as a late-stage interrupted Fischer indolization to install the furoindoline and construct the natural product's pentacyclic framework. PMID- 21553861 TI - Solution blowing of soy protein fibers. AB - Solution blowing of soy protein (sp)/polymer blends was used to form monolithic nanofibers. The monolithic fibers were blown from blends of soy protein and nylon 6 in formic acid. The sp/nylon-6 ratio achieved in dry monolithic nanofibers formed using solution blowing of the blend was equal to 40/60. In addition, solution blowing of core-shell nanofibers was realized with soy protein being in the core and the supporting polymer in the shell. The shells were formed from nylon-6. The sp/nylon-6 ratio achieved in dry core-shell fibers was 32/68. The nanofibers developed in the present work contain significant amounts of soy protein and hold great potential in various applications of nonwovens. PMID- 21553862 TI - Mixed phosphane eta5-CpRuCl(PR3)2 complexes as ambifunctional catalysts for anti Markovnikov hydration of terminal alkynes. AB - The catalytic activity of [CpRu(L)(2)(MeCN)]PF(6) (L = 2 diphenylphosphinopyridine with bulky groups at C-6) for anti-Markovnikov hydration of terminal alkynes to aldehydes is retained when one heterocyclic ligand L is replaced by L' = PPh(3). Equal amounts of CpRuCl(PPh(3))(2) (1) and phosphane L in acetone solution equilibrate to a mixture of 1, CpRuCl(L)(PPh(3)) (2), and CpRuCl(L)(2) (3), which acts as highly active in situ catalyst for preparative anti-Markovnikov hydration of alkynes in water-rich media (2 mol % [Ru], 60 degrees C, 3-18 h in 4:1 (v/v) acetone/water). Reactions were completed in <15 min at 160 degrees C. PMID- 21553864 TI - Gas sensing with Au-decorated carbon nanotubes. AB - The sensing properties of carbon nanotubes (CNTs) decorated with gold nanoparticles have been investigated by means of combined theoretical and experimental approaches. On one hand, first-principles and nonequilibrium Green's functions techniques give access to the microscopic features of the sensing mechanisms in individual nanotubes, such as electronic charge transfers and quantum conductances. On the other hand, drop coating deposition of carbon nanotubes decorated with gold nanoparticles onto sensor substrates and their characterization in the detection of pollutants such as NO(2), CO, and C(6)H(6) provide insight into the sensing ability of nanotube mats. Using the present combined approaches, the improvement in the detection of some specific gases (NO(2) and CO) using Au-functionalized nanotubes is explained. However, for other gases such as C(6)H(6), the Au nanoparticles do not seem to play a crucial role in the sensing process when compared with pristine CNTs functionalized with oxygen plasma. Indeed, these different situations can be explained by identifying the relationship between the change of resistance (macroscopic feature) and the shift of the Fermi level (microscopic feature) after gas adsorption. The understanding of the sensing ability at the atomic level opens the way to design new gas sensors and to tune their selectivity by predicting the nature of the metal that is the most appropriate to detect specific molecular species. PMID- 21553863 TI - Protein database and quantitative analysis considerations when integrating genetics and proteomics to compare mouse strains. AB - Decades of genetics research comparing mouse strains has identified many regions of the genome associated with quantitative traits. Microarrays have been used to identify which genes in those regions are differentially expressed and are therefore potentially causal; however, genetic variants that affect probe hybridization lead to many false conclusions. Here we used spectral counting to compare brain striata between two mouse strains. Using strain-specific protein databases, we concluded that proteomics was more robust to sequence differences than microarrays; however, some proteins were still significantly affected. To generate strain-specific databases, we used a complete database that contained all of the putative genetic isoforms for each protein. While the increased proteome coverage in the databases led to a 6.8% gain in peptide assignments compared to a nonredundant database, it also necessitated the development of a strategy for grouping similar proteins due to a large number of shared peptides. Of the 4563 identified proteins (2.1% FDR), there were 1807 quantifiable proteins/groups that exceeded minimum count cutoffs. With four pooled biological replicates per strain, we used quantile normalization, ComBat (a package that adjusts for batch effects), and edgeR (a package for differential expression analysis of count data) to identify 101 differentially expressed proteins/groups, 84 of which had a coding region within one of the genomic regions of interest identified by the Portland Alcohol Research Center. PMID- 21553865 TI - Institutional disposition and management of end-of-life electronics. AB - Institutions both public and private face a challenge to develop policies to manage purchase, use, and disposal of electronics. Environmental considerations play an increasing role in addition to traditional factors of cost, performance and security. Characterizing current disposition practices for end-of-life electronics is a key step in developing policies that prevent negative environmental and health impacts while maximizing potential for positive social and economic benefits though reuse. To provide a baseline, we develop the first characterization of quantity, value, disposition, and flows of end-of-life electronics at a major U.S. educational institution. Results of the empirical study indicate that most end-of-first-life electronics were resold through public auction to individuals and small companies who refurbish working equipment for resale or sell unusable products for reclamation of scrap metal. Desktop and laptop computers sold for refurbishing and resale averaged U.S. $20-100 per unit, with computers sold directly to individuals for reuse reaching $250-350 per unit. This detailed assessment was coupled with a benchmarking survey of end-of-life electronics management practices at other U.S. universities. Survey results indicate that while auctions are still commonplace, an increasing number of institutions are responding to environmental concerns by creating partnerships with local recycling and resale entities and mandating domestic recycling. We use the analyses of current disposition practices as input to discuss institutional strategies for managing electronics. One key issue is the tension between benefits of used equipment sales, in terms of income for the institution and increased reuse for society, and the environmental risks because of unknown downstream practices. PMID- 21553866 TI - Acute and chronic toxicity effects of silver nanoparticles (NPs) on Drosophila melanogaster. AB - The use of nanoscaled materials is rapidly increasing, however, their possible ecotoxicological effects are still not precisely known. This work constitutes the first complex study focused on in vivo evaluation of the acute and chronic toxic effects and toxic limits of silver nanoparticles (NPs) on the eukaryotic organism Drosophila melanogaster. For the purpose of this study, silver NPs were prepared in the form of solid dispersion using microencapsulation method, where mannitol was used as an encapsulation agent. This newly prepared solid dispersion with a high concentration of silver NPs was exploited to prepare the standard Drosophila culture medium at a silver concentration range from 10 mg.L(-1) to 100 mg.L(-1) of Ag in the case of the acute toxicity testing and at a concentration equal to 5 mg.L(-1) in the case of the chronic toxicity testing. The acute toxic effect of silver NPs on Drosophila melanogaster was observed for the silver concentration equal to 20 mg.L(-1). At this silver concentration, 50% of the tested flies were unable to leave the pupae, and they did not finish their developmental cycle. Chronic toxicity of silver NPs was assessed by a long-term exposure of overall eight filial generations of Drosophila melanogaster to silver NPs. The long-term exposure to silver NPs influenced the fertility of Drosophila during the first three filial generations, nevertheless the fecundity of flies in subsequent generations consequently increased up to the level of the flies from the control sample due to the adaptability of flies to the silver NPs exposure. PMID- 21553867 TI - A device for gated autosynchronous luminescence detection. AB - The sensitive detection of delayed luminescence (tau > 100 MUs) can be achieved with an optomechanical instrument, the gated autosynchronous luminescence detector (GALD). The device effectively combines an excitation chopper, a detection chopper, and a dichroic mirror into a single element. With dimensions of 12 mm (H), 32 mm (W), and 90 mm (L), it is designed for insertion into the differential interference contrast (DIC) prism slot of a BX51 Olympus microscope. The GALD described here employed a compact high-power UV LED as the excitation source to capture images of Giardia lamblia cysts indirectly labeled with a europium chelate/streptavidin conjugate. Labeled cells were clearly visible in the complete absence of autofluorescence and signal intensity was sufficient to capture high-resolution color images within several seconds. Shorter exposure intervals of 100 ms on a monochrome Andor iXON camera delivered time-gated luminescence images with a signal-to-noise ratio better than 114:1. PMID- 21553868 TI - Borane-mediated silylation of a metal-oxo ligand. AB - The addition of 1 equiv of HSiPh(3) to UO(2)((Ar)acnac)(2) ((Ar)acnac = ArNC(Ph)CHC(Ph)O; Ar = 3,5-(t)Bu(2)C(6)H(3)), in the presence of 1 equiv of B(C(6)F(5))(3), results in the formation of U(OSiPh(3))(OB{C(6)F(5)}(3))((Ar)acnac)(2) (1), via silylation of an oxo ligand and reduction of the uranium center. The addition of 1 equiv of Cp(2)Co to 1 results in a reduction to uranium(IV) and the formation of [Cp(2)Co][U(OSiPh(3))(OB{C(6)F(5)}(3))((Ar)acnac)(2)] (2) in 78% yield. Complexes 1 and 2 have been characterized by X-ray crystallography, while the solution phase redox properties of 1 have been measured with cyclic voltammetry. PMID- 21553869 TI - Rare-earth-doped bifunctional alkaline-earth metal fluoride nanocrystals via a facile microwave-assisted process. AB - Rare-earth-doped magnetic-optic bifunctional alkaline-earth metal fluoride nanocrystals have been successfully synthesized via a facile microwave-assisted process. The as-prepared nanocrystals were monodisperse and could form stable colloidal solutions in polar solvents, such as water and ethanol. They show bright-green fluorescence emisson. Furthermore, Gd(3+)-doped ones exhibit paramagnetic behavior at room temperature and superparamagnetic behavior at 2 K. PMID- 21553870 TI - Modeling energy landscapes of proton motion in nonaqueous, tethered proton wires. AB - We have modeled structures and energetics of anhydrous proton-conducting wires: tethered hydrogen-bonded chains of the form ...HX...HX...HX..., with functional groups HX = imidazole, triazole, and formamidine; formic, sulfonic, and phosphonic acids. We have applied density functional theory (DFT) to model proton wires up to 19 units long, where each proton carrier is linked to an effective backbone to mimic polymer tethering. This approach allows the direct calculation of hydrogen bond strengths. The proton wires were found to be stabilized by strong hydrogen bonds (up to 50 kJ/mol) whose strength correlates with the proton affinity of HX [related to pK(b)(HX)] and not to pK(a)(HX) as is often assumed. Geometry optimizations and ab initio molecular dynamics near 400 K on imidazole based proton wires both predict that adding a proton to the end of such wires causes the excess charge to embed into the interior segments of these wires. Proton translocation energy landscapes for imidazole-based wires are sensitive to the imidazole attachment point (head or feet) and to wire architecture (linear or interdigitated). Linear imidazole wires with head-attachment exhibit low barriers for intrawire proton motion, rivaling proton diffusion in liquid imidazole. Excess charge relaxation from the edge of wires is found to be dominated by long range Grotthuss shuttling for distances as long as 42 A, especially for interdigitated wires. For imidazole, we predict that proton translocation is controlled by the energetics of desorption from the proton wire, even for relatively long wires (600 imidazole units). Proton desorption energies show no correlation with functional group properties, suggesting that proton desorption is a collective process in proton wires. PMID- 21553872 TI - Rapid detection of a cocaine-binding aptamer using biological nanopores on a chip. AB - This paper describes a methodology for the rapid and highly selective detection of cocaine using a membrane protein channel combined with a DNA aptamer. The DNA aptamer recognizes the cocaine molecule with high selectivity. We successfully detected a low concentration of cocaine (300 ng/mL, the drug test cutoff limit) within 60 s using a biological nanopore embedded in a microchip. PMID- 21553871 TI - Conformational and aggregation properties of a PEGylated alanine-rich polypeptide. AB - The conformational and aggregation behavior of PEG conjugates of an alanine-rich polypeptide (PEG-c17H6) were investigated and compared to that of the polypeptide equipped with a deca-histidine tag (17H6). These polypeptides serve as simple and stimuli-responsive models for the aggregation behavior of helix-rich proteins, as our previous studies have shown that the helical 17H6 self-associates at acidic pH and converts to beta-sheet structures at elevated temperature under acidic conditions. In the work here, we show that PEG-c17H6 also adopts a helical structure at ambient/subambient temperatures, at both neutral and acidic pH. The thermal denaturation behavior of 17H6 and PEG-c17H6 is similar at neutral pH, where the alanine-rich domain has no self-association tendency. At acidic pH and elevated temperature, however, PEGylation slows beta-sheet formation of c17H6, and reduces the apparent cooperativity of thermally induced unfolding. Transmission electron microscopy of PEG-c17H6 conjugates incubated at elevated temperatures showed fibrils with widths of ~20-30 nm, wider than those observed for fibrils of 17H6. These results suggest that PEGylation reduces beta-sheet aggregation in these polypeptides by interfering, only after unfolding of the native helical structure, with interprotein conformational changes needed to form beta-sheet aggregates. PMID- 21553873 TI - Spectra and integrated band intensities of the low order OH stretching overtones in peroxyformic acid: an atmospheric molecule with prototypical intramolecular hydrogen bonding. AB - The gas phase spectra of several vibrational bands of peroxyformic acid (PFA), an atmospheric molecule exhibiting intramolecular hydrogen bonding, are presented. In the fundamental region, Fourier transform infrared (FT-IR) spectroscopy is used to probe the C-O, O-H and C-H stretching vibrations, while in the region of the first and second OH-stretching overtones (2nu(OH) and 3nu(OH)) photoacoustic spectroscopy is used. Integrated absorption cross sections for the PFA vibrational bands are determined by comparing their respective peak areas with that for the OH-stretching bands of n-propanol for which the absorption cross section is known. The measured integrated intensities of the OH stretching bands are then compared with a local mode model using a one-dimensional dipole moment function in conjunction with the OH stretching potential computed at both the MP2/aug-cc-pVDZ and CCSD(T)/aug-cc-pVDZ levels. The data allow us to investigate changes in the OH stretch band position and intensity as a function of overtone order arising from the influence of hydrogen bonding. Furthermore, calculations at the MP2/aug-cc-pVDZ level show that there are three stable conformers of PFA with relative energies of 0, 13.54, and 13.76 kJ/mol, respectively. In the room temperature spectra, however, we see evidence for transitions from only the lowest energy conformer. The geometrical parameters and vibrational frequencies of the most stable conformer are presented. PMID- 21553874 TI - Neutron reflectometry and QCM-D study of the interaction of cellulases with films of amorphous cellulose. AB - Improving the efficiency of enzymatic hydrolysis of cellulose is one of the key technological hurdles to reduce the cost of producing ethanol and other transportation fuels from lignocellulosic material. A better understanding of how soluble enzymes interact with insoluble cellulose will aid in the design of more efficient enzyme systems. We report a study involving neutron reflectometry (NR) and quartz crystal microbalance with dissipation monitoring (QCM-D) of the interaction of a fungal enzyme extract ( T. viride ) and an endoglucanse from A. niger with amorphous cellulose films. The use of amorphous cellulose is motivated by that the fact that several biomass pretreatments currently under investigation disrupt the native crystalline structure of cellulose and increase the amorphous content. NR reveals the profile of water through the film at nanometer resolution and is highly sensitive to interfacial roughness, whereas QCM-D provides changes in mass and film stiffness. NR can be performed using either H(2)O- or D(2)O based aqueous reservoirs. NR measurement of swelling of a cellulose film in D(2)O and in H(2)O revealed that D/H exchange on the cellulose chains must be taken into account when a D(2)O-based reservoir is used. The results also show that cellulose films swell slightly more in D(2)O than in H(2)O. Regarding enzymatic digestion, at 20 degrees C in H(2)O buffer the T. viride cocktail rapidly digested the entire film, initially roughening the surface, followed by penetration and activity throughout the bulk of the film. In contrast, over the same time period, the endoglucanase was active mainly at the surface of the film and did not increase the surface roughness. PMID- 21553875 TI - Synthesis and catalytic properties of nanoparticulate intermetallic Ga-Pd compounds. AB - A two-step synthesis for the preparation of single-phase and nanoparticulate GaPd and GaPd(2) by coreduction of ionic metal-precursors with LiHBEt(3) in THF without additional stabilizers is described. The coreduction leads initially to the formation of Pd nanoparticles followed by a Pd-mediated reduction of Ga(3+) on their surfaces, requiring an additional annealing step. The majority of the intermetallic particles have diameters of 3 and 7 nm for GaPd and GaPd(2), respectively, and unexpected narrow size distributions as determined by disk centrifuge measurements. The nanoparticles have been characterized by XRD, TEM, and chemical analysis to ensure the formation of the intermetallic compounds. Unsupported nanoparticles possess high catalytic activity while maintaining the excellent selectivity of the ground bulk materials in the semihydrogenation of acetylene. The activity could be further increased by depositing the particles on alpha-Al(2)O(3). PMID- 21553876 TI - Combination anti-HIV therapy with the self-assemblies of an asymmetric bolaamphiphilic zidovudine/didanosine prodrug. AB - Combination anti-HIV therapy is important for AIDS treatment. A bolaamphiphilic prodrug, zidovudine-phosphoryl-deoxycholyl didanosine (ZPDD), was synthesized, combining zidovudine (AZT) and didanosine (ddI) in one molecule. As one lipid derivative of nucleosides, ZPDD showed special solubility with free soluble in chloroform and tetrahydrofuran but was slightly soluble in cyclohexane. The amphiphilicity of ZPDD was shown according to the monolayers at the air-water interface. ZPDD self-assembled to the spherical vesicles in water with 174 nm in size and -31.3 mV of zeta potential. The stability of assemblies depended on pH because the phosphoryl zidovudine group could release hydrogen ions. ZPDD was rapidly degraded to AZT in the plasma and tissues of mice. ZPDD self-assemblies had high anti-HIV activity in vitro with the half effective concentration (EC50) of 5 nM. ZPDD self-assemblies may be targeting macrophages since ZPDD was found in macrophage-rich tissues in vivo and rapidly released AZT in the targeted tissues after intravenous administration to mice. The bioavailability of ZPDD was 90.5% and 30.8% for the intraperitoneal and oral administrations compared with the venous route. The self-assemblies of bolaamphiphilic prodrugs could simultaneously deliver two types of drugs to targeted tissues and would become a promising nanomedicine. PMID- 21553877 TI - Reduction of uranium(VI) by soluble iron(II) conforms with thermodynamic predictions. AB - Soluble Fe(II) can reduce soluble U(VI) at rapid rates and in accordance with thermodynamic predictions. This was established by initially creating acidic aqueous solutions in which the sole oxidants were soluble U(VI) species and the sole reductants were soluble Fe(II) species. The pH of the solution was then increased by stepwise addition of OH(-), thereby increasing the potential for electron transfer from Fe(II) to U(VI). For each new pH value resulting from addition of base, values of DeltaG for the Fe(II)-mediated reduction of U(VI) were calculated using the computed distribution of U and Fe species and possible half reaction combinations. For initial conditions of pH 2.4 and a molar ratio of Fe(II) to U(VI) of 5:1 (1 mM Fe(II) and 0.2 mM U(VI)), DeltaG for U(VI) reduction was greater than zero, and U(VI) reduction was not observed. When sufficient OH( ) was added to exceed the computed equilibrium pH of 5.4, DeltaG for U(VI) reduction was negative and soluble Fe(II) species reacted with U(VI) in a molar ratio of ~2:1. X-ray absorption near-edge structure (XANES) spectroscopy confirmed production of U(IV). A decrease in pH confirmed production of acidity as the reaction advanced. As solution pH decreased to the equilibrium value, the rate of reaction declined, stopping completely at the predicted equilibrium pH. Initiation of the reaction at a higher pH resulted in a higher final ratio of U(IV) to U(VI) at equilibrium. PMID- 21553878 TI - Nickel-catalyzed Kumada cross-coupling reactions of tertiary alkylmagnesium halides and aryl bromides/triflates. AB - We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component. PMID- 21553879 TI - Highly efficient CdS quantum dot-sensitized solar cells based on a modified polysulfide electrolyte. AB - A modified polysulfide redox couple, [(CH(3))(4)N](2)S/[(CH(3))(4)N](2)S(n), in an organic solvent (3-methoxypropionitrile) was employed in CdS quantum dot (QD) sensitized solar cells (QDSSCs), and an unprecedented energy conversion efficiency of up to 3.2% was obtained under AM 1.5 G illumination. The QDs were linked to nanoporous TiO(2) via covalent bonds by using thioglycolic acid, and chemical bath deposition in an organic solvent was then used to prepare the QDSSCs, facilitating high wettability and superior penetration capability of the TiO(2) films. A very high fill factor of 0.89 was observed with the optimized QDSSCs. PMID- 21553880 TI - Magnetic anisotropy in a heavy atom radical ferromagnet. AB - High-field, single-crystal EPR spectroscopy on a tetragonal bisdiselenazolyl ferromagnet has provided evidence for the presence of easy-axis magnetic anisotropy, with the crystallographic c axis as the easy axis and the ab plane as the hard plane. The observation of a zero-field gap in the resonance frequency is interpreted in terms of an anisotropy field several orders of magnitude larger than that observed in light-heteroatom, nonmetallic ferromagnets and comparable (on a per-site basis) to that observed in hexagonal close packed cobalt. The results indicate that large spin-orbit-induced magnetic anisotropies, typically associated with 3d-orbital-based ferromagnets, can also be found in heavy p-block radicals, suggesting that there may be major opportunities for the development of heavy p-block organic magnetic materials. PMID- 21553881 TI - Inverse design and synthesis of acac-coumarin anchors for robust TiO2 sensitization. AB - An inverse design methodology suitable to assist the synthesis and optimization of molecular sensitizers for dye-sensitized solar cells is introduced. The method searches for molecular adsorbates with suitable photoabsorption properties through continuous optimization of "alchemical" structures in the vicinity of a reference molecular framework. The approach is illustrated as applied to the design and optimization of linker chromophores for TiO(2) sensitization, using the recently developed phenyl-acetylacetonate (i.e., phenyl-acac) anchor [McNamara et al. J. Am. Chem. Soc.2008, 130, 14329-14338] as a reference framework. A novel anchor (3-acac-pyran-2-one) is found to be a local optimum, with improved sensitization properties when compared to phenyl-acac. Its molecular structure is related to known coumarin dyes that could be used as lead chromophore anchors for practical applications in dye-sensitized solar cells. Synthesis and spectroscopic characterization confirms that the linker provides robust attachment to TiO(2), even in aqueous conditions, yielding improved sensitization to solar light and ultrafast interfacial electron injection. The findings are particularly relevant to the design of sensitizers for dye sensitized solar cells because of the wide variety of structures that are possible but they should be equally useful for other applications such as ligand design for homogeneous catalysis. PMID- 21553882 TI - Surface-directed structure formation of beta-lactoglobulin inside droplets. AB - The morphology of beta-lactoglobulin structures inside droplets was studied during aggregation and gelation using confocal laser scanning microscopy (CLSM) equipped with a temperature stage and transmission electron microscopy (TEM). The results showed that there is a strong driving force for the protein to move to the interface between oil and water in the droplet, and the beta-lactoglobulin formed a dense shell around the droplet built up from the inside of the droplets. Less protein was found inside the droplets. The longer the beta-lactoglobulin was allowed to aggregate prior to gel formation, the larger the part of the protein went to the interface, resulting in a thicker shell and very little material being left inside the droplets. The droplets were easily deformed because no network stabilizes them. When 0.5% emulsifier, polyglycerol polyresinoleat (PGPR), was added to the oil phase, the beta-lactoglobulin was situated both inside the droplets and at the interface between the droplets and the oil phase; when 2% PGPR was added, the beta-lactoglobulin structure was concentrated to the inside of the droplets. The possibility to use the different morphological structures of beta-lactoglobulin in droplets to control the diffusion rate through a beta-lactoglobulin network was evaluated by fluorescence recovery after photobleaching (FRAP). The results show differences in the diffusion rate due to heterogeneities in the structure: the diffusion of a large water-soluble molecule, FITC-dextran, in a dense particulate gel was 1/4 of the diffusion rate in a more open particulate beta-lactoglobulin gel in which the diffusion rate was similar to that in pure water. PMID- 21553883 TI - Ultrasensitive and selective electrochemical identification of hepatitis C virus genotype 1b based on specific endonuclease combined with gold nanoparticles signal amplification. AB - This work proposes a new strategy for the electrochemical detection of hepatitis C virus (HCV) RNA level and identification of HCV-1b genotype based on the site specific cleavage of BamHI endonuclease combined with gold nanoparticles (AuNPs) signal amplification. The assay procedures include the reverse transcription, polymerase chain reaction (PCR) amplification, and electrochemical detection. The samples of 244 mer sequence of HCV RNA from the highly conserved region of HCV 1a, HCV-1b, HCV-1, and HCV-6a, respectively, were first reverse transcribed into complementary cDNA and amplified by PCR. The PCR-amplified samples were then analyzed using a synthetic 21 mer DNA probe, which has been assembled on the electrode surface via a bifunctional molecule of p-aminobenzoic acid (ABA). The results demonstrated that the developed approach can be used for specifically identification of the HCV-1b genotype and selective and sensitive detection of HCV-1b cDNA (244 mer) with a detection limit as low as (3.1 +/- 0.8) * 10(-22) M (less than 200 molecules; the concentration refers to the one before PCR amplification). Moreover, the developed method has an ability to discriminate the HCV-1b cDNA sequence from even single-base mismatched DNA sequence, to assay the HCV-1b cDNA level precisely from the mixture of HCV-1, HCV-1b, HCV-1a, and HCV 6a, and to detect HCV in real clinical samples. The protocol has high potential application in molecular diagnostics of HCV in clinical environments. PMID- 21553884 TI - Aptamer-conjugated nanobubbles for targeted ultrasound molecular imaging. AB - Targeted ultrasound contrast agents can be prepared by some specific bioconjugation techniques. The biotin-avidin complex is an extremely useful noncovalent binding system, but the system might induce immunogenic side effects in human bodies. Previous proposed covalently conjugated systems suffered from low conjugation efficiency and complex procedures. In this study, we propose a covalently conjugated nanobubble coupling with nucleic acid ligands, aptamers, for providing a higher specific affinity for ultrasound targeting studies. The sgc8c aptamer was linked with nanobubbles through thiol-maleimide coupling chemistry for specific targeting to CCRF-CEM cells. Further improvements to reduce the required time and avoid the degradation of nanobubbles during conjugation procedures were also made. Several investigations were used to discuss the performance and consistency of the prepared nanobubbles, such as size distribution, conjugation efficiency analysis, and flow cytometry assay. Further, we applied our conjugated nanobubbles to ex vivo ultrasound targeted imaging and compared the resulting images with optical images. The results indicated the availability of aptamer-conjugated nanobubbles in targeted ultrasound imaging and the practicability of using a highly sensitive ultrasound system in noninvasive biological research. PMID- 21553885 TI - Controlled growth of well-aligned GaS nanohornlike structures and their field emission properties. AB - Here, we report the synthesis of vertically aligned gallium sulfide (GaS) nanohorn arrays using simple vapor-liquid-solid (VLS) method. The morphologies of GaS nano and microstructures are tuned by controlling the temperature and position of the substrate with respect to the source material. A plausible mechanism for the controlled growth has been proposed. It is important to note that the turn-on field value of GaS nanohorns array is found to be the low turn on field 4.2 V/MUm having current density of 0.1 MUA/cm(2). The striking feature of the field emission behavior of the GaS nanohorn arrays is that the average emission current remains nearly constant over long time without any degradation. PMID- 21553886 TI - Formation of a donor-stabilized tetrasilacyclobutadiene dication by a Lewis acid assisted reaction of an N-heterocyclic chloro silylene. AB - The first donor-stabilized tetrasilacyclobutadiene dication species has been synthesized and fully characterized. Its unexpected formation occurs by the Lewis acid assisted reaction of the N-heterocyclic chloro silylene [L(Si:)Cl] (L = PhC(NtBu)(2); amidinate) with Cp*ZrCl(3) (Cp* = pentamethylcyclopentadienyl) in the molar ratio of 3:2. Remarkably, the four-membered Si(4) core consists of two N-donor stabilized silylium subunits and two silylene-like moieties. The dicationic charge is somewhat delocalized on the Si(4) core, which is supported by DFT calculations. PMID- 21553887 TI - Fiber-like TiO2 nanomaterials with different crystallinity phases fabricated via a green pathway. AB - Fiber-like TiO(2) nanomaterials were designed and created, for the first time, by in situ synthesis of TiO(2) nanoparticles in regenerated cellulose fibers in the wet state, followed by calcination at 400-800 degrees C to remove the cellulose matrix. The cellulose fibers were prepared in an NaOH/urea aqueous system with cooling via an industrial machine. The structure and properties of the fiber-like TiO(2) nanomaterials were characterized with scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and photocatalytic degradation tests. The results revealed that the mean diameter of the fiber-like TiO(2) nanomaterials, which consisted of TiO(2) nanoparticles with a mean size from 21 to 37 nm, was 7-8 MUm. The TiO(2) nanomaterials exhibited different crystallinity phases from anatase to rutile, depending on the calcinating temperature. With a decrease in the calcinating temperature from 800 to 400 degrees C, the surface area of the TiO(2) nanomaterials increased. The photocatalytic activity for the degradation of methyl orange of the anatase T-400 fibers calcined at 400 degrees C was the highest, compared with that at 600 and 800 degrees C. This work provided a simple and "green" pathway for the preparation of inorganic nanomaterials with different crystal structures by using porous regenerated cellulose matrix. PMID- 21553888 TI - Desymmetrizing asymmetric ring expansion of cyclohexanones with alpha diazoacetates catalyzed by chiral aluminum Lewis acid. AB - Chiral aluminum Lewis acid catalyst composed of Me(3)Al and 3,3' bis(trimethylsilyl)-BINOL in a 2:1 ratio was found to promote novel catalytic asymmetric ring expansion of cyclohexanone with alpha-substituted alpha diazoacetates to give seven-membered rings with an all-carbon quaternary center. Application of this strategy to 4-substituted cyclohexanones opened up a novel way for the catalytic desymmetrizing asymmetric construction of cycloheptanones bearing remote alpha,delta-chiral centers. PMID- 21553889 TI - Enantiomeric segregation in the gel phase of lipid bilayers. AB - Enantiospecific interactions within a monoglyceride lipid bilayer are investigated using molecular dynamics simulations. Preferential homochiral interactions are observed in the gel phase, whereas no detectable enantiospecificity is seen in the liquid-crystal phase. On the basis of these results and available experimental data, a mechanism is proposed for the formation of the coagel phase of monoglycerides. Enantiomeric segregation in the gel phase is also discussed in terms of its possible implications for prebiological evolution and membrane raft function. PMID- 21553890 TI - Frontier residues lining globin internal cavities present specific mechanical properties. AB - The internal cavity matrix of globins plays a key role in their biological function. Previous studies have already highlighted the plasticity of this inner network, which can fluctuate with the proteins breathing motion, and the importance of a few key residues for the regulation of ligand diffusion within the protein. In this Article, we combine all-atom molecular dynamics and coarse grain Brownian dynamics to establish a complete mechanical landscape for six different globins chain (myoglobin, neuroglobin, cytoglobin, truncated hemoglobin, and chains alpha and beta of hemoglobin). We show that the rigidity profiles of these proteins can fluctuate along time, and how a limited set of residues present specific mechanical properties that are related to their position at the frontier between internal cavities. Eventually, we postulate the existence of conserved positions within the globin fold, which form a mechanical nucleus located at the center of the cavity network, and whose constituent residues are essential for controlling ligand migration in globins. PMID- 21553891 TI - Effect of sensitizer adsorption temperature on the performance of dye-sensitized solar cells. AB - Employing a mesoscopic titania photoanode whose bilayer structure was judiciously selected to fit the optoelectronic characteristics of the Ru-based heteroleptic complex Na-cis-Ru(4,4'-(5-hexyltiophen-2-yl)-2,2'-bipyridine)(4-carboxylic-acid 4'-carboxylate-2,2'-bipyridine)(thiocyanate)(2), coded as C101, we investigated the effect of temperature for dye adsorption on the photovoltaic performance of dye-sensitized solar cells (DSCs). We found a significant efficiency enhancement upon lowering the temperature applied during the sensitizer uptake from solution. When the dye adsorption was performed at 4 degrees C, the photovoltaic performance parameters measured under standard reporting conditions (AM1.5 G sunlight at 1000 W/m(2) intensity and 25 degrees C), i.e., the open circuit voltage (V(oc)), the short circuit photocurrent density (J(sc)), the fill factor (FF), and consequently the power conversion efficiency (PCE), improved in comparison to cells stained at 20 and 60 degrees C. Results from electrochemical impedance spectroscopy (EIS) and attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) show that the self-assembled layer of C101 formed at lower temperature impairs the back-electron transfer from the TiO(2) conduction band to the triiodide ions in the electrolyte more strongly than the film produced at 60 degrees C. Profiting from the favorable influence that the low-temperature dye uptake exerts on photovoltaic performance, we have realized DSCs showing a power conversion efficiency of 11.5%. PMID- 21553892 TI - Synthesis of carbohydrates in mineral-guided prebiotic cycles. AB - One present obstacle to the "RNA-first" model for the origin of life is an inability to generate reasonable "hands off" scenarios for the formation of carbohydrates under conditions where they might have survived for reasonable times once formed. Such scenarios would be especially compelling if they deliver pent(ul)oses, five-carbon sugars found in terran genetics, and exclude other carbohydrates (e.g., aldotetroses) that may also be able to function in genetic systems. Here, we provide detailed chemical analyses of carbohydrate premetabolism, showing how borate, molybdate, and calcium minerals guide the formation of tetroses (C(4)H(8)O(4)), heptoses (C(7)H(14)O(7)), and pentoses (C(5)H(10)O(5)), including the ribose found in RNA, in "hands off" experiments, starting with formaldehyde and glycolaldehyde. These results show that pent(ul)oses would almost certainly have formed as stable borate complexes on the surface of an early Earth beneath a humid CO(2) atmosphere suffering electrical discharge. While aldotetroses form extremely stable complexes with borate, they are not accessible by pathways plausible under the most likely early Earth scenarios. The stabilization by borate is not, however, absolute. Over longer times, material is expected to have passed from borate-bound pent(ul)oses to a branched heptulose, which is susceptible to Cannizzaro reduction to give dead end products. We show how this fate might be avoided using molybdate-catalyzed rearrangement of a branched pentose that is central to borate-moderated cycles that fix carbon from formaldehyde. Our emerging understanding of the nature of the early Earth, including the presence of hydrated rocks undergoing subduction to form felsic magmas in the early Hadean eon, may have made borate and molydate species available to prebiotic chemistry, despite the overall "reduced" state of the planet. PMID- 21553893 TI - Aromatic aldehyde and hydrazine activated peptide coated quantum dots for easy bioconjugation and live cell imaging. AB - We present a robust scheme for preparation of semiconductor quantum dots (QDs) and cognate partners in a conjugation ready format. Our approach is based on bis aryl hydrazone bond formation mediated by aromatic aldehyde and hydrazinonicotinate acetone hydrazone (HyNic) activated peptide coated quantum dots. We demonstrate controlled preparation of antibody--QD bioconjugates for specific targeting of endogenous epidermal growth factor receptors in breast cancer cells and for single QD tracking of transmembrane proteins via an extracellular epitope. The same approach was also used for optical mapping of RNA polymerases bound to combed genomic DNA in vitro. PMID- 21553894 TI - Lipogels: single-lipid-bilayer-enclosed hydrogel spheres. AB - We have fabricated Lipogels consisting of a single POPC lipid bilayer supported by a micrometer-sized, thermoresponsive, hydrophobically modified (HM), hydrogel sphere. The hydrogel consists of a lightly cross-linked poly(N isopropylacrylamide) (pNIPAM) core surrounded by a highly cross-linked acrylic acid (AA)-rich p(NIPAM-co-AA) shell. The lipid bilayer was assembled by binding liposomes to HM microgels, followed by several cycles of freeze-thaw. The pNIPAM volume phase transition (VPT) at ~32 degrees C was present both before and after hydrophobic modification and after lipid bilayer coating. Fluorescence studies confirmed the fusion of liposomes into a continuous single bilayer. At a temperature above the VPT, it was found that the volume decrease in the hydrogel was coupled to the appearance of highly curved obtrusions of the uncompromised lipid bilayer into the surroundings. It is anticipated that these properties of Lipogels will prove to be useful in drug delivery applications and in fundamental biophysical studies of membranes. PMID- 21553896 TI - Determination of 24 pesticide residues in fortified wines by solid-phase microextraction and gas chromatography-tandem mass spectrometry. AB - The present work describes a solid-phase microextraction (SPME) gas chromatography-tandem mass spectrometry (MS/MS) method to quantify 24 pesticides in fortified white wine and fortified red wine. In this study "fortified wine" refers to a wine in which fermentation is arrested before completion by alcohol distillate addition, allowing sugar and alcoholic contents to be higher (around 80-100 g/L total sugars and 19-22% alcohol strength (v/v)). The analytical method showed good linearity, presenting correlation coefficients (R(2)) >= 0.989 for all compounds. Limits of detection (LOD) and quantitation (LOQ) in the ranges of 0.05-72.35 and 0.16-219.23 MUg/L, respectively, were obtained. LOQs are below the maximum residue levels (MRL) set by European Regulation for grapes. The proposed method was applied to 17 commercial fortified wines. The analyzed pesticides were not detected in the wines tested. PMID- 21553895 TI - Tunable mechanical stability and deformation response of a resilin-based elastomer. AB - Resilin, the highly elastomeric protein found in specialized compartments of most arthropods, possesses superior resilience and excellent high-frequency responsiveness. Enabled by biosynthetic strategies, we have designed and produced a modular, recombinant resilin-like polypeptide bearing both mechanically active and biologically active domains to create novel biomaterial microenvironments for engineering mechanically active tissues such as blood vessels, cardiovascular tissues, and vocal folds. Preliminary studies revealed that these recombinant materials exhibit promising mechanical properties and support the adhesion of NIH 3T3 fibroblasts. In this Article, we detail the characterization of the dynamic mechanical properties of these materials, as assessed via dynamic oscillatory shear rheology at various protein concentrations and cross-linking ratios. Simply by varying the polypeptide concentration and cross-linker ratios, the storage modulus G' can be easily tuned within the range of 500 Pa to 10 kPa. Strain stress cycles and resilience measurements were probed via standard tensile testing methods and indicated the excellent resilience (>90%) of these materials, even when the mechanically active domains are intercepted by nonmechanically active biological cassettes. Further evaluation, at high frequencies, of the mechanical properties of these materials were assessed by a custom-designed torsional wave apparatus (TWA) at frequencies close to human phonation, indicating elastic modulus values from 200 to 2500 Pa, which is within the range of experimental data collected on excised porcine and human vocal fold tissues. The results validate the outstanding mechanical properties of the engineered materials, which are highly comparable to the mechanical properties of targeted vocal fold tissues. The ease of production of these biologically active materials, coupled to their outstanding mechanical properties over a range of compositions, suggests their potential in tissue regeneration applications. PMID- 21553897 TI - Structural and conformational analysis of proanthocyanidins from Parapiptadenia rigida and their wound-healing properties. AB - Structure elucidation and conformation analysis of four proanthocyanidins isolated from the bark of Parapiptadenia rigida were performed by two-dimensional NMR spectroscopy, HRESIMS, CD, and molecular mechanics (MM+) force field calculations. The known prodelphinidin, epigallocatechin-(4beta->8) epigallocatechin-3-O-gallate (1) was accompanied by the new epigallocatechin (4beta->8)-4'-O-methylgallocatechin (2), epicatechin-(4beta->8)-4'-O methylgallocatechin (3), and (4alpha->8)-bis-4'-O-methylgallocatechin (4). Compound 4 was previously published but the earlier structure must presumably be revised to 4'-O-methylgallocatechin-(4alpha->8)-4'-O-methylepigallocatechin. Conformational studies showed the compact rotamer with B and E rings in quasi equatorial orientations as the preferred conformation for compounds 1-3, whereas 4 consists of two stable rotamers, each with a quasi-equatorial orientation of ring B and E, respectively. The isolated compounds were studied for their wound healing effects in a scratch assay and showed promising results. PMID- 21553898 TI - Trimeric plasmonic molecules: the role of symmetry. AB - Artificial plasmonic molecules possess excitation modes that are defined by their symmetry and obey group theory rules, just like conventional molecules. We follow the evolution of surface-plasmon spectra of plasmonic trimers, assembled from equal-sized silver nanoparticles, as gradual geometric changes break their symmetry. The spectral modes of an equilateral triangle, the most symmetric structure of a trimer, are degenerate. This degeneracy is lifted as the symmetry is lowered when one of the vertex angles in opened, which also leads to a subtle transition between bright and dark modes. Our experimental results are quantitatively explained using numerical simulations and plasmon hybridization theory. PMID- 21553899 TI - Power factor enhancement by modulation doping in bulk nanocomposites. AB - We introduce the concept of modulation doping in three-dimensional nanostructured bulk materials to increase the thermoelectric figure of merit. Modulation-doped samples are made of two types of nanograins (a two-phase composite), where dopants are incorporated only into one type. By band engineering, charge carriers could be separated from their parent grains and moved into undoped grains, which would result in enhanced mobility of the carriers in comparison to uniform doping due to a reduction of ionized impurity scattering. The electrical conductivity of the two-phase composite can exceed that of the individual components, leading to a higher power factor. We here demonstrate the concept via experiment using composites made of doped silicon nanograins and intrinsic silicon germanium grains. PMID- 21553900 TI - A complete fabrication route for atomic-scale, donor-based devices in single crystal germanium. AB - Despite the rapidly growing interest in Ge for ultrascaled classical transistors and innovative quantum devices, the field of Ge nanoelectronics is still in its infancy. One major hurdle has been electron confinement since fast dopant diffusion occurs when traditional Si CMOS fabrication processes are applied to Ge. We demonstrate a complete fabrication route for atomic-scale, donor-based devices in single-crystal Ge using a combination of scanning tunneling microscope lithography and high-quality crystal growth. The cornerstone of this fabrication process is an innovative lithographic procedure based on direct laser patterning of the semiconductor surface, allowing the gap between atomic-scale STM-patterned structures and the outside world to be bridged. Using this fabrication process, we show electron confinement in a 5 nm wide phosphorus-doped nanowire in single crystal Ge. At cryogenic temperatures, Ohmic behavior is observed and a low planar resistivity of 8.3 kOmega/? is measured. PMID- 21553901 TI - Quantification of the electrophilic reactivities of aldehydes, imines, and enones. AB - The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of alpha,beta unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k(2)) have been combined with the known nucleophilicity parameters (N, s(N)) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and alpha,beta-unsaturated ketones (3a-f) according to the linear free-energy relationship log k(2) = s(N)(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-pi complexes within our comprehensive electrophilicity scale. PMID- 21553902 TI - Effects of static magnetic field on electrolyte solutions under kinetic condition. AB - Electrolyte solutions were exposed for different time to weak static magnetic field (MF) generated from a stack of magnets (B = 15 mT) at the flow rate of 1.4 mL/s. The conductivity was measured as a function of time following the application of MF. It was found that the changes in conductivity depend on the kind of electrolyte and the magnetic exposure time and are related to the thermodynamic function of hydration. PMID- 21553903 TI - On-line, on-campus education: a mixed bag. PMID- 21553904 TI - Attachment of noncognate chromophores to CpcA of Synechocystis sp. PCC 6803 and Synechococcus sp. PCC 7002 by heterologous expression in Escherichia coli. AB - Many cyanobacteria use brilliantly pigmented, multisubunit macromolecular structures known as phycobilisomes as antenna to enhance light harvesting for photosynthesis. Recent studies have defined the enzymes that synthesize phycobilin chromophores as well as many of the phycobilin lyase enzymes that attach these chromophores to their cognate apoproteins. The ability of the phycocyanin alpha-subunit (CpcA) to bind alternative linear tetrapyrrole chromophores was examined through the use of a heterologous expression system in Escherichia coli. E. coli strains produced phycocyanobilin, phytochromobilin, or phycoerythrobilin when they expressed 3Z-phycocyanobilin:ferredoxin oxidoreductase (PcyA), 3Z-phytochromobilin:ferredoxin oxidoreductase (HY2) from Arabidopsis thaliana, or phycoerythrobilin synthase (PebS) from the myovirus P SSM4, respectively. CpcA from Synechocystis sp. PCC 6803 or Synechococcus sp. PCC 7002 was coexpressed in these strains with the phycocyanin alpha-subunit phycocyanobilin lyase, CpcE/CpcF, or the phycoerythrocyanin alpha-subunit phycocyanobilin isomerizing lyase, PecE/PecF, from Noctoc sp. PCC 7120. Both lyases were capable of attaching three different linear tetrapyrrole chromophores to CpcA; thus, up to six different CpcA variants, each with a unique chromophore, could be produced with this system. One of these chromophores, denoted phytoviolobilin, has not yet been observed naturally. The recombinant proteins had unexpected and potentially useful properties, which included very high fluorescence quantum yields and photochemical activity. Chimeric lyases PecE/CpcF and CpcE/PecF were used to show that the isomerizing activity that converts phycocyanobilin to phycoviolobilin resides with PecF and not PecE. Finally, spectroscopic properties of recombinant phycocyanin R-PCIII, in which the CpcA subunits carry a phycoerythrobilin chromophore, are described. PMID- 21553905 TI - Vibrational softening of a protein on ligand binding. AB - Neutron scattering experiments have demonstrated that binding of the cancer drug methotrexate softens the low-frequency vibrations of its target protein, dihydrofolate reductase (DHFR). Here, this softening is fully reproduced using atomic detail normal-mode analysis. Decomposition of the vibrational density of states demonstrates that the largest contributions arise from structural elements of DHFR critical to stability and function. Mode-projection analysis reveals an increase of the breathing-like character of the affected vibrational modes consistent with the experimentally observed increased adiabatic compressibility of the protein on complexation. PMID- 21553906 TI - Ultrafast exciton dissociation followed by nongeminate charge recombination in PCDTBT:PCBM photovoltaic blends. AB - The precise mechanism and dynamics of charge generation and recombination in bulk heterojunction polymer:fullerene blend films typically used in organic photovoltaic devices have been intensively studied by many research groups, but nonetheless remain debated. In particular the role of interfacial charge-transfer (CT) states in the generation of free charge carriers, an important step for the understanding of device function, is still under active discussion. In this article we present direct optical probes of the exciton dynamics in pristine films of a prototypic polycarbazole-based photovoltaic donor polymer, namely poly[N-11''-henicosanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3' benzothiadiazole)] (PCDTBT), as well as the charge generation and recombination dynamics in as-cast and annealed photovoltaic blend films using methanofullerene (PC(61)BM) as electron acceptor. In contrast to earlier studies we use broadband (500-1100 nm) transient absorption spectroscopy including the previously unobserved but very important time range between 2 ns and 1 ms, which allows us not only to observe the entire charge carrier recombination dynamics but also to quantify the existing decay channels. We determine that ultrafast exciton dissociation occurs in blends and leads to two separate pools of products, namely Coulombically bound charge-transfer (CT) states and unbound (free) charge carriers. The recombination dynamics are analyzed within the framework of a previously reported model for poly(3-hexylthiophene):PCBM (Howard, I. A. J. Am. Chem. Soc. 2010, 132, 14866) based on concomitant geminate recombination of CT states and nongeminate recombination of free charge carriers. The results reveal that only ~11% of the initial photoexcitations generate interfacial CT states that recombine exclusively by fast nanosecond geminate recombination and thus do not contribute to the photocurrent, whereas ~89% of excitons create free charge carriers on an ultrafast time scale that then contribute to the extracted photocurrent. Despite the high yield of free charges the power conversion efficiency of devices remains moderate at about 3.0%. This is largely a consequence of the low fill factor of devices. We relate the low fill factor to significant energetic disorder present in the pristine polymer and in the polymer:fullerene blends. In the former we observed a significant spectral relaxation of exciton emission (fluorescence) and in the latter of the polaron induced ground-state bleaching, implying that the density of states (DOS) for both excitons and charge carriers is significantly broadened by energetic disorder in pristine PCDTBT and in its blend with PCBM. This disorder leads to charge trapping in solar cells, which in turn causes higher carrier concentrations and more significant nongeminate recombination. The nongeminate recombination has a significant impact on the IV curves of devices, namely its competition with charge carrier extraction causes a stronger bias dependence of the photocurrent of devices, in turn leading to the poor device fill factor. In addition our results demonstrate the importance of ultrafast free carrier generation and suppression of interfacial CT-state formation and question the applicability of the often used Braun-Onsager model to describe the bias dependence of the photocurrent in polymer:fullerene organic photovoltaic devices. PMID- 21553907 TI - The Infinite Chain Nitride Na5Ba3N. A One-Dimensional Void Metal? PMID- 21553908 TI - Phosphorus-containing polymers: a great opportunity for the biomedical field. AB - This Review is focused on the growing interest brought to phosphorus-containing organic materials for applications in the biomedical field, mainly because of their properties such as biocompatibility, hemocompatibility, and protein adsorption resistance. It mainly describes relevant works achieved on these materials for various applications: dentistry, regenerative medicine, and drug delivery. Special attention was given to 2-methacryloyloxyethyl phosphorylcholine (MPC) monomer as the latter appeared of great importance because of its biomimetic structure due to the presence of the phospholipid group on its structure. As a result, much research effort is currently concentrated on the development of phosphorylcholine-containing (co)polymers that represent a promising class of materials. PMID- 21553909 TI - Thermodynamic, diffusional, and structural anomalies in rigid-body water models. AB - Structural, density, entropy, and diffusivity anomalies of the TIP4P/2005 model of water are mapped out over a wide range of densities and temperatures. The locus of temperatures of maximum density (TMD) for this model is very close to the experimental TMD locus for temperatures between 250 and 275 K. Four different water models (mTIP3P, TIP4P, TIP5P, and SPC/E) are compared with the TIP4P/2005 model in terms of their anomalous behavior. For all the water models, the density regimes for anomalous behavior are bounded by a low-density limit at around 0.85 0.90 g cm(-3) and a high-density limit at about 1.10-1.15 g cm(-3). The onset temperatures of the density anomaly in the various models show a much greater variation, ranging from 202 K for mTIP3P to 289 K for TIP5P. The order maps for the various water models are qualitatively very similar with the structurally anomalous regions almost superimposable in the q(tet)-tau plane. Comparison of the phase diagrams of water models with the region of liquid-state anomalies shows that the crystalline phases are much more sensitive to the choice of water models than the liquid state anomalies; for example, SPC/E and TIP4P/2005 show qualitatively similar liquid state anomalies but very different phase diagrams. The anomalies in the liquid in all the models occur at much lower pressures than those at which the melting line changes from negative to positive slope. The results in this study demonstrate several aspects of structure-entropy diffusivity relationships of water models that can be compared with experiment and used to develop better atomistic and coarse-grained models for water. PMID- 21553910 TI - Insight into asphaltene nanoaggregate structure inferred by small angle neutron and X-ray scattering. AB - Complementary neutron and X-ray small angle scattering results give prominent information on the asphaltene nanostructure. Precise SANS and SAXS measurements on a large q-scale were performed on the same dilute asphaltene-toluene solution, and absolute intensity scaling was carried out. Direct comparison of neutron and X-ray spectra enables description of a fractal organization made from the aggregation of small entities of 16 kDa, exhibiting an internal fine structure. Neutron contrast variation experiments enhance the description of this nanoaggregate in terms of core-shell disk organization, giving insight into core and shell dimensions and chemical compositions. The nanoaggregates are best described by a disk of total radius 32 A with 30% polydispersity and a height of 6.7 A. Composition and density calculations show that the core is a dense and aromatic structure, contrary to the shell, which is highly aliphatic. These results show a good agreement with the general view of the Yen model (Yen, T. F.; et al. Anal. Chem.1961, 33, 1587-1594) and as for the modified Yen model (Mullins, O. C. Energy Fuels2010, 24, 2179-2207), provide characteristic dimensions of the asphaltene nanoaggregate in good solvent. PMID- 21553911 TI - Enantioselective gem-chlorofluorination of active methylene compounds using a chiral spiro oxazoline ligand. AB - Highly enantioselective gem-chlorofluorination of active methylene compounds was carried out by using a copper(II) complex of a chiral spiro pyridyl monooxazoline ligand. This reaction yielded alpha-chloro-alpha-fluoro-beta-keto esters and alpha-chloro-alpha-fluoro-beta-keto phosphonates with up to 92% ee. The resulting dihalo beta-keto ester was converted into various alpha-fluoro-alpha-heteroatom substituted carbonyl compounds via nucleophilic substitution without loss of optical purity. A fully protected beta-amino acid with a gem chlorofluoromethylene function was also synthesized. PMID- 21553912 TI - Conformational folding and stability of the HET-C2 glycolipid transfer protein fold: does a molten globule-like state regulate activity? AB - The glycolipid transfer protein (GLTP) superfamily is defined by the human GLTP fold that represents a novel motif for lipid binding and transfer and for reversible interaction with membranes, i.e., peripheral amphitropic proteins. Despite limited sequence homology with human GLTP, we recently showed that HET-C2 GLTP of Podospora anserina is organized conformationally as a GLTP fold. Currently, insights into the folding stability and conformational states that regulate GLTP fold activity are almost nonexistent. To gain such insights into the disulfide-less GLTP fold, we investigated the effect of a change in pH on the fungal HET-C2 GLTP fold by taking advantage of its two tryptophans and four tyrosines (compared to three tryptophans and 10 tyrosines in human GLTP). pH induced conformational alterations were determined by changes in (i) intrinsic tryptophan fluorescence (intensity, emission wavelength maximum, and anisotropy), (ii) circular dichroism over the near-UV and far-UV ranges, including thermal stability profiles of the derivatized molar ellipticity at 222 nm, (iii) fluorescence properties of 1-anilinonaphthalene-8-sulfonic acid, and (iv) glycolipid intermembrane transfer activity monitored by Forster resonance energy transfer. Analyses of our recently determined crystallographic structure of HET C2 (1.9 A) allowed identification of side chain electrostatic interactions that contribute to HET-C2 GLTP fold stability and can be altered by a change in pH. Side chain interactions include numerous salt bridges and interchain cation-pi interactions, but not intramolecular disulfide bridges. Histidine residues are especially important for stabilizing the local positioning of the two tryptophan residues and the conformation of adjacent chains. Induction of a low-pH-induced, molten globule-like state inhibited glycolipid intermembrane transfer by the HET C2 GLTP fold. PMID- 21553913 TI - Application of designed enzymes in organic synthesis. PMID- 21553914 TI - Surface-induced patterns from evaporating droplets of aqueous carbon nanotube dispersions. AB - Evaporation of aqueous droplets of carbon nanotubes (CNTs) coated with a physisorbed layer of humic acid (HA) on a partially hydrophilic substrate induces the formation of a film of CNTs. Here, we investigate the role that the global geometry of the substrate surfaces has on the structure of the CNT film. On a flat mica or silica surface, the evaporation of a convex droplet of the CNT dispersion induces the well-known "coffee ring", while evaporation of a concave droplet (capillary meniscus) of the CNT dispersion in a wedge of two planar mica sheets or between two crossed-cylinder sheets induces a large area (>mm(2)) of textured or patterned films characterized by different short- and long-range orientational and positional ordering of the CNTs. The resulting patterns appear to be determined by two competing or cooperative sedimentation mechanisms: (1) capillary forces between CNTs giving micrometer-sized filaments parallel to the boundary line of the evaporating droplet and (2) fingering instability at the boundary line of the evaporating droplet and subsequent pinning of CNTs on the surface giving micrometer-sized filaments of CNTs perpendicular to this boundary line. The interplay between substrate surface geometry and sedimentation mechanisms gives an extra control parameter for manipulating patterns of self assembling nanoparticles at substrate surfaces. PMID- 21553915 TI - Flow-through dispersed carbon nanofiber-based microsolid-phase extraction coupled to liquid chromatography for automatic determination of trace levels of priority environmental pollutants. AB - Handling of carbon nanoparticles as sorptive materials in a flow-through packed bed mode has been to date hampered by undue pressure drop and deteriorated retention efficiency because of nanoparticle bundling and entanglement. To surmount this limitation, a dedicated stirred-flow sorptive microchamber integrated in a fully automated sequential injection (SI) assembly is herein proposed for expedient handling and reuse of carbon nanoparticles in microsolid phase extraction (MUSPE) procedures. The assembled setup features automatic uptake, preconcentration, and retrieval of target organic species using dispersed nanoparticles as a front-end to liquid chromatographic (LC) assays. Chlorotriazine residues (atrazine, simazine, and propazine) and dealkylated metabolites thereof (deisopropyltriazine (DIA) and deethylatrazine (DEA)) were selected as model compounds because of their electron-poor aromatic structure and potentially strong pi-pi interactions with electron-rich sorptive materials. The effect of several parameters on the analytical performance including the type and amount of nanoparticles (carbon nanofibers (CNFs), multiwalled carbon nanotubes (MWCNTs) and oxidized carbon nanotubes (MWCNT-COOH), the sample volume (breakthrough volume), the nature and volume of eluent, and the interface between the sample processing module and LC was explored in detail. Using dispersed CNFs at-line coupled to LC, absolute recovery percentages for 10 mL sample percolation were >94% for the overall herbicides with enrichment factors of ca. 20, limits of detection (S/N = 3) of 0.004-0.03 ng mL(-1), limits of quantification (S/N = 10) of 0.01-0.09 ng mL(-1) and repeatability within the range 0.5-1.8%. The SI-CNF-LC hyphenated system was harnessed to the analysis of not merely untreated environmental waters at concentration levels below those endorsed by the current EU Water Framework Directives but to crude soil extracts for which CNF reuse with no loss of retention efficiency was proven feasible by resorting to appropriate automatic regeneration procedures and internal standardization. PMID- 21553916 TI - One-electron oxidation of electronically diverse manganese(III) and nickel(II) salen complexes: transition from localized to delocalized mixed-valence ligand radicals. AB - Ligand radicals from salen complexes are unique mixed-valence compounds in which a phenoxyl radical is electronically linked to a remote phenolate via a neighboring redox-active metal ion, providing an opportunity to study electron transfer from a phenolate to a phenoxyl radical mediated by a redox-active metal ion as a bridge. We herein synthesize one-electron-oxidized products from electronically diverse manganese(III) salen complexes in which the locus of oxidation is shown to be ligand-centered, not metal-centered, affording manganese(III)-phenoxyl radical species. The key point in the present study is an unambiguous assignment of intervalence charge transfer bands by using nonsymmetrical salen complexes, which enables us to obtain otherwise inaccessible insight into the mixed-valence property. A d(4) high-spin manganese(III) ion forms a Robin-Day class II mixed-valence system, in which electron transfer is occurring between the localized phenoxyl radical and the phenolate. This is in clear contrast to a d(8) low-spin nickel(II) ion with the same salen ligand, which induces a delocalized radical (Robin-Day class III) over the two phenolate rings, as previously reported by others. The present findings point to a fascinating possibility that electron transfer could be drastically modulated by exchanging the metal ion that bridges the two redox centers. PMID- 21553917 TI - Stereoconvergent amine-directed alkyl-alkyl Suzuki reactions of unactivated secondary alkyl chlorides. AB - A new family of stereoconvergent cross-couplings of unactivated secondary alkyl electrophiles has been developed, specifically, arylamine-directed alkyl-alkyl Suzuki reactions. This represents the first such investigation to be focused on the use of alkyl chlorides as substrates. Structure-enantioselectivity studies are consistent with the nitrogen, not the aromatic ring, serving as the primary site of coordination of the arylamine to the catalyst. The rate law for this asymmetric cross-coupling is compatible with transmetalation being the turnover limiting step of the catalytic cycle. PMID- 21553918 TI - Determination of the shear modulus of spin-coated lipid multibilayer films by the spontaneous embedment of submicrometer-sized particles. AB - A novel submicrometer particle embedment technique has been used to determine the shear modulus of 1,2-dipalmitoyl-sn-glycero-3-phosphotidylcholine (DPPC) lipid multibilayers. The depth of the spontaneous embedment of polystyrene and silica spherical particles of 200 nm nominal size has been determined from atomic force microscopy measurements on colloidal particles dispersed onto the surfaces of the DPPC multibilayers. The standard JKR model was used to relate the shear modulus of the lipid multibilayer films to the depth of embedment of the particles. The thus-determined modulus of the DPPC is within the range of reported literature values. Gold particles are also considered, and it is found that for the smallest particles (13 nm) complete engulfment by the DPPC multibilayer film takes place. PMID- 21553919 TI - Physical and water sorption properties of chemically modified pectin with an environmentally friendly process. AB - A synthetic process was developed to modify pectin samples under solvent free conditions, obtaining pectin at increasing concentration of palmitic, oleic, and linoleic acids. The weight loss of the modified powders showed a degradation path very similar to the pure pectin, indicating that the pristine structure was preserved after the chemical modification. A decreasing mass of evaporating water on increasing the fatty acid concentration, in particular for the palmitic acid modification, indicated a reduced water sorption by the modified powders. Differential scanning calorimetry confirmed the thermogravimetric results and in addition indicated the crystallization of the lateral chains in the case of palmitic-acid-modified pectins. This result was confirmed by X-ray diffractograms of the palmitic acid samples, indicating the main crystallization of the form C, although possible orientation phenomena can be inferred. The sorption curves of either the pristine pectin or the modified samples showed a dual sorption behavior. The sorption curves were interpreted by the BET and GAB equations, both giving very similar results. Palmitic acid modification was very effective in reducing all sorption parameters, whereas in the case of oleic and linoleic acids, only at high concentrations was the hydrophobic influence detected. PMID- 21553920 TI - Fluorescence anisotropy spectra disclose the role of disorder in optical spectra of branched intramolecular-charge-transfer molecules. AB - Fluorescence excitation and emission spectra and corresponding anisotropies of branched intramolecular charge-transfer (ICT) chromophores are reported. To unravel the role of disorder related to polar solvation, we collected spectra of molecules with octupolar (C(3)) symmetry in glasses obtained from solvents of different polarity. Thermal disorder related to polar solvation is demonstrated by the dependence of fluorescence excitation/emission spectra and anisotropy spectra on the emission/excitation wavelength. In particular, for excitation in the red edge of the absorption band, the fluorescence anisotropy signal deviates from the 0.1 value expected for octupolar chromophores, approaching the limiting 0.4 value. A qualitatively different result is observed in nonpolar solvents. Based on essential-state models for ICT chromophores, we develop an original approach for the calculation of anisotropy spectra that quantitatively reproduces experimental data. The model, accounting for the coupling between electrons and molecular vibrations and polar solvation, leads to a thorough understanding of the phenomena at the basis of solute-solvent interactions in branched ICT chromophores. A clear distinction is made between symmetry-breaking phenomena in the excited state and disorder-induced lowering of the molecular symmetry. Their relation with red-edge effects is pointed out. PMID- 21553921 TI - Rapid point of care analyzer for the measurement of cyanide in blood. AB - A simple, sensitive optical analyzer for the rapid determination of cyanide in blood in point of care applications is described. HCN is liberated by the addition of 20% H(3)PO(4) and is absorbed by a paper filter impregnated with borate-buffered (pH 9.0) hydroxoaquocobinamide (hereinafter called cobinamide). Cobinamide on the filter changes color from orange (lambda(max) = 510 nm) to violet (lambda(max) = 583 nm) upon reaction with cyanide. This color change is monitored in the transmission mode by a light emitting diode (LED) with a 583 nm emission maximum and a photodiode detector. The observed rate of color change increases 10 times when the cobinamide solution for filter impregnation is prepared in borate-buffer rather than in water. The use of a second LED emitting at 653 nm and alternate pulsing of the LEDs improves the limit of detection by 4 times to ~0.5 MUM for a 1 mL blood sample. Blood cyanide levels of imminent concern (>=10 MUM) can be accurately measured in ~2 min. The response is proportional to the mass of cyanide in the sample: smaller sample volumes can be successfully used with proportionate change in the concentration LODs. Bubbling air through the blood-acid mixture was found effective for mixing of the acid with the sample and the liberation of HCN. A small amount of ethanol added to the top of the blood was found to be the most effective means to prevent frothing during aeration. The relative standard deviation (RSD) for repetitive determination of blood samples containing 9 MUM CN was 1.09% (n = 5). The technique was compared blind with a standard microdiffusion-spectrophotometric method used for the determination of cyanide in rabbit blood. The results showed good correlation (slope 1.05, r(2) 0.9257); independent calibration standards were used. PMID- 21553922 TI - Specific indolo[3,2,1-jk]carbazole conducting thin-film materials production by selective substitution. AB - Selectively substituted indolo[3,2,1-jk] carbazole (IC) molecules have been synthesized through flash vacuum pyrolysis (FVP) and then electro-oxidized, resulting in the formation of redox-active and electronically conducting thin films consisting exclusively of three highly luminescent dimer species, the 2,2' , 2,10'-, and 10,10'-coupled dimers. DFT calculation has enabled both the accurate calculation of monomer oxidation potentials and the prediction of the nature of the resulting dimers through consideration of the coupling of the oxidized monomer radical cations. This demonstrates that substituted ICs represent a class of molecules able to form redox-active and conducting dimer films of controlled composition upon oxidation and that DFT calculations can be used to inform the synthesis of specific IC monomers most likely to both produce electronically conducting thin-film materials and yield specific luminescent dimers with desirable materials properties. PMID- 21553923 TI - Iron-catalyzed asymmetric epoxidation of beta,beta-disubstituted enones. AB - The combination of Fe(OTf)(2) and novel phenanthroline ligands enables the catalytic asymmetric epoxidation of acyclic beta,beta-disubstituted enones, which have been a heretofore inaccessible substrate class. The reaction provides highly enantioenriched alpha,beta-epoxyketones (up to 92% ee) that can be further converted to functionalized beta-ketoaldehydes with an all-carbon quaternary center. PMID- 21553924 TI - Copper selenide nanocrystals for photothermal therapy. AB - Ligand-stabilized copper selenide (Cu(2-x)Se) nanocrystals, approximately 16 nm in diameter, were synthesized by a colloidal hot injection method and coated with amphiphilic polymer. The nanocrystals readily disperse in water and exhibit strong near-infrared (NIR) optical absorption with a high molar extinction coefficient of 7.7 * 10(7) cm(-1) M(-1) at 980 nm. When excited with 800 nm light, the Cu(2-x)Se nanocrystals produce significant photothermal heating with a photothermal transduction efficiency of 22%, comparable to nanorods and nanoshells of gold (Au). In vitro photothermal heating of Cu(2-x)Se nanocrystals in the presence of human colorectal cancer cell (HCT-116) led to cell destruction after 5 min of laser irradiation at 33 W/cm(2), demonstrating the viabilitiy of Cu(2-x)Se nanocrystals for photothermal therapy applications. PMID- 21553925 TI - Outermost and inner-shell electronic properties of ClC(O)SCH2CH3 studied using HeI photoelectron spectroscopy and synchrotron radiation. AB - A study of valence electronic properties of S-ethyl chlorothioformate (S-ethyl chloromethanethioate), ClC(O)SCH(2)CH(3), using HeI photoelectron spectra (PES) and synchrotron radiation is presented. Moreover, the photon impact excitation and dissociation dynamics of ClC(O)SCH(2)CH(3) excited at the S 2p and Cl 2p levels are elucidated by analyzing the total ion yield (TIY) spectra and time-of flight mass spectra acquired in multicoincidence mode [photoelectron-photoion coincidence (PEPICO) and photoelectron-photoion-photoion coincidence (PEPIPICO)]. The HeI photoelectron spectrum is dominated by features associated with lone-pair electrons from the ClC(O)S- group, the HOMO at 9.84 eV being assigned to the n(pi)(S) sulfur lone-pair orbital. Whereas the formation of C(2)H(5)(+) ion dominates the fragmentation in the valence energy region, the most abundant ion formed in both the S and Cl 2p energy ranges is C(2)H(3)(+). Comparison with related XC(O)SR (X = H, F, Cl and R = -CH(3), -C(2)H(5)) species reveals the impact of the alkyl chain on the photodissociation behavior of S-alkyl (halo)thioformates. PMID- 21553926 TI - One-pot synthesis and physicochemical properties of an organo-modified saponite clay. AB - An organo-saponite clay containing intercalated cetyltrimethylammonium (CTA(+)) cations was synthesized by an efficient one-step hydrothermal method and was compared with a CTA-exchanged saponite prepared by a classical postsynthesis intercalation route. In both hybrid samples, surfactant loading up to 10% was achieved. A comparative investigation of the physicochemical properties of both solids was carried out by a multidisciplinary approach, by using a combination of spectroscopic, structural, and thermal characterization tools. Powder X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM) data indicated that the one-pot-prepared solid showed that the presence of CTA(+) molecules in the synthesis gel did not affect the clay structure. In addition, thermal analysis suggested that the inorganic layers play an active role in stabilizing and protecting the surfactant molecules by increasing their thermal stability. A different arrangement of intercalated CTA(+) ions in the two hybrid clays was observed by solid state NMR in combination with Fourier transform infrared (FTIR) spectroscopy and assigned to a different all-trans/gauche conformation ratio of the surfactant depending on the synthetic method used to prepare the two final materials. The surfactant organization is also influenced by the lamellae charge density, which is different in the two organo-modified materials as found by (27)Al and (29)Si MAS NMR experiments. PMID- 21553927 TI - Concentration dependence of 5-aminosalicylic acid pharmacological actions in intestinal mucosa after oral administration of a pH-dependent formulation. AB - Asacol, a medication that delivers delayed release 5-aminosalicylic acid (5-ASA), is a useful therapeutic agent for inflammatory bowel disease (IBD), but the relationship between its pharmacological actions and intestinal concentrations has not been studied in detail. Therefore, our aim was to assess 5-ASA's pharmacological actions as a function of its concentration at its target site. We first evaluated 5-ASA's release profiles in vitro by the paddle method and found that Asacol starts to release 5-ASA at pH >= 7. Orally administered Asacol pharmacokinetic parameters were evaluated in dogs. Asacol's T(max) was much longer than that of the time-dependent release 5-ASA formulation. We also determined 5-ASA's distribution in the intestinal mucosa and found that it is effectively delivered there by Asacol. These results indicated that Asacol released 5-ASA in a pH-dependent manner, resulting in efficient delivery to the large intestine. We also compared the mucosal 5-ASA concentrations with the IC(50) values for scavenging free radicals or suppressing LTB(4) production. The 5-ASA concentration in the large intestine was higher than IC(50) values necessary to suppress inflammatory processes. We also report the release characteristics of Asacol and the targeted delivery of 5-ASA to affected sites in IBD patients. PMID- 21553928 TI - Single-molecule atomic force microscopy force spectroscopy study of Abeta-40 interactions. AB - Misfolding and aggregation of amyloid beta-40 (Abeta-40) peptide play key roles in the development of Alzheimer's disease (AD). However, very little is known about the molecular mechanisms underlying these molecular processes. We developed a novel experimental approach that can directly probe aggregation-prone states of proteins and their interactions. In this approach, the proteins are anchored to the surface of the atomic force microscopy substrate (mica) and the probe, and the interaction between anchored molecules is measured in the approach-retraction cycles. We used dynamic force spectroscopy (DFS) to measure the stability of transiently formed dimers. One of the major findings from DFS analysis of alpha synuclein (alpha-Syn) is that dimeric complexes formed by misfolded alpha-Syn protein are very stable and dissociate over a range of seconds. This differs markedly from the dynamics of monomers, which occurs on a microsecond to nanosecond time scale. Here we applied the same approach to quantitatively characterize interactions of Abeta-40 peptides over a broad range of pH values. These studies showed that misfolded dimers are characterized by lifetimes in the range of seconds. This value depends on pH and varies between 2.7 s for pH 2.7 and 0.1 s for pH 7, indicating that the aggregation properties of Abeta-40 are modulated by the environmental conditions. The analysis of the contour lengths revealed the existence of various pathways for dimer dissociation, suggesting that dimers with different conformations are formed. These structural variations result in different aggregation pathways, leading to different types of oligomers and higher-order aggregates, including fibrils. PMID- 21553929 TI - Dynamic ensemble view of the conformational landscape of HIV-1 TAR RNA and allosteric recognition. AB - RNA conformational dynamics and the resulting structural heterogeneity play an important role in RNA functions, e.g., recognition. Recognition of HIV-1 TAR RNA has been proposed to occur via a conformational capture mechanism. Here, using ultrafast time-resolved fluorescence spectroscopy, we have probed the complexity of the conformational landscape of HIV-1 TAR RNA and monitored the position dependent changes in the landscape upon binding of a Tat protein-derived peptide and neomycin B. In the ligand-free state, the TAR RNA samples multiple families of conformations with various degrees of base stacking around the three nucleotide bulge region. Some subpopulations partially resemble those ligand bound states, but the coaxially stacked state is below the detection limit. When Tat or neomycin B binds, the bulge region as an ensemble undergoes a conformational transition in a position-dependent manner. Tat and neomycin B induce mutually exclusive changes in the TAR RNA underlying the mechanism of allosteric inhibition at an ensemble level with residue-specific details. Time resolved anisotropy decay measurements revealed picosecond motions of bases in both ligand-free and ligand-bound states. Mutation of a base pair at the bulge- stem junction has differential effects on the conformational distributions of the bulge bases. A dynamic model of the ensemble view of the conformational landscape for HIV-1 TAR RNA is proposed, and the implication of the general mechanism of RNA recognition and its impact on RNA-based therapeutics are discussed. PMID- 21553930 TI - Diastereoselectively switchable enantioselective trapping of carbamate ammonium ylides with imines. AB - The diastereoselectively switchable enantioselective trapping of protic carbamate ammonium ylides with imines is reported. The intriguing Rh(2)(OAc)(4) and chiral Bronsted acid cocatalyzed three-component Mannich-type reaction of a diazo compound, a carbamate, and an imine provides rapid and efficient access to both syn- and anti-alpha-substituted alpha,beta-diamino acid derivatives with a high level control of chemo-, diastereo-, and enantioselectivity. PMID- 21553931 TI - Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data. AB - Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-beta-boswellic acid (KBA) and acetyl-11-keto-beta boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for beta-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials. PMID- 21553933 TI - Pharmacokinetics of subcutaneous IgPro20 in patients with primary immunodeficiency. AB - BACKGROUND AND OBJECTIVES: Immunoglobulin replacement is a standard therapy for patients with primary immunodeficiencies. Subcutaneous administration of immunoglobulin offers more constant IgG levels than intravenous administration and simplifies administration for some patients. Use of L-proline as an excipient contributes to the stability of highly concentrated IgG preparations. The aims of the present study were to evaluate the pharmacokinetics of IgPro20 (Hizentra(r)), a new 20% subcutaneous IgG solution, and compare the area under the serum concentration-time curve (AUC) with that of a similar intravenous 10% IgG solution (IgPro10; Privigen(r)). At the request of the US FDA, an algorithm for determining IgG trough level ratios (TLRs) was developed in order to provide physicians with a practical tool for monitoring doses during steady-state IgPro20 therapy. METHODS: This was a prospective, open-label, multicentre, single-arm, phase III clinical trial conducted in the US. The study was performed in a primary-care setting. Eligible patients were males or females aged 6-75 years with a primary immunodeficiency (common variable immunodeficiency or X-linked agammaglobulinaemia) who had received regular treatment with IgPro10 for at least 3 months prior to entering this study and had achieved serum trough concentration (C(trough)) values >=5 g/L. IgPro20 was administered subcutaneously once weekly at initial doses equivalent to 130% of patients' previous doses, based on the results obtained in a Vivaglobin(r) study and due to an FDA request. After run in, each patient's dose was adjusted to achieve an AUC comparable to that achieved with IgPro10 administered intravenously. RESULTS: Eighteen patients completed the study. Mean IgPro20 : IgPro10 dose ratio (dose adjustment coefficient) was 1.53 (range 1.26-1.87). The resulting mean AUCs were 105.6 g . day/L for IgPro20 versus 103.2 g . day/L for IgPro10 (geometric mean ratio 1.002; lower one-sided 95% confidence limit [CL] 0.951). Thus, the primary endpoint of the study was met, as this result exceeded the pre-specified criterion of the lower one-sided 95% CL of >=0.8 for non-inferiority. At these AUCs, which were considered equivalent, the mean IgPro20 : IgPro10 TLR, determined by the developed algorithm, was 1.29 (range 1.18-1.73). Titres of specific antibodies tested were well above respective product specifications, suggesting that protection against infection would be effective. CONCLUSION: Steady-state AUCs with subcutaneous IgPro20 and intravenous IgPro10 were equivalent. Mean dose adjustment coefficient and mean TLR can be used for initial dose conversion without risk of under-protection but vary too widely to be considered measures of equivalence. Trial registration number (clinicaltrials.gov): NCT00419341. PMID- 21553932 TI - Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4 anilinoquinazolines. AB - The 4-anilinoquinazolines (gefitinib, erlotinib and lapatinib) are members of a class of potent and selective inhibitors of the human epidermal growth factor receptor (HER) family of tyrosine kinases that have been developed to treat patients with tumours with defined genetic alterations of the HER tyrosine kinase domain. They are characterized by a moderate rate of absorption after oral administration with peak plasma concentrations at several hours post-dose. Absolute bioavailability of gefitinib and erlotinib is about 60%. Low bioavailability is assumed for lapatinib. The drugs are extensively distributed in human tissues, including tumour tissues, have a large volume of distribution at least 3-fold exceeding the volume of body water and are extensively (about 95%) protein bound to alpha(1)-acid glycoprotein and albumin. Existing human data for gefitinib and erlotinib indicate that these substances penetrate into the central nervous system and accumulate in brain tumours, possibly due to leaks in the blood-brain barrier. Gefitinib, erlotinib and the absorbed fraction of lapatinib undergo extensive metabolism - mainly via hepatic and intestinal cytochrome P450 (CYP) 3A4 and also via CYP2D6 (gefitinib) and CYP1A2 (erlotinib) and are primarily eliminated by biotransformation. The excretion of unchanged gefitinib, erlotinib, lapatinib and their metabolites occurs predominantly in the faeces and only a minor fraction is excreted in the urine. No relevant effects of age, sex, bodyweight or race on their pharmacokinetics have been reported to date. Limited available data indicate that genetic polymorphisms in enzymes and transporters involved in the pharmacokinetics of gefitinib (CYP2D6) and erlotinib (CYP3A4, CYP3A5 and ABCG2 [breast cancer resistance protein]) alter the exposure to these drugs. Modification of drug dose should be considered in patients with severe hepatic impairment receiving these tyrosine kinase inhibitors and in current smokers receiving erlotinib. Existing recommendations for dose adjustment (i.e. a dose decrement or increment for gefitinib, erlotinib and lapatinib in the presence of CYP3A4 inhibitors or inducers, respectively; a dose increase for erlotinib in smoking patients) need to be validated in clinical studies. Further investigations are required to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess the clinical relevance of interaction potential and inhibitory effects on the metabolizing enzymes and transporters. PMID- 21553934 TI - When are adaptive strategies most predictive of psychopathology? AB - In recent work, we showed that putatively adaptive emotion regulation strategies, such as reappraisal and acceptance, have a weaker association with psychopathology than putatively maladaptive strategies, such as rumination, suppression, and avoidance (e.g., Aldao & Nolen-Hoeksema, 2010; Aldao, Nolen Hoeksema, & Schweizer, 2010). In this investigation, we examined the interaction between adaptive and maladaptive emotion regulation strategies in the prediction of psychopathology symptoms (depression, anxiety, and alcohol problems) concurrently and prospectively. We assessed trait emotion regulation and psychopathology symptoms in a sample of community residents at Time 1 (N = 1,317) and then reassessed psychopathology at Time 2 (N = 1,132). Cross-sectionally, we found that the relationship between adaptive strategies and psychopathology symptoms was moderated by levels of maladaptive strategies: adaptive strategies had a negative association with psychopathology symptoms only at high levels of maladaptive strategies. In contrast, adaptive strategies showed no prospective relationship to psychopathology symptoms either alone or in interaction with maladaptive strategies. We discuss the implications of this investigation for future work on the contextual factors surrounding the deployment of emotion regulation strategies. PMID- 21553935 TI - Hooked on a feeling: rumination about positive and negative emotion in inter episode bipolar disorder. AB - Rumination has been consistently implicated in the onset and maintenance of depression. Less work has examined rumination in the context of bipolar disorder, especially rumination about positive emotion. The present study examined rumination about negative and positive emotion in interepisode bipolar disorder (BD; n = 39) and healthy controls (CTL; n = 34). Trait rumination about positive and negative emotion, as well as experiential and physiological responses to a rumination induction, was measured. Illness course was also assessed for the BD group. Results indicated that the BD group reported greater trait rumination about positive and negative emotion compared with the CTL group, though no group differences emerged during the rumination induction. For the BD group, trait rumination about positive and negative emotion, as well as increased cardiovascular arousal (i.e., heart rate), was associated with greater lifetime depression frequency; trait rumination about positive emotion was associated with greater lifetime mania frequency. These findings suggest that interepisode BD is associated with greater rumination about positive and negative emotion, which in turn is associated with illness course. PMID- 21553936 TI - Towards a cognitive resource limitations model of diminished expression in schizotypy. AB - Diminished expression of speech is a pernicious feature of both schizophrenia and schizotypy--defined as the personality organization reflecting a putative genetic schizophrenia liability. As yet, the mechanism underlying diminished expression is unclear. We tested the hypothesis that diminished expression reflects a cognitive resource issue--that is, as cognitive resources are depleted, expression becomes diminished in individuals with psychometrically defined schizotypy. Acoustic analysis of natural speech was procured during experimentally manipulated baseline and high cognitive-load dual tasks and examined in 38 individuals with psychometrically defined schizotypy and 34 controls. For both groups, expression significantly decreased as a function of increased task demands, although there were no group differences in expression or magnitude of change across baseline to high cognitive-load conditions. Participants with self-reported constricted affect showed significant reductions in expression under high-load versus baseline speaking conditions relative to other schizotypal and control participants. Moreover, psychometrically defined schizotypal participants with poor cognitive performance on the high-load task, suggestive of depleted cognitive resources, also showed expressivity reductions compared with other participants. These findings suggest that diminished expression occurs as a function of limited cognitive resources in psychometrically defined schizotypy. PMID- 21553937 TI - Are impulsive adolescents differentially influenced by the good and bad of neighborhood and family? AB - Using the differential susceptibility perspective (Belsky & Pluess, 2009) as a guiding frame-work, age 12 neighborhood disadvantage (ND) and family characteristics (parental knowledge) were examined as moderators of the relations between age 12 youth impulsivity and the development (ages 13, 14, and 15) of positive (community activities) and negative (antisocial behavior; ASB) adolescent behavior. An interaction between ND and youth impulsivity (age 12) operated with differential susceptibility, but only for female community activities at age 13: under low levels of ND, impulsive adolescent females engaged in the highest levels of community activities, whereas under high ND, they engaged in the lowest levels. Exploratory analysis showed the association between community activities and ND to be partially related to parents' or adults' engagement in informal social controls (e.g., alerting the police with misbehavior in the neighborhood). Differential susceptibility effects were not identified for: (i) parental knowledge and impulsivity; (ii) ASB (ages 13, 14 or 15); or (iii) community involvement at ages 14 and 15. Findings provide limited evidence for impulsivity as a differential susceptibility phenotype. PMID- 21553938 TI - Depressed people are not less motivated by personal goals but are more pessimistic about attaining them. AB - Despite its theoretical importance, personal goal motivation has rarely been examined in clinical depression. Here we investigate whether clinically depressed persons (n = 23) differ from never-depressed persons (n = 26) on number of freely generated approach and avoidance goals, appraisals of these goals, and reasons why these goals would and would not be achieved. Participants listed approach and avoidance goals separately and generated explanations for why they would (pro) and would not (con) achieve their most important approach and avoidance goals, before rating the importance, likelihood, and perceived control of goal outcomes. Counter to hypothesis, depressed persons did not differ from never-depressed controls on number of approach or avoidance goals, or on the perceived importance of these goals. However, compared to never-depressed controls, depressed individuals gave lower likelihood judgments for desirable approach goal outcomes, tended to give higher likelihood judgments for undesirable to-be-avoided goal outcomes, and gave lower ratings of their control over goal outcomes. Furthermore, although controls generated significantly more pro than con reasons for goal achievement, depressed participants did not. These results suggest that depressed persons do not lack valued goals but are more pessimistic about their likelihood, controllability, and reasons for successful goal attainment. PMID- 21553939 TI - Walk on the bright side: physical activity and affect in major depressive disorder. AB - Although prescribed exercise has been found to improve affect and reduce levels of depression, we do not know how self-initiated everyday physical activity influences levels of positive affect (PA) and negative affect (NA) in depressed persons. Fifty-three individuals diagnosed with Major Depressive Disorder (MDD) and 53 never-depressed controls participated in a seven-day experience sampling study. Participants were prompted randomly eight times per day and answered questions about their physical activity and affective state. Over the week, the two groups of participants did not differ in average level of physical activity. As expected, participants with MDD reported lower average PA and higher average NA than did never-depressed controls. Both participants with MDD and controls reported higher levels of PA at prompts after physical activity than at prompts after inactive periods; moreover, for both groups of participants, PA increased from a prompt after an inactive period to a subsequent prompt at which activity was reported. Depressed participants in particular showed a dose-response effect of physical activity on affect: longer duration and/or higher intensity of physical activity increased their PA significantly more than did short duration and/or lower intensity physical activity. Physical activity did not influence NA in either group. In contrast to previous treatment studies that examined the effects of prescribed structured exercise, this investigation showed that self initiated physical activity influences PA. These findings also underscore the importance of distinguishing between PA and NA to gain a more comprehensive understanding of the effects of physical activity on affect in MDD. PMID- 21553940 TI - Rumination as a vulnerability factor to depression during the transition from early to middle adolescence: a multiwave longitudinal study. AB - The current study examined vulnerability to depression during the transition from early to middle adolescence from the perspective of the response styles theory. During an initial assessment, 382 adolescents (ages 11-15 years) completed self report measures assessing rumination and depressive symptoms as well as a semistructured clinical interview assessing current and past major depressive episodes. Every 3 months for the subsequent 2 years, adolescents completed self report measures assessing depressive symptoms and negative events. Every 6 months, adolescents completed a semistructured clinical interview assessing the onset of new major depressive episodes. Higher levels of rumination were associated with a greater likelihood of exhibiting a past history of major depressive episodes, a greater likelihood of experiencing the onset of a future major depressive episode, and greater duration of future depressive episodes. Consistent with a vulnerability-stress perspective, rumination moderated the association between the occurrence of negative events and the development of future depressive symptoms and major depressive episodes. PMID- 21553941 TI - Depression and anxious apprehension distinguish frontocingulate cortical activity during top-down attentional control. AB - A network consisting of left dorsolateral prefrontal cortex (LDLPFC) and dorsal anterior cingulate cortex (dACC) has been implicated in top-down attentional control. Few studies have systematically investigated how this network is altered in psychopathology, despite evidence that depression and anxiety are associated with attentional control impairments. Functional MRI and dense-array event related brain potential (ERP) data were collected in separate sessions from 100 participants during a color-word Stroop task. Functional MRI results guided ERP source modeling to characterize the time course of activity in LDLPFC (300-440 ms) and dACC (520-680 ms). At low levels of depression, LDLPFC activity was indirectly related to Stroop interference and only via dACC activity. In contrast, at high levels of depression, dACC did not play an intervening role, and increased LDLPFC activity was directly related to decreased Stroop interference. Specific to high levels of anxious apprehension, higher dACC activity was related to more Stroop interference. Results indicate that depression and anxious apprehension modulate temporally and functionally distinct aspects of the frontocingulate network involved in top-down attention control. PMID- 21553942 TI - Interpersonal pathoplasticity in individuals with generalized anxiety disorder. AB - Recent theories of generalized anxiety disorder (GAD) have emphasized interpersonal and personality functioning as important aspects of the disorder. We examined heterogeneity in interpersonal problems in 2 studies of individuals with GAD (n = 47 and n = 83). Interpersonal subtypes were assessed with the Inventory of Interpersonal Problems-Circumplex (Alden, Wiggins, & Pincus, 1990). Across both studies, individuals with GAD exhibited heterogeneous interpersonal problems, and cluster analyses of these patients' interpersonal characteristics yielded 4 replicable clusters, identified as intrusive, exploitable, cold, and nonassertive subtypes. Consistent with our pathoplasticity hypotheses, clusters did not differ with GAD severity, anxiety severity, or depression severity. Clusters in Study 2 differed on rates of personality disorders, including avoidant personality disorder, further providing support for the validity of interpersonal subtypes. The presence of interpersonal subtypes in GAD may have important implications for treatment planning and efficacy. PMID- 21553943 TI - Low-level temporal coding impairments in psychosis: preliminary findings and recommendations for further studies. AB - The authors investigated whether difficulties with temporal event coding, previously reported in patients with schizophrenia, are already present during first-episode psychosis (FEP). In this experiment, the subjective judgments of the simultaneity of visually presented stimuli were compared between 11 healthy controls, 9 patients with chronic schizophrenia (CSZ), and a sample of 11 FEP patients. Participants were asked to indicate whether 2 vertical bars appeared at the same time or at different times on a computer monitor. CSZ patients' thresholds were elevated, and the FEP sample showed higher thresholds relative to controls. Although preliminary, these findings indicate a generalized disturbance in event-structure coding at early stages of psychosis and question the specificity of its disturbance. Considering the proposed relationship between event-structure coding and the experience of time in general, this study recommends that future studies refocus on psychosis in general, rather than on schizophrenia as a particular case of abnormal temporal processing. In addition, it is suggested that the relevant psychopathology will be best determined by means of a comprehensive analysis of low-level temporal coding performance in different types of psychosis. PMID- 21553944 TI - Early age alcohol use and later alcohol problems in adolescents: individual and peer mediators in a bi-national study. AB - This paper examines whether there is cross-national similarity in the longitudinal relationship between early age alcohol use and adolescent alcohol problems. Potential mechanisms underlying this relationship also are examined, testing adolescent alcohol use, low self-regulation, and peer deviance as possible mediators. Students (N = 1,945) participating in the International Youth Development Study, a longitudinal panel survey study, responded to questions on alcohol use and influencing factors, and were followed annually over a 3-year period from 2002 to 2004 (98% retention rate). State-representative, community student samples were recruited in grade 7 in Washington State, United States (US, n = 961, 78% of those eligible; Mage = 13.09, SD = .44) and Victoria, Australia (n = 984, 76% of those eligible; Mage = 12.93, SD = .41). Analyses were conducted using multiple-group structural equation modeling. In both states, early age alcohol use (age 13) had a small but statistically significant association with subsequent alcohol problems (age 15). Overall, there was little evidence for mediation of early alcohol effects. Low self-regulation prospectively predicted peer deviance, alcohol use, and alcohol problems in both states. Peer deviance was more positively related to alcohol use and low self-regulation among students in Victoria compared to students in Washington State. The small but persistent association of early age alcohol use with alcohol problems across both samples is consistent with efforts to delay alcohol initiation to help prevent problematic alcohol use. Self-regulation was an important influence, supporting the need to further investigate the developmental contribution of neurobehavioral disinhibition. PMID- 21553945 TI - Use of protective behavioral strategies and their association to 21st birthday alcohol consumption and related negative consequences: a between- and within person evaluation. AB - The purpose of the present study was to examine between- and within-person relationships among protective behavioral strategies (PBS), alcohol consumption, and related negative consequences during the 21st birthday week. Participants for the present study included undergraduate college students (n = 1,028) who turned 21 during three academic quarters at a large public northwestern university in the United States. Students completed a Web-based survey that comprised measures of 21st birthday PBS, alcohol consumption, and alcohol-related negative consequences. Between-person findings indicated that participants who used more manner of drinking PBS and fewer serious harm reduction PBS consumed fewer drinks and reached lower BACs. Results also showed that participants who used a greater number of limiting/stopping PBS and who used more manner of drinking PBS experienced fewer negative consequences. Within-person findings demonstrated that on days when participants used more limiting/stopping PBS, fewer manner of drinking PBS, and more serious harm reduction PBS than average they also consumed more drinks and reached higher BACs. When examining negative consequences, within person results showed that on days when participants used more limiting/stopping PBS, fewer manner of drinking PBS, and more serious harm reduction PBS than usual they experienced more negative consequences. Discussion focuses on clarification of the association between PBS and drinking and implications for preventive interventions. PMID- 21553946 TI - Dispositions to rash action moderate the associations between concurrent drinking, depressive symptoms, and alcohol problems during emerging adulthood. AB - "Impulsivity" has been consistently identified as a key personality predictor of alcohol-related problems and subsequent alcohol use disorder. Multiple prior studies have demonstrated impulsivity is an individual difference factor that strengthens the effects of some risk factors, such as alcohol consumption and depressive symptoms, on alcohol problems. However, recent research indicated common measures of impulsivity actually reflect multiple dispositions toward rash action, and that alcohol problems were most consistently related to one of those dispositions, negative urgency. Little research has examined how specific dispositions to rash action may act as putative moderators of other risk factors for alcohol problems. The goal of the current study was to test which dispositions to rash action moderated the effects of concurrent alcohol use or depressive symptoms on alcohol problems. Using a large cross-sectional sample of college students (n = 573), the current study utilized semicontinuous regression models, which allow prediction of both the likelihood and level of alcohol problems. Negative urgency was found to be the main predictor of alcohol problems, above and beyond other dispositions to rash action, which replicates prior research. However, each of the other dispositions exhibited risk-enhancing effects on the relations between either depressive symptoms or alcohol use and concurrent alcohol problems. Specifically, lower levels of premeditation enhanced the association between depressive symptoms and alcohol problems, while lower perseverance and higher sensation seeking were related to more alcohol problems at higher levels of alcohol use. Results suggest that multiple dispositions to rash action were related to problematic alcohol use both directly and via their interaction with other risk factors. PMID- 21553947 TI - Cue-reactivity in the natural environment of cigarette smokers: the impact of photographic and in vivo smoking stimuli. AB - The cue-reactivity paradigm has been used extensively in laboratory settings to study cue-specific craving responses to drug-related cues. However, this procedure has been used in only one study to assess craving in the drug user's natural environment (Warthen & Tiffany, 2009). The present study combined cue reactivity with ecological momentary assessment (CREMA) to evaluate smokers' cue reactions in natural environments as a further validation and extension of this procedure. A total of 66 daily cigarette smokers carried a personal digital assistant (PDA) and had the opportunity to respond to 32 cue-reactivity sessions across 8 days. Cues were presented through in vivo and photographic modes. During in vivo sessions, participants handled and looked at a cigarette or neutral object, while during photographic sessions, participants looked at a smoking related or neutral photograph on the PDA. Craving and mood were assessed before and after cue presentations. Cues were also presented in the laboratory both before (Lab I) and after (Lab II) the 8-day CREMA procedure. Participants completed over 90% of cue-reactivity sessions delivered with the CREMA procedure. Analyses revealed robust cue-reactivity in the natural environment and laboratory across both modes of presentation. Photographic cues elicited significantly stronger cue-reactivity effects than in vivo cues across all sessions. The CREMA procedure has been shown to elicit robust cue-reactivity effects across multiple modes of cue presentation. Results support the use of the CREMA procedure for examining cue-specific craving in the natural environment of smokers. PMID- 21553948 TI - The relationship between depression level and smoking motives in college smokers. AB - While the link between cigarette smoking and depression symptomatology has been well established, more research is needed to determine how smoking motives are related to depression levels in smokers. Specifically, smoking motives related to the friendship-like attachment to smoking (i.e., affiliative attachment) may play an important role in individuals reporting depressive symptomatology. The present study examined the relationship between three smoking motives and depression levels in a sample of 79 mildly nicotine-dependent, college student cigarette smokers. A hierarchical multiple regression analysis was conducted with depression as the dependent variable and gender and cigarettes per day as the independent variables (Step 1), positive and negative reinforcement motives (Step 2), and affiliative attachment motives (Step 3). Results of regression analyses indicated that affiliative attachment motives explained significant variance in participant depression level above and beyond that explained by positive and negative reinforcement motives. These findings suggest that smokers with elevated depression should be assessed for social functioning and affiliative attachment smoking motives, and future research should be conducted to determine if individuals with high levels of affiliative attachment may benefit from smoking cessation treatment programs with an enhanced social support component. PMID- 21553949 TI - A test of positive affect induction for countering self-control depletion in cigarette smokers. AB - The self-control strength model posits that exerting self-control on one task, such as resisting temptations, will deplete self-control and impair subsequent self-regulatory performance, such as controlling smoking. The current study examined interventions designed to replenish depleted self-control strength to prevent tobacco use by inducing positive affect. In a 2 * 2 design, 200 participants were randomized to either (1) resist eating from a plate of desserts (high temptation) or from a plate of raw vegetables (low temptation) and then (2) undergo a positive or neutral affect induction. Two inductions were compared (video vs. writing technique). Participants were then given a 10-min recess. Whether or not participants smoked during the recess, assessed by self-report and biochemical verification, served as the primary dependent variable. The interaction between depletion and exposure group was significant, Wald's chi2 = 9.66, df = 3, p < .05. Among those assigned to resist desserts, 65.5% to 85% smoked if they were in the neutral video or writing conditions versus 10.5% in the positive affect video group. Positive affect elicited with a video was able to counteract the detrimental effects of self-control depletion on smoking behavior, while writing exercises were associated with smoking. Implications for tobacco cessation intervention are discussed. PMID- 21553950 TI - Psychology's contributions to understanding and addressing global climate change. AB - Global climate change poses one of the greatest challenges facing humanity in this century. This article, which introduces the American Psychologist special issue on global climate change, follows from the report of the American Psychological Association Task Force on the Interface Between Psychology and Global Climate Change. In this article, we place psychological dimensions of climate change within the broader context of human dimensions of climate change by addressing (a) human causes of, consequences of, and responses (adaptation and mitigation) to climate change and (b) the links between these aspects of climate change and cognitive, affective, motivational, interpersonal, and organizational responses and processes. Characteristics of psychology that cross content domains and that make the field well suited for providing an understanding of climate change and addressing its challenges are highlighted. We also consider ethical imperatives for psychologists' involvement and provide suggestions for ways to increase psychologists' contribution to the science of climate change. PMID- 21553951 TI - Human behavioral contributions to climate change: psychological and contextual drivers. AB - We are facing rapid changes in the global climate, and these changes are attributable to human behavior. Humans produce this global impact through our use of natural resources, multiplied by the vast increase in population seen in the past 50 to 100 years. Our goal in this article is to examine the underlying psychosocial causes of human impact, primarily through patterns of reproduction and consumption. We identify and distinguish individual, societal, and behavioral predictors of environmental impact. Relevant research in these areas (as well as areas that would be aided by greater attention by psychologists) are reviewed. We conclude by highlighting ethical issues that emerge when considering how to address human behavioral contributions to climate change. PMID- 21553952 TI - The psychological impacts of global climate change. AB - An appreciation of the psychological impacts of global climate change entails recognizing the complexity and multiple meanings associated with climate change; situating impacts within other social, technological, and ecological transitions; and recognizing mediators and moderators of impacts. This article describes three classes of psychological impacts: direct (e.g., acute or traumatic effects of extreme weather events and a changed environment); indirect (e.g., threats to emotional well-being based on observation of impacts and concern or uncertainty about future risks); and psychosocial (e.g., chronic social and community effects of heat, drought, migrations, and climate-related conflicts, and postdisaster adjustment). Responses include providing psychological interventions in the wake of acute impacts and reducing the vulnerabilities contributing to their severity; promoting emotional resiliency and empowerment in the context of indirect impacts; and acting at systems and policy levels to address broad psychosocial impacts. The challenge of climate change calls for increased ecological literacy, a widened ethical responsibility, investigations into a range of psychological and social adaptations, and an allocation of resources and training to improve psychologists' competency in addressing climate change-related impacts. PMID- 21553953 TI - Adapting to and coping with the threat and impacts of climate change. AB - This article addresses the nature and challenge of adaptation in the context of global climate change. The complexity of "climate change" as threat, environmental stressor, risk domain, and impacting process with dramatic environmental and human consequences requires a synthesis of perspectives and models from diverse areas of psychology to adequately communicate and explain how a more psychological framing of the human dimensions of global environmental change can greatly inform and enhance effective and collaborative climate change adaptation and mitigation policies and research. An integrative framework is provided that identifies and considers important mediating and moderating parameters and processes relating to climate change adaptation, with particular emphasis given to environmental stress and stress and coping perspectives. This psychological perspective on climate change adaptation highlights crucial aspects of adaptation that have been neglected in the arena of climate change science. Of particular importance are intra-individual and social "psychological adaptation" processes that powerfully mediate public risk perceptions and understandings, effective coping responses and resilience, overt behavioral adjustment and change, and psychological and social impacts. This psychological window on climate change adaptation is arguably indispensable to genuinely multidisciplinary and interdisciplinary research and policy initiatives addressing the impacts of climate change. PMID- 21553954 TI - The dragons of inaction: psychological barriers that limit climate change mitigation and adaptation. AB - Most people think climate change and sustainability are important problems, but too few global citizens engaged in high-greenhouse-gas-emitting behavior are engaged in enough mitigating behavior to stem the increasing flow of greenhouse gases and other environmental problems. Why is that? Structural barriers such as a climate-averse infrastructure are part of the answer, but psychological barriers also impede behavioral choices that would facilitate mitigation, adaptation, and environmental sustainability. Although many individuals are engaged in some ameliorative action, most could do more, but they are hindered by seven categories of psychological barriers, or "dragons of inaction": limited cognition about the problem, ideological world views that tend to preclude pro environmental attitudes and behavior, comparisons with key other people, sunk costs and behavioral momentum, discredence toward experts and authorities, perceived risks of change, and positive but inadequate behavior change. Structural barriers must be removed wherever possible, but this is unlikely to be sufficient. Psychologists must work with other scientists, technical experts, and policymakers to help citizens overcome these psychological barriers. PMID- 21553955 TI - Contributions of psychology to limiting climate change. AB - Psychology can make a significant contribution to limiting the magnitude of climate change by improving understanding of human behaviors that drive climate change and human reactions to climate-related technologies and policies, and by turning that understanding into effective interventions. This article develops a framework for psychological contributions, summarizes what psychology has learned, and sets out an agenda for making additional contributions. It emphasizes that the greatest potential for contributions from psychology comes not from direct application of psychological concepts but from integrating psychological knowledge and methods with knowledge from other fields of science and technology. PMID- 21553956 TI - Public understanding of climate change in the United States. AB - This article considers scientific and public understandings of climate change and addresses the following question: Why is it that while scientific evidence has accumulated to document global climate change and scientific opinion has solidified about its existence and causes, U.S. public opinion has not and has instead become more polarized? Our review supports a constructivist account of human judgment. Public understanding is affected by the inherent difficulty of understanding climate change, the mismatch between people's usual modes of understanding and the task, and, particularly in the United States, a continuing societal struggle to shape the frames and mental models people use to understand the phenomena. We conclude by discussing ways in which psychology can help to improve public understanding of climate change and link a better understanding to action. (PsycINFO Database Record (c) 2011 APA, all rights reserved). PMID- 21553957 TI - Examining the dimensionality of effortful control in preschool children and its relation to academic and socioemotional indicators. AB - Effortful control (EC) is an important developmental construct, associated with socioemotional growth, academic performance, and psychopathology. EC is defined as the ability to execute goal-directed behavior to inhibit or delay a prepotent response in favor of a subdominant response. Extant research indicates that EC may be multidimensional. Confirmatory factor analysis with a sample of 234 preschoolers was used to determine if tasks designed to measure EC were best described by hot (affectively salient) and cool (affectively neutral) dimensions or by a single factor. Analyses revealed that EC is best described by a single factor, even when variance associated with children's language skills was removed. This EC factor was strongly related to measures of academic performance and significantly less related to measures of socioemotional development. PMID- 21553958 TI - Verbal deception from late childhood to middle adolescence and its relation to executive functioning skills. AB - The present investigation examined 8- to 16-year-olds' tendency to lie, the sophistication of their lies, and related cognitive factors. Participants were left alone and asked not to look at the answers to a test, but the majority peeked. The researcher then asked a series of questions to examine whether the participants would lie about their cheating and, if they did lie, evaluate the sophistication of their lies. Additionally, participants completed measures of working memory, inhibitory control, and planning skills. Results revealed that the sophistication of 8- to 16-year-olds' lies, but not their decision to lie, was significantly related to executive functioning skills. PMID- 21553959 TI - Relationship adjustment, depression, and anxiety during pregnancy and the postpartum period. AB - The associations between relationship adjustment and symptoms of depression and anxiety were evaluated in a sample of pregnant married or cohabiting women (N = 113) who were at risk for perinatal depression because of a prior history of major depression. Women completed self-report measures of relationship adjustment, depressive symptoms, and anxiety symptoms monthly during pregnancy and for the first six months following the birth of their child. Multilevel modeling was used to examine concurrent and time-lagged within-subjects effects for relationship adjustment and depressive and anxiety symptoms. Results revealed that (a) relationship adjustment was associated with both depressive symptoms and anxiety symptoms in concurrent analyses; (b) relationship adjustment was predictive of subsequent anxiety symptoms but not subsequent depressive symptoms in lagged analyses; and (c) depressive symptoms were predictive of subsequent relationship adjustment in lagged analyses with symptoms of depression and anxiety examined simultaneously. These results support the continued investigation into the cross-sectional and longitudinal associations between relationship functioning and depressive and anxiety symptoms in women during pregnancy and the postpartum period. PMID- 21553960 TI - What we don't expect when expecting: evidence for heterogeneity in subjective well-being in response to parenthood. AB - A recent article in New York Magazine echoed what psychological studies of parenthood have consistently demonstrated since the 1970s: "Most people assume that having children will make them happier. Yet a wide variety of academic research shows that parents are not happier than their childless peers, and in many cases are less so" (Senior, 2010). There is consistent evidence that, as opposed to other life events that cause transient disruptions in life satisfaction, becoming a parent appears to cause harm to individual subjective well-being (Twenge, Campbell, & Foster, 2003), and that this harm is sustained over time (Clark, Diener, Georgellis, & Lucas, 2008). The current investigation was predicated on the concern that these findings may be the result of the methodology used to examine them. As the experience of parenthood does not represent a unified phenomenon, we employed a methodological approach that allows for the exploration of heterogeneity as well as its predictors. By modeling heterogeneous trajectories within a prospective design from 4 years prior to 4 years after the birth of a parent's first child, we find that the majority of individuals (84.2%) demonstrate no long-term effects on life satisfaction in response to childbirth. Only a small percentage demonstrate the sustained declines (7.2%), and a significant cohort, previously unobserved in the literature, demonstrate dramatic and sustained improvements in response to parenthood (4.3%), providing compelling evidence for heterogeneity in life satisfaction among parents. Key demographic covariates that distinguish between trajectories of response are also explored. PMID- 21553961 TI - Revisiting the effect of marital support on depressive symptoms in mothers and fathers: a genetically informed study. AB - This article uses a genetically informed design to evaluate whether (1) the well documented association between marital support and depressive symptoms is accounted for by genetic and/or shared environmental selection, (2) gender differences are found after controlling for selection effects, and (3) parenthood moderates any nonshared environmental relation between depressive symptoms and marital support. We used a sample of 1,566 pairs of same-sexed, married twins from the Australian Twin Registry to evaluate our hypotheses that (1) the predicted effect of marital support on depressive symptoms is not fully an artifact of selection, (2) the etiological sources accounting for this effect differ between husbands and wives, and (3) parenthood status moderates the effect of marital support on depressive symptoms adjusting for selection effects. The results support the first hypotheses. However, after controlling for selection, the effect of marital support on depressive symptoms was not significantly different for husbands and wives. Parenthood moderated the effect of marital support, such that after controlling for selection, marital support is more strongly associated with depressive symptoms for full-time parents than nonfull time parents. PMID- 21553962 TI - Development and psychometric properties of the OCD Family Functioning (OFF) Scale. AB - Obsessive-compulsive disorder (OCD) influences not only patients but also family members. Although the construct of family accommodation has received attention in OCD literature, no measures of overall family functioning are currently available. The OCD Family Functioning (OFF) Scale was developed to explore the context, extent, and perspectives of functional impairment in families affected by OCD. It is a three-part, self-report measure capturing independent perspectives of patients and relatives. A total of 400 subjects were enrolled between 2008 and 2010 from specialized OCD clinics and OCD research studies. Psychometric properties of this scale were examined including internal consistency, test-retest reliability, convergent and divergent validity, and exploratory factor analyses. Both patient and relative versions of the OFF Scale demonstrated excellent internal consistency (Cronbach's alpha coefficient = 0.96). The test-retest reliability was also adequate (ICC = 0.80). Factor analyses determined that the OFF Scale comprises a family functioning impairment factor and four OCD symptom factors that were consistent with previously reported OCD symptom dimension studies. The OFF Scale demonstrated excellent convergent validity with the Family Accommodation Scale and the Work and Social Adjustment Scale. Information gathered regarding emotional impact and family role-specific impairment was novel and not captured by other examined scales. The OFF Scale is a reliable and valid instrument for the clinical and research assessment of family functioning in pediatric and adult OCD. This will facilitate the exploration of family functioning impairment as a potential risk factor, as a moderator and as a treatment outcome measure in OCD. PMID- 21553963 TI - Marital conflict and children's sleep: reciprocal relations and socioeconomic effects. AB - We examined reciprocal relations between parental marital conflict and children's sleep disruptions over two years. The roles of ethnicity (African American and European American) and socioeconomic status were tested as moderators of the examined relations. A community sample of 176 school-age children (M age = 8.68 at T1) and their parents participated at T1 and T2 with a 2-year interval between waves. Mothers, fathers, and children reported on parental marital conflict, and children's sleep was measured via actigraphy and self-reports. Latent variable modeling indicated that T1 marital conflict predicted increases in children's sleep disruptions longitudinally; results were more pronounced for African American children and those from lower SES homes. Further, children's sleep disruptions at T1 predicted increases in marital conflict over time. Results demonstrate the importance of reciprocal relations between a prevalent familial stressor and a fundamental facet of children's health, especially when considering the sociocultural milieu. PMID- 21553964 TI - A two-dimensional approach to relationship conflict: meta-analytic findings. AB - This meta-analysis of 64 studies (5,071 couples) used a metacoding system to categorize observed couple conflict behaviors into categories differing in terms of valence (positive to negative) and intensity (high to low) and resulting in five behavioral categories: hostility, distress, withdrawal, problem solving, and intimacy. Aggregate effect sizes indicated that women were somewhat more likely to display hostility, distress, and intimacy during conflict, whereas men were somewhat more likely to display withdrawal and problem solving. Gender differences were of a small magnitude. For both men and women, hostility was robustly associated with lower relationship satisfaction (medium effect), distress and withdrawal were somewhat associated (small effect), and intimacy and problem solving were both closely associated with relationship satisfaction (medium effect). Effect sizes were moderated in several cases by study characteristics including year of publication, developmental period of the sample, recruitment design, duration of observed conflict, method used to induce conflict, and type of coding system used. Findings from this meta-analysis suggest that high-intensity conflict behaviors of both a positive and negative nature are important correlates of relationship satisfaction and underscore the relatively small gender differences in many conflict behaviors. PMID- 21553965 TI - Workload and the trajectory of marital satisfaction in newlyweds: job satisfaction, gender, and parental status as moderators. AB - Stress, on average, is bad for relationships. Yet stress at work is not always associated with negative relationship outcomes. The premise of the current study was that associations between workload and trajectories of marital satisfaction depend on circumstances that may constrain or facilitate partners' ability to negotiate their multiple roles. We hypothesized that the covariance between changes in workload and marital satisfaction over time should be moderated by (a) the extent to which spouses like their work, (b) their parental status, and (c) their gender. Analyses drawing upon eight waves of data on workload, work satisfaction, and marital satisfaction from 169 newlywed couples assessed over four years confirmed these predictions. Specifically, across couples, demands at work covaried positively with marital satisfaction for spouses who were more satisfied with their jobs. For nonparent couples, increases in husbands' workload covaried with increases in marital satisfaction for both spouses. For parent couples, however, increases in husbands' workload covaried with declines in marital satisfaction for both spouses. Unexpectedly, for parent couples, increases in wives' workload corresponded with increased marital satisfaction. Finally, consistent with predictions, wives were more affected by their husbands' workload than vice versa. Thus, tension between work and marriage is not inevitable, instead depending on circumstances that facilitate or impair performance in multiple roles. Couples, employers, and practitioners should recognize the role that external circumstances play in determining how work and marital life interact. PMID- 21553966 TI - Evidence that self-affirmation reduces alcohol consumption: randomized exploratory trial with a new, brief means of self-affirming. AB - OBJECTIVE: To test the ability of a new, brief means of affirming the self (the "self-affirming implementation intention") to decrease alcohol consumption against a standard means of self-affirmation (the self-affirming "kindness" questionnaire) and an active control condition; to test whether self-affirmation effects can be sustained beyond the experimental session; and to examine potential moderators of the effects. METHOD: Two hundred seventy-eight participants were randomly allocated to one of three conditions: control questionnaire, self-affirming questionnaire, and self-affirming implementation intention. All participants were exposed to a threatening health message, designed to inform them about the health risks associated with consuming alcohol. MAIN OUTCOME MEASURES: The main outcome measure was subsequent alcohol intake. RESULTS: There were significant public health gains and statistically significant decreases (>1 unit/day) in alcohol consumption in the two experimental conditions but not in the control condition. At the end of the study, participants in the control condition were consuming 2.31 units of alcohol per day; people in the self-affirming questionnaire condition were consuming 1.52 units of alcohol per day; and people in the self-affirming implementation intention condition were consuming 1.53 units of alcohol per day. There were no significant differences between the self-affirming questionnaire and self-affirming implementation intention, and adherence did not moderate the effects. Self-affirmation also improved message processing, increased perceived threat, and led to lower message derogation. CONCLUSIONS: The findings support the efficacy of a new, brief self affirmation manipulation to enhance the effectiveness of health risk information over time. Further research is needed to identify mediators of the effects of self-affirmation on health behavior change. PMID- 21553967 TI - Health Psychology 2011-2016: welcome and opening comments. PMID- 21553968 TI - Glycemic control among Latinos with type 2 diabetes: the role of social environmental support resources. AB - OBJECTIVE: Although active diabetes self-management is required to achieve glycemic control, adherence is poor among ethnic minorities, especially Latinos. Research shows that individuals who report greater social-environmental support resources for disease management manage their diabetes more effectively than those with fewer support resources. METHODS: Path analysis was conducted to investigate the value of a multiple-mediator model in explaining how support resources for disease management influence hemoglobin A1c (HbA1c) levels in a sample of 208 Latinos with Type 2 diabetes recruited from low-income serving community clinics in San Diego County. We hypothesized that the relationship between support resources for disease-management and HbA1c would be mediated by diabetes self-management and/or depression. RESULTS: Participants who perceived greater support resources for disease-management reported better diabetes self management (beta = .40, p < .001) and less depression (beta = -.19, p < .01). In turn, better diabetes self-management and less depression were associated with tighter glycemic control (HbA1c; beta = -.17, p < .05 and beta = .15, p < .05, respectively). Once the indirect effects via diabetes self-management (95% CI [ .25; -.03]) and depression (95% CI [-.14; -.01]) were statistically controlled, the direct pathway from support resources to HbA1c was markedly reduced (p = .57). CONCLUSIONS: These findings demonstrate the important connection that support resources for disease management can have with diabetes self-management, emotional well-being, and glycemic control among Latinos. Thus, programs targeting diabetes self-management and glycemic control in this population should consider culturally relevant, multilevel influences on health outcomes. PMID- 21553969 TI - A prospective study of positive psychological well-being and coronary heart disease. AB - OBJECTIVE: Research suggests that positive psychological well-being is associated with cardiovascular health. However, much of this research uses elderly samples and has not determined the pathways by which psychological well-being influences cardiovascular disease or whether effects are similar for men and women. This study investigates the association between two aspects of well-being (emotional vitality and optimism) and coronary heart disease (CHD) in a sample of middle aged men and women, and considers potential mediating factors. METHOD: Between 1991 and 1994, well-being and coronary risk factors were assessed among 7,942 individuals without a prior cardiovascular event from the Whitehall II cohort. Incident CHD (fatal CHD, first nonfatal myocardial infarction, or first definite angina) was tracked during 5 person-years of follow-up. RESULTS: Positive psychological well-being was associated with reduced risk of CHD with an apparent threshold effect. Relative to people with the lowest levels of well-being, those with the highest levels had minimally adjusted hazard ratios of 0.74, 95% confidence interval [0.55, 0.98] for emotional vitality and 0.73, 95% confidence interval [0.54, 0.99] for optimism. Moreover, the association was strong for both genders and was only weakly attenuated when accounting for ill-being. Neither health-related behaviors nor biological factors explained these associations. CONCLUSIONS: Positive psychological well-being was associated with a modest, but consistent reduced risk of incident CHD. The relationship was comparable for men and women, and was maintained after controlling for cardiovascular risk factors and ill-being. Additional research is needed to identify underlying mechanisms and investigate whether interventions to increase well-being may enhance cardiovascular health. PMID- 21553970 TI - Work-based predictors of mortality: a 20-year follow-up of healthy employees. AB - OBJECTIVES: This study investigated the effects of the Job-Demand-Control-Support (JDC-S) model's components, workload, control, peer and supervisor social support, on the risk of all-cause mortality. Also examined was the expectation that the above work-based components interact in predicting all-cause mortality. The study's hypotheses were tested after controlling for physiological variables and health behaviors known to be risk factors for mortality. MAIN OUTCOME MEASURE: The design used was prospective. Baseline data were obtained from healthy employees (N = 820) who underwent periodic health examinations in 1988. Follow-up data on all-cause mortality were obtained from the participants' computerized medical file, kept by their HMO, in 2008. The baseline data covered socioeconomic, behavioral, and biological risk factors in addition to the components of the JDC-S model. During the period of follow-up, 53 deaths were recorded. Data were analyzed using Cox regressions. RESULTS: Only one main effect was found: the risk of mortality was significantly lower for those reporting high levels of peer social support. The study found two significant interactions. Higher levels of control reduced the risk of mortality for the men and increased it for the women. The main effect of peer social support on mortality risk was significantly higher for those whose baseline age ranged from 38 to 43 but not for the older than 43 or the younger than 38 participants. CONCLUSION: Peer social support is a protective factor, reducing the risk of mortality, while perceived control reduces the risk of mortality among men but increases it among women. PMID- 21553971 TI - Thinking about a close relationship differentially impacts cardiovascular stress responses among depressed and nondepressed women. AB - OBJECTIVE: Individuals with depression and low social support are at elevated risk for developing cardiovascular disease--presumptively through mechanisms involving dysregulated stress physiology. While depressed individuals often report diminished social support and elevated levels of social distress, few studies have examined how social factors impact stress-related cardiovascular activity in depressed samples. Accordingly, we evaluated the social modulation of stress-related cardiovascular activity in a sample of 38 medically healthy, unmedicated depressed and nondepressed individuals. METHODS: Cardiovascular and psychological measures were obtained before and after depressed and nondepressed women engaged in a speech stress task. To evaluate the impact of social factors on stress responses, half of the women completed the speech stress task first, while the other half completed the speech stress after engaging in a relationship focused imagery task. RESULTS: Nondepressed women who first thought about a close relationship displayed global attenuations in blood pressure throughout the subsequent stress task, consistent with a stress-buffering effect of perceived social support. Conversely, depressed women who first thought about a close relationship displayed global elevations in blood pressure throughout the subsequent stress task, consistent with a stress-enhancing effect of perceived social distress in depressed women. CONCLUSION: Thinking about a close relationship differentially impacted subsequent cardiovascular activity during an evocative stressor in depressed and nondepressed women. Understanding the social context in which stress is experienced may aid in identifying, and ultimately attenuating, cardiovascular risks observed among patients with major depressive disorder. PMID- 21553972 TI - Physical activity program delivery by professionals versus volunteers: the TEAM randomized trial. AB - OBJECTIVE: Older adults have low rates of physical activity participation, but respond positively to telephone-mediated support programs. Programs are often limited by reliance on professional staff. This study tested telephone-based physical activity advice delivered by professional staff versus trained volunteer peer mentors. DESIGN: A 12-month, randomized, controlled clinical trial was executed from 2003-2008. Twelve volunteer peer mentors and 181 initially inactive adults ages 50 years and older were recruited from the San Francisco Bay Area. Participants were randomized to: (1) telephone-based physical activity advice delivered by professional staff, (2) telephone-based physical activity advice delivered by trained volunteer peers, or (3) an attention-control arm of staff delivered telephone support for nutrition. MAIN OUTCOME MEASURES: Moderate intensity or more vigorous physical activity (MVPA) was assessed at baseline, 6, and 12 months with the Community Healthy Activities Model Program for Seniors (CHAMPS) Questionnaire, with accelerometry validation (Actigraph) in a randomly selected subsample. Treatment fidelity was examined through analysis of quantity and quality of intervention delivery. RESULTS: At 6 and 12 months, both physical activity arms significantly increased MVPA relative to the control arm. Both physical activity arms were comparable in quantity of intervention delivery, but peers demonstrated more versatility and comprehensiveness in quality of intervention content. CONCLUSIONS: This study demonstrates that trained peer volunteers can effectively promote physical activity increases through telephone based advice. The results support a program delivery model with good dissemination potential for a variety of community settings. PMID- 21553973 TI - Framing flu prevention--an experimental field test of signs promoting hand hygiene during the 2009-2010 H1N1 pandemic. AB - OBJECTIVE: During the 2009-2010 H1N1 flu pandemic, many institutions installed alcohol-based hand sanitizer dispensers in public settings in an effort to prevent the spread of the virus. Yet, usage of these dispensers remained low. METHOD: Point-of-use reminder signs were designed to emphasize four theoretically grounded health beliefs: perceived susceptibility, social norms, consequences of the behavior framed as gains, and consequences of the behavior framed as losses. From October 2009 to March 2010, 58 sanitizer dispensers in public buildings were randomly assigned to have one of the four signs placed next to it, and dispenser usage was continually monitored. RESULTS: All signs were associated with greater sanitizer usage compared to no sign. The gain-framed sign was associated with greatest usage (66% over no sign). Signs emphasizing susceptibility to H1N1 were associated with the lowest usage (41% over no sign). Although usage declined over time and closely mirrored trends in public interest about H1N1, the influence of the signs was not dependent on degree of public interest. CONCLUSION: This experimental field study shows how simple, theoretically grounded signs can serve as cues to action in promoting the adoption of preventive behaviors. Gain-framed signage is particularly effective in promoting hand hygiene in a flu pandemic. PMID- 21553974 TI - Using the question-behavior effect to promote disease prevention behaviors: two randomized controlled trials. AB - OBJECTIVE: To test the efficacy of interventions based on the question-behavior effect in promoting the adoption of disease prevention behaviors. DESIGN: In Study 1, adults from the general public were randomly allocated to complete a questionnaire about health checks (question-behavior effect condition) or not (control) and later received an invitation to attend for screening. In Study 2, health care professionals were randomly allocated to complete a questionnaire about influenza vaccination or not and later had the opportunity to receive a vaccination. MAIN OUTCOME MEASURES: We objectively assessed health check attendance (Study 1) and influenza vaccination (Study 2). RESULTS: In Study 1, intention-to-treat analyses indicated that health check attendance was significantly higher in the question-behavior effect condition (68.3%) compared with the control condition (53.5%). In Study 2, intention-to-treat analyses indicated that influenza vaccination was significantly higher among participants in the question-behavior effect condition (42.0%) compared with the control condition (36.3%), and this effect persisted after controlling for demographic variables. Explanatory analyses indicated that the effects in both studies were attributable to completing rather than merely receiving the questionnaire and were stronger for those with positive attitudes or intentions about the target behavior. CONCLUSION: The question-behavior effect represents a simple, cost effective means to increase disease prevention behaviors among the general public and health professionals. Implications for promoting health behaviors are discussed. PMID- 21553975 TI - Condom use among young women: modeling the theory of gender and power. AB - OBJECTIVE: This study sought to articulate pathways between constructs from the theory of gender and power and their associations with sexual behavior. DESIGN: The data were collected preintervention during a randomized controlled HIV prevention trial. Participants were 701 sexually active, unmarried African American females, aged 14-20, who were not pregnant, and were recruited from three health clinics in a southeastern US city. Structural equation modeling was used for the analyses. MAIN OUTCOME MEASURE: Self-reported condom use. RESULTS: Theoretical associations yielded a well-fitting structural model across initial and cross-validation samples. A significant amount of variance was explained for the variables of condom use (R2 = .31, .18), partner communication (R2 = .30, .26), substance use during sex (R2 = .32, .51), and negative personal affect (R2 = .36, .48). Partner communication (.35, .38) was the strongest predictor of condom use, negative personal affect (-.41, -.37) was the strongest predictor of partner communication, and physical risk (.54, .54) was the strongest predictor of negative personal affect. CONCLUSION: This model provides evidence to support both direct and indirect associations between social and behavioral risk factors and condom use. Associations between theory of gender and power constructs and condom use can facilitate future development and analyses of interventions based on this theory. PMID- 21553976 TI - Resources for health: differential effects of optimistic self-beliefs and social support according to socioeconomic status. AB - OBJECTIVE: This study examined whether socioeconomic status (SES) determines the degree to which psychological and social resources such as optimistic self beliefs and social support affect health. DESIGN: We used data from the representative German Ageing Survey (N = 2,454, aged 40-85 years). Structural equation modeling was employed to examine whether relationships between psychological (self-esteem, control beliefs, optimism) and social resources (perceived emotional and informational support, network size) and health differ between education and income groups. MAIN OUTCOME MEASURES: Self-reported physical health, functional health, and subjective health. RESULTS: Psychological resources positively affected health in all groups but were stronger predictors of functional and subjective health in low compared to higher educated participants. A higher level of social resources was associated with better functional and subjective health mainly in the low-income group. Social resources were particularly important for financially disadvantaged older people. CONCLUSION: Our results provide evidence for differential effects of optimistic self-beliefs and social support on health depending on whether individuals are challenged by low incomes or low education. Future research, especially aimed at intervention, should consider that different aspects of SES have differential meanings and that the impact of health-protective factors may vary according to SES facet. PMID- 21553977 TI - Do low-numeracy people avoid shared decision making? AB - OBJECTIVES: Doctors have been increasingly encouraged to involve patients in decision making rather than pursuing the paternalistic model in which they make the decisions for their patients. But do patients want to participate in making decisions about their health? Is there a relationship between their preferences for shared decision making and numeracy skills? Are those preferences different in countries with different medical systems, and for different age groups? Extant studies cannot answer these questions because most are based on nonprobabilistic, highly selective patient samples that prevent generalizations to a broader population. DESIGN: In a survey on probabilistic national samples in the United States and Germany, we interviewed participants with low numeracy skills (Germany: n = 127, mean numeracy = 37; United States: n = 117, mean numeracy = 36) and high numeracy skills (Germany: n = 133, mean numeracy = 96; U.S.: n = 121, mean numeracy = 91). MAIN OUTCOME MEASURES: Usual and preferred role in medical decision making. RESULTS: A significant number of people with low numeracy in both the United States (35%, SE = 8.2) and Germany (30%, SE = 6.1) preferred to be more passive than they currently were. High-numeracy people, in contrast, were mostly satisfied with their current role. On average, Americans were more active than Germans. Middle-aged participants preferred to be more active compared to both younger and older ones. CONCLUSIONS: Shared decision making preferences are related to numeracy skills, country, and age. Education efforts to increase numeracy, as well as using nonquantitative communication formats, may foster involvement of low-numeracy patients in decisions about their health. PMID- 21553978 TI - Patient-centered culturally sensitive health care: model testing and refinement. AB - OBJECTIVES: This article presents the results of an empirical test of a literature-based Patient-Centered Culturally Sensitive Health Care Model. The model was developed to explain and improve health care for ethnically diverse patients seen in community-based primary care clinics. DESIGN: Samples of predominantly low-income African American (n = 110) and non-Hispanic White American (n = 119) patients were recruited to complete questionnaires about their perceived health care provider cultural sensitivity and adherence to their provider's treatment regimen recommendations. MAIN OUTCOME MEASURES: Patients completed written measures of their perceived provider cultural sensitivity, trust in provider, interpersonal control, satisfaction with their health care provider, physical stress, and adherence to provider-recommended treatment regimen variables (i.e., engagement in a health promoting lifestyle, and dietary and medication adherence). RESULTS: Two-group path analyses revealed significant links between patient-perceived provider cultural sensitivity and adherence to provider treatment regimen recommendations, with some differences in associations emerging by race/ethnicity. CONCLUSION: The findings provide empirical support for the potential usefulness of the Patient-Centered Culturally Sensitive Health Care Model for explaining the linkage between the provision of patient-centered, culturally sensitive health care, and the health behaviors and outcomes of patients who experience such care. PMID- 21553980 TI - Bias for the (un)attractive self: on the role of attention in causing body (dis)satisfaction. AB - OBJECTIVE: Body dissatisfaction plays a key role in the maintenance of eating disorders, and selective attention might be crucial for the origin of body dissatisfaction. A. Jansen, C. Nederkoorn, and S. Mulkens (2005) showed that eating disorder patients attend relatively more to their own unattractive body parts, whereas healthy controls attend relatively more to their own attractive body parts. In 2 studies, we investigated whether this bias in selective attention is causal to body dissatisfaction and whether an experimentally induced bias for attractive body parts might lead to increased body satisfaction in women who are highly dissatisfied with their bodies. DESIGN: We used a between-subjects design in which participants were trained to attend to either their self-defined unattractive body parts or their self-defined attractive body parts by use of an eye tracker. MAIN OUTCOME MEASURES: State body and weight satisfaction. RESULTS: Inducing a temporary attentional bias for self-defined unattractive body parts led to a significant decrease in body satisfaction and teaching body-dissatisfied women to attend to their own attractive body parts led to a significant increase in body satisfaction. CONCLUSION: Selective attention for unattractive body parts can play a role in the development of body dissatisfaction, and changing the way one looks may be a new way for improving body dissatisfaction in women. PMID- 21553979 TI - Unfair treatment is associated with poor sleep in African American and Caucasian adults: Pittsburgh SleepSCORE project. AB - OBJECTIVE: To test the association between self-reported unfair treatment and objective and self-reported sleep characteristics in African American and Caucasian adults. DESIGN: Cross-sectional study of 97 African American and 113 Caucasian middle-aged adults. MAIN OUTCOME MEASURES: Participants completed: (a) two-night in-home, polysomnography (PSG) sleep study, (b) sleep diaries and actigraph assessments across 9 days and nights, and (c) self-report measures of sleep quality in the past month, and daytime sleepiness in the past 2 weeks. RESULTS: Greater unfair treatment was associated with reports of poorer self reported sleep quality and greater daytime sleepiness, shorter sleep duration, and lower sleep efficiency as measured by actigraphy and PSG, and a smaller proportion of rapid eye movement (REM) sleep. Racial/ethnic differences were few. Exploratory analyses showed that nightly worry partially mediated the associations of unfair treatment with sleep quality, daytime sleepiness, sleep efficiency (actigraphy), and proportion of REM sleep. CONCLUSION: Perceptions of unfair treatment are associated with sleep disturbances in both African American and Caucasian adults. Future studies are needed to identify the pathways that account for the association between unfair treatment and sleep. PMID- 21553981 TI - Durable effects of implementation intentions: reduced rates of confirmed pregnancy at 2 years. AB - OBJECTIVE: To assess the long-term impact of implementation intention formation in reducing consultations for emergency contraception and pregnancy testing among teenage women. DESIGN: Teenage women visiting a family planning clinic were randomly assigned to implementation intention versus control conditions. MAIN OUTCOME MEASURES: Objective measures of consultation outcomes were obtained from clinic records at 2-year follow-up (N = 227). RESULTS: Rates of consultation for emergency contraception and pregnancy testing in the implementation intentions condition were 19% and 33% lower, respectively, compared to the rates observed in the control condition. Pregnancy rates were 43% lower. Intervention participants who consulted for emergency contraception and pregnancy testing at baseline were more than twice as likely to change to consulting for contraceptive supplies over the follow-up period compared to equivalent control participants (19% vs. 9%). CONCLUSION: The impact of implementation intention formation on reducing pregnancy risk among teenagers is durable over 2 years. Implementation intentions were successful in changing behavior among precisely those participants who were at greatest risk of becoming pregnant. PMID- 21553982 TI - Confirmatory bias and the persistent influence of discredited data in interpreting the stress-cancer link: commentary on Michael et al. (2009). AB - Comments on the original article, "Influence of stressors on breast cancer incidence in the Women's Health Initiative" by Y. L. Michael et al (see record 2009-03297-001). The current authors assert that Michael et al (2009) missed an opportunity for a straightforward reporting of null findings concerning the association between stress and incidence of cancer. They urge greater skepticism toward the claims about a stress-cancer link more generally. Using data from the Women's Health Initiative, Michael and colleagues suggested an association between stress and the incidence of breast cancer. However, the current authors believe their results and those from other studies failed to confirm that stress is a risk factor of breast cancer. Starting with their abstract and continuing in their discussion, Michael et al selectively and inaccurately reported findings with a strong confirmatory bias, and with further selective and uncritical reference to the existing literature. Moreover, they inadvertently perpetuated the direct and indirect influence of discredited data in the literature purporting to show a stress-cancer link. PMID- 21553984 TI - Numeracy and Medicare Part D: the importance of choice and literacy for numbers in optimizing decision making for Medicare's prescription drug program. AB - Studies on decision making have come to challenge the idea that having more choice is necessarily better. The Medicare prescription drug program (Part D) has been designed to maximize choice for the consumer but has simultaneously created a highly complex decision task with dozens of options. In this study, in a sample of 121 adults, we examined the impact that increasing choice options has on decision-making abilities in older versus younger adults. Consistent with our hypotheses, we found that participants performed better with less choice versus more choice, and that older adults performed worse than younger adults across conditions. We further examined the role that numeracy may play in making these decisions and the role of more traditional cognitive variables such as working memory, executive functioning, intelligence, and education. Finally, we examined how personality style may interact with cognitive variables and age in decision making. Regression analysis revealed that numeracy is related to performance across the lifespan. When controlling for additional measures of cognitive ability, we found that although age was no longer associated with performance, numeracy remained significant. In terms of decision style, personality characteristics were not related to performance. Our results add to the mounting evidence for the critical role of numeracy in decision making across decision domains and across the lifespan. PMID- 21553987 TI - Is all sparing created equal? Comparing lag-1 sparing and extended sparing in temporal object perception. AB - When two targets (T1, T2) are presented amongst a rapid stream of distractors, T2 accuracy is impaired if the targets are separated by at least one distractor (attentional blink). However, this impairment largely disappears if the targets follow one another directly (lag-1 sparing), and, in fact, as many as four or five consecutive targets may be identified quite accurately under these conditions (extended sparing). Although all current models propose a common mechanism for both lag-1 and extended sparing, this hypothesis has yet to be tested. To this end, we examined the effect of various types of attentional switches, known to impact lag-1 sparing, on extended sparing in order to determine whether they would have a similar effect. Results suggested substantial parallels between the two types of sparing. We discuss these results in terms of a unified account of sparing in temporal object perception. PMID- 21553988 TI - Priming of reach and grasp actions by handled objects. AB - Pictures of handled objects such as a beer mug or frying pan are shown to prime speeded reach and grasp actions that are compatible with the object. To determine whether the evocation of motor affordances implied by this result is driven merely by the physical orientation of the object's handle as opposed to higher level properties of the object, including its function, prime objects were presented either in an upright orientation or rotated 90 degrees from upright. Rotated objects successfully primed hand actions that fit the object's new orientation (e.g., a frying pan rotated 90 degrees so that its handle pointed downward primed a vertically oriented power grasp), but only when the required grasp was commensurate with the object's proper function. This constraint suggests that rotated objects evoke motor representations only when they afford the potential to be readily positioned for functional action. PMID- 21553989 TI - Multisensory integration affects visuo-spatial working memory. AB - In the present study, we investigate how spatial attention, driven by unisensory and multisensory cues, can bias the access of information into visuo-spatial working memory (VSWM). In a series of four experiments, we compared the effectiveness of spatially-nonpredictive visual, auditory, or audiovisual cues in capturing participants' spatial attention towards a location where to-be remembered visual stimuli were or were not presented (cued/uncued trials, respectively). The results suggest that the effect of peripheral visual cues in biasing the access of information into VSWM depend on the size of the attentional focus, while auditory cues did not have direct effects in biasing VSWM. Finally, spatially congruent multisensory cues showed an enlarged attentional effect in VSWM as compared to unimodal visual cues, as a likely consequence of multisensory integration. This latter result sheds new light on the interplay between spatial attention and VSWM, pointing to the special role exerted by multisensory (audiovisual) cues. PMID- 21553990 TI - Temporal coordination and adaptation to rate change in music performance. AB - People often coordinate their actions with sequences that exhibit temporal variability and unfold at multiple periodicities. We compared oscillator- and timekeeper-based accounts of temporal coordination by examining musicians' coordination of rhythmic musical sequences with a metronome that gradually changed rate at the end of a musical phrase (Experiment 1) or at the beginning of a phrase (Experiment 2). The rhythms contained events that occurred at the same periodic rate as the metronome and at half the period. Rate change consisted of a linear increase or decrease in intervals between metronome onsets. Musicians coordinated their performances better with a metronome that decreased than increased in tempo (as predicted by an oscillator model), at both beginnings and ends of musical phrases. Model performance was tested with an oscillator period or timekeeper interval set to the same period as the metronome (1:1 coordination) or half the metronome period (2:1 coordination). Only the oscillator model was able to predict musicians' coordination at both periods. These findings suggest that coordination is based on internal neural oscillations that entrain to external sequences. PMID- 21553991 TI - When seeing doesn't matter: assessing the after-effects of tactile distractor processing in the blind and the sighted. AB - Negative priming (NP) refers to the finding that people's responses to probe targets previously presented as prime distractors are usually slower than to unrepeated stimuli. Intriguingly, the effect sizes of tactile NP were much larger than the effect sizes for visual NP. We analyzed whether the large tactile NP effect is just a side effect of the higher difficulty when processing tactile compared to visual stimuli. Thus, we analyzed tactile NP in a sample of blind participants and in a control sample of sighted participants. Although the blind participants handled the tactile stimuli with ease, we found no evidence that the size of the tactile NP effect diminished. In two control experiments with sighted participants, we varied the processing difficulty in the visual and tactile modality and found that both modality and processing difficulty had an effect on the size of NP. Taken together, our data show that the difficulty associated with processing tactile stimuli is only partially the reason for the unusual large tactile NP effect. These results suggest that non-spatial tactile distractors are processed and selected quite differently from visual distractors. PMID- 21553992 TI - Specific previous experience affects perception of harmony and meter. AB - Prior knowledge shapes our experiences, but which prior knowledge shapes which experiences? This question is addressed in the domain of music perception. Three experiments were used to determine whether listeners activate specific musical memories during music listening. Each experiment provided listeners with one of two musical contexts that was presented simultaneously with a melody. After a listener was familiarized with melodies embedded in contexts, the listener heard melodies in isolation and judged the fit of a final harmonic or metrical probe event. The probe event matched either the familiar (but absent) context or an unfamiliar context. For both harmonic (Experiments 1 and 3) and metrical (Experiment 2) information, exposure to context shifted listeners' preferences toward a probe matching the context that they had been familiarized with. This suggests that listeners rapidly form specific musical memories without explicit instruction, which are then activated during music listening. These data pose an interesting challenge for models of music perception which implicitly assume that the listener's knowledge base is predominantly schematic or abstract. PMID- 21553993 TI - Cue and target processing modulate the onset of inhibition of return. AB - Inhibition of return (IOR) is modulated by task set and appears later in discrimination tasks than in detection tasks. Several hypotheses have been suggested to account for this difference. We tested three of these hypotheses in two experiments by examining the influence of cue and target level of processing on the onset of IOR. In the first experiment, participants were required to respond to both the cue and target. The pattern of results showed that deeper processing of the cue or target advanced the onset of IOR. In the second experiment, participants were not required to respond to the cue and a reverse pattern of results emerged, which replicated the general findings in cuing tasks. We conclude that in more-demanding tasks, an additional process slows down the processing of a nonpredictive cue in order to enhance the processing of the target. PMID- 21553994 TI - Target-to-target repetition cost and location negative priming are dissociable: evidence for different mechanisms. AB - In a location-selection task, the repetition of a prior distractor location as the target location would slow down the response. This effect is termed the location negative priming (NP) effect. Recently, it has been demonstrated that repetition of a prior target location as the current target location would also slow down response. Because such target-to-target repetition cost is similar to the phenomenon of inhibition of return (IOR), the possibility of a common mechanism underlying target-to-target repetition cost, location NP, and IOR has been proposed. The current study evaluated this hypothesis by combining a spatial cuing task with a location NP task. The results of three experiments demonstrated that although IOR interacted with target-to-target repetition cost, there was no interaction between IOR and location NP. These findings suggest that target-to target repetition cost is more likely to share a common mechanism with IOR, and target-to-target repetition cost and location NP should be attributed to different processes. PMID- 21553995 TI - Flexible feature-based inhibition in visual search mediates magnified impairments of selection: evidence from carry-over effects under dynamic preview-search conditions. AB - Evidence for inhibitory processes in visual search comes from studies using preview conditions, where responses to new targets are delayed if they carry a featural attribute belonging to the old distractor items that are currently being ignored-the negative carry-over effect (Braithwaite, Humphreys, & Hodsoll, 2003). We examined whether inhibition was applied in the same manner across different types of displays or whether the inhibitory weighting applied to different features varied with their utility for the search task. To test this, we present the first empirical investigation of negative carry-over effects under the ecologically valid conditions of dynamic visual search. Experiment 1 investigated preview search using dynamic moving and static displays. Detection was very poor when new targets carried the color of the old distractors, and this negative carry-over effect was significantly exaggerated with moving, compared with static, displays. Experiments 2a and 2b demonstrated that this effect could not be attributed to an increased role of preattentive grouping between new and old items for dynamic displays. Collectively, the findings suggest that feature-based inhibition contributes strongly to preview search through dynamic displays, and this leads to an amplified attentional blindness to new targets. The data specifically indicate that inhibitory processes in search differentially weight color and location in moving and static displays, and that feature-based inhibition may underlie many instances of sustained inattentional blindness in everyday life. PMID- 21553996 TI - Parafoveal processing of word n + 2 during reading: do the preceding words matter? AB - We used the boundary paradigm (Rayner, 1975) to test two hypotheses that might explain why no conclusive evidence has been found for the existence of n + 2 preprocessing effects. In Experiment 1, we tested whether parafoveal processing of the second word to the right of fixation (n + 2) takes place only when the preceding word (n + 1) is very short (Angele, Slattery, Yang, Kliegl, & Rayner, 2008); word n + 1 was always a three-letter word. Before crossing the boundary, preview for both words n + 1 and n + 2 was either incorrect or correct. In a third condition, only the preview for word n + 1 was incorrect. In Experiment 2, we tested whether word frequency of the preboundary word (n) had an influence on the presence of preview benefit and parafoveal-on-foveal effects. Additionally, Experiment 2 contained a condition in which only preview of n + 2 was incorrect. Our findings suggest that effects of parafoveal n + 2 preprocessing are not modulated by either n + 1 word length or n frequency. Furthermore, we did not observe any evidence of parafoveal lexical preprocessing of word n + 2 in either experiment. PMID- 21553997 TI - Switching in the cocktail party: exploring intentional control of auditory selective attention. AB - Using a novel variant of dichotic selective listening, we examined the control of auditory selective attention. In our task, subjects had to respond selectively to one of two simultaneously presented auditory stimuli (number words), always spoken by a female and a male speaker, by performing a numerical size categorization. The gender of the task-relevant speaker could change, as indicated by a visual cue prior to auditory stimulus onset. Three experiments show clear performance costs with instructed attention switches. Experiment 2 varied the cuing interval to examine advance preparation for an attention switch. Experiment 3 additionally isolated auditory switch costs from visual cue priming by using two cues for each gender, so that gender repetition could be indicated by a changed cue. Experiment 2 showed that switch costs decreased with prolonged cuing intervals, but Experiment 3 revealed that preparation did not affect auditory switch costs but only visual cue priming. Moreover, incongruent numerical categories in competing auditory stimuli produced interference and substantially increased error rates, suggesting continued processing of task relevant information that often leads to responding to the incorrect auditory source. Together, the data show clear limitations in advance preparation of auditory attention switches and suggest a considerable degree of inertia in intentional control of auditory selection criteria. PMID- 21553998 TI - Conversations on telemental health: listening to remote and rural First Nations communities. AB - INTRODUCTION: Telemental health involves technologies such as videoconferencing to deliver mental health services and education, and to connect individuals and communities for healing and health. In remote and rural First Nations communities there are often challenges to obtaining mental healthcare in the community and to working with external mental health workers. Telemental health is a service approach and tool that can address some of these challenges and potentially support First Nations communities in their goal of improving mental health and wellbeing. Community members' perspectives on the usefulness and appropriateness of telemental health can greatly influence the level of engagement with the service. It appears that no research or literature exists on First Nations community members' perspectives on telemental health, or even on community perspectives on the broader area of technologies for mental health services. Therefore, this article explores the perspectives on telemental health of community members living in two rural and remote First Nations communities in Ontario, Canada. METHODS; This study was part of the VideoCom project, a collaborative research project exploring how remote and rural First Nations communities are using ICTs. This current exploration was conducted with the support of Keewaytinook Okimakanak (KO), our partner in Northwestern Ontario. With the full collaboration of the communities' leadership, a team involving KO staff and VideoCom researchers visited the two communities in the spring of 2010. Using a participatory research design, we interviewed 59 community members, asking about their experiences with and thoughts on using technologies and their attitudes toward telemental health, specifically. A thematic analysis of this qualitative data and a descriptive quantitative analysis of the information revealed the diversity of attitudes among community members. Finally, based on a discussion with the community telehealth staff, a 'ways forward' section was proposed as a way to begin addressing certain issues that were raised by community members. RESULTS: This article explores the continuum of community members' perspectives that range from interest and enthusiasm to hesitancy and concern. One participant reported personal experience with using telemental health and found the approach helpful in increasing her comfort in the therapeutic situation. In addition, concerns relating to appropriateness and safety were voiced. A variety of advantages (eg facilitation of disclosure, increased access to services, usefulness) and disadvantages or concerns (eg interference with capacity building, concerns about privacy) are reported and discussed. Following a coding procedure, a descriptive quantitative analysis demonstrated that 47% of the participants were categorized as having a positive response toward telemental health, 32% as having a negative response, and 21% as being neutral or undecided. CONCLUSIONS: Valuing Indigenous knowledge can help us understand community members' experiences of and concerns with telemental health and inform more successful and appropriate initiatives. With the invaluable support of the KO Telemedicine co-authors, we offer ways forward to address concerns identified by the community members. Most importantly, any ways forward for community telemental health initiatives need to be community driven and community led. PMID- 21553999 TI - Contextualizing Indigenous suicide. PMID- 21554000 TI - In vitro effects of rosmarinic acid on glutathione reductase and glucose 6 phosphate dehydrogenase. AB - CONTEXT: Glutathione reductase (GR, NADPH:oxidized glutathione oxidoreductase, E.C 1.6.4.2) is a flavoprotein that catalyzes the NADPH-dependent reduction of oxidized glutathione (GSSG). GR is a crucial enzyme in the antioxidant system by maintaining reduced glutathione (GSH). Glucose 6-phosphate dehydrogenase (G6PD, glucose 6-phosphate (G6P):NADP(+) oxidoreductase, EC 1.1.1.49) is the key regulatory enzyme of the pentose phosphate pathway and maintains NADPH for reductive reactions. OBJECTIVE: Rosmarinic acid (RA; alpha-O-caffeoyl-3,4 dihydroxyphenyl lactic acid) is an ester of caffeic acid (CA) and 3,4 dihydroxyphenyllactic acid. It has a number of interesting biological activities. The inhibiting activities of the RA on GR and G6PD are investigated here for the first time. MATERIALS AND METHODS: GR and G6PD were purified from tissues, then the effects of RA are investigated. RESULTS: This study reports that RA, which was isolated from Echium vulgare L. (Boraginaceae), inhibits purified GR and G6PD in a concentration-dependent manner. Kinetic characterizations and inhibition constants are investigated. DISCUSSION AND CONCLUSION: Because of their importance in the antioxidative defense system, investigation of the inhibitors of these enzymes is important for drug development. PMID- 21554001 TI - Fingerprint quality detection of Solanum nigrum using high-performance liquid chromatography-evaporative light scattering detection. AB - CONTEXT: Solanum nigrum Linn. (Solanaceae), a traditional Chinese medicine (TCM), has been used for cancer therapy. It is urgent to develop a novel quality standard to validly detect its quality. OBJECTIVE: To control its quality, a novel, accurate, and valid fingerprint method was developed by high-performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) in the current case. We could evaluate the quality of different batches and assure the stability of herbs' quality in subsequent research. MATERIALS AND METHODS: The HPLC-ELSD fingerprints have been developed through analyzing 41 batches of raw herbs collected from different areas in different harvesting time. RESULTS: We have determined the optimum extraction and detection conditions in the process of establishing herb fingerprint. And, we could establish reference fingerprint to control such herb quality. Also, we could determine optimum collecting location and harvesting time according to the fingerprint. DISCUSSION AND CONCLUSION: It is the first time a new method has been established to control the quality of S. nigrum through HPLC-ELSD. We developed combining similarity evaluation to identify and distinguish raw materials efficiently from different sources. For S. nigrum the most influenced factor on herb quality was the collecting location, and the next was the harvesting time. So, in order to get the consistent raw materials, the collecting location and the harvesting time should be fixed. PMID- 21554002 TI - Evaluation of anti-inflammatory activity of derivatives from aerial parts of Baccharis uncinella. AB - CONTEXT: Species of Baccharis exhibit antibiotic, antiseptic, and wound-healing properties, and have been used in the traditional medicine of South America for the treatment of inflammation, headaches, diabetes, and hepatobiliary disorders. OBJECTIVE: To investigate the anti-inflammatory activity of organic phases from EtOH extract of the aerial parts of Baccharis uncinella DC (Asteraceae). MATERIALS AND METHODS: The crude EtOH extract from the aerial parts of B. uncinella was subjected to partition procedures and the corresponding CH(2)Cl(2) and EtOAc phases were subjected to several chromatographic separation procedures. Thus, these phases and their purified compounds were assayed for evaluation of anti-inflammatory activity. RESULTS: The CH(2)Cl(2) phase from EtOH extract from B. uncinella contained two triterpenoids (oleanolic and ursolic acids) and one flavonoid (pectolinaringenin), whereas the respective EtOAc phase showed to be composed mainly by two phenylpropanoid derivatives (caffeic and ferulic acids). The CH(2)Cl(2) and EtOAc phases as well as their isolated compounds exhibited anti-inflammatory effects against inflammatory reactions induced by phospholipase A2 (from Crotalus durissus terrificus venom) and by carrageenan. DISCUSSION AND CONCLUSION: The results suggested that the components obtained from partition phases of EtOH extract of B. uncinella could represent lead molecules for the development of anti-inflammatory agents. Additionally, the results confirmed the use of Baccharis genus in the traditional medicine of South America for the treatment of inflammation and other heath disorders. To date, the present work describes for the first time the anti-inflammatory effects of compounds isolated from B. uncinella. PMID- 21554003 TI - Antiviral activities of phosphonoformate sodium to pseudorabies herpesvirus infection in vitro. AB - CONTEXT: Phosphonoformate sodium (PFS) has been used as an anti-herpesvirus drug; nevertheless, studies of the use of PFS for treatment of pseudorabies herpesvirus (PrV) infection in the veterinary setting have not been widely reported. OBJECTIVE: The present study aimed to analyze the inhibitory effect of PFS on cell infection and apoptosis induced by PrV. MATERIALS AND METHODS: The infectivity of PrV was determined by plaque assays when PFS was applied to the virus, to the virus-infected cells, and to the cells prior to infection. PCR amplifying DNA polymerase, gE, gG, and gD genes of PrV was performed. PrV-induced cell apoptosis was analyzed by immunofluorescence and flow cytometry. RESULTS: PFS inhibits cell infection by PrV. Addition of the drug decreased the number of apoptotic cells. Amplification of DNA polymerase and other viral structural genes detected in this study by PCR was reduced, because there were fewer viral DNA copies being made in the presence of the drug. The drug has an inhibitory effect on cell apoptosis induced by PrV. DISCUSSION AND CONCLUSION: PFS has inhibitory effects on cell infection by PrV, which may be used as an anti-PrV agent or combined with other anti-PrV agents. PrV-induced cell apoptotic cells and viral DNA copies decreased in the presence of the PFS. PMID- 21554004 TI - The anti-angiogenic herbal composition Ob-X from Morus alba, Melissa officinalis, and Artemisia capillaris regulates obesity in genetically obese ob/ob mice. AB - CONTEXT: The growth and development of adipose tissue leading to obesity is suggested to depend on angiogenesis. Our previous study showed that Melissa officinalis L. (Labiatae), Morus alba L. (Moraceae), and Artemisia capillaris Thunb. (Compositae) are involved in the regulation of angiogenesis. We hypothesized that Ob-X, a mixture of three herbs, M. alba, M. officinalis, and A. capillaris, can regulate obesity. OBJECTIVE: To investigate the inhibitory effect of Ob-X on obesity in genetically obese ob/ob mice. MATERIALS AND METHODS: The effect of Ob-X on angiogenesis was measured using a mouse Matrigel plug assay. The effects of Ob-X on obesity were investigated in ob/ob mice. RESULTS: Ob-X inhibited angiogenesis in a dose-dependent manner, as evidenced by decreased blood vessel density in a mouse matrigel plug assay. Administration of Ob-X to ob/ob mice for 5 weeks produced a significant reduction in body weight gain by 27% compared with control (12.1 +/- 3.01 vs. 16.6 +/- 2.24 g, respectively). Ob-X also significantly decreased visceral adipose tissue mass by 15% (0.87 +/- 0.12 vs. 1.02 +/- 0.15 g, respectively). The size of adipocytes in visceral adipose tissue was reduced by 46% in Ob-X-treated mice. Ob-X treatment inhibited hepatic lipid accumulation and significantly decreased circulating glucose levels compared with controls (197 +/- 56.5 vs. 365 +/- 115 mg/dL, respectively). DISCUSSION AND CONCLUSION: These results suggest that Ob-X, which has an anti angiogenic activity, reduces body weight gain and visceral adipose tissue mass in genetically obese mice, providing evidence that obesity can be prevented by angiogenesis inhibitors. PMID- 21554005 TI - Anti-inflammatory, antioxidant and antifungal activity of Chuquiraga spinosa. AB - CONTEXT: Stem and leaves infusion of Chuquiraga spinosa (R&P) Don. (Asteraceae) is used in the Peruvian traditional medicine for its anti-inflammatory properties and for the treatment of vaginal infections. OBJECTIVE: This study evaluated the antioxidant, anti-inflammatory and antifungal activities of C. spinosa for the first time. MATERIALS AND METHODS: Extracts of methanol, 50% methanol and water were obtained from C. spinosa aerial parts. Antioxidant activity of the extracts was evaluated (DPPH, ABTS(+) and superoxide radical-scavenging activity). The correlation between these results and total polyphenolic content was determined by Pearson's Correlation Coefficient. Anti-inflammatory activity of 50% methanol extract was evaluated with the rat model of carrageenan-induced acute inflammation and mouse model of TPA-induced acute inflammation. The antifungal activity of the extracts against Cladosporium cucumerinum and Candida albicans was studied by direct bioautography, and antifungal activity against phytopathogenic fungi was performed by culture in potato dextrose agar plates. RESULTS: All the extracts showed high antioxidant activity, and there was correlation between the activity and total polyphenolic compounds. As 50% methanol extract was administered orally, the paw edema in rats was reduced significantly (52.5%). This extract, by topical administration, produced a reduction of 88.07% of the edema TPA-induced in ear of mice. The aqueous and 50% methanol extracts were active against C. albicans (minimum inhibitory concentration of 2.5 and 6.25 ug, respectively). The aqueous extract showed antifungal activity against C. cucumerinum (MIC: 2.5 ug). DISCUSSION AND CONCLUSION: Preliminary phytochemical screening and the analysis of the three extracts by high-performance liquid chromatography diode-array detection showed the majority compounds are flavonoids and phenolic acid derivatives. These compounds may be responsible of the radical-scavenging activity of these extracts as well as responsible of anti-inflammatory effect in vivo of 50% methanol extract. Several authors have demonstrated the antioxidant and anti-inflammatory properties of some flavonoids and phenolic acids. The antifungal activity of the extracts obtained from aerial parts of C. spinosa has been investigated here for the first time. Other studies are necessary to determine the mechanism of action and to identify the bioactive compounds of this plant. PMID- 21554006 TI - Investigation of antitussive and toxicological activity of Ballota limbata in mice. AB - CONTEXT: Ballota limbata Benth. (Lamiaceae) (syn, Otostegia limbata Hook.f.) is a species grown in the North West Frontier Province and the lower hills of West Punjab, Pakistan. Ballota species are renowned for their antispasmodic, antiulcer, diuretic, vermifuge, and especially sedative effects. However, little is known about the biological activity of B. limbata. OBJECTIVE: Evaluation of antitussive activity and safety profile of dried B. limbata extract. MATERIALS AND METHODS: Whole air-dried plants were partitioned with various solvents and the butanol fraction was subjected to antitussive evaluation using a sulfur dioxide (SO(2))-induced cough model in mice. Codeine and dextromethorphan were used as positive control. Safety profile of the testing material was established using standard toxicity tests. RESULTS: B. limbata extract inhibited cough provoked by SO(2) gas in mice in a dose-dependent manner. The extract exhibited maximum protection against SO(2)-induced cough after 60 min of administration. B. limbata offered maximum cough suppressive effects, that is, number of coughs during 60 min was 11.66 +/- 1.2 (mean +/- SEM), after s.c. administration of 800 mg/kg, as compared with codeine 10 mg/kg, s.c., dextromethorphan 10 mg/kg, s.c., and saline showing a frequency of cough of 11.75 +/- 1.18, 12.25 +/- 0.83, and 46.25 +/- 1.52, respectively. LD(50) value of B. limbata was greater than 5000 mg/kg. No sign of neural impairment was observed at antitussive doses and the extract has been well-tolerated at higher doses. DISCUSSION AND CONCLUSION: This study demonstrates that the extract of B. limbata has shown strong cough suppressive effect in mice without yielding any notable toxicity. PMID- 21554007 TI - Ethanol extract of Justicia gendarussa inhibits lipopolysaccharide stimulated nitric oxide and matrix metalloproteinase-9 expression in murine macrophage. AB - CONTEXT: Justicia gendarussa Burm (Acanthaceae) is a plant used to treat inflammatory diseases such as rheumatoid arthritis. However, the mechanism involved in the anti-inflammatory properties of this plant has not been studied well. OBJECTIVE: The in vitro anti-inflammatory activities of ethanol extract of Justicia gendarussa leaves (J-01) are studied here for the first time. MATERIALS AND METHODS: The ethanol extract, J-01 was prepared from the leaves of Justicia gendarussa. The inhibitory effect of J-01 in nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-9 (MMP-9) gene expressions were studied in lipopolysaccharide (LPS) stimulated macrophage cell line RAW 264.7. RESULTS: J-01 in a concentration dependent manner (200-50 MUg/mL) attenuated NO production from macrophage stimulated with LPS (1 MUg/mL). Further, J-01 significantly suppressed iNOS mRNA expression in these cells. J-01 has also downregulated the MMP-9 gene expression in LPS stimulated macrophage. DISCUSSION AND CONCLUSION: The modulatory function of J-01 in inhibiting NO, iNOS, and MMP-9 as obtained from the present in vitro studies provide first scientific evidence to support the anti-inflammatory properties of Justicia gendarussa. This plant may have potential use in the management of inflammatory conditions such as arthritis. PMID- 21554008 TI - Soluble expression of active recombinant human tissue plasminogen activator derivative (K2S) in Escherichia coli. AB - CONTEXT: The kringle 2 plus serine protease domains (K2S) of human tissue plasminogen activator (tPA) is an efficacious thrombolytic drug, which has been used to treat heart attacks and strokes by breaking up the clots that cause them. It has nine disulfide bridges, which are needed for proper folding and be the bottleneck in improving the production in the Escherichia coli system. So far, few reports have described the production of soluble active K2S from E. coli. OBJECTIVE: To achieve high-level expression of active K2S in the E. coli system. MATERIALS AND METHODS: The DNA fragment coding for K2S was fused with the E. coli disulfide isomerase DsbC. The constructed fusion protein was expressed in E. coli, and then purified with the Ni(2+)-chelating affinity chromatography. K2S was released by cleavage with Factor Xa protease, and the thrombolytic activity was determined using the fibrin plate assay. RESULTS: The fusion protein DsbC-K2S was found in the culture supernatant of recombinant E. coli as a soluble form of ~40%. The result of fibrinolysis fibrin plate assay showed that the purified recombinant K2S exhibited significant fibrinolysis activity in vitro. DISCUSSION AND CONCLUSION: These works provided a novel approach for the production of active K2S in E. coli without the requirements of in vitro refolding process, and might establish a significant foundation for the following production of K2S. PMID- 21554009 TI - Optimization and application of a fluorimetric assay for the identification of histone deacetylase inhibitors from plant origin. AB - CONTEXT: Histonedeacetylase inhibitors (HDACi) are the focus of enormous interest as a new class of anticancer drugs and discussed as novel treatment in cardiovascular diseases or memory enhancement. In the search for new active substances the structural diversity of secondary plant metabolites provides an indispensable resource. Several molecules from the plant kingdom have gained importance as anticancer drugs. Thus, a search for new therapeutic agents inhibiting histonedeacetylases (HDACs) is an important topic. To accelerate the isolation of potential candidates from plants bioassays well suited for screenings of extracts are an indispensable prerequisite. OBJECTIVE: In the presented study an enzymatic assay was modified, optimized and validated for the search for HDACi from plant origin. MATERIALS AND METHODS: A fluorimetric assay was validated with respect to parameters such as temperature, incubation times, reproducibility, applicability of different enzyme sources and HDAC substrate. For the determination of the HDAC inhibitory potential of extracts the detailed study of the influence of different classes of primary and secondary metabolites probably interfering with the assay was most important. RESULTS: In the experimental design autofluorescent coumarins and tannins were identified to disrupt the assay. Possibilities to avoid disturbances are demonstrated and the applicability of the method in the bioactivity-guided search for new HDACi was proven on the example Leonuri herba (Leonurus cardiaca L.; Lamiaceae). CONCLUSION: The optimization of the assay led to a highly efficient fluorimetric method to study plant extracts and fractions of medium/high polarity for HDAC inhibition. In the bioactivity-guided fractionation of extracts from Leonuri herba the applicability for the aimed purpose was clearly demonstrated. PMID- 21554010 TI - Antiproliferative and antioxidant activities of Juglans regia fruit extracts. AB - CONTEXT: Cancer chemopreventive action of walnut [Juglans regia L. (Juglandaceae)] has been explored. OBJECTIVE: This study evaluated antiproliferative and antioxidant activities of walnut. MATERIALS AND METHODS: Various fractions of walnut extract have been screened for antiproliferative activity against human cancer cell lines using the MTT assay. All these fractions have also been evaluated for total phenolic content, antioxidant activity, and reducing power capacity. RESULTS AND DISCUSSION: Chloroform and ethyl acetate fractions exhibited a high level of antiproliferation against HepG-2, liver cancer cell line (IC(50) = 9 and 15 ug/mL, respectively). CONCLUSION: Exhibiting high phenolic content, antioxidant activity, and potent antiproliferative activity, walnut may act as a cancer chemopreventive agent. PMID- 21554011 TI - Non-degradable polymer nanocomposites for drug delivery. AB - INTRODUCTION: The need to optimize therapeutic outcomes while minimizing side effects is a major driving force for research and development in the controlled drug delivery field. Polymer nanocomposites (NCs) are an emerging class of materials with remarkable potential for controlled drug delivery. There are a range of release mechanisms that characterize polymer NC systems, and these may be perturbed not only by the addition of nanofillers, but also by the type of drug and the interactions of the drug with the components of the system. AREAS COVERED: The focus of this review is on non-degradable polymer NC systems. In particular, the types of drug delivery approach from these polymer NCs and the theoretical models developed to describe those approaches are discussed. The importance of component interactions and factors affecting drug delivery from polymer NCs is also addressed. EXPERT OPINION: Despite the remarkable potential and extensive research being conducted on polymer NCs for use in drug delivery, commercialization and large-scale production are limited by the cost and difficulty in consistently producing fully exfoliated NCs. A continuing challenge for the field is to understand better the key interactions and structure-property relationships arising from different polymer, filler and drug combinations. PMID- 21554012 TI - Assessments in Australian stroke rehabilitation units: a systematic review of the post-stroke validity of the most frequently used. AB - PURPOSE: In Australia, stroke is the leading cause of adult disability. For most stroke survivors, the recovery process is challenging, and in the first few weeks their recovery is supported with stroke rehabilitation services. Stroke clinicians are expected to apply an evidence-based approach to stroke rehabilitation and, in turn, use standardised and validated assessments to monitor stroke recovery. In 2008, the National Stroke Foundation conducted the first national audit of Australia's post acute stroke rehabilitation services and findings identified a vast array of assessments being used by clinicians. This study undertook a sub-analysis of the audit's assessment tools data with the aim of making clinically relevant recommendations concerning the validity of the most frequently selected assessments. METHOD: Data reduction ranked the most frequently selected assessments across a series of sub-categories. A serial systematic review of relevant literature using Medline and the Cumulative Index to Nursing and Allied Health Literature identified post-stroke validity ranking. RESULTS: The study found that standardised and non-standardised assessments are currently in use in stroke rehabilitation. It recommends further research in the sub-categories of strength, visual acuity, dysphagia, continence and nutrition and found strengths in the sub-categories of balance and mobility, upper limb function and mood. CONCLUSIONS: This is the first study to map national usage of post-stroke assessments and review that usage against the evidence. It generates new knowledge concerning what assessments we currently use post stroke, what we should be using and makes some practical post stroke clinical recommendations. PMID- 21554013 TI - Effect of CdTe QDs on the protein-drug interactions. AB - Recently, investigations of biological toxicity of cadmium QDs and their toxic interaction with plasma proteins have attracted great interest. In this work, flavonoids were studied for the affinities for human serum albumin (HSA) in the presence and absence of CdTe G-QDs by fluorescence quenching method. CdTe G-QDs obviously enhanced the binding affinities of kaempferol, genistein and biochanin A by 3.78 to 154.88 times depending on the QDs concentration. However, the affinity of kaempferide for HSA was slightly weakened in the presence of G-QDs. The non-methylated flavonoids were more sensitive to G-QDs than their methylated forms. The affinities of kaempferide and kaempferol for HSA at first were slightly improved and then obviously decreased with increasing G-QDs concentration. For genistein, the affinities for HSA decreased with increasing G QDs concentration. However, the G-QDs concentration showed no obvious effect on the affinity of biochanin A. The binding affinities of flavonoids for HSA improved with increasing QDs size. PMID- 21554014 TI - Effects of a cationic PAMAM dendrimer on photosynthesis and ROS production of Chlamydomonas reinhardtii. AB - Poly(amidoamine) (PAMAM) dendrimers hold great promises for biomedicine. This study sought to examine the toxicity of generation 4 (G4) cationic PAMAM dendrimer to the green microalga, Chlamydomonas reinhardtii, using physiological and molecular biomarkers. Results revealed that the G4 dendrimer at 15 and 25 nM stimulated the photosynthetic process and the production of reactive oxygen species (ROS) in algae. However, the over-production of ROS did not induce the expression of antioxidant enzyme genes, catalase and glutathione peroxidase. In addition, genes encoding light-harvesting proteins (lhca and lhcb), a ferredoxin (fdx) and an oxygen-evolving enhancer protein (psb) involved in photosynthesis were repressed after treatment. Nevertheless, the expression of the lhcbm9 gene, encoding a major light harvesting polypeptide, was increased. These results suggest that the strong modulation of photosynthesis induced by the dendrimer could lead to elevated ROS levels in microalgae. PMID- 21554015 TI - The toxicity evaluation of nano-trititanate with bactericidal properties in vitro. AB - Three forms of nano-trititanate (H(2)Ti(3)O(7) nanomaterial) were prepared by a hydrothermal method to replace nano-TiO(2) for sterilizing the environment. The bactericidal capabilities of these nano-trititanates were observed to be more significant compared to nano-TiO(2) both with and without exposure to UV light. For the future commercial applications of those nano-trititanates, we investigated their cytotoxicity and genotoxicity to HEp-2 cells. As data in our study shows, nanoplate, one of the nano-trititanates, possesses the lowest toxicity to HEp-2 cells. The results indicated that the shape and length of the material only affect the toxicity of nano-trititanate but not its bactericidal effect. Thus, through manipulating the shape or length of nano-trititanate, we may obtain a more powerful bactericidal reagent with lower toxicity to the human body. PMID- 21554016 TI - Sequence alignment as hypothesis testing. AB - Sequence alignment depends on the scoring function that defines similarity between pairs of letters. For local alignment, the computational algorithm searches for the most similar segments in the sequences according to the scoring function. The choice of this scoring function is important for correctly detecting segments of interest. We formulate sequence alignment as a hypothesis testing problem, and conduct extensive simulation experiments to study the relationship between the scoring function and the distribution of aligned pairs within the aligned segment under this framework. We cut through the many ways to construct scoring functions and showed that any scoring function with negative expectation used in local alignment corresponds to a hypothesis test between the background distribution of sequence letters and a statistical distribution of letter pairs determined by the scoring function. The results indicate that the log-likelihood ratio scoring function is statistically most powerful and has the highest accuracy for detecting the segments of interest that are defined by the statistical distribution of aligned letter pairs. PMID- 21554017 TI - Finding nearly optimal GDT scores. AB - Global Distance Test (GDT) is one of the commonly accepted measures to assess the quality of predicted protein structures. Given a set of distance thresholds, GDT maximizes the percentage of superimposed (or matched) residue pairs under each threshold, and reports the average of these percentages as the final score. The computation of GDT score was conjectured to be NP-hard. All available methods are heuristic and do not guarantee the optimality of scores. These heuristic strategies usually result in underestimated GDT scores. Contrary to the conjecture, the problem can be solved exactly in polynomial time, albeit the method would be too slow for practical usage. In this paper we propose an efficient tool called OptGDT to obtain GDT scores with theoretically guaranteed accuracies. Denote l as the number of matched residue pairs found by OptGDT for a given threshold d. Let l' be the optimal number of matched residues pairs for threshold d/(1 + epsilon), where epsilon is a parameter in our computation. OptGDT guarantees that l >= l'. We applied our tool to CASP8 (The eighth Critical Assessment of Structure Prediction Techniques) data. For 87.3% of the predicted models, better GDT scores are obtained when OptGDT is used. In some cases, the number of matched residue pairs were improved by at least 10%. The tool runs in time O(n3) log n/epsilon5) for a given threshold d and parameter epsilon. In the case of globular proteins, the tool can be improved to a randomized algorithm of O(n log2 n) runtime with probability at least 1 - O(1/n). Released under the GPL license and downloadable from http://bioinformatics.uwaterloo.ca/~scli/OptGDT/ . PMID- 21554018 TI - Exploratory factor analysis of pathway copy number data with an application towards the integration with gene expression data. AB - Realizing that genes often operate together, studies into the molecular biology of cancer shift focus from individual genes to pathways. In order to understand the regulatory mechanisms of a pathway, one must study its genes at all molecular levels. To facilitate such study at the genomic level, we developed exploratory factor analysis for the characterization of the variability of a pathway's copy number data. A latent variable model that describes the call probability data of a pathway is introduced and fitted with an EM algorithm. In two breast cancer data sets, it is shown that the first two latent variables of GO nodes, which inherit a clear interpretation from the call probabilities, are often related to the proportion of aberrations and a contrast of the probabilities of a loss and of a gain. Linking the latent variables to the node's gene expression data suggests that they capture the "global" effect of genomic aberrations on these transcript levels. In all, the proposed method provides an possibly insightful characterization of pathway copy number data, which may be fruitfully exploited to study the interaction between the pathway's DNA copy number aberrations and data from other molecular levels like gene expression. PMID- 21554019 TI - Motif finding in DNA sequences based on skipping nonconserved positions in background Markov chains. AB - One strategy to identify transcription factor binding sites is through motif finding in upstream DNA sequences of potentially co-regulated genes. Despite extensive efforts, none of the existing algorithms perform very well. We consider a string representation that allows arbitrary ignored positions within the nonconserved portion of single motifs, and use O(2(l)) Markov chains to model the background distributions of motifs of length l while skipping these positions within each Markov chain. By focusing initially on positions that have fixed nucleotides to define core occurrences, we develop an algorithm to identify motifs of moderate lengths. We compare the performance of our algorithm to other motif finding algorithms on a few benchmark data sets, and show that significant improvement in accuracy can be obtained when the sites are sufficiently conserved within a given sample, while comparable performance is obtained when the site conservation rate is low. A software program (PosMotif ) and detailed results are available online at http://faculty.cse.tamu.edu/shsze/posmotif. PMID- 21554020 TI - Regular language constrained sequence alignment revisited. AB - Imposing constraints in the form of a finite automaton or a regular expression is an effective way to incorporate additional a priori knowledge into sequence alignment procedures. With this motivation, the Regular Expression Constrained Sequence Alignment Problem was introduced, which proposed an O(n2t4) time and O(n2t2) space algorithm for solving it, where n is the length of the input strings and t is the number of states in the input non-deterministic automaton. A faster O(n2t3) time algorithm for the same problem was subsequently proposed. In this article, we further speed up the algorithms for Regular Language Constrained Sequence Alignment by reducing their worst case time complexity bound to O(n2t3)/log t). This is done by establishing an optimal bound on the size of Straight-Line Programs solving the maxima computation subproblem of the basic dynamic programming algorithm. We also study another solution based on a Steiner Tree computation. While it does not improve the worst case, our simulations show that both approaches are efficient in practice, especially when the input automata are dense. PMID- 21554021 TI - Outpatient palliative care for chronic heart failure: a case series. AB - BACKGROUND/OBJECTIVES: Although the palliative care needs of outpatients with chronic heart failure (HF) are numerous, there is limited published experience in providing outpatient HF palliative care. This article describes the patients seen and the issues addressed in an outpatient palliative care program for patients with HF. METHODS: Case series involving a retrospective medical record review using descriptive quantitative and qualitative analysis. RESULTS: Over a 3 1/2 year time period, 50 patients were seen, resulting in 228 total visits. Fifty percent of patients were seen only once. Fifty-eight percent of patients had New York Heart Association (NYHA) Class III-IV HF. Within a year of the initial palliative care visit, 14% of patients died. Depression, anxiety, pain, fatigue, breathlessness, and sleep disturbance were common symptoms addressed during visits. Advance care planning topics were discussed with 48% of patients; hospice and resuscitation status were each discussed with 16% of patients. Fears or concerns about the future arose in 34% of patients. Care coordination was commonly addressed with patients' other health care providers (58%). The most common referrals were to social work (26%) and rehabilitation/physical therapy (20%). CONCLUSIONS: Several findings reflect how outpatient HF palliative care differs from that of inpatient hospital-based palliative care. Many of the issues addressed, including care coordination, advance care planning, and psychosocial issues, imply that palliative HF care is complementary to standard HF care at all stages of the disease process and that future programs should consider dedicating a nurse and/or social worker. Research is needed to test how such a care model affects patient-centered outcomes, utilization, and cost. PMID- 21554022 TI - Mitochondrial effects of plant-made compounds. AB - SIGNIFICANCE: Plants produce many small molecules with biomedical potential. Their absorption from foods, metabolism, their effects on physiological and pathological processes, and the mechanisms of action are intensely investigated. Many are known to affect multiple cellular functions. Mitochondria are coming to be recognized as a major target for these compounds, especially redox-active ones, but the mechanisms involved still need clarification. At the same time, frontline research is uncovering the importance of processes involving these organelles for the cell and for an array of physiological and pathological processes. We review the major functions and possible dysfunctions of mitochondria, identify signaling pathways through which plant-derived molecules have an impact, and show how this may be relevant for major pathologies. RECENT ADVANCES: Antioxidant, protective effects may arise as a reaction to a low-level pro-oxidant activity, largely taking place at mitochondria. Some plant-derived molecules can activate AMP-dependent kinase, with a consequent upregulation of mitochondrial biogenesis and a potential favorable impact on aging, pathologies like diabetes and neurodegeneration, and on ischemic damage. CRITICAL ISSUES: The extrapolation of in vitro results and the verification of paradigms in vivo is a key issue for current research on both plant-derived compounds and mitochondria. The low bioavailability of many of these molecules poses a problem for both the study of their activities and their utilization. FUTURE DIRECTIONS: The further clarification of the role of mitochondria in the activities of plant dietary compounds and their metabolites, mitochondrial targeting, the development of analogs and pro-drugs are all topics for promising research. PMID- 21554023 TI - The World Journal of Biological Psychiatry vol. 12, issue 4. PMID- 21554024 TI - Flow rates and inorganic composition of whole saliva in purging bulimic patients treated with a fluoxetine. AB - OBJECTIVES: The current study established whether vomiting bulimic and/or non bulimic depressive patients, both treated with a serotonin reuptake inhibitor (fluoxetine), have changes in their whole salivary secretion and inorganic components: Na(+), K(+), Ca(2+). METHODS: From 108 female subjects, namely bulimics (Group B) (fluoxetine: 40 mg/day) (n=33), non-bulimic depressives (Group D) (fluoxetine: 20 mg/day) (n=25) and a Group C of 50 healthy controls, unstimulated and stimulated saliva was collected. The concentrations of Na(+), K(+), Ca(2+) were determined by colorimetric photometry method (Effox 5053, Eppendorf, Germany). RESULTS: The bulimic group reported significant lower output in salivary flow and sodium concentration. In the group (D) only flow was lower than in healthy controls but not significant. CONCLUSION: This study supports the hypothesis that salivary flow is an unreliable indicator of bulimia, the lack of increase in sodium level in stimulated saliva in bulimic subjects could be a more reliable confirmation of the eating disorder. PMID- 21554025 TI - Obsessive-compulsive symptoms in schizophrenia: prevalence, clinical features and treatment. A literature review. AB - OBJECTIVES: To investigate the prevalence of obsessive-compulsive symptoms in schizophrenia, the clinical features of the sub-group of patients with schizophrenia and obsessive-compulsive symptoms and treatment options for these patients. METHOD: A literature review of studies investigating the prevalence, clinical features and treatment of patients with schizophrenia and obsessive compulsive symptoms. RESULTS: The prevalence of obsessive-compulsive symptoms in schizophrenic patients, while generally found to be higher than in the general population, varies widely between different studies. Differences in symptom severity between schizophrenic patients with obsessive-compulsive symptoms and those without have been found, however findings so far have been inconsistent. A number of case reports have implicated atypical antipsychotic medication in the emergence of obsessive-compulsive symptoms. There is evidence to support a combined treatment with an antipsychotic agent and an anti-obsessional agent. CONCLUSION: Studies investigating the prevalence of obsessive-compulsive symptoms in schizophrenia and their effect on the clinical symptoms have yielded inconsistent results and further studies using larger samples of patients and looking at different subgroups of schizophrenic patients are required. Treatment options need further research to investigate whether the results of relatively small studies can be replicated. PMID- 21554026 TI - Measuring state trait properties of detail processing and global integration ability in eating disorders. AB - OBJECTIVES: Women with eating disorders (EDs) are reported to have strengths in local or detailed information processing and difficulties with coherence or global processing/integration. METHODS: This study aimed to replicate these findings and additionally explore a global integration task which has not previously been reported for an ED group, the Fragmented Pictures Task (FPT). Two hundred and twenty-two women (50 with anorexia nervosa (AN), 48 with bulimia nervosa (BN), 35 recovered from AN and 89 controls (HC)) completed the Rey Osterrieth Complex Figure Task (RCFT) to measure global/local processing strategies, the Group Embedded Figures Task (GEFT) to measure local processing and the FPT to measure global integration. RESULTS: Superior detail processing skills (GEFT) and a tendency to utilise detail processing strategies (RCFT) were associated with having AN, BN and being in recovery from AN. Global integration difficulties (FPT) were only observed in acute AN, whereas participants in the BN and recovered group performed similarly to HCs. CONCLUSIONS: People currently ill with, and recovered from EDs are skilled at detail processing. The acute phase of AN is associated with difficulties in global integration. PMID- 21554027 TI - The effects of breast cancer diagnosis and surgery on cognitive functions. AB - BACKGROUND: Women with breast cancer (BC) report cognitive impairment. Receiving a BC diagnosis may have a negative psychological impact. We sought to determine whether a diagnosis of BC and subsequent surgical treatment reduced cognitive function. MATERIAL AND METHODS: We recruited women, who had a positive radiographic finding, consecutively from the mammography screening program at Stockholm South General Hospital. All subjects completed the Headminder Web-based neuropsychological battery Cognitive Stability Index (CSI) for response speed, processing speed, memory, and attention at enrolment (T1, Baseline). CSI was administered again, after BC was ruled out, or after sector resection or mastectomy, if BC was confirmed by cytology or biopsy (T2, Retest). RESULTS AND CONCLUSION: Of the 148 women approached, 146 were enrolled; 69 were healthy and 77 had BC. Comparison between groups at baseline, according to independent t test, showed significant differences in response speed and processing speed. Cognitive abilities did not decline in either group on any of the measured domains. Our results suggest that a diagnosis of BC and subsequent surgery is not associated with substantial cognitive decline at retest. However, the lack of improvement in attention at retest among BC patients may be suggestive of a decline. PMID- 21554028 TI - Anti-vascular endothelial growth factor antibody bevacizumab reduced the risk of anemia associated with chemotherapy-A meta-analysis. AB - INTRODUCTION: Vascular endothelial growth factor (VEGF) may play a role in erythropoiesis. We performed a meta-analysis of randomized controlled trials (RCT) to determine the effect of the anti-VEGF antibody bevacizumab on anemia in cancer patients treated with chemotherapy. METHODS: Databases from PUBMED, the Web of Science, Embase, the Cochrane Library, and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences until May 2010 were searched to identify relevant studies. Eligible studies included prospective RCTs in which the combination of bevacizumab and chemotherapy was compared with chemotherapy alone. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated. RESULTS: A total of 6439 patients with a variety of solid tumors were included for analysis from 11 RCTs. Among those patients receiving bevacizumab and chemotherapy, the incidences of all-grade and high-grade (grade 3 and above) anemia were 17.8% (95% CI: 11.1-27.1%) and 2.8% (95% CI: 1.6-5.0%) respectively. In comparison with chemotherapy alone, bevacizumab significantly reduced all-grade (RR, 0.79; 95% CI: 0.66-1.0, p = 0.007) and high-grade anemia (RR, 0.72; 95% CI: 0.57-0.90, p = 0.005). The effect did not vary significantly among bevacizumab doses (p = 0.88), tumor types (p = 0.75) or chemotherapy regimens (p = 0.98). DISCUSSION: Bevacizumab may significantly reduce the risk of anemia with chemotherapy in cancer patients. PMID- 21554029 TI - Compassionate use of stem cells for ALS: popovers and hot air. PMID- 21554030 TI - Advanced statistical methods to study the effects of gastric tube and non invasive ventilation on functional decline and survival in amyotrophic lateral sclerosis. AB - A few studies suggest that non-invasive ventilation (1) and gastric tube (G-tube) may have a positive impact on survival but the effect on functional decline is unclear. Confounding by indication may have produced biased estimates of the benefit seen in some of these retrospective studies. The objective of this study was to evaluate the effects of G-tube and NIV on survival and functional decline using advanced statistical models that adjust for confounding by indications. A database of 331 subjects enrolled in previous clinical trials in ALS was available for analysis. Marginal structural models (MSM) were used to compare the mortality hazards and ALSFRS-R slopes between treatment and non-treatment groups, after adjusting for confounding by indication. Results showed that the placement of a G-tube was associated with an additional 1.42 units/month decline in the ALSFRS-R slope (p < 0.0001) and increased mortality hazard of 0.28 (p = 0.02). The use of NIV had no significant effect on ALSFRS-R decline or mortality. In conclusion, marginal structural models can be used to adjust for confounding by indication in retrospective ALS studies. G-tube placement could be followed by a faster rate of functional decline and increased mortality. Our results may suffer from some of the limitations of retrospective analyses. PMID- 21554031 TI - Mirror movements in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive motor syndrome with clinical evidence of upper and lower motor neuron dysfunction. Mirror movements (MM) in ALS have been reported and attributed to a disturbed transcallosal inhibition (TI). Hence, occurrence of MM in ALS might be explained by involvement of transcallosal projecting fibre tracts into the degenerative process of the motor system. Twenty-six consecutive ALS patients were studied by clinical investigation of MM and by transcranial magnetic stimulation testing of TI using evaluation of the ipsilateral silent period. MM were observed in 39% of ALS patients. There was a significant correlation between the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and occurrence of MM (correlation coefficient -0.315; p = 0.044). In conclusion, all MM patients had pathological TI at least in one hemisphere, which indicates involvement of transcallosally projecting output neurons in ALS patients, which in turn may be an early feature of the disease process with the potential of a diagnostic biomarker. PMID- 21554032 TI - The use of subcutaneous glycopyrrolate in the management of sialorrhoea and facilitating the use of non-invasive ventilation in amyotrophic lateral sclerosis. AB - Sialorrhoea is a recognized complication of bulbar amyotrophic lateral sclerosis (ALS) that leads to an increased risk of potentially harmful aspiration and often prevents patients from tolerating non-invasive ventilation (NIV). A case of treatment-resistant sialorrhoea in bulbar ALS is described where subcutaneous glycopyrrolate was effective without significant side-effects. The patient went on to markedly increase the length of time she could tolerate NIV each night. PMID- 21554033 TI - Upper trapezius electromyography aids in the early diagnosis of bulbar involvement in amyotrophic lateral sclerosis. AB - Electromyography (EMG), particularly measurements of the tongue or sternocleidomastoid, aids in the diagnosis of amyotrophic lateral sclerosis (ALS) and may be used to identify lower motor neuron lesions in the bulbar region. Abnormal trapezius EMG recordings were recently shown to be useful in diagnosing ALS. Here, we investigated the role of upper trapezius EMG in assessing bulbar involvement in ALS. Standard EMG measurements were recorded from the upper trapezius in ALS, cervical spondylotic myelopathy (CSM), and normal controls (NC). Forty-three CSM patients were examined pre-operatively and three months post-operatively. Greater spontaneous activity levels were observed in upper trapezius EMG measurements of ALS patients with a disease duration of <=8 months (70%), compared with patients with a disease duration of >8 months (40%). Significant differences in motor unit action potential parameters were also noted between ALS and CSM or NC. Fewer spontaneous EMG recordings were detected in CSM post-operatively. Furthermore, no differences in neurogenic EMG measurements were observed in ALS between the trapezius and sternocleidomastoid muscles (p = 0.22). In conclusion, upper trapezius EMG recordings may provide valuable information for assessing the clinical and subclinical involvement of bulbar lower motor neurons in ALS patients, particularly at early disease stages. PMID- 21554034 TI - Self-reported rates of sleep disturbance in patients with symptomatic bone metastases attending an outpatient radiotherapy clinic. AB - PURPOSE: To examine the reported rates and predictive factors for sleep disturbance in patients with bone metastases. METHODS: Patients with symptomatic bone metastases treated with palliative radiotherapy (RT) were eligible. At initial consultation, demographic information, baseline Brief Pain Inventory (BPI) questionnaire, and analgesic consumption were recorded. The BPI functional interference sleep item was categorized into none (0), mild (1-3), moderate (4 6), and severe (7-10). Follow-up BPI was collected in person or via telephone post-RT at week 4, 8, and 12. Subgroup analysis for BPI between responders and nonresponders was performed. Ordinal logistic regression analysis was used to search for the relationship between sleep disturbance and other covariates. RESULTS: Four hundred patients were enrolled between May 2003 and June 2007. Two hundred thirty-five males (59%) were accrued. The median age was 68 years old (range, 30-91). Within the study population, primary cancer sites included breast (25%), lung (25%), prostate (24%), bladder (4%), pancreas/gastric (3%), and other primaries (18%). In the BPI functional interference items, the mean baseline score for sleep disturbance was 4.8. When categorized in terms of severity, 99 (25%) patients had moderate sleep disturbance and 144 (36%) patients had severe sleep disturbance, respectively. There was an improvement in sleep scores for both responders and nonresponders at week 4 and 8, but scores worsened for nonresponders at week 12. CONCLUSION: Age, Karnofsky Performance Scale (KPS), pain score, and lung primary were the significant variables associated with sleep disturbance. The scores for sleep disturbance improved significantly post-RT in responders at week 4 and 12. PMID- 21554035 TI - Antiangiogenic therapy for patients with glioblastoma: current challenges in imaging and future directions. PMID- 21554036 TI - Clinical end points in recurrent glioblastoma: are antiangiogenic agents friend or foe? PMID- 21554037 TI - Trends in melanoma incidence among children: possible influence of sun-protection programs. PMID- 21554038 TI - Prognostication in Merkel cell carcinoma. PMID- 21554040 TI - The LUX-Lung clinical trial program of afatinib for non-small-cell lung cancer. AB - Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) represents a distinct disease entity whose molecular phenotype predicts exquisite sensitivity to the reversible EGFR-tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. However, primary or acquired resistance to these agents remains a major clinical problem. Afatinib is a novel dual irreversible EGFR/HER2 TKI that has been shown in preclinical studies to potentially prevent, delay or overcome resistance to reversible EGFR-TKIs. On this basis, the LUX-Lung clinical trial program has been recently launched for testing this molecule in advanced NSCLC patients. Notably, early results from the randomized LUX-Lung 1 trial indicate that afatinib significantly prolongs progression-free survival compared with placebo in pretreated patients with clinically acquired resistance to gefitinib or erlotinib. On the other hand, the LUX-Lung 2 trial shows that afatinib is highly active in the EGFR-mutant subgroup of patients. While these preliminary data open a new exciting scenario for the future development of anti-EGFR therapies in NSCLC, ongoing afatinib trials will definitively establish a role for this molecule in the treatment of advanced NSCLC. PMID- 21554041 TI - Global experience with ixabepilone in breast cancer. AB - Ixabepilone approval in a number of countries across the world as monotherapy and in combination with capecitabine has led to widespread uptake in the later-line breast cancer setting. However, individualized data for ixabepilone in different ethnic groups are limited. Overall, data from small numbers of ethnic subgroups including Hispanic, Japanese and Chinese patients have revealed no clinically significant variation in the disposition, efficacy or tolerability of ixabepilone from that established in pivotal trials. Global use of ixabepilone, while usually along the lines of standard practice, may vary because of local regulatory decisions, clinical practice guidelines and cost considerations. Further information on the global patterns of use of ixabepilone will assist in optimizing the use of this novel therapy. PMID- 21554042 TI - Third annual forum on T-cell lymphoma. AB - The Third Annual T-cell Lymphoma Forum, held on 27-29 January 2011 in San Francisco (CA, USA), continued in the spirit of the two earlier conferences and provided a collegial venue for clinicians and scientists to discuss advances in the science and treatment of T-cell lymphomas. More than 40 experts from around the world presented updates on classification, epidemiology and prognosis; rare and T-cell lymphomas of unspecified origin, CD30(+) T-cell lymphomas; new treatment strategies; new agents and rational combinations; and transplantation. Of particular interest this year was a discussion on the link between breast implants and anaplastic large-cell lymphoma, which coincided with the US FDA announcement of this rare but noteworthy relationship. Submitted abstracts and poster presentations rounded off each of the sessions. PMID- 21554043 TI - Joint genitourinary cancer symposium between Egyptian and American centers. AB - A joint symposium between Mansoura and Cleveland Universities, and the University of California, San Francisco (CA, USA) was held by the Egyptian Cancer Society in Mansoura, Egypt. The Symposium extensively discussed two topics: prostate and bladder cancer. The experiences of American and Egyptian scientists were shared in a trial to increase understanding, improve management, increase treatment outcome and decrease morbidity. Comparisons between treatment policies, management techniques and survival end results in Egypt and the USA, as well as internationally, were performed in both bladder and prostate cancer in order to determine the best policies for their management. PMID- 21554044 TI - Highlights from the 3rd Breast-Gynecological International Cancer Conference 2011. AB - The 3rd Breast-Gynecological International Cancer Conference, supported by the European Society of Medical Oncology (ESMO), was held in Cairo (Egypt) on 13-14 January 2011. The meeting was conducted under the patronage of Egypt's Ministry of Health, with the scientific committee led by Heba El Zawahry from the National Cancer Institute (Cairo, Egypt), and Yasser Abdel Kader from Cairo University (Cairo, Egypt). Several important updates and multifaceted issues in the management of various breast and gynecological cancers were addressed in this conference. Leading physicians and scientists from 12 different countries shared their expertise and views. This meeting was a good opportunity to meet fellow professionals from all parts of the world and discuss complex and interesting case studies. In this article, we highlight pertinent sessions and important topics discussed in this meeting. PMID- 21554045 TI - Outcomes in unresectable and locally advanced resected cholangiocarcinoma. AB - Patients with cholangiocarcinomas often present with unresectable disease, which is associated with a poor clinical outcome and survival. A number of palliative options are available to patients; the evaluated article presented experience from a single institution of treating cholangiocarcinoma, either unresectable or locally advanced, with conformal radiotherapy and concurrent chemotherapy. Patients who had received biliary radiation for cholangiocarcinoma were identified from the hospital database, and information on the patients sourced from notes and reports. In total, 20 patients with a diagnosis of biliary tract cancer were included and received radical conformal radiotherapy with concurrent cisplatin/5-fluorouracil and sequential gemcitabine. The median overall survival was 20.4 months and the relapse-free survival was 9.6 months. Treatment failure within the radiotherapy field was recorded in 45% of patients; adverse events were minimal. This study adds to the retrospective data available regarding the management of patients with biliary tract carcinomas, and we have found in our own cohort of 45 patients that gemcitabine/platinum was a more effective combination than monotherapy. PMID- 21554046 TI - Identification of BRAF mutations in eruptive melanocytic nevi: new insights into melanomagenesis? AB - Eruptive melanocytic nevi (EMN) is an unusual phenomenon characterized by the abrupt, simultaneous appearance of hundreds of melanocytic nevi on previously uninvolved sun-exposed skin. The mechanisms underlying this phenomenon are not well understood, but have been associated with both systemic immunosuppression and bullous dermatoses. The paper under evaluation brings new insight into the molecular events underlying EMN development in a patient receiving 6 mercaptopurine immunosuppressive therapy for ulcerative colitis. Sequencing of DNA from 20 eruptive nevi revealed the presence of BRAF V600E mutations in 85% of the lesions tested. The role of mutated BRAF in the initiation and progression of melanoma in conjunction with the strong correlation between nevus number and melanoma risk suggests the need for photoprotection in patients receiving thiopurine therapy. The study under evaluation further points to the possible interaction between environmental mutagens and UV radiation in the acquisition of BRAF mutations that may in turn increase the risk of melanoma development. PMID- 21554047 TI - State of the art of diagnostic technology for early-stage melanoma. AB - In the past few decades, rapid improvements in noninvasive optical technologies have revolutionized the diagnosis of early-stage melanoma. Current knowledge and limitations of these tools will be reviewed in this article. Dermoscopy has been recognized as the 'gold standard' in the screening phase. Digital dermoscopy monitoring and total-body photography are used to identify so-called 'featureless' melanoma only on the criteria of change over time. Automated instruments, as well as optical and nonmorphological methods, are still under development, and offer many opportunities to improve the speed and accuracy of the diagnosis of melanoma and/or to reduce the need for expertise. Despite a penetration depth limited to the upper dermis, the quasi-histological imaging achieved by in vivo reflectance confocal microscopy has been demonstrated to significantly aid diagnostic accuracy for selected melanocytic lesions. Future perspectives on diagnostic instrumentation will also be explored. PMID- 21554048 TI - Therapy for metastatic melanoma: an overview and update. AB - Malignant melanoma, a tumor arising from the transformation of melanocytes, has been increasing in incidence worldwide for the past three decades. Melanoma that has metastasized is usually highly resistant to standard chemotherapy. The standard of care for patients with metastatic melanoma has not changed significantly in the past 20 years, and new strategies for treatment of metastatic melanoma are urgently needed. Significant insights have recently been gained into the molecular events underpinning the development of melanoma. A number of novel compounds designed to target these molecular events, as well as monoclonal antibodies to key immune regulatory functions, have been developed and used in clinical trials. The results of these trials hold great promise for the treatment of subsets of patients with metastatic melanoma. PMID- 21554049 TI - Estrogens, estrogen receptors and melanoma. AB - The skin is the largest nonreproductive target tissue on which estrogen plays many beneficial and protective roles. Although neither exogenous hormones nor pregnancy represent significant risk factors for melanoma, epidemiological data suggest a higher survival rate in women with metastatic disease versus men and in premenopausal versus postmenopausal patients. Despite the fact that hyperestrogenic signaling has long been implicated in the initiation and progression of several tumors, the role of estrogens in malignant melanoma is still unclear. The cellular effects of estrogens are mediated by two subtypes of estrogen receptors (ERs). Estrogen receptor beta (ERbeta), the predominant ER in the skin, antagonizes the proliferative action mediated by estrogen receptor alpha. According to recent immunohistochemical studies, ERbeta protein expression decreases progressively with increased Breslow thickness and results in more invasive melanomas; thus, ERbeta immunophenotype may distinguish melanomas linked to poor prognosis from those with a favorable course and lead to melanoma unresponsiveness to both estrogen and anti-estrogen treatment. Therefore, if future large-scale immunohistochemical and molecular studies point towards ERbeta as an important factor in malignant melanoma progression, they will open up novel and targeted prognostic and therapeutic perspectives. PMID- 21554050 TI - Specific challenges in the management of subungual melanoma. AB - Subungual melanoma (SUM) is infrequent in the general population, accounting for 0.7-3.5% of all cutaneous melanomas. SUM absolute incidence is similar among different racial groups; however, the relative proportion among overall cutaneous melanoma cases within each population varies in relation to the frequency of sun induced melanoma. Subungual melanoma most commonly presents as a discoloration of the nail, followed by a recalcitrant wound, a tumor, nail splitting and nail bed bleeding. In most cases, the clinical presentation will already exhibit features typical of late-stage lesions because many patients wait for several months or even years before consulting a physician for evaluation of nail changes. Misdiagnosis of SUM as subungual hematoma, chronic trauma or onychomycosis is still a frequent occurrence, significantly reducing the chances for early treatment. An appropriate diagnostic approach is crucial to allow early-stage diagnosis. The correct management of SUM hinges on early diagnosis and selection of the most appropriate surgical technique. Curative treatment of SUM currently entails surgical excision when the extent of invasion is limited. PMID- 21554051 TI - Management of high-risk squamous cell carcinoma of the skin. AB - Cutaneous squamous cell cancer (SCC) is the second most common skin cancer, accounting for one-fifth of all cutaneous malignancies. The majority arise on the head and neck skin, and cumulative UV exposure is thought to be the most likely etiological factor. The majority of deaths from SCC occur in a high-risk subgroup of patients. This high-risk subgroup of patients can be identified as those with tumors greater than 2 cm in diameter; tumor thickness over 4 mm; moderately/poorly differentiated or desmoplastic histological SCC subtype; ear, lip, hand, feet or genital tumor site; presence of perineural or lymphovascular invasion; nodal metastasis at presentation; recurrent SCC; SCC arising from scars or chronic skin disease, for example, chronic ulcers; and SCC arising in immunosuppressed patients. It is important to identify and aggressively treat these patients, as high-risk SCC are associated with a greater mortality and morbidity. This article reviews the diagnosis and management of such high-risk SCC. PMID- 21554052 TI - Risk-adapted chemotherapy in childhood medulloblastoma. AB - Medulloblastoma is the most common malignant brain tumor in children. The treatment strategy in this tumor mainly includes surgery and radiotherapy, but chemotherapy has been successfully applied in medulloblastoma. The survival rates have improved over the last decade with chemotherapy. The most important prognostic factors were the amount and the extent of metastases, surgery and age. Risk factors have been defined in recent years, but chemotherapy has not been planned according to these defined risk factors on a worldwide basis. The aim of this article was to examine the use of chemotherapy in childhood medulloblastoma according to risk group. A secondary aim was to examine high-dose chemotherapy with autologous stem cell transplantation and the treatment of infant medulloblastoma. PMID- 21554053 TI - Predictive and prognostic factors for gliomas. AB - Despite recent therapeutic advances, gliomas, in particular the most frequent and malignant glioblastoma, remain devastating tumors and need a better molecular characterization to improve both classification and treatment. Currently, three molecular markers, related to better outcome, are particularly useful and complement the histological classification: the 1p/19q codeletion strongly predicts prolonged response to treatment and prolonged survival in oligodendroglial tumors; the O(6)-methylguanine-DNA methyltransferase promoter methylation, which is hypothesized to render the cell more vulnerable to alkylants, is associated with a stronger benefit of concomitant chemoradiotherapy in glioblastomas; mutations of the IDH1 (more rarely IDH2) gene affects 40% of gliomas (but 100% of the 1p/19q codeleted gliomas) and is inversely correlated to grade. IDH1 mutation is a strong and independent predictor of survival, whatever grade considered. The consequences of IDH1/IDH2 mutation (that results in a new enzymatic activity transforming alphacetoglutarate into 2-hydroxyglutarate) are currently under investigation. Recently, integrated genomic, transcriptomic and epigenetic studies have unraveled new glioblastoma subgroups that further refines the molecular classification of these tumors. Such an approach should be extended to lower grade gliomas. PMID- 21554054 TI - Low-dose radiation therapy of cancer: role of immune enhancement. AB - The efficacy of conventional radiation therapy, one of the most widely used treatment modalities of cancer, is limited by resistance of tumors as well as normal tissue toxicity. In the last decade, several studies have shown that protocols using low-dose radiation (LDR) are more effective in providing local tumor control with negligible normal tissue toxicity. LDR stimulates antioxidant capacity, repair of DNA damage, apoptosis and induction of immune responses, which might be collectively responsible for providing effective local tumor control. This article focuses on the immunostimulatory effects of LDR in in vivo models and its clinical efficacy, supporting the use of LDR regimens (alone or as adjuvant) as an anticancer treatment. PMID- 21554056 TI - Laboratory signs of aspirin response in haemodialysis patients. AB - INTRODUCTION: Aspirin is effective in the secondary prevention and high-risk primary prevention of cardiovascular events. However, clinical and laboratory evidence demonstrates diminished or no response to aspirin in some patients. This study was designed to assess aspirin response in haemodialysis patients. METHODS: We prospectively enrolled 78 haemodialysis patients (28 female; 58.4 +/- 12.6 years old) and 79 patients (29 female; 58.4 +/- 10.6 years old) with normal renal function (glomerular filtration rate (GFR) >60 mL/min/1.73 m(2)). All subjects in both the haemodialysis patient group and the control group were taking aspirin (80-300 mg) for at least 30 days and were not taking other antiplatelet agents. Platelet function was assessed by arachidonic acid-induced aggregometry with a Multiplate analyser (Dynabyte Medical, Munich, Germany). Multiplate electrode aggregometry values below 300 AU were applied as a cut-off for response to aspirin. RESULTS: Aspirin non-response was two-fold more prevalent in haemodialysis patients (42.3%) than in patients with normal renal function (21.5%), and this difference was statistically significant (p = 0.005). The two groups were similar in terms of sex, age, tobacco use, the presence of diabetes mellitus, and platelet count. CONCLUSIONS: The frequency of aspirin non-response as defined in this study was higher in haemodialysis patients than in patients with normal renal function. However, larger subsets of patients are needed to confirm the present study. PMID- 21554058 TI - An educational program for spiritual care providers on end of life care in the critical care setting. PMID- 21554057 TI - Toxin models of mitochondrial dysfunction in Parkinson's disease. AB - SIGNIFICANCE: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. RECENT ADVANCES: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. CRITICAL ISSUES: Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD. FUTURE DIRECTIONS: Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide disease-modifying therapeutics for human PD patients. PMID- 21554059 TI - Frailty scales--their potential in interprofessional working with older people: a discussion paper. AB - New models of interprofessional working are continuously being proposed to address the burgeoning health and social care needs of older people with complex and long-term health conditions. Evaluations of the effectiveness of these models tend to focus on process measures rather than outcomes for the older person. This discussion paper argues that the concept of frailty, and measures based on it, may provide a more user-centred tool for the evaluation of interprofessional services - a tool that cuts across unidisciplinary preoccupations and definitions of effectiveness. Numerous frailty scales have been developed for case identification and stratification of risk of adverse outcomes. We suggest that they may also be particularly suitable for evaluating the effectiveness of interprofessional working with community-dwelling older people. Several exemplars of frailty scales that might serve this purpose are identified, and their potential contributions and limitations are discussed. Further work is required to establish which is the most suitable scales for this application. The development of an appropriate frailty scale could provide an opportunity for interprofessional debate about the forms of care and treatment that should be prioritised to improve the health and well-being of this population. PMID- 21554060 TI - Developing an integrated approach to the mental health issues in Pakistan. PMID- 21554061 TI - Measuring empathy in healthcare profession students using the Jefferson Scale of Physician Empathy: health provider--student version. AB - While empathy is commonly accepted as a mutually beneficial aspect of the health provider-patient relationship, evidence exists that many health profession students are unable to demonstrate this important skill. This study, the initial phase of a 2-year longitudinal series, examined measurement properties of the Jefferson Scale of Physician Empathy (JSPE) adapted for administration to health profession students (JSE-HPS version), and investigated group differences of empathy scores in the baccalaureate nursing (BSN) program within the College of Health Professions at a public university in the southeastern part of the USA. The 20-item survey and a demographic questionnaire were completed by 265 BSN students. Correlational analyses, t-test, and analysis of variance were used to examine internal relationships and group differences. Results showed the median item-total score correlation was statistically significant (0.42). The internal consistency of the scale (Cronbach's coefficient alpha) was 0.78, falling within the generally agreed standard. Test-retest reliability coefficients were acceptable at 0.58 (within 3 months interval) and 0.69 (within 6 months interval) between testing. Women scored higher than men and older students outscored younger classmates. No significant relationship was found between empathy scores and ethnicity, previous non-nursing degree, or importance of religion to the participant. These findings support measurement properties of the JSE-HPS version, and can bolster the confidence of researchers in using the Scale for measuring empathy in diverse health profession students, as one component of program evaluation as well as evaluating interprofessional learning activities among diverse healthcare professional students and interprofessional collaboration. PMID- 21554062 TI - Consensus group session of experts to describe interprofessional collaboration processes in team meetings. PMID- 21554063 TI - Reconstructing professional identity for professional and interprofessional practice: a mixed methods study of joint training programmes in learning disability nursing and social work. AB - This article draws on the findings from a mixed methods study with practitioners who qualified from joint training programmes in learning disability nursing and social work and explores the impact on professional identity of such programmes. Although several joint programmes are well established, very little research has been carried out with those who have qualified from them. These practitioners have experienced a kind of training quite unlike that offered by singular education programmes, incorporating a dual socialisation process, which has been neither analysed nor theorised. The study reported in this article comprised a postal survey to graduates from five programmes followed by in depth semi structured interviews. Survey data were analysed by use of SPSS, while the interviews were analysed by use of a content analysis approach. The article discusses findings in relation to theoretical conceptions of professional status, boundaries and identity and relates these to the perceptions of respondents about their professional identities. It explores the ambiguities and uncertainties inherent in this type of professional training programme and argues that these reflect aspects of the current context of professions as a whole. The article concludes that a new professional identity is emerging in learning disability practice, generated by such programmes. PMID- 21554064 TI - Establishing face and content validity of the McMaster-Ottawa team observed structured clinical encounter (TOSCE). PMID- 21554065 TI - Transforming primary care: improving on the medical home model. PMID- 21554066 TI - Who's who in healthcare: findings from a student-led interprofessional pilot project. PMID- 21554067 TI - Creating a public health cadre in India: the development of a framework for interprofessional and inter-sector collaboration. PMID- 21554068 TI - Collaboration across private and public sector primary health care services: benefits, costs and policy implications. AB - Ongoing care for chronic conditions is best provided by interprofessional teams. There are challenges in achieving this where teams cross organisational boundaries. This article explores the influence of organisational factors on collaboration between private and public sector primary and community health services involved in diabetes care. It involved a case study using qualitative methods. Forty-five participants from 20 organisations were purposively recruited. Data were collected through semi-structured interviews and from content analysis of documents. Thematic analysis was used employing a two-level coding system and cross case comparisons. The patterns of collaborative patient care were influenced by a combination of factors relating to the benefits and costs of collaboration and the influence of support mechanisms. Benefits lay in achieving common or complementary health or organisational goals. Costs were incurred in bridging differences in organisational size, structure, complexity and culture. Collaboration was easier between private sector organisations than between private and public sectors. Financial incentives were not sufficient to overcome organisational barriers. To achieve more coordinated primary and community health care structural changes are also needed to better align funding mechanisms, priorities and accountabilities of the different organisations. PMID- 21554069 TI - SYBR Green I and TaqMan quantitative real-time polymerase chain reaction methods for the determination of amplification of Plasmodium falciparum multidrug resistance-1 gene (pfmdr1). AB - The pfmdr1 gene, which encodes P-glycoprotein homolog 1, has been shown to be a reliable marker of resistance for Plasmodium falciparum related to artesunate and mefloquine combination therapy. The aims of this study are to investigate the copy number of pfmdr1 in P. falciparum isolates collected from the 4 malaria endemic areas of Thailand (Kanchanaburi, Mae Hongson, Ranong, and Tak) along the Thailand-Myanmar (Burma) border (Thai-Myanmar border) by using SYBR Green I and the standard method TaqMan real-time polymerase chain reaction (RT-PCR) and to compare the efficiency (sensitivity and specificity) of SYBR Green I with TaqMan RT-quantitative (q)PCR methods in determining pfmdr1 gene copy number. Ninety-six blood samples were collected onto filter paper from patients with uncomplicated falciparum malaria who attended malaria clinics in the Kanchanaburi (n = 45), Mae Hongson (n = 18), Ranong (n = 11), and Tak (n = 22) provinces in Thailand. Parasite genomic DNA was extracted from dried blood spots by using QIAcubeTM automated sample preparation. Pfmdr1 gene copy number was determined by TaqMan (63 samples) and SYBR Green I (96 samples) real-time PCR. Seventy-one (74.0%), 14 (14.6%), 10 (10.4%), and 1 (1%) isolates carried 1, 2, 3, and 4 pfmdr1 gene copies, respectively. Forty-three of 48 (89.6%), 6 of 11 (54.5%), and 3 of 4 (75.0%) samples, respectively, showed agreement with results of 1, 2, and 3 pfmdr1 gene copies as determined by both methods. The efficiency of SYBR Green I in identifying pfmdr1 gene copy number was found to be significantly correlated with that of TaqMan. Considering its simplicity and relatively low cost, SYBR Green I RT-qPCR is therefore a promising alternative technique for the determination of pfmdr1 copy number. PMID- 21554070 TI - Effects of the herbicide atrazine's metabolites on host snail mortality and production of trematode cercariae. AB - Environmental stressors have the potential to greatly impact the transmission of parasites with complex, multi-host life cycles such as those of trematodes. The commonly used herbicide atrazine has been shown to affect the susceptibility of second intermediate hosts (such as larval amphibians) to trematode infection, as well as the longevity and infectivity of the free-swimming cercariae, but not eggs or the free-swimming miracidia that infect the gastropod first intermediate hosts. However, we do not know if this pesticide influences the survival of infected snails or whether it affects cercariae production within, or emergence from, these hosts. In addition, previous studies of host-parasite dynamics have only examined the parent atrazine compound, not any of the long-lasting metabolites commonly present in water bodies. Here, we report that a concentration of 0.33 ug/L of an atrazine metabolite, desethyl atrazine, increased the mortality of freshwater gastropods ( Stagnicola elodes ) infected with a gymnocephalus type of cercaria but not that of uninfected snails or those harboring a mature or dormant infection of Echinoparyphium sp. In contrast, 2 wk of exposure to desethyl atrazine did not affect the emergence of gymnocephalus cercariae from snails, although a trend for a decrease in the emergence of Echinoparyphium sp. cercariae was observed. We suggest that simultaneous trematode infection and exposure to contaminants may represent a significant combined stress to gastropods, but this is likely parasite species-specific as well as dependent on whether cercariae are being actively produced. PMID- 21554071 TI - Computational medicinal chemistry: part II. PMID- 21554073 TI - Trade-off between accuracy and interpretability for predictive in silico modeling. AB - BACKGROUND: Accuracy concerns the ability of a model to make correct predictions, while interpretability concerns to what degree the model allows for human understanding. Models exhibiting the former property are many times more complex and opaque, while interpretable models may lack the necessary accuracy. The trade off between accuracy and interpretability for predictive in silico modeling is investigated. METHOD: A number of state-of-the-art methods for generating accurate models are compared with state-of-the-art methods for generating transparent models. CONCLUSION: Results on 16 biopharmaceutical classification tasks demonstrate that, although the opaque methods generally obtain higher accuracies than the transparent ones, one often only has to pay a quite limited penalty in terms of predictive performance when choosing an interpretable model. PMID- 21554074 TI - Molecular dynamics simulations and docking studies on 3D models of the heterodimeric and homodimeric 5-HT(2A) receptor subtype. AB - BACKGROUND: G-protein coupled receptors may exist as functional homodimers, heterodimers and even as higher aggregates. In this work, we investigate the 5 HT(2A) receptor, which is a known target for antipsychotic drugs. Recently, 5 HT(2A) has been shown to form functional homodimers and heterodimers with the mGluR2 receptor. The objective of this study is to build up 3D models of the 5 HT(2A)/mGluR2 heterodimer and of the 5-HT(2A)-5-HT(2A) homodimer, and to evaluate the impact of the dimerization interface on the shape of the 5-HT(2A) binding pocket by using molecular dynamics simulations and docking studies. RESULTS AND DISCUSSION: The heterodimer, homodimer and monomeric 5-HT(2A) receptors were simulated by molecular dynamics for 40 ns each. The trajectories were clustered and representative structures of six clusters for each system were generated. Inspection of the these representative structures clearly indicate an effect of the dimerization interface on the topology of the binding pocket. Docking studies allowed to generate receiver operating characteristic curves for a set of 5 HT(2A) ligands, indicating that different complexes prefer different classes of 5 HT(2A) ligands. CONCLUSION: This study clearly indicates that the presence of a dimerization interface must explicitly be considered when studying G-protein coupled receptors known to exist as dimers. Molecular dynamics simulation and cluster analysis are appropriate tools to study the phenomenon. PMID- 21554075 TI - Physics-based scoring of protein-ligand interactions: explicit polarizability, quantum mechanics and free energies. AB - The ability to accurately predict the interaction of a ligand with its receptor is a key limitation in computer-aided drug design approaches such as virtual screening and de novo design. In this article, we examine current strategies for a physics-based approach to scoring of protein-ligand affinity, as well as outlining recent developments in force fields and quantum chemical techniques. We also consider advances in the development and application of simulation-based free energy methods to study protein-ligand interactions. Fuelled by recent advances in computational algorithms and hardware, there is the opportunity for increased integration of physics-based scoring approaches at earlier stages in computationally guided drug discovery. Specifically, we envisage increased use of implicit solvent models and simulation-based scoring methods as tools for computing the affinities of large virtual ligand libraries. Approaches based on end point simulations and reference potentials allow the application of more advanced potential energy functions to prediction of protein-ligand binding affinities. Comprehensive evaluation of polarizable force fields and quantum mechanical (QM)/molecular mechanical and QM methods in scoring of protein-ligand interactions is required, particularly in their ability to address challenging targets such as metalloproteins and other proteins that make highly polar interactions. Finally, we anticipate increasingly quantitative free energy perturbation and thermodynamic integration methods that are practical for optimization of hits obtained from screened ligand libraries. PMID- 21554076 TI - Use of secondary structure element information in drug design: polypharmacology and conserved motifs in protein-ligand binding and protein-protein interfaces. AB - The structure-based design of small-molecule inhibitors of protein-ligand and protein-protein interfaces is a key component of drug discovery. The underlying protein interactions can be regarded based on structural similarity of the secondary structure elements: similarities around the binding site ('ligand sensing cores') or in the protein interface ('interface-sensing surfaces') in otherwise unrelated proteins can be useful in predicting polypharmacology and identifying new lead structures. Even small conserved motifs can provide similar interaction patterns in proteins with a completely different fold and function. The identification of these structural similarities can help in the design of new drugs by guiding further optimization. Here, the concepts and ideas based on secondary structure element similarities and their successful applications in drug design are reviewed and discussed. PMID- 21554077 TI - The use of G-protein coupled receptor models in lead optimization. AB - With the emerging new crystal structures of G-protein coupled receptors (GPCRs), the number of reported in silico receptor models vastly increases every year. The use of these models in lead optimization (LO) is investigated here. Although there are many studies where GPCR models are used to identify new chemotypes by virtual screening, the classical application in LO is rarely reported. The reason for this may be that the quality of a model, which is appropriate for atomistic modeling, must be very high, and the biology of GPCR ligand-dependent signaling is still not fully understood. However, the few reported studies show that GPCR models can be used efficiently in LO for various problems, such as affinity optimization or tuning of physicochemical parameters. PMID- 21554078 TI - Binding-interaction prediction of RNA-binding ligands. AB - RNA molecules are involved in a wide range of biological processes and have been recognized as very important therapeutic targets. Mainly owing to the scarcity of information and experimental studies, the application of computational approaches and, in particular, of docking methodologies in the RNA field has developed slowly. However, in recent years the docking of RNA-binding ligands has experienced significant expansion. This article focuses attention on the docking of RNA-binding ligands, analyzing the development of RNA-docking approaches, the reliability of the docking methods and, finally, evaluating the results of docking-based virtual screening studies reported in the literature. PMID- 21554079 TI - Integrating structure-based and ligand-based approaches for computational drug design. AB - Methods utilized in computer-aided drug design can be classified into two major categories: structure based and ligand based, using information on the structure of the protein or on the biological and physicochemical properties of bound ligands, respectively. In recent years there has been a trend towards integrating these two methods in order to enhance the reliability and efficiency of computer aided drug-design approaches by combining information from both the ligand and the protein. This trend resulted in a variety of methods that include: pseudoreceptor methods, pharmacophore methods, fingerprint methods and approaches integrating docking with similarity-based methods. In this article, we will describe the concepts behind each method and selected applications. PMID- 21554080 TI - Recent trends and observations in the design of high-quality screening collections. AB - The design of a high-quality screening collection is of utmost importance for the early drug-discovery process and provides, in combination with high-quality assay systems, the foundation of future discoveries. Herein, we review recent trends and observations to successfully expand the access to bioactive chemical space, including the feedback from hit assessment interviews of high-throughput screening campaigns; recent successes with chemogenomics target family approaches, the identification of new relevant target/domain families, diversity oriented synthesis and new emerging compound classes, and non-classical approaches, such as fragment-based screening and DNA-encoded chemical libraries. The role of in silico library design approaches are emphasized. PMID- 21554083 TI - Modified titanium surfaces alter osteogenic differentiation: a comparative microarray-based analysis of human mesenchymal cell response to commercial titanium surfaces. AB - The differential effects of dual-acid etched (Osseotite), hydroxyapatite coated (HA) and sand-blasted/acid-etched (SLA) titanium surfaces on human bone marrow derived mesenchymal cells (hMSCs) were investigated. Proliferation was significantly promoted on the SLA surfaces. 16 genes were significantly upregulated when hMSCs were cultured on the Osseotite and the HA surfaces and 15 genes on the SLA surfaces. Upregulated genes control cell differentiation, signal transduction, cell cycle regulation, angiogenesis, cell adhesion, and extracellular matrix and bone formation. PMID- 21554084 TI - Attenuation of sulfur mustard toxicity by S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) in mouse liver. AB - Sulfur mustard (SM) (bis-(2-chloroethyl) sulfide) is a chemical warfare agent. Evaluation of toxicity and protective effect of DRDE-07 (S-2(2 aminoethylamino)ethyl phenyl sulfide) was studied in mouse liver after SM challenging. Female mice were given orally 0.2 LD(50) of DRDE-07 (249 mg/kg body weight) and exposed percutaneously with 1.0 LD(50) of SM (8.1 mg/kg body weight). Gene expression profiles were determined using global genome microarray analysis at 3 days post-exposure. DRDE-07 alone treated animal showed significant upregulation to metabolism of xenobiotics by cytochrome P450 pathways. Genes related to cell adhesion molecules (CAMs), were downregulated. DRDE-07 pretreated SM exposed animals showed upregulation of xenobiotic cytochrome P450 pathway genes. Antigen presenting, cell adhesion molecules, cytokine, cytokine receptor metabolism, fatty acid metabolism, glutathione metabolism, cell cycle signaling pathway genes showed downregulation. The present study showed that SM-induced toxicity in mouse liver was attenuated by the pretreatment with DRDE-07. PMID- 21554085 TI - Exposure to dibenzofuran affects lung mitochondrial function in vitro. AB - Environmental pollutants, such as dioxins and furans, are extremely toxic and related with pulmonary diseases development. Impairment of mitochondrial function has been shown in pollutant-induced hepatic injury, but it has not been addressed in lungs, even though lung mitochondria are primary cellular targets for pollutants-induced toxicity. In isolated lung mitochondria, dibenzofuran significantly increased the lag phase preceding mitochondrial repolarization, suggesting a decrease in the efficiency of the mitochondrial phosphorylative system. PMID- 21554086 TI - Stat3-driven cancer-related inflammation as a key therapeutic target for cancer immunotherapy. PMID- 21554088 TI - Do human lymphocyte antigens play a role in the clinical antimelanoma activity of ipilimumab? AB - Evaluation of: Wolchok JD, Weber JS, Hamid O et al.: Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 10, 9-14 (2010). For the first time, a pivotal Phase III clinical trial has demonstrated an overall survival benefit for an antimelanoma drug, ipilimumab, in previously treated advanced melanoma patients. Ipilimumab is a T-cell-potentiating monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4. All patients in this study were HLA A2*0201 positive because the active control arm contained a HLA-A2*0201 restricted peptide derived from the melanocyte differentiation antigen, gp100. Hence, the following question arises: does the survival benefit conferred by ipilimumab treatment only benefit HLA-A2*0201-positive melanoma patients? However, the current paper reveals a retrospective analysis to show that advanced melanoma patients obtain a survival benefit from ipilimumab irrespective of HLA A2*0201 status. This analysis also raises other interesting questions regarding the HLA dependence of mechanisms underlying the toxicity and antimelanoma activity of ipilimumab, which are discussed. PMID- 21554089 TI - Cancer vaccination reprograms regulatory T cells into helper CD4 T cells to promote antitumor CD8 T-cell responses. AB - Evaluation of: Sharma MD, Hou DY, Baban B et al. : Reprogrammed Foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33, 942-954 (2010). It has been recognized that natural CD4(+)Foxp3(+) Tregs could display a phenotypic and functional plasticity in an inflammatory microenvironment. Following the loss of key transcription factor, Foxp3 and core inhibitory molecules associated with suppression, Tregs are reprogrammed into proinflammatory effector cells in vivo. However, the biological significance of this conversion is elusive. Sharma et al. demonstrate that in response to vaccines containing antigens, IFA and CpG, a large proportion of Tregs are dedifferentiated into Th1-like effector cells, which coexpress CD40L - a key molecule for CD8 help by licensing dendritic cells. Under certain experimental conditions, these reprogrammed Tregs are absolutely essential in helping the differentiation of CD8 T cells primed by antigen cross presentation pathways. Treg conversion is diminished by tumor-induced indoleamine 2,3-dioxygenase in tumor-bearing mice, and blockade of indoleamine 2,3 dioxygenase activity in vivo is able to rescue Treg reprogramming. Collectively, in response to signaling from innate immune cells, Tregs are rapidly reprogrammed into Th1-like effector cells, which are also capable of providing timely help for antigen-specific CD8 T cells in the early phase of activation, when the traditional cognate help from conventional CD4 T cells has not yet became available. PMID- 21554090 TI - mRNA: delivering an antitumor message? AB - Evaluation of: Fotin-Mleczek M, Duchardt KM, Lorenz C et al.: Messenger RNA-based vaccines with dual activity induce balanced TLR7-dependent adaptive immune responses and provide antitumor activity. J. Immunother. 34(1), 1-15 (2011). Two decades ago, mRNA was proposed as an active pharmaceutical ingredient for the therapy of cancer. Although direct delivery of mRNA to mice was shown to be feasible, mRNA has been mainly used for ex vivo modification of antigen presenting cells, such as dendritic cells. Fotin-Mleczek et al. introduces a two component mRNA vaccine, consisting of antigen mRNA (firefly luciferase, ovalbumin or prostate carcinoma-specific antigen) and mRNA that is formulated in protamine as a source of not only antigen but also Toll-like receptor 7 ligands. Direct administration of the mRNA vaccine in mice results in sustained humoral and cellular immune responses, comprising, among others, antigen-specific cytotoxic T cells that mediate strong antitumor responses, in both prophylactic and therapeutic settings. In conclusion, this study highlights the potential of mRNA vaccines to induce immune responses and mediate sustained antitumor activity. PMID- 21554092 TI - One century of allergen-specific immunotherapy for respiratory allergy. AB - Among the treatments available for respiratory allergy, which include allergen avoidance and pharmacotherapy, specific immunotherapy (SIT) is the only treatment able to not only act on the symptoms of allergy but also act on the causes. SIT is the practice of administering gradually increasing doses of the specific causative allergen to reduce the clinical reactivity of allergic subjects and was introduced one century ago. SIT remained an empirical treatment for more than 40 years, but the first controlled trial in 1954 paved the way for the scientific era. At present, SIT may be administered in two forms: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). A large number of trials, globally analyzed in several meta-analyses, evaluated the efficacy and safety of SCIT and SLIT in allergic rhinitis and asthma. Current available data give solid evidence to the clinical efficacy of both SCIT and SLIT in allergic rhinitis and asthma. Providing the recommended doses and administration schedules are adhered to, the safety and tolerability are very good; however, adverse systemic reactions remain a drawback for SCIT. After one century of use, accumulating evidence surrounds SIT and the central role in the management of respiratory allergy. PMID- 21554093 TI - Venom immunotherapy in patients with mastocytosis and hymenoptera venom anaphylaxis. AB - Systemic mastocytosis (SM) is typically suspected in patients with cutaneous mastocytosis (CM). In recent years, the presence of clonal mast cells (MCs) in a subset of patients with systemic symptoms associated with MC activation in the absence of CM has been reported and termed monoclonal MC activation syndromes or clonal systemic MC activation syndromes. In these cases, bone marrow (BM) MC numbers are usually lower than in SM with CM, there are no detectable BM MC aggregates, and serum baseline tryptase is often <20 ug/l; thus, diagnosis of SM in these patients should be based on careful evaluation of other minor WHO criteria for SM in reference centers, where highly sensitive techniques for immunophenotypic analysis and investigation of KIT mutations on fluorescence activated cell sorter-purified BM MCs are routinely performed. The prevalence of hymenoptera venom anaphylaxis (HVA) among SM patients is higher than among the normal population and it has been reported to be approximately 5%. In SM patients with IgE-mediated HVA, venom immunotherapy is safe and effective and it should be prescribed lifelong. Severe adverse reactions to hymenoptera stings or venom immunotherapy have been associated with increased serum baseline tryptase; however, presence of clonal MC has not been ruled out in most reports and thus both SM and clonal MC activation syndrome might be underdiagnosed in such patients. In fact, clonal BM MC appears to be a relevant risk factor for both HVA and severe reactions to venom immunotherapy, while the increase in serum baseline tryptase by itself should be considered as a powerful surrogate marker for anaphylaxis. The Spanish Network on Mastocytosis has developed a scoring system based on patient gender, the clinical symptoms observed during anaphylaxis and serum baseline tryptase to predict for the presence of both MC clonality and SM among individuals who suffer from anaphylaxis. PMID- 21554091 TI - Anti-inflammatory therapy for diabetic retinopathy. AB - Diabetic retinopathy (DR) is one of the most common complications of diabetes. This devastating disease is a leading cause of blindness in people of working age in industrialized countries and affects the daily lives of millions of people. Despite tight glycemic control, blood pressure control and lipid-lowering therapy, the number of DR patients keeps growing and therapeutic approaches are limited. Moreover, there are significant limitations and side effects associated with the current therapies. Thus, there is a great need for development of new strategies for prevention and treatment of DR. Studies have shown that DR has prominent features of chronic, subclinical inflammation. This article focuses on the role of inflammation in DR and summarizes the progress of studies of anti inflammatory strategies for DR. PMID- 21554094 TI - Re-inventing intratumoral immunotherapy for melanoma. AB - Immunotherapeutics have been applied intratumorally to manage accessible lesions and to induce systemic immunity in malignant melanoma. Intratumoral bacillus Calmette-Guerin (BCG) has been used for 40 years, and intratumoral BCG, IL-2, IFN alpha and imiquimod are recommended as treatment options for patients with in transit melanoma metastases. Regression of cutaneous metastases can be achieved. Subcutaneous metastases are more refractory, and regression of uninjected, visceral metastases is infrequent. Other microbial products, cytokines, chemicals, immune cells, antibody and viral and plasmid vectors expressing immunologically active molecules have been tested. Antitumor activity has not been demonstrated to be superior to that of intratumoral BCG. There are few controlled trials, and whether survival is impacted with any approach has not yet been established. The immunotherapeutics applied and the intratumoral administration procedure itself can activate responses that are immune inhibitory. More rigorous clinical testing and improved understanding and modulation of regulatory immune responses are necessary. PMID- 21554097 TI - Chronic beta-adrenergic stimulation increases ErbB receptors and cell proliferation in mouse kidney. AB - Although the sympathetic nervous system is involved in injury caused to the kidney by several stressors such as hypertension or ischemia/reperfusion, little is known about the effect of chronic adrenergic stimulation in the kidneys. Upon injury, however, the kidney possesses a high capacity for tubular cell regeneration and functional recovery. The ErbB1 receptor and its ligands play an essential role in this process. We studied the effects of chronic isoproterenol (ISO) administration (beta-adrenoceptor agonist) in the mouse kidney. ISO induced a moderate and reversible loss of kidney weight and protein content that was not associated with renal dysfunction. We observed an increase in tubular cell proliferation (bromodeoxyuridine labeling) in ISO-treated mice in both the outer and inner cortex. ErbB1 (epidermal growth factor receptor) along with ErbB2 and ErbB3 (neuregulin receptor) were transiently overexpressed in ISO-treated mice, with an increase in protein but not mRNA content. All receptors were localized in the same nephron segments and cell types. Immunoprecipitation studies after epidermal growth factor or neuregulin-1beta stimulation showed dynamic interaction of all four ErbB receptors. Therefore, we conclude that ErbB receptors may cooperate in the response to chronic beta-adrenergic stimulation. PMID- 21554095 TI - Immunomodulatory cytokines as therapeutic agents for melanoma. AB - Melanoma is the most aggressive form of skin cancer whose worldwide incidence is rising faster than any other cancer. Few treatment options are available to patients with metastatic disease, and standard chemotherapeutic agents are generally ineffective. Cytokines such as IFN-alpha or IL-2 can promote immune recognition of melanoma, occasionally inducing dramatic and durable clinical responses. Here, we discuss several immunomodulatory agents, the safety of which are being evaluated in clinical trials. Challenges include an incomplete understanding of signaling pathways, appropriate clinical dose and route, and systemic immunosuppression in advanced melanoma patients. We consider how targeted cytokine therapy will integrate into the clinical arena, as well as the low likelihood of success of single cytokine therapies. Evidence supports a synergy between cytokine immunotherapy and other therapeutic approaches in melanoma, and strengthening this area of research will improve our understanding of how to use cytokine therapy better. PMID- 21554098 TI - Effect of different low electric field conditions on the dielectric properties of Ehrlich tumor. AB - Studies of low electric fields (LEFs) effects on the permeability of the cell membrane are of great interest in molecular medicine. Electroendocytosis is a novel technique depends on using LEFs to incorporate macromolecules as anticancer drugs or genes into the cells. There are wide debates about the optimum electric conditions for electroendocytosis. In this article, Ehrlich tumor tissues were exposed to different LEFs voltages and frequencies in vitro. Dielectric properties before and after the exposure were determined. The results indicated that the exposed groups have significant high permittivity and conductivity compared to unexposed group, as well as having significant low impedance. The results indicated that dielectric measurements can be used to indicate the efficiency of electroendocytosis that as permittivity and conductivity of cell membranes increase, more molecules can passed into the cells. It was also indicated that, as the pulse amplitude increases, the LEFs influence increases, while changing pulse frequency has no obvious effect on dielectric properties of Ehrlich tumor. PMID- 21554099 TI - Intracellular Ca(2+) levels in rat ventricle cells exposed to extremely low frequency magnetic field. AB - OBJECTIVE: Electromagnetic fields can affect intracellular Ca(2+) levels. The aim of this study was to determine the changes intracellular Ca(2+) concentration in cardiac ventricle cells of rats exposed to 0.25 mT (2.5 Gauss) magnetic field. METHODS: Forty-five male rats were introduced to this study. The rats were divided into three groups: control, sham, and experiment. The experimental group was exposed to 0.25 mT extremely low frequency (ELF) magnetic field for 14 days, 3 h/day. The sham group was treated like the experimental group, except for elf magnetic field exposure. The control group was not subjected to anything and differed from the experimental group and sham group. In the end of experiment, rats were sacrificed, cardiac tissue was removed, and these were fixed in 10% neutral formalin. Then, ventricular cells were stained by Alizarin red staining method. RESULTS: In the light microscopic examinations of control groups, in myofibril structures between groups, changes were not observed. In myofibril regions of the experimental group compared to other groups, increased heterogen Ca(2+) accumulations were found. CONCLUSION: ELF magnetic fields are used in daily life. The results of this study show that intracellular Ca(2+) accumulation in cardiac ventricles can increase in rats exposed to ELF magnetic field. PMID- 21554100 TI - Pulsed radio frequency energy (PRFE) use in human medical applications. AB - A number of electromagnetic field-based technologies are available for therapeutic medical applications. These therapies can be broken down into different categories based on technical parameters employed and type of clinical application. Pulsed radio frequency energy (PRFE) therapy is a non invasive, electromagnetic field-based therapeutic that is based on delivery of pulsed, shortwave radio frequency energy in the 13-27.12 MHz carrier frequency range, and designed for local application to a target tissue without the intended generation of deep heat. It has been studied for use in a number of clinical applications, including as a palliative treatment for both postoperative and non postoperative pain and edema, as well as in wound healing applications. This review provides an introduction to the therapy, a summary of clinical efficacy studies using the therapy in specific applications, and an overview of treatment-related safety. PMID- 21554101 TI - Functionality of natural killer cells from end-stage cancer patients exposed to coherent electromagnetic fields. AB - The main objective of our study is to investigate whether an enhancement of the immune system in end-stage cancer patients is achieved by exposure to coherent electromagnetic fields. For this reason, 15 end-stage cancer patients were exposed at low intensity, coherent electromagnetic fields at radiofrequencies ranging from 600 kHz-729 Hz, for 8 h/day, 6 days/week for 4 weeks. NKs number and cytotoxicity of NK T-lymphocytes versus K562 cancer cell line were estimated by flow cytometry, before and after exposure. Data showed that the exposure of the end-stage cancer patients to the coherent electromagnetic fields resulted in a significant increase of the number and the cytotoxicity of the NK T-lymphocytes against cancer cells, in all patients. Exposure to coherent EMFs at radiofrequencies increases the number and cytotoxicity of NK T-lymphocytes, which may contribute to the improvement of cancer patients' status. PMID- 21554102 TI - Changes in Paramecium caudatum (protozoa) near a switched-on GSM telephone. AB - The protozoan Paramecium caudatum was examined under normal conditions versus aside a switched-on GSM telephone (900 MHz; 2 Watts). Exposed individuals moved more slowly and more sinuously than usual. Their physiology was affected: they became broader, their cytopharynx appeared broader, their pulse vesicles had difficult in expelling their content outside the cell, their cilia less efficiently moved, and trichocysts became more visible. All these effects might result from some bad functioning or damage of the cellular membrane. The first target of communication electromagnetic waves might thus be the cellular membrane. PMID- 21554103 TI - Lentivirus production is influenced by SV40 large T-antigen and chromosomal integration of the vector in HEK293 cells. AB - Currently, lentiviral vectors for research and gene therapy are produced from 293 T cells that are transiently transfected with plasmids encoding the vector and helper functions. However, transiently transfected vectors as well as the presence of SV40 virus large T-antigen (T-Ag) cause serious technical and safety considerations. We aimed to exploit single copy integration sites in the HEK293 genome supporting lentiviral vector production. We found that lentiviral vectors result in minimal infectious particle production from single copy integrants in HEK293. Moreover, once this cell line harbors single copy integrations of lentiviral vectors, its ability to transiently produce lentiviral vectors becomes strongly impaired. T-Ag has a dramatic effect on virus production. Low levels of constitutive T-Ag expression can overcome the production restriction imposed by integrated lentiviral vectors copies. Interestingly, T-Ag does not exert its role at the level of transcriptional activity of the vector; rather, it seems to impose an indirect effect on the cell thereby enabling lentiviral vector production. Altogether, our study highlights the restrictions for integrated lentiviral vectors that are relevant for the establishment of stable and safe producer cell lines. PMID- 21554104 TI - Regulation of ERK2 phosphorylation by histamine in splenocytes. AB - Histamine is implicated in allergic disease and asthma and ERK1/2 is involved in allergic inflammation including Th2 differentiation and proliferation. This study was designed to study the effects of histamine on ERK1/2 phosphorylation in splenocytes. C57/BL6 splenocytes were treated with different concentrations of histamine (10(-4) to 10(-11) M). Histamine (10(-4) M) increased ERK2 phosphorylation. There was, however, no significant effect seen at other concentrations (10(-11) to 10(-6) M). Surprisingly, H1 receptor agonist beta histine (10(-5) M), H2 agonist amthamine (10(-5) M), H3 agonist methimepip (10( 6) M), and H4 agonist 4-methyl histamine (10(-6) M), all increased ERK2 phosphorylation. H1R antagonist pyrilamine (10(-6) M), H2R antagonist ranitidine (10(-5) M), H3/H4R antagonist thioperamide (10(-6) M), and H3R antagonist clobenpropit (10(-5) M) inhibited histamine-mediated ERK2 phosphorylation suggesting that all four histamine receptor subtypes played some role in this phosphorylation. Because tumor necrosis factor-alpha (TNF-alpha) causes phosphorylation of ERK1/2, we investigated whether histamine acted via secretion of TNF-alpha to affect ERK1/2 phosphorylation. As a consequence, TNF-alpha knockout mice were used and we found that there was inhibition of ERK1 and ERK2 phosphorylation by H2, H3, and H4 agonists. This was in contrast to the wild-type splenocytes where histamine augmented the phosphorylation of ERK2 via H2, H3, and H4 receptors. In TNF-alpha knockout mice histamine did not affect the phosphorylation of ERK2 via H1 receptors. The results suggested that histamine indirectly caused the ERK2 phosphorylation via its effects on the secretion of TNF-alpha and these effects were mediated via H1, H2, H3, and H4 receptors. PMID- 21554105 TI - Protection of immunocompromised mice from fungal infection with a thymus growth stimulatory component from Selaginella involvens, a fern. AB - CONTEXT: Recent studies have shown that the water extract of Selaginella involvens (Sw.) Spring, a wild fern, exhibits thymus growth-stimulatory activity in adult mice (reversal of involution of thymus) and remarkable anti-lipid peroxidation activity. Follow-up studies were carried out in the present study. MATERIALS AND METHODS: Activity-guided isolation of the active component (AC) was carried out. The effect of AC on immune function was studied using fungal (Aspergillus fumigatus) challenge in cortisone-treated mice. The in vitro antifungal activity of AC was assayed using disc diffusion assay. In vitro and in vivo effect of AC on DNA synthesis in thymus was studied using (3)H-thymidine incorporation. In in vitro anti-lipid peroxidation, hydroxyl radical scavenging and inhibition of superoxide production were assayed. RESULTS: The active principle/component (AC) was isolated in a chromatographically pure form from the water extract of S. involvens. AC showed positive reaction to glycosides. AC possessed both thymus growth-stimulatory and antioxidant properties. It protected cortisone-treated mice from A. fumigatus challenge. It did not exhibit in vitro antifungal activity. Increased (3)H-thymidine incorporation was observed in the reticuloepithelium of thymus obtained from AC-treated mice. However, in vitro AC treatment to thymus for 5 h did not result in an increase in (3)H-thymidine incorporation. DISCUSSION AND CONCLUSION: AC (named as Selagin), from S. involvens, could reverse involution of thymus to a large extent, exhibit remarkable antioxidant activity, and protect immunocompromised mice from fungal infection. Therefore, it is very promising for the development of a drug to ameliorate old age-related health problems and prolong lifespan. PMID- 21554106 TI - Thiolated polycarbophil/glutathione: defining its potential as a permeation enhancer for oral drug administration in comparison to sodium caprate. AB - Thiolated polyacrylates were shown to be permeation enhancers with notable potential. The aim of this study was to evaluate the permeation enhancing properties of a thiolated polycarbophil/glutathione (PCP-Cys/GSH) system for oral drug application in comparison to a well-established permeation enhancer, namely sodium caprate. In vitro permeation studies were conducted in Ussing-type chambers with sodium fluoresceine (NaFlu) and fluoresceine isothiocyanate labeled dextran (molecular mass 4 kDa; FD4) as model compounds. Bioavailability studies were carried out in Sprague Dawley rats with various formulations. Moreover, cytotoxic effects of both permeation enhancers were compared. Permeation enhancement ratios of 1% sodium caprate were found to be 3.0 (FD4) and 2.3 (NaFlu), whereas 1% PCP-Cys/0.5% GSH displayed enhancement ratios of 2.4 and 2.2. Both excipients performed at a similar level in vivo. Sodium caprate solutions increased oral bioavailability 2.2-fold (FD4) and 2.3-fold (NaFlu), while PCP-Cys hydrogels led to a 3.2-fold and 2.2-fold enhancement. Cell viability experiments revealed a significantly higher tolerance of Caco-2 cells towards 0.5% PCP-Cys (81% survival) compared to 0.5% sodium caprate (5%). As PCP-Cys is not absorbed from mucosal membranes due to its comparatively high molecular mass, systemic side-effects can be excluded. In conclusion, both systems displayed a similar potency for permeation enhancement of hydrophilic compounds. However, PCP-Cys seems to be less harmful to cultured cells. PMID- 21554107 TI - Intravesical interleukin-15 gene therapy in an orthotopic bladder cancer model. AB - Interleukin-15 (IL-15) is known to stimulate the proliferation of CD8(+) T-cells and natural killer cells, and also to help to maintain memory CD8(+) T cells, suggesting that it may be of value in cytokine treatment of bladder cancer. In this experiment, we tested the efficiency of intravesical liposomal IL-15 gene delivery and its antitumor effect in a mouse orthotopic bladder cancer model. We established an orthotopic bladder cancer model by implanting 5*10(5) MBT-2 cells into female C3H/HeN mice through the urethra. The mice received repeated intravesical gene delivery injected with liposome-mediated plasmids (5 MUg) transurethrally. On day 23, the bladder weights in the group receiving medium alone, the beta-galactosidase gene delivery control group, and the IL-15 gene therapy group were 196+/-36 mg, 201+/-35 mg, and 96+/-29 mg, respectively (p<0.05), demonstrating the antitumor effect of intravesical IL-15 gene therapy in this model. In the bladders treated with IL-15 gene plasmid instillation, histological analysis revealed that many inflammatory cells were induced around the tumors. Immunohistochemical analysis confirmed that there was predominant infiltration of CD8(+) T cells around the tumor nest. After the intravesical IL 15 gene therapy, the growth of rechallenged subcutaneous MBT-2 cells in surviving mice was inhibited again via tumor-specific cytotoxic T lymphocytes, although newly implanted FM3A cells in the same mice were not rejected. The present findings indicate that IL-15 gene therapy may be a promising new adjuvant therapy for bladder cancer. PMID- 21554109 TI - A new educational film control for use in studies of active mind-body therapies: acceptability and feasibility. AB - OBJECTIVES: The study objectives were to ascertain whether a novel educational film class is an acceptable and feasible comparison group for a randomized controlled trial regarding the effects of an active mind-body therapy on cardiovascular disease risk in postmenopausal women. METHODS: Seventy-five (75) participants attended a baseline assessment visit and were randomly assigned to either a yoga group or an educational film (control) group. Both groups attended two 90-minute classes/week for 8 weeks, followed by a second assessment visit. Those not attending the second assessment were classified as dropouts. Over 60 films covering a range of topics relevant to the study population were evaluated; 15 were selected by consensus of at least 2 researchers and 1 layperson. Each film session followed the same format: an informal greeting period, viewing of the film, and a 15-minute postfilm discussion. To determine acceptability and feasibility of the film class, potential between-group differences in dropout and attendance were examined, and participant feedback given during class and on end of-study questionnaires were evaluated. RESULTS: The relation between group assignment and dropout was not significant (chi(2) [1, N = 75] = 0.14, p = 0.71). One-way analysis of variance (ANOVA) indicated no significant between-group difference in number of classes attended for the yoga (X = 13.67 +/- 3.10) versus film group (13.26 +/- 1.97), F(1,63) = 0.39, p = 0.53). Participant feedback regarding the film program was positive. CONCLUSIONS: These findings support the feasibility and acceptability of this educational film control. Easy to standardize and tailor to a variety of populations, this film program may offer an attractive alternative to the more traditional educational control. PMID- 21554111 TI - Prebiological evolution and the metabolic origins of life. AB - The chemoton model of cells posits three subsystems: metabolism, compartmentalization, and information. A specific model for the prebiological evolution of a reproducing system with rudimentary versions of these three interdependent subsystems is presented. This is based on the initial emergence and reproduction of autocatalytic networks in hydrothermal microcompartments containing iron sulfide. The driving force for life was catalysis of the dissipation of the intrinsic redox gradient of the planet. The codependence of life on iron and phosphate provides chemical constraints on the ordering of prebiological evolution. The initial protometabolism was based on positive feedback loops associated with in situ carbon fixation in which the initial protometabolites modified the catalytic capacity and mobility of metal-based catalysts, especially iron-sulfur centers. A number of selection mechanisms, including catalytic efficiency and specificity, hydrolytic stability, and selective solubilization, are proposed as key determinants for autocatalytic reproduction exploited in protometabolic evolution. This evolutionary process led from autocatalytic networks within preexisting compartments to discrete, reproducing, mobile vesicular protocells with the capacity to use soluble sugar phosphates and hence the opportunity to develop nucleic acids. Fidelity of information transfer in the reproduction of these increasingly complex autocatalytic networks is a key selection pressure in prebiological evolution that eventually leads to the selection of nucleic acids as a digital information subsystem and hence the emergence of fully functional chemotons capable of Darwinian evolution. PMID- 21554112 TI - Engineering the evolution of self-organizing behaviors in swarm robotics: a case study. AB - Evolutionary robotics (ER) is a powerful approach for the automatic synthesis of robot controllers, as it requires little a priori knowledge about the problem to be solved in order to obtain good solutions. This is particularly true for collective and swarm robotics, in which the desired behavior of the group is an indirect result of the control and communication rules followed by each individual. However, the experimenter must make several arbitrary choices in setting up the evolutionary process, in order to define the correct selective pressures that can lead to the desired results. In some cases, only a deep understanding of the obtained results can point to the critical aspects that constrain the system, which can be later modified in order to re-engineer the evolutionary process towards better solutions. In this article, we discuss the problem of engineering the evolutionary machinery that can lead to the desired result in the swarm robotics context. We also present a case study about self organizing synchronization in a swarm of robots, in which some arbitrarily chosen properties of the communication system hinder the scalability of the behavior to large groups. We show that by modifying the communication system, artificial evolution can synthesize behaviors that scale properly with the group size. PMID- 21554113 TI - "If you can't be with the one you love, love the one you're with": how individual habituation of agent interactions improves global utility. AB - Simple distributed strategies that modify the behavior of selfish individuals in a manner that enhances cooperation or global efficiency have proved difficult to identify. We consider a network of selfish agents who each optimize their individual utilities by coordinating (or anticoordinating) with their neighbors, to maximize the payoffs from randomly weighted pairwise games. In general, agents will opt for the behavior that is the best compromise (for them) of the many conflicting constraints created by their neighbors, but the attractors of the system as a whole will not maximize total utility. We then consider agents that act as creatures of habit by increasing their preference to coordinate (anticoordinate) with whichever neighbors they are coordinated (anticoordinated) with at present. These preferences change slowly while the system is repeatedly perturbed, so that it settles to many different local attractors. We find that under these conditions, with each perturbation there is a progressively higher chance of the system settling to a configuration with high total utility. Eventually, only one attractor remains, and that attractor is very likely to maximize (or almost maximize) global utility. This counterintuitive result can be understood using theory from computational neuroscience; we show that this simple form of habituation is equivalent to Hebbian learning, and the improved optimization of global utility that is observed results from well-known generalization capabilities of associative memory acting at the network scale. This causes the system of selfish agents, each acting individually but habitually, to collectively identify configurations that maximize total utility. PMID- 21554114 TI - Global adaptation in networks of selfish components: emergent associative memory at the system scale. AB - In some circumstances complex adaptive systems composed of numerous self interested agents can self-organize into structures that enhance global adaptation, efficiency, or function. However, the general conditions for such an outcome are poorly understood and present a fundamental open question for domains as varied as ecology, sociology, economics, organismic biology, and technological infrastructure design. In contrast, sufficient conditions for artificial neural networks to form structures that perform collective computational processes such as associative memory/recall, classification, generalization, and optimization are well understood. Such global functions within a single agent or organism are not wholly surprising, since the mechanisms (e.g., Hebbian learning) that create these neural organizations may be selected for this purpose; but agents in a multi-agent system have no obvious reason to adhere to such a structuring protocol or produce such global behaviors when acting from individual self interest. However, Hebbian learning is actually a very simple and fully distributed habituation or positive feedback principle. Here we show that when self-interested agents can modify how they are affected by other agents (e.g., when they can influence which other agents they interact with), then, in adapting these inter-agent relationships to maximize their own utility, they will necessarily alter them in a manner homologous with Hebbian learning. Multi-agent systems with adaptable relationships will thereby exhibit the same system-level behaviors as neural networks under Hebbian learning. For example, improved global efficiency in multi-agent systems can be explained by the inherent ability of associative memory to generalize by idealizing stored patterns and/or creating new combinations of subpatterns. Thus distributed multi-agent systems can spontaneously exhibit adaptive global behaviors in the same sense, and by the same mechanism, as with the organizational principles familiar in connectionist models of organismic learning. PMID- 21554116 TI - Autocatalysis: at the root of self-replication. AB - Autocatalysis is a fundamental concept, used in a wide range of domains. From its most general definition, that is, a process in which a chemical compound is able to catalyze its own formation, several different systems can be described. We detail the different categories of autocatalyses, and compare them on the basis of their mechanistic, kinetic, and dynamic properties. It is shown how autocatalytic patterns can be generated by different systems of chemical reactions. The notion of autocatalysis covers a large variety of mechanistic realizations with very similar behaviors; it is proposed that its key signature is its kinetic pattern expressed in a mathematical form. This notion, while describing dynamic behaviors at the most fundamental level, is at the basis for developing higher-level concepts towards life: autocatalytic sets, and autopoietic systems. PMID- 21554117 TI - Happiness is assortative in online social networks. AB - Online social networking communities may exhibit highly complex and adaptive collective behaviors. Since emotions play such an important role in human decision making, how online networks modulate human collective mood states has become a matter of considerable interest. In spite of the increasing societal importance of online social networks, it is unknown whether assortative mixing of psychological states takes place in situations where social ties are mediated solely by online networking services in the absence of physical contact. Here, we show that the general happiness, or subjective well-being (SWB), of Twitter users, as measured from a 6-month record of their individual tweets, is indeed assortative across the Twitter social network. Our results imply that online social networks may be equally subject to the social mechanisms that cause assortative mixing in real social networks and that such assortative mixing takes place at the level of SWB. Given the increasing prevalence of online social networks, their propensity to connect users with similar levels of SWB may be an important factor in how positive and negative sentiments are maintained and spread through human society. Future research may focus on how event-specific mood states can propagate and influence user behavior in "real life." PMID- 21554118 TI - Chronic toxicity, genotoxic assay, and phytochemical analysis of four traditional medicinal plants. AB - Four medicinal plants--Tecoma stans, Ligusticum porteri, Monarda austromontana, and Poliomintha longiflora, which are distributed in tropical and subtropical countries of the American continent--are widely used in folk medicine to treat diseases such as diarrhea and dysentery. In addition, T. stans and P. longiflora are extensively used as hypoglycemic agents, and M. austromontana and P. longiflora are used as condiments. The plants were collected, identified, dried, and pulverized. Solvent extraction was prepared by maceration of the plant samples, and the phytochemical composition of the extracts was determined by using standard analysis procedures. Phytochemical analysis showed the presence of triterpenoids/steroids, flavonoids, and phenols/tannins and, in L. porteri, traces of alkaloids. After the elimination of solvents in vacuo, the extracts were administrated to Drosophila larvae to test their toxicity and genotoxicity. Third instar larvae were chronically fed with the phytoextracts. The extract from L. porteri was toxic, whereas those from T. stans, P. longiflora, and M. austromontana were not. Genotoxic activities of the 4 plants were investigated by using the wing-spot assay of D. melanogaster. Mitomycin C was used as a positive control. No statistically significant increase was observed between treated sample series and a concurrent negative (water) or solvent control sample series. PMID- 21554119 TI - Effect of Rheedia longifolia leaf extract and fractions on the P2X7 receptor in vitro: novel antagonists? AB - Recently, the P2X(7) receptor has been reported to be associated with chronic inflammatory and neuropathic pain. Because Rheedia longifolia extract has analgesic and anti-inflammatory activity, we evaluated the in vitro inhibitory potential of methanol extract and fractions from its leaves on the P2X(7) purinergic receptor. The activity of P2X(7) was studied with a dye uptake assay and with the whole-cell patch clamp technique in mouse peritoneal macrophages treated with methanol extract of R. longifolia leaves and fractions. The dye uptake was evaluated by flow cytometry and fluorescence microscopy. The R. longifolia extract and some fractions showed an inhibitory effect on the P2X(7) purinergic receptor in a dose-dependent manner. The ethyl acetate fraction exhibited the most potent inhibitory effects. The methanol extract and the butanol fraction showed the same inhibitory effects, despite their lower potency compared with the other fractions. The R. longifolia extract and some of its fractions may be anti-inflammatory because of their inhibitory effect on the P2X(7) receptor. Further investigation is needed to determine the pattern of inhibition and selectivity. Chromatographic analysis indicated the presence of bisflavonoids in the methanol extract fractions. A member of this chemical family is the most probable active compound responsible for the P2X(7) inhibitory effects present in the R. Longifolia extract and fractions. PMID- 21554120 TI - Antioxidant activity of eugenol: a structure-activity relationship study. AB - Eugenol (4-allyl-2-methoxyphenol), a major phenolic component from clove oil (Eugenia caryophyllata), has several biological activities. To estimate the capacity of eugenol to act as an antioxidant, the following were studied: 1,1 diphenyl-2-picryl-hydrazyl-, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)-, and N,N-dimethyl-p-phenylenediamine-scavenging activity; total antioxidant activity; and ability to reduce ferric ions and cupric ions. Eugenol inhibited 96.7% (r(2)=0.9319) lipid peroxidation of a linoleic acid emulsion at a 15-MUg/mL concentration. Butylated hydroxyanisole, butylated hydroxytoluene, alpha-tocopherol, and Trolox((r)) displayed 95.4% (r(2)=0.8482), 99.7% (r(2)=0.7798), 84.6% (r(2)=0.9272), and 95.6% (r(2)=0.8511) inhibition of peroxidation, respectively, at the 15-MUg/mL concentration. According to the results of this study, eugenol had the most powerful antioxidant activity and radical-scavenging activity. This study should prompt further studies of the antioxidant properties of eugenol. PMID- 21554121 TI - Pectin from Passiflora edulis shows anti-inflammatory action as well as hypoglycemic and hypotriglyceridemic properties in diabetic rats. AB - Flour made from Passiflora edulis fruit peel has been used in Brazil to treat diabetes. This study evaluated the effects of pectin from P. edulis on rats with alloxan-induced diabetes, on myeloperoxidase release from human neutrophils, and on carrageenan-induced paw edema. In the experiments on carrageenan-induced paw edema, paws were dissected for hematoxylin-eosin staining and immunohistochemistry determinations of tumor necrosis factor-alpha and inducible nitric oxide synthase. Male Wistar rats were divided into the following groups: diabetic controls and diabetic treated with pectin daily for 5 days (0.5-25 mg/kg orally). Glibenclamide and metformin were used as reference drugs. Forty-eight hours after alloxan administration, blood measures were determined (before treatment) and again 5 days later (after treatment). Pectin decreased blood glucose and triglyceride levels in diabetic rats. Pectin also decreased edema volume and release of myeloperoxidase (0.1-100 MUg/mL). It also significantly decreased neutrophil infiltration and partially decreased immunostaining for tumor necrosis factor-alpha and inducible nitric oxide synthase. In conclusion, these data indicated that pectin, a bioactive compound present in P. edulis, has potential as a useful alternative treatment for type 2 diabetes. Its anti inflammatory properties are probably involved in its antidiabetic action. PMID- 21554122 TI - Copper and zinc bioaccumulation and bioavailability of Ganoderma lucidum. AB - Ganoderma lucidum is a widely recognized medicinal mushroom. The bioaccumulation and potential bioavailability of copper (Cu) and zinc (Zn), which are essentials for human health, were analyzed in G. lucidum mycelium and fruit bodies grown in the presence of these metals to test their potential utility as a food dietary supplement. Mycelia grown in culture medium with non-mycotoxic doses of Cu or Zn (25 and 50 mg/kg) were selected for evaluation of the bioavailability of these metals in the gastrointestinal tract by using an in vitro simulated digestion system. One gram of dried mycelium grown in the presence of 50 mg/kg Cu or Zn showed a bioavailability of 19% for Cu and 2% for Zn of the recommended daily intake (RDI). When production of fruit bodies was evaluated, the highest biological efficiency (23%) was reached when the substrate was enriched with 100 mg/kg Cu. Cu and Zn contents obtained either before or after digestion of fruit bodies from all metal-enriched treatments were substantially lower than those from metal-enriched mycelia. The metal bioavailability was also low: 1.5% of the Cu RDI and almost negligible for Zn. The results are discussed in relation to the RDI values exhibited by two commercial supplements. The potential incorporation of these mineral-enriched mycelia/fruit bodies in capsules, infusions, and dietary supplements is evaluated. PMID- 21554123 TI - Structure-activity relationship of resveratrol and its analogue, 4,4'-dihydroxy trans-stilbene, toward the endothelin axis in human endothelial cells. AB - Resveratrol inhibits endothelin-1, a vascular tension regulator. We synthesized the resveratrol analogue 4,4'-dihydroxy-trans-stilbene with 2 hydroxyl groups in the 4 and 4' position to obtain a molecule more active than resveratrol (3,4',5 trihydroxy-trans-stilbene). The results demonstrate that 4,4'-dihydroxy-trans stilbene led to a significant decrease in total endothelin-1 secretion and in endothelin-1 messenger RNA (mRNA) levels in human endothelial cells. In addition, resveratrol and its analogue decreased endothelin-converting enzyme-1 mRNA levels and further reduced the activity of the enzyme. 4,4'-dihydroxy-trans-stilbene was more active than resveratrol because the new molecule exerted greater activity at the level of endothelin synthesis and conversion, even at a lower concentration. Although 4,4'-dihydroxy-trans-stilbene and resveratrol inhibited formation of reactive oxygen species and lipid peroxidation, the treatment of cells with different oxidant agents did not modify the endothelin-1 release. This finding suggests that the inhibition of endothelin-1 secretion is independent of the antioxidant properties of the 2 compounds. On the basis of these results, the resveratrol analogue 4,4'-dihydroxy-trans-stilbene could be a promising chemopreventive agent against cardiovascular diseases. PMID- 21554124 TI - Growth performance of weanling Wistar rats fed on accessions of cooked Colocasia esculenta-based diets. AB - The growth performance of weanling albino rats (Rattus norvegicus) maintained on different accessions (offspring of a variety that was planted/collected at a specific location and time but differing in certain morphologic characteristics) of cooked Colocasia esculenta (cocoyam)-based diets (UFCe1-UFCe7) for 28 days was investigated. Proximate analysis of the formulated diets revealed that UFCe3, UFCe4, UFCe5, UFCe6, and UFCe7 had significantly (P<.05) higher moisture contents than the corn starch-based diet (control). All the accession-based diets of C. esculenta had higher ash contents. Similarly, all the accessions of the C. esculenta-based diet had lower crude lipid content, whereas UFCe3-UFCe7 had significantly lower protein content. Although the crude fiber content was significantly higher in UFCe2, UFCe4, and UFCe5, only UFCe3 had significantly higher carbohydrate content among all the accessions of C. esculenta-based diets. UFCe1, UFCe2, UFCe4, UFCe5, and UFCe6 increased the average weekly water intake, feed consumption, total body weight, liver-body weight ratio, and kidney-body weight ratio of the animals; UFCe3 and UFCe7 decreased these measures. Overall, UFCe1, UFCe2, UFCe4, UFCe5, and UFCe6 are recommended as diets with promise to enhance growth performance in the animals. PMID- 21554125 TI - Antiemetics for chemotherapy-induced nausea and vomiting occurring despite prophylactic antiemetic therapy. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect. Previous studies have primarily focused on prophylactic therapy, but no published reports have evaluated the treatment of breakthrough CINV. METHODS: A prospective, pilot study was performed to provide preliminary prospective evidence of the efficacy of individual agents prescribed for the treatment of breakthrough CINV. Enrolled patients were receiving moderately or highly emetogenic chemotherapy and prophylactic treatment of CINV based on antiemetic guidelines. Patients were prescribed an antiemetic for breakthrough CINV at the discretion of their treating oncologist. If patients had breakthrough CINV that required a breakthrough antiemetic medication, they were instructed to complete a questionnaire every 30 minutes for 4 hours after taking the antiemetic. Levels of nausea (0-10), vomiting, and side effects were recorded. RESULTS: Of the 96 patients enrolled, 27 (28%) reported breakthrough nausea and/or vomiting requiring medication and completed the questionniare. Eighty-eight percent (n = 24) reported the use of prochlorperazine; they experienced a 75% median nausea reduction after 4 hours, with minimal side effects. Three patients (12%) reported the use of a 5-hydroxytryptophan (5-HT) receptor antagonist for treatment of breakthrough nausea. These patients reported a median nausea reduction of 75% after 4 hours and no perceived toxicities. CONCLUSIONS: Prochlorperazine and 5-HT receptor antagonists appear to be effective breakthrough antiemetic therapies. The described study methodology can be used to conduct randomized clinical trials to find more effective drugs for treating established nausea. PMID- 21554126 TI - Are cyberbullies less empathic? Adolescents' cyberbullying behavior and empathic responsiveness. AB - Meta-analyses confirm a negative relationship between aggressive behavior and empathy, that is, the ability to understand and share the feelings of others. Based on theoretical considerations, it was, therefore, hypothesized that a lack of empathic responsiveness may be characteristic for cyberbullies in particular. In the present study, 2.070 students of Luxembourg secondary schools completed an online survey that included a cyberbullying questionnaire(4) and a novel empathy short scale. According to the main hypothesis, analyses of variances indicated that cyberbullies demonstrated less empathic responsiveness than non cyberbullies. In addition, cyberbullies were also more afraid of becoming victims of cyberbullying. The findings confirm and substantially extend the research on the relationship between empathy and aggressive behavior. From an educational point of view, the present findings suggest that training of empathy skills might be an important tool to decrease cyberbullying. PMID- 21554127 TI - Use of acupuncture and other CAM methods in obstetrics: an analysis of 409,413 deliveries from Hesse, Germany. AB - OBJECTIVES: This study was done to analyze the frequency of use of acupuncture and other complementary and alternative medicine (CAM) methods during labor and to investigate the different characteristics of women being treated with or without acupuncture and CAM methods, as well as try to analyze birth-related outcome measures. STUDY DESIGN: Data were analyzed from 409,413 deliveries, registered between 2001 and 2008 by the agency for quality assurance in Hesse (the Hessian Perinatal Registry [HEPE] survey), which made up more than 95% of all deliveries in this German state during the given time period. RESULTS: Interest in the use of CAM seems to have decreased within the given time period. On average, acupuncture was used in 3.7% (15,345/409,295) of all deliveries and other CAM methods in 4.8% (19,507/409,295). The most important determinant for the use of one or both methods was the type of hospital. It was also found that German women with higher job qualifications were more likely to receive CAM treatment during delivery. Interestingly, application of CAM methods was associated with a higher use of analgesics during labor. The risk status of the pregnancy or the delivery was of minor importance. CONCLUSIONS: This analysis shows that the determinants of CAM use are similar to those in the field of oncology. In order to assess the efficacy of acupuncture or other CAM methods in the field of obstetrics, it seems necessary to extend the HEPE survey to cover these areas. PMID- 21554129 TI - Determining a singleton attractor of a boolean network with nested canalyzing functions. AB - In this article, we study the problem of finding a singleton attractor for several biologically important subclasses of Boolean networks (BNs). The problem of finding a singleton attractor in a BN is known to be NP-hard in general. For BNs consisting of n nested canalyzing functions, we present an O(1.799(n)) time algorithm. The core part of this development is an O(min(2(k/2) . 2(m/2), 2(k)) . poly(k, m)) time algorithm for the satisfiability problem for m nested canalyzing functions over k variables. For BNs consisting of chain functions, a subclass of nested canalyzing functions, we present an O(1.619(n)) time algorithm and show that the problem remains NP-hard, even though the satisfiability problem for m chain functions over k variables is solvable in polynomial time. Finally, we present an o(2(n)) time algorithm for bounded degree BNs consisting of canalyzing functions. PMID- 21554128 TI - Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia. AB - OBJECTIVES: The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. DESIGN: CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. SUBJECTS: The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. RESULTS: The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. CONCLUSIONS: Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated study population. PMID- 21554130 TI - Natural products from Garcinia brasiliensis as Leishmania protease inhibitors. AB - The infections by protozoans of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The drugs of choice for the treatment of leishmaniasis are the pentavalent antimonials, which cause renal and cardiac toxicity. As part of a search for new drugs against leishmaniasis, we evaluated the in vitro Leishmania protease inhibition activity of extracts (hexanic, ethyl-acetate, and ethanolic) and fukugetin, a bioflavonoid purified from the ethyl-acetate extract of the pericarp of the fruit of Garcinia brasiliensis, a tree native to Brazilian forests. The isolated compound was characterized by using spectral analyses with nuclear magnetic resonance, mass spectroscopy, ultraviolet, and infrared techniques. The ethyl-acetate extract and the compound fukugetin showed significant activity as inhibitors of Leishmania's proteases, with mean (+/-SD) IC(50) (50% inhibition concentration of protease activity) values of 15.0+/-1.3 MUg/mL and 3.2+/-0.5 MUM/mL, respectively, characterizing a bioguided assay. In addition, this isolated compound showed no activity against promastigote and amastigote forms of L. (L.) amazonensis and mammalian cells. These results suggest that fukugetin is a potent protease inhibitor of L. (L.) amazonensis and does not cause toxicity in mammalian or Leishmania cells in vitro. This study provides new perspectives on the development of novel drugs that have leishmanicidal activity obtained from natural products and that target the parasite's proteases. PMID- 21554131 TI - Phenolic content and antioxidant and antiacetylcholinesterase properties of honeys from different floral origins. AB - Twenty-three honey samples of Apis mellifera L. forged on plants from northeastern Brazil were analyzed to determine total phenolic content, flavonoid content, antioxidant activity, and antiacetylcholinesterase activity. The total phenol content was determined by using the Folin-Ciocalteu method, and the flavonoid content was analyzed using by the aluminum chloride method. The antioxidant activity was evaluated using the diphenyl-1-picrylhydrazyl-scavenging test. Honey samples from Lippia sidoides Cham. (mean [+/-standard deviation] 50% inhibitory concentration [IC(50)], 4.20+/-1.07 mg/mL) and Myracrodruon urundeuva Fr. All. (IC(50), 28.27+/-1.41 mg/mL) showed better antioxidant activity and presented higher total phenol values (108.50+/-3.52 mg gallic acid equivalents/100 g for L. sidoides and 68.55+/-1.01 mg gallic acid equivalents/100 g for M. urundeuva). Several honey samples had relevant results on antiacetylcholinesterase assay. The biological activity of honeys is related to their floral origin, and medicinal plants constitute a useful resource for the generation of functional foods. PMID- 21554132 TI - The dietary compounds resveratrol and genistein induce activating transcription factor 3 while suppressing inhibitor of DNA binding/differentiation-1. AB - Various chemopreventive compounds alter gene expression, possibly explaining their biological activity. One gene induced by a variety of chemopreventive compounds is the one coding for the transcription factor activating transcription factor 3 (ATF3). In this study, we performed microarray analysis on mRNA isolated from human colorectal cancer cells overexpressing ATF3 to ascertain the biological activity of this gene in cancer. As a result, 64 genes were induced or repressed. One gene identified by microarray analysis as repressed by overexpression of ATF3 was inhibitor of DNA binding/differentiation-1 (Id1). Id1 is important to cell growth and proliferation and therefore may represent an important downstream target of ATF3 responsible for the biological activity of ATF3. Id1 interacts with ATF3, thereby sequestering its activity, making it an ideal candidate for further study. The induction of ATF3 and repression of Id1 in these cells were confirmed at the mRNA and protein levels by semiquantitative real-time reverse transcription-polymerase chain reaction and western blot analysis, respectively. To determine if the repression of Id1 seen following microarray analysis of these cells occurred following treatment with dietary compounds with known chemotherapeutic activity, human colorectal cancer cells were treated with resveratrol and genistein, and their expression was determined. As a result, ATF3 was induced, and Id1 was repressed, by these compounds and by sulindac sulfide, a positive control, at the mRNA and protein level. Further work is needed to determine the molecular mechanism(s) responsible for the regulation of Id1 and to determine if biological activity of ATF3 overexpression is mediated by repression of Id1 by these compounds. PMID- 21554133 TI - Assessment of phenolic acid content and in vitro antiradical characteristics of hawthorn. AB - The infusions and extracts obtained from leaves with flowers, fruit peel, and seed from hawthorn (Crataegus monogyna Jacq., Family Rosaceae) were subjected to evaluation as potential sources of antioxidant phytochemicals on the basis of their total content of phenolics, levels of phenolic acids, and in vitro antiradical activity. Total phenolic content of extracts was determined using the modified Folin-Ciocalteau method. Antioxidant activity was determined for phenolic extracts by a method involving the use of the free radical 2,2-diphenyl 1-picrylhydrazyl (DPPH). Phenolic acids containing extracts and infusions from hawthorn leaves, fruit peel, and seeds were obtained using different polarity solvents and separated by reverse-phase high-performance liquid chromatography, which enabled improved separation by the use of a C(18) column, an acidic mobile phase, and gradient elusion. The highest total phenolic content (343.54 mg of gallic acid equivalents/g) and the highest DPPH radical scavenging activity as the inhibition percentage (60.36%) were obtained in ethyl acetate extract from hawthorn leaves with flower. Also, the highest phenolic acid content was measured in the extracts of hawthorn leaves with flowers: protocathechuic (108-128 mg/100 g), p-hydroxy benzoic (141-468 mg/100 g), caffeic (137-3,580 mg/100 g), chlorogenic (925-4,637 mg/100 g), ferulic (3,363-3,462 mg/100 g), vanillic (214 mg/100 g), and syringic (126 mg/100 g) acids. The results indicate that hawthorn is a promising plant because of its high antioxidant activity. PMID- 21554134 TI - Antiobesity effect of oil extract of ginseng. AB - In a preliminary study we found that incubating raw ginseng in oil facilitated autolysis and extensive metabolism of ginseng, releasing flavor and lipophilic compounds into the oil so that it could be used as an ingredient for high value added foods, while the residue could be utilized for making ginseng extract. Here, we report the effect of oil (grapeseed oil [GSO]) extract of ginseng (OEG) on body weight gain and lipid metabolism in a mouse model. OEG, but not GSO, inhibited porcine pancreatic lipase. Plasma triglyceride (TG) levels were lower in male ICR mice at 1, 2, 3, and 4 hours after oral administration of the lipid emulsion plus OEG (1 g/kg of body weight) than in the group administered only the lipid emulsion or lipid emulsion plus GSO. Next, male C57BL/6J mice were fed a standard diet, a high fat (HF) diet containing 30% lard, or diets including 30% OEG or GSO based on the standard diet for 14 weeks. Consumption of OEG-containing diet significantly lowered the body weight gain, feed efficiency, visceral fat accumulation, plasma TG, and hepatic and white epididymal adipocyte sizes, as well as expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in liver and adipose tissue. In conclusion, dietary OEG improved obesity-related parameters in blood, liver, and adipose tissue in a mouse model and suppressed obesity induced by HF diet, possibly by regulating lipid metabolism by modulating PPARgamma protein expression. PMID- 21554135 TI - Gastrodia elata Bl. Attenuated learning deficits induced by forced-swimming stress in the inhibitory avoidance task and Morris water maze. AB - This study adopted the forced-swimming paradigm to induce depressive symptoms in rats and evaluated the effects on learning and memory processing. Furthermore, the effects of the water extract of Gastrodia elata Bl., a well-known Chinese traditional medicine, on amnesia in rats subjected to the forced-swimming procedure were studied. Rats were subjected to the forced-swimming procedure, and the inhibitory avoidance task and Morris water maze were used to assess learning and memory performance. The acquisition of the two tasks was mostly impaired after the 15-minute forced-swimming procedure. Administration of the water extract of G. elata Bl. for 21 consecutive days at a dosage of 0.5 or 1.0 g/kg of body weight significantly improved retention in the inhibitory avoidance test, and the lower dose showed a better effect than the higher one and the antidepressant fluoxetine (18 mg/kg of body weight). In the Morris water maze, the lower dose of the water extract of G. elata Bl. significantly improved retention by shortening escape latency in the first test session and increasing the time in searching the target zone during the probe test. These findings suggest that water extracts of G. elata Bl. ameliorate the learning and memory deficits induced by forced swimming. PMID- 21554136 TI - Effect of Shengmai-san on cognitive performance and cerebral oxidative damage in BALB/c mice. AB - The aim of this study was to examine the effect of Shengmai-san (SMS) on learning and memory impairment induced by scopolamine (1 mg/kg, i.p.) in mice. The passive avoidance task (PAT) and Morris water maze (MWM) test served as the behavioral models for testing memory. To elucidate the mechanism of its cognitive-enhancing activity, the effects of SMS (2, 4, or 8 g/kg) on activities of acetylcholinesterase (AChE) and antioxidant enzymes and levels of acetylcholine (ACh) and nitrite were evaluated in brain homogenate. Tacrine (THA) (10 mg/kg, p.o.) was used as a reference drug. SMS (4 or 8 g/kg) significantly prevented scopolamine-induced impairments as measured by the PAT and MWM (probe trial session). SMS (4 or 8 g/kg) also significantly reduced the oxidative-nitrative stress, as evidenced by decreased malondialdehyde and nitrite levels and by its prevention of decreases in glutathione and superoxide dismutase levels. The activity of AChE was decreased in scopolamine-treated mice but was inhibited significantly by SMS treatment (4 or 8 g/kg) in both salt- and detergent-soluble fractions of brain homogenates. Further SMS treatment (4 or 8 g/kg) significantly increased the ACh levels in the brain homogenate to a level similar to that observed in THA treatment. Thus, the significant cognitive enhancement observed after 7 days of administration of SMS is closely related to the strong antioxidant properties of SMS in addition to its inhibition of brain AChE activity. These findings stress the critical impact of SMS on higher brain functions such as learning and memory. PMID- 21554137 TI - Triterpene glycoside cucumarioside A(2)-2 from sea cucumber stimulates mouse immune cell adhesion, spreading, and motility. AB - Holothurian triterpene glycosides are known to possess multiple biological activities. Here we show that cucumarioside A(2)-2 from the Far-Eastern edible holothurian Cucumaria japonica possesses potent immunomodulatory properties. The present studies were done to determine if cucumarioside A(2)-2 would affect macrophage adhesion, spreading, and motility. Resident peritoneal macrophages, collected from BALB/c mice, were exposed in vitro to low concentrations of cucumarioside A(2)-2 and compared with appropriate controls. Results indicate that 0.02 MUg/mL cucumarioside A(2)-2 significantly enhanced macrophage morphology parameters and behavior. The glycoside stimulated these parameters by increasing the number of cells with increased adhesion properties as well as the spreading reaction and motility velocity by at least almost twofold. The data are discussed in terms of possible mechanisms underlying the immunomodulatory properties of cucumarioside A(2)-2. PMID- 21554138 TI - The inhibitory effect of Lactobacillus plantarum KY1032 cell extract on the adipogenesis of 3T3-L1 Cells. AB - Some probiotics and their cell components are known to modulate lipid metabolism in vitro and/or in vivo. This study was carried out to investigate possible anti adipogenic action of a probiotic cell extract, Lactobacillus plantarum KY1032 cell extract (KY1032-CE), in vitro using 3T3-L1 cells. Lipid regulation in the cell culture system was assessed by AdipoRed assay and Oil red O staining of intracellular lipids and real-time polymerase chain reaction and western blot analysis of adipogenesis-related factors. AdipoRed assay revealed that KY1032-CE treatment significantly decreased lipid accumulation in maturing 3T3-L1 preadipocytes in a dose-dependent manner. Oil red O staining demonstrated that KY1032-CE reduced the number of lipid-containing rounded cells. KY1032-CE down regulated the mRNA and protein expression of four adipocyte-specific genes: peroxisome proliferator-activated receptor-gamma2, CCAAT/enhancer binding protein alpha, fatty acid synthase, and adipocyte-fatty acid binding protein. Accordingly, these results indicate that KY1032-CE can reduce fat mass by modulating adipogenesis in maturing preadipocytes. Further studies are needed to elucidate its mode of actions in efficacy tests of KY1032-CE in vivo. PMID- 21554139 TI - Fibrinolytic and antiplatelet aggregation properties of a recombinant Cheonggukjang kinase. AB - This study characterized the efficacy of recombinant Cheonggukjang kinase (CGK) 3 5-rich fraction as a thrombolytic agent, which we overexpressed in Bacillus licheniformis ATCC10716, a strain normally lacking fibrinolytic activity. We found that CGK3-5 is a plasmin-like protease that directly degrades fibrin clots and does not activate plasminogen during fibrin clot lysis and platelet-rich clot lysis assays. We also confirmed antiplatelet and antithrombotic activity by CGK3 5-rich fraction both in vitro and in vivo. CGK3-5-rich fraction inhibited collagen-induced platelet aggregation in platelet-rich plasma in a concentration dependent manner. The concentration of 1.5 mg/mL CGK3-5-rich fraction completely inhibited collagen-induced platelet aggregation. Furthermore, injection of CGK3-5 rich fraction into tail veins dose-dependently protected mice from death by pulmonary embolism induced by collagen and epinephrine. The survival rates were 30%, 70%, and 100%, respectively, with doses of 130 mg/kg, 260 mg/kg, and 520 mg/kg. These findings suggest that CGK3-5 holds promise as a treatment to mitigate the potentially effects of stroke and heart failure. PMID- 21554143 TI - Effects of alendronate plus alfacalcidol in osteoporosis patients with a high risk of fracture: the Japanese Osteoporosis Intervention Trial (JOINT) - 02. AB - OBJECTIVES: The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting. RESEARCH DESIGN AND METHODS: Eligible patients were postmenopausal women with severe osteoporosis who were aged 70 years or older and had several risk factors for incident fractures. The primary endpoint was prevention of incident fractures, and the anti-fracture efficacy was evaluated in relation to the baseline serum 25(OH)D level. RESULTS: A total of 2164 patients were randomized to alendronate plus alfacalcidol (combination therapy) or alendronate alone (monotherapy). Although the overall difference in the incidence of vertebral fracture between the two groups was not significant, the combination therapy group had a significantly reduced risk of vertebral fractures after the first 6 months (HR, 0.53). In subgroup analyses, the combination therapy group was superior in the strata of number of prevalent vertebral fractures of >=2 (HR, 0.51) and grade 3 of prevalent vertebral fractures (HR, 0.55). The rate of non vertebral weight-bearing bone fractures was significantly lower in the combination therapy group than in the monotherapy group during the follow-up period (HR, 0.31). A lower baseline 25(OH)D level was associated with a higher incidence of non-vertebral weight-bearing bone fractures (HR, 3.42) despite alendronate use. Although one patient given the combination therapy had mild hypercalcemia, serious hypercalcemia and unknown adverse events were not encountered. Because of the limitations presented in this study, these results may not apply to female patients with longer than 2 years of treatments, and to male osteoporosis patients. CONCLUSIONS: The combination therapy was no more effective for overall vertebral fracture prevention. However, subgroup analysis has shown that it was more effective for fracture prevention in patients with severe vertebral deformity, multiple prevalent vertebral fractures, and for non vertebral weight-bearing bone fracture prevention. PMID- 21554144 TI - Use of hypomethylating agents and associated care in patients with myelodysplastic syndromes: a claims database study. AB - OBJECTIVE: The purpose of this study is to describe patterns of hypomethylating agents (HMA) use and to compare treatment outcomes of decitabine (DAC) and azacitidine (AZA) with respect to transfusion dependence and the use of erythropoiesis-stimulating agents (ESA) treatment in commercially-insured patients with Myelodysplastic Syndromes (MDS). RESEARCH DESIGN AND METHODS: A retrospective study using MarketScan Research Data, a large claims database studied patients who received DAC, AZA, or Supportive Care (SC) with at least two claims for MDS between January 1, 2006 and December 31, 2008. Poisson regressions were used to compare DAC and AZA on post-index number of red blood cell/platelet (RBC/PLT) transfusions and ESA treatment, controlling for age, gender, Charlson Comorbidity Index (CCI), time to HMA initiation, number of HMA cycles, and pretreatment RBC/PLT or ESA claims. No other adjustment for disease severity was made. RESULTS: Approximately 48% of the patients were males with a mean age of 73 years (N = 2525). There were 37 DAC-treated and 60 AZA-treated patients. The length of follow-up did not significantly differ between the DAC- and AZA-treated groups (DAC = 349.2; AZA = 350.5 days); however, the number of days from MDS diagnosis to HMA therapy initiation was longer in the DAC cohort than in the AZA cohort (mean 93.7 days vs. 50.8 days, respectively, p = 0.029). Both DAC- and AZA treated patients received similar number of treatment cycles (mean: 4.8 vs. 5.6 in DAC vs. AZA, p > 0.05), with means of 4.6 days per cycle for patients receiving DAC and 7.4 days for those receiving AZA (p = 0.003). Following treatment with HMA using Poisson regression analysis, DAC-treated patients had significantly lower use of RBC/PLT transfusions (RR 0.206, p = 0.034) and similar use of ESAs compared with AZA-treated patients. Limitations of the study included the small sample size, and the fact that the majority of patients were unspecified regarding their International Prognostic Scoring System (IPSS) risk category, which did not allow for accounting for differences in disease severity. CONCLUSIONS: In MDS patients treated with an HMA, treatment with DAC was associated with less frequent transfusions than with AZA treatment. Further studies with the ability to control for disease severity are warranted. PMID- 21554145 TI - Human JC virus-like particles as a gene delivery vector. AB - INTRODUCTION: As a viral gene delivery vector, the recombinant JC virus-like particles (VLPs) can be easily generated in large quantities and at low cost. Exogenous genes of interest can be packaged by the VLP without the involvement of viral genetic material and then delivered into any tissue susceptible to JC virus (JCV) to allow gene transduction. Therefore, it should be possible in the future to develop a gene delivery vector using the human JC VLPs that will allow gene therapy. AREAS COVERED: Development of a gene delivery vector using the polyomavirus VLPs is reviewed in this article. The advantages and disadvantages of using JC VLP for gene delivery are discussed. EXPERT OPINION: Human JC VLPs are readily produced and can be engineered with ease; they allow specific targeting without the presence of any viral genetic material. For therapeutic purposes, gene(s) of interest or other compounds can be packaged into the VLP and delivered to JCV-susceptible cells at high efficiency. PMID- 21554146 TI - Pharmacokinetics and pharmacodynamics of isothiocyanates. AB - Isothiocyanates from Brassica vegetables are of great interest for use in the cure of bacterial infections, as is their potential application in the prevention and treatment of cancer. Although much information is available on their mode of action within the cell, when it comes to the question of whether the necessary pharmacologic concentration has been reached at the target organ, detailed knowledge is still lacking. However, a basic prerequisite for clinical application to humans is knowledge of isothiocyanate pharmacokinetic and dynamic behavior in the human body (e.g., to define intake intervals or to ascertain constant levels of the active compound). In this context, we, therefore, reviewed the available literature on in vitro studies, as well as animal and human intervention trials conducted with isothiocyanate and isothiocyanate-containing food preparations. PMID- 21554147 TI - Ligustrazine improves atherosclerosis in rat via attenuation of oxidative stress. AB - CONTEXT: Ligustrazine (Lig) is a compound isolated from the rhizome of Ligusticum chuanxiong Hort. (Umbelliferae) and has been reported to be effective for the treatment of a variety of vascular diseases. OBJECTIVE: The anti-atherosclerotic activities of Lig are evaluated in vivo for the first time in the present study. MATERIALS AND METHODS: We gave rats a single injection of vitamin D3 and then fed them with an atherogenic diet for 6 weeks to induce atherosclerosis. Lig was simultaneously given to rats by gavage at the dose of 20 or 80 mg/kg in the therapy groups. Multiple approaches including spectrophotometry, hematoxylin and eosin (H&E) staining, and quantitative RT-PCR were applied to investigate the effects of Lig on blood parameters, aorta and liver histology, and gene expression. In addition, the solely effects of Lig on food intake, body weight gain, and taste preference were also evaluated. RESULTS: We found that two doses of Lig treatment decreased the total cholesterol levels by 65.2 and 76.7%, respectively, in the plasma. Triglyceride (by 53.2 and 77.9%) and low-density lipoprotein (by 71.2 and 79.0%) levels were also decreased. However, high-density lipoprotein level was slightly increased. The circulating endothelial cells were decreased by 42.2 and 60.0% in Lig-treated rats, indicating the attenuation of endothelial injury. In contrast, Lig restored the total antioxidant capacity and superoxide dismutase 1 (SOD1) activity while decreasing the MDA generation. Furthermore, Lig improved liver dysfunction by decreasing ALT (by 13.0 and 49.7%) and AST (by 10.7 and 14.3%) levels. Histological examinations revealed that Lig suppressed atherosclerotic plaque progression in the thoracic aorta and lipid accumulation in the liver. At the transcriptional level, Lig inhibited the induction of antioxidant genes both in aorta and in liver. Lig also suppressed the mRNA expression of the genes involved in the hepatic fatty acid oxidation. Finally, Lig had a minimum effect on food intake, body weight gain, and taste preference. DISCUSSION AND CONCLUSION: Our results suggest that Lig suppresses the development of atherosclerosis and hepatic lipid accumulation via the alleviation of oxidative stress and the improvement of dyslipidemia. PMID- 21554148 TI - Sedative effects of Iranian Artemisia annua in mice: possible benzodiazepine receptors involvement. AB - CONTEXT: Artemisia annua L. (Asteraceae), commonly known as sweet wormwood or Qinghao, is an annual herb/shrub native of Asia. The plant grows broadly in Caspian Sea shores in North of Iran. In China, the aerial parts of this plant are source of artemisinin, which is an antimalarial compound. OBJECTIVE: This study aimed to establish the scientific basis of reported ethnomedicinal use of A. annua as sedative agent. MATERIAL AND METHODS: The plants were gathered from Gilan Province in Iran. Plant aerial parts were extracted with methanol and concentrated in vacuum. Methanol extract was partitioned into chloroform, petroleum ether, and ethyl acetate. Each fraction was administered intraperitoneally (i.p.) in male mice with different concentrations (50, 100, and 200 mg/kg), and for evaluation of sedative activity, immobility time was determined. In effort to clarify the mechanism of action, flumazenil (3 mg/kg, i.p.) as a benzodiazepine (BZD) receptor antagonist was injected 15 min before chloroform fraction (200 mg/kg, i.p.). RESULTS: Compared with control group (saline-treated mice), the chloroform fraction significantly increased immobility time in a dose-dependent manner. Flumazenil decreased immobility time induced by chloroform fraction significantly. DISCUSSION AND CONCLUSION: The results of the present study suggest that A. annua growing in Iran has sedative effects, which are probably mediated via BZD receptors pathways. PMID- 21554149 TI - Challenges in assessing regional distribution of inhaled drug in the human lungs. AB - INTRODUCTION: Both the total amount of drug deposited in the lungs (whole lung deposition) and the amount deposited in different lung regions (regional lung deposition) are potentially important factors that determine the safety and efficacy of inhaled drugs. Radionuclide imaging is well established for quantifying the whole lung deposition of inhaled drugs, but the assessment of regional lung deposition is less straightforward, because of the complex nature of the lung anatomy. AREAS COVERED: This review describes the challenges and problems associated with quantifying regional lung deposition by the two dimensional (2D) radionuclide imaging method of gamma scintigraphy, and by the three-dimensional (3D) radionuclide imaging methods of single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET). The advantages and disadvantages of each method for assessing regional lung deposition are discussed. EXPERT OPINION: Owing to its 2D nature, gamma scintigraphy provides limited information about regional lung deposition. SPECT provides regional lung deposition data in three dimensions, but usually involves a (99m)Tc radiolabel. PET enables the regional lung deposition of radiolabeled drug molecules to be quantified in three dimensions, but poses the greatest logistical and technical difficulties. Despite their more challenging nature, 3D imaging methods should be considered as an alternative to gamma scintigraphy whenever the determination of regional lung deposition of pharmaceutical aerosols is a major study objective. PMID- 21554150 TI - Efficacy and safety of adalimumab treatment in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. AB - INTRODUCTION: In the last couple of years, the number of patients with chronic inflammatory rheumatic diseases being treated with TNF alpha antagonist has increased dramatically. Adalimumab, a fully human monoclonal antibody against TNF alpha, is one of the most frequently administered TNF alpha antagonists. Yet, unresolved issues are the long-term safety of TNF alpha antagonists and high treatment costs. AREAS COVERED: The authors summarize the available data on short and long-term efficacy and safety of adalimumab in the treatment of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The reader will find a comprehensive overview on the safety and efficacy of adalimumab for these conditions. Clinically relevant questions of adalimumab therapy are discussed. A special focus of this review is on the safety of adalimumab therapy. EXPERT OPINION: Adalimumab is effective and reasonably safe in the short- and long-term treatment of patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis who do not respond to the standard therapy. It inhibits radiographic progression in rheumatoid and psoriatic arthritis. Treatment with a TNF alpha inhibitor such as adalimumab is associated with high treatment costs. PMID- 21554151 TI - Results of the first bortezomib-based induction therapy in the treatment of multiple myeloma. AB - This is a comment on the IFM 2005-01 Phase III trial that compared, for the first time, the efficacy and the safety of a bortezomib-containing induction regimen with conventional chemotherapy before autologous stem-cell transplantation in multiple myeloma (MM) patients. Between 2005 and 2008, 482 patients were randomized to vincristin/doxorubicin/dexamethasone (VAD), VAD + dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) consolidation, bortezomib + dexamethasone and bortezomib + dexamethasone + DCEP consolidation followed by autologous stem-cell transplantation. The trial was conducted in 89 sites in France, Belgium and Switzerland. The novel agent-based induction therapy (bortezomib/dexamethasone) achieved higher complete remission (CR)/nearCR rates, as well as less treatment-related mortality, but higher rates of polyneuropathy than the conventional chemotherapy-based induction therapy (VAD/VAD + DCEP). The difference in progression-free survival (PFS) difference was not statistically significant but a trend to longer PFS was seen to favor to the bortezomib containing regimen; bortezomib and dexamethason (BD) was, therefore, proposed to be a standard of care by the authors of the study. PMID- 21554152 TI - Novel biomaterial for transdermal application: in vitro and in vivo characterization. AB - The objective of the present study was to evaluate a novel film forming biomaterial for its potential application in the preparation of unilaminate transdermal adhesive matrix systems. The biomaterial, Damar Batu (DB), was tried alone and in combination with Eudragit RL100 as a matrixing agent in the preparation of transdermal patches. Developed transdermal patches of Diltiazem hydrochloride (DH) were evaluated for thickness uniformity, weight uniformity, folding endurance and drug content. USP dissolution apparatus V was used for in vitro drug release studies. Modified Franz diffusion cell used for permeation study using excised human cadaver skin. Total 6 formulations were developed and on the basis of in vitro drug release and in vitro skin permeation profile F5 composed of DB: Eudragit RL100 (60:40) and carrying 20 %w/w DH was selected as an optimized formulation for in vivo study. The in vivo study results showed that F5 achieved the Cmax of about 269.76 +/- 1.52 ng/mL in 6 h and sustained the release of the drug till 24 h. The skin irritation study results proved that the novel biomaterial is non-sensitizing and non-irritating. Drug-polymer interaction study carried out to check the compatibility of drug and polymer showed the intactness of the drug in the formulation proving the compatibility of the polymer. It can be proposed from the outcome of the present study that by applying suitable adhesive layer and backing membrane, DB: Eudragit RL100 (60:40) transdermal patches can be of potential therapeutic use. PMID- 21554153 TI - Cell lines expressing mutant FX proteins to generate proteins with reduced rate of fucosylation: WO2010/141478. AB - BACKGROUND: The application (WO 2010/141478) is in the field of glycobiology and deals with the synthesis of recombinant proteins with a reduced rate of fucosylation. OBJECTIVE: It aims at generating mammalian cell lines that express mutant forms of GDP-4-keto-deoxy-mannose-3,5,-epimerase-4-reductase (FX) and cells that conditionally fucosylate proteins. METHODS: Mutant forms of FX were synthesized, and mammalian cell lines genetically engineered to express mutant FX proteins and the protein of interest. Cell lines that conditionally fucosylate proteins were generated from a mutant FX form that has reduced ability to fucosylate glycoproteins at 37 degrees C and not at 34 degrees C. RESULTS: Cells genetically engineered to express mutant forms of FX protein show reduced ability to fucosylate proteins, particularly antibodies, with rates as low as 5 - 0.5% fucosylation, compared to cells expressing wild-type FX. CONCLUSION: Cells genetically engineered to express the mutant forms of FX protein provide a means to synthesize and express proteins with a reduced rate of fucosylation. The paradigm may be used to synthesize antibodies that mediate antibody-dependent cell-mediated cytotoxicity more efficiently. The application uses mammalian cell lines, genetically engineered to express mutant FX proteins, to synthesize and produce proteins with a reduced rate of fucosylation. The application claims the conditional control of protein fucosylation by FX mutant proteins. PMID- 21554154 TI - NADPH oxidase inhibitors: a patent review. AB - INTRODUCTION: NADPH oxidases, a family of multi-subunit enzyme complexes, catalyze the production of reactive oxygen species (ROS), which may contribute to the pathogenesis of a variety of diseases. In addition to the first NADPH oxidase found in phagocytes, four non-phagocytic NADPH oxidase isoforms have been identified, which all differ in their catalytic subunit (Nox1-5) and tissue distribution. AREAS COVERED: This paper provides a comprehensive review of the patent literature on NADPH oxidase inhibitors, small molecule Nox inhibitors, peptides and siRNAs. EXPERT OPINION: Since each member of the NADPH oxidase family has great potential as a therapeutic target, several different compounds have been registered as NADPH oxidase inhibitors in the patent literature. As yet, none have gone through clinical trials, and some have not completed preclinical trials, including safety and specificity evaluation. Recently, small molecule pyrazolopyridine and triazolopyrimidine derivatives have been submitted as potent NADPH oxidase inhibitors and reported as first-in-class inhibitors for idiopathic pulmonary fibrosis and acute stroke, respectively. Further clinical efficacy and safety data are warranted to prove their actual clinical utility. PMID- 21554155 TI - 4-Azetidinyl-1-heteroatom linked cyclohexane antagonists of CCR2: patent evaluation. AB - This application discloses a series of di- and tri-substituted cyclohexanes as CCR2 receptor antagonists which are stated to be useful in treating inflammation and autoimmune diseases, such as type 2 diabetes and asthma. Although receptor binding of the compounds to CCR2 is demonstrated, there are no data to support the idea that these molecules are functional antagonists. PMID- 21554156 TI - Preparation and in vitro, in vivo evaluations of norfloxacin-loaded solid lipid nanopartices for oral delivery. AB - This work aims to develop norfloxacin-solid lipid nanoparticles (NFX-SLN) as an oral delivery formulation. Hot homogenization and ultrasonic technique was employed to prepare NFX-SLN using stearic acid as lipid matrix and polyvinyl alcohol as surfactant. The physicochemical characteristics of SLN were investigated by optical microscope scanning electron microscopy and photon correlation spectroscopy. Antibacterial experiments of NFX-SLN were carried out by broth dilution technique. Pharmacokinetics was studied after oral administration in male Sprague-Dawley rats. The results showed that NFX-SLN was spherical and the SLN of the optimized formulation had diameters 301 +/- 16.64 nm, polydispersity index 0.15 +/- 0.04, zeta potential -30.8 +/- 0.69 mv, loading capacity 8.58 +/- 0.21% and encapsulation efficiency 92.35 +/- 2.24% with good stability at 4 degrees C. The NFX-SLN had sustained release effect and sustained bactericidal activity. Cytotoxicity studies in cell culture demonstrated that the nanoparticles were not toxic. NFX-SLN resulted in significantly higher plasma drug concentration than native NFX. The SLN increased the relative bioavailability of NFX by 12 folds, prolonged the plasma drug level above the average minimum inhibition concentration from 14 to 168 h. These studies demonstrate that NFX-SLN could be a promising oral formulation for enhanced bioavailability and pharmacological activities. PMID- 21554157 TI - Development and evaluation of dual controlled release microballoons containing riboflavin and citric acid: in vitro and in vivo evaluation. AB - The objective of this work was to optimize the incorporation of citric acid (CA) in the gastroretentive microballoons containing riboflavin (RF) in order to achieve dual controlled release system and consequently enhance the bioavailability of RF. Microballoons of 739 +/- 1.9 um containing RF-CA were prepared by modified emulsion solvent diffusion method and were evaluated both for in vitro and in vivo performance. RF-CA microballoons with 22.8% RF and 37.2% CA entrapped in the shell matrix composed of Eudragit(r) S 100 and HPMCK4M and in vitro buoyancy of 86.0 +/- 0.88% (RCM3) was selected for further studies. RCM3 exhibited biphasic, pH-dependent in vitro dual controlled release of RF (0.9933 0.9962) and CA (0.996-0.9984) beyond 1 h in both simulated fasted and fed state conditions. RCM3 was able to achieve higher mean plasma concentrations than reference formulation RM2 (RF microballoon) both in fed and fasted states in rabbits. The mean AUC(0-24) estimate of RCM3 was 55% higher in fasted state (p < 0.01) and about 51% higher in fed state (p < 0.05) relative to mean AUC(0-24) from RM2 formulation. Conclusively, enhancement in RF in the presence of CA along the entire plasma level curve suggests a possibility of reduction in dosing frequency. This controlled release drug delivery system of RF, where CA is incorporated in the microballoons can be easily encapsulated in capsule dosage form negating the need of CA solution as vehicle for administration of RF microballoons. PMID- 21554158 TI - Hepatoprotective and neuroprotective activity of liposomal quercetin in combating chronic arsenic induced oxidative damage in liver and brain of rats. AB - CONTEXT: Arsenic is a naturally occurring toxicant that causes acute and chronic adverse health effects, including cancer. OBJECTIVE: The study was performed to evaluate the therapeutic efficacy of liposome entrapped flavonoidal quercetin in combating arsenic toxicity mediated oxidative damage in hepatocytes and brain cells in rat model. MATERIALS AND METHODS: Hepatic and neuronal cell damage in rats was made by daily arsenic (6 mg/kg b wt, 9 mg/kg b wt and 12 mg/kg b wt) treatment via oral route for four consecutive months. Liposomal quercetin (2.71 mg QC/kg b. wt) were injected s.c. on rats treated with 12 mg/kg b. wt. NaAsO(2) twice a week for four months. RESULTS AND DISCUSSION: Inorganic arsenic deposition was found to be most significant in hepatic (9.32 +/- 0.100 ug/g tissue) and neuronal (6.21 +/- 0.090 ug/g tissue) cells of rats treated with 12 mg/kg b wt of arsenite. Antioxidant levels in hepatic and neuronal cells were reduced significantly by the induction of arsenic. Liposomal quercetin was found most potent for a complete prevention of arsenite-induced reduction in antioxidant levels in the liver and brain of rats. Arsenic induced a substantial increase in hepatic hydroxyproline (HP) and Liposomal quercetin treatment resulted in complete replenishment of the HP level to normal. Liposomal quercetin completely prevented the arsenite-induced upregulation of cytochrome c expression in liver and brain significantly suggesting that the protective effect of Liposomal quercetin could be related to the reduction of arsenic deposition in both the organs. CONCLUSION: Thus, Liposomal quercetin might prove to be of therapeutic potential against arsenite-induced hepatic and neuronal cell damage in rats. PMID- 21554159 TI - Necrotic arachnidism of the eyelid due to Loxosceles rufescens spider bite. AB - A 69-year-old woman was awakened with redness and swelling of the left upper eyelid a few days before her presentation. She also noticed a dead spider on her bed. Ophthalmic examination revealed severe left periorbital hyperemia, edema and a wide necrotic area on the upper eyelid. Systemic condition of the patient was well. She was hospitalized with the diagnosis of necrotic arachnidism of the left upper eyelid. Systemic corticosteroid and antibiotic treatment was commenced. No surgical intervention was carried out. A week later, whole upper eyelid was covered with a black eschar. This black eschar shrank with time, and it detached completely within 8 weeks and the lesion healed without a disfiguring scar. Meanwhile, the offending spider was identified as Loxosceles rufescens. Although rare, eyelid may be a biting site for Loxosceles spiders and a favorable result may be obtained with conservative management. PMID- 21554160 TI - Nuclear factor kappa B may increase insight into the management of neuroinflammation and excitotoxicity in autism. PMID- 21554161 TI - Dynamic electrostatic charge of lactose-salbutamol sulphate powder blends dispersed from a Cyclohaler(r). AB - CONTEXT: Electrostatic forces have been claimed to be a mechanism for aerosol deposition in the lungs. However, the extent of its influence on aerosol performance is not clear, particularly for carrier-drug formulations. OBJECTIVES: To prepare lactose-salbutamol powder blends, varying in blend ratio, and identify any relationships between salbutamol dose, electrostatic characteristics and in vitro aerosol performance. METHODS: Decanted lactose and micronized salbutamol sulfate was mixed to produce five blends (equivalent to 50, 100, 200, 300 and 400 ug salbutamol per 33 mg of powder). 33 +/- 1 mg of a blend was loaded into a CyclohalerTM and dispersed into the electrical Next Generation Impactor (eNGI) at an air flow rate of 60 L/min. This was conducted in triplicate for all five lactose-salbutamol blends. RESULTS: Fine particle fraction increased with salbutamol dose, from 5.89 +/- 1.42 to 21.35 +/- 2.91%. Specific charge (charge divided by mass) distributions for each blend were greatest in magnitude for the 50 ug blend and similar in magnitude between all other blends. However, in eNGI Stage 1 (>8.06 um), specific charge decreased from 100 ug (-170.4 +/- 45.8 pC/ug) to 400 ug (-10.0 +/- 9.1 pC/ug). CONCLUSIONS: The improvement in fine particle fraction with increased salbutamol dose was indicative of fine drug binding to high and low energy sites on the lactose carrier surface. This finding was supported by electrostatic charge results, but the aerosol charge itself was not found to influence aerosol performance by electrostatic forces. PMID- 21554162 TI - Mocetinostat (MGCD0103): a review of an isotype-specific histone deacetylase inhibitor. AB - INTRODUCTION: HDAC inhibitors (HDACIs) have the potential to restore gene expression and display antitumor effects in vitro. As single agents, HDACIs have clinical activity in lymphoma. In myeloid leukemias, combinations of DNA methylation inhibitors and HDACIs are promising. Other combinations are being studied in solid tumors. AREAS COVERED: This article covers basic information and an update on preclinical and clinical experience with the oral isotype-selective HDACI MGCD0103 (mocetinostat) in hematological malignancies and solid tumors. It also examines data concerning MGCD0103 from recent conferences and articles through to November 2010, including new data regarding responses in lymphoma and toxicities. EXPERT OPINION: MGCD0103 is well-tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules. In 2008, new patient enrollment in trials was temporarily suspended due to potential cardiac complications. This restriction was lifted in 2009 as no correlation between MGCD0103 exposure and pericardial effusions was found. New patient enrollment in MGCD0103 clinical trials requires the exclusion of patients diagnosed with significant cardiac abnormalities prior to enrollment. Clinical and pharmacodynamic data support a three-times-weekly administration at a 90 mg fixed dose. MGCD0103 displays promising antitumor activity in several hematological diseases. PMID- 21554163 TI - Rivaroxaban in the contemporary treatment of acute coronary syndromes. AB - INTRODUCTION: Rivaroxaban is the first orally bioavailable direct factor Xa inhibitor and its role in acute coronary syndrome is not fully understood. A significant residual risk of recurrent ischemia remains in patients with acute coronary syndrome despite optimal medical therapy. Warfarin has demonstrated modest benefit that is offset by the risk of bleeding and complexity in its management. Rivaroxaban may be an attractive agent for the treatment of acute coronary syndromes given its predictable pharmacodynamics and favorable safety profile. AREAS COVERED: The current guideline-based antithrombotic and adjunctive medical therapies in acute coronary syndrome are summarized in this review. Rivaroxaban's drug profile, its current applications, ongoing trials and experience in patients with acute coronary syndrome are also described. EXPERT OPINION: Current experience of rivaroxaban in acute coronary syndrome demonstrates its safety and a trend towards benefit when added to current optimal medical therapy. The benefits were observed primarily in patients receiving aspirin monotherapy and increased bleeding among those receiving dual anti platelet therapy. This suggests that there may be a narrow window between the optimal clinically achievable antithrombotic effect and the point where bleeding risk outweighs the benefits. Though promising, it remains to be seen if this drug will achieve the right balance between efficacy and bleeding risk. PMID- 21554164 TI - Helicobacter pylori and risk of upper gastrointestinal bleeding among users of selective serotonin reuptake inhibitors. AB - BACKGROUND: A number of studies have reported a possible association between use of selective serotonin reuptake inhibitors (SSRIs) and serious upper gastrointestinal bleeding (UGB). We conducted this case-control study to assess if Helicobacter pylori (H. pylori) potentiates the risk of serious UGB in SSRI users. MATERIAL AND METHODS: A population-based case-control study was conducted in the county of Funen, Denmark. Cases were 53 SSRI users with serious UGB whose H. pylori status on their bleeding date could be established. Controls (n = 723) were selected among subjects who participated in a population H. pylori screening study, and who were users of SSRIs. Data on drug exposure and medical history were retrieved from a prescription database and the county's patient register. Confounders were controlled for by unconditional logistic regression. RESULTS: H. pylori infection increased the risk of serious UGB in patients using SSRI with an adjusted odds ratio (OR) of 2.73 (95% confidence interval (CI), 1.17-6.36). The adjusted OR for serious UGB among users of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) were 3.91 (95% CI, 2.03-7.52) and 3.00 (95% CI, 0.94-9.54), respectively. CONCLUSION: H. pylori infection increases the risk of SSRI-related serious UGB. PMID- 21554165 TI - On the cover. PMID- 21554166 TI - Preface. PMID- 21554167 TI - Natural product drug discovery in the next millennium. AB - Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. In the past century, however, an increasing role has been played by microorganisms in the production of antibiotics and other drugs for the treatment of some serious diseases. Advances in the description of the human genome, as well as the genomes of pathogenic microbes and parasites, is permitting the determination of the structures of many proteins associated with disease processes. With the development of new molecular targets based on these proteins, there is an increasing demand for novel molecular diversity for screening. Natural products will play a crucial role in meeting this demand through the continued investigation of world's biodiversity, much of which remains unexplored. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, will provide access to a vast untapped reservoir of genetic and metabolic diversity. The same holds true for nucleic acids isolated from symbiotic and endophytic microbes associated with terrestrial and marine macroorganisms. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents. The investigation of these resources requires multi-disciplinary, national, and international collaboration in the discovery and development process. PMID- 21554168 TI - Modern screening techniques for plant extracts. AB - In order to discover new bioactive compounds from plant sources which could become new leads or new drugs, extracts should be simultaneously evaluated by chemical screening and by various biological or pharmacological targets. Chemical screening using hyphenated techniques such as LC/UV and LC/MS, and more recently LC/NMR, quickly provides ample structural information, leading in many cases to the identification of compounds. This allows researchers to distinguish between known compounds (dereplication) and new molecules directly from crude plant extracts. Thus, the tedious isolation of known compounds can be avoided, and a targeted isolation of constituents presenting novel or unusual spectroscopic features can be undertaken. In parallel, extracts are also subjected to various bioassays that should be simple, reproducible, and rapid. This approach will be illustrated by the search for new molluscicidal, antioxidant, and antifungal compounds from tropical plants. PMID- 21554169 TI - Ensuring equitable benefits: the falealupo covenant and the isolation of anti viral drug prostratin from a samoan medicinal plant. AB - Equitable sharing of benefits from pharmacological development of biodiversity has been the topic of much discussion, but few concrete examples of recent plant derived pharmaceuticals exist. The discovery of prostratin as an anti-viral phorbol isolated from healer preparations of the rain forest tree Homalanthus nutans in Samoa illustrates the importance of careful liaison between western scientists and indigenous leaders. Development of prostratin as an anti-AIDS drug candidate was based on a carefully negotiated covenant between the chiefs and orators of Falealupo village and western researchers, with the concurrence of the Samoan Prime Minister and members of parliament. Since, like all drug candidates, potential commercial development of prostratin still remains uncertain, the case of prostratin indicates the importance of providing benefits to indigenous peoples in advance of royalty or license income. To date, over US$ 480,000 have been supplied to Falealupo village for schools, medical clinics, water supplies, trails, an aerial rain forest canopy walkway, and an endowment for the rain forest based on the Falealupo Covenant. And, in August 2001 the AIDS Research Alliance (ARA) signed an agreement with the Prime Minister of Samoa guaranteeing a total of 20% of all ARA profits from the development of prostratin to be returned to Samoa. PMID- 21554170 TI - A database model for integrating and facilitating collaborative ethnomedicinal research. AB - A model for a database system that provides a standardized environment for submission, storage, and retrieval of ethnomedicinal data was developed. The model is based on object oriented database technology, and is suitable for not only storing data, digital images, sound and video, but also for modeling domain knowledge associated with plant-based medicinal preparations utilized in systems of traditional medicine. The model incorporates both linguistic and semantic elements. Terms in natural language are mapped to database objects that represent knowledge in various ethnomedicinal domains. The distributed object infrastructure permits integration with other authoritative taxonomic databases and includes an interface capable of supporting existing and emerging standards of data. The model provides a foundation for a globally current dynamic data resource that encourages comparative ethnomedicinal research through direct contributions by members of the research community. Examples of integrated domain models are presented incorporating medical terminology, plant systematics, ecology, and pharmacology. PMID- 21554171 TI - Cardenolides and diterpenes as a source of and model for positive ionotropic agents. AB - Taking the natural cardenolides as a model for new inotropic agents, pimaranic, cyclohexanic and hydroindenic derivatives have been synthesized and tested. Several of these derivatives are positive inotropics and two of the D3a unsaturated bis(amidinohydrazono)hydroinenes also are selective Na(+), K(+) ATPase inhibitors. PMID- 21554172 TI - The ethnomedicinal uses of magnoliaceae from the southeastern United States as leads in drug discovery. AB - In Asia and North America, members of the family Magnoliaceae have been and are presently used extensively in indigenous herbal medicine. Many taxa of the genus Magnolia produce lignans and sesquiterpene lactones, some with considerable in vitro bioactivities. This review focuses on selected natural products of the genus Magnolia from the southeastern United States with demonstrated biological and pharmacological properties. Ethnomedicinal data obtained from the Native Americans of the southeastern United States correlate well with the results of pharmacological investigations. PMID- 21554173 TI - African ethnobotany and healthcare: emphasis on mozambique. AB - The relationship between common medicinal plants and major health problems in Africa, specifically Mozambique, is presented here. Emphasis is given to plant species largely used to solve or slow down diarrhoea, malaria, respiratory, and sexual complaints. These diseases, together with malnutrition/ anaemia, mental diseases, and rheumatism/arthritis are the main concern of healthcare countrywide. Diarrhoea is divided into common diarrhoea, bloody-diarrhoea, and cholera; plant species are normally used to slow down diarrhoea recurrence. Tannin is the main chemical compound with both anti-diarrhoeal and antiseptic properties. Traditional medicine seems to be rather helpful in alleviating malaria symptoms such as fever, vomiting, and diarrhoea. Special reference is made to Momordica balsamina, which is highly used to cure vomiting apparently associated with bilis and fever. Rauvolfia caffra contains reserpine, a compound used as anti-hypertension agent. This species is also used as an anti-malarial agent. Traditional medicine seems to have a role in slowing opportunistic infections related to the AIDS virus such as diarrhoea, pneumonia, and skin infections. Prostate hypertrophy is traditionally medicated using mostly Prunus africana and Hypoxis hemerocallidea, species known to contain phytosterol. Research for bioactive compounds in African plants is still in its infancy. PMID- 21554174 TI - Ethnobotanical approaches of traditional medicine studies: some experiences from Asia. AB - Ethnobotany, as a research field of science, has been widely used for the documentation of indigenous knowledge on the use of plants and for providing an inventory of useful plants from local flora in Asian countries. Plants that are used for traditional herbal medicine in different countries are an important part of these studies. However, in some countries in recent years, ethnobotanical studies have been used for the discovery of new drugs and new drug development. In general, experiences gained from ethnobotanical approaches of traditional medicinal studies in China and Himalayan countries have helped drug production and new drug development. At the same time, in many cases, over-harvesting, degradation of medical plants, and loss of traditional medical knowledge in local communities are common problems in these resource areas. Issues of indigenous knowledge, intellectual property rights, and uncontrolled transboundary trade in medicinal plants occur frequently in the region. This paper discusses ethnobotanical approaches of traditional medicinal studies, in reference to experiences from China and Himalayan countries, with an emphasis on the conservation of traditional medical knowledge and medical plant resources. PMID- 21554175 TI - Natural products research in latin america. AB - The biodiversity found in Latin America is one of the richest in the world, yet its potential as a source of new pharmaceuticals has not been fully investigated. This paper will explore the present status of natural products research in 19 Latin American countries. Future research needs will be presented along with reports on the ethnobotanical and bioprospection projects under way in Latin America. The presentation will be based on data collected over the last five years and will be presented within the framework of the Fine Pharmaceutical Subprogram of the Iberoamerican Program of Science and Technology for Development (CYTED), a novel international cooperation program. PMID- 21554176 TI - Therapeutic plasticity of stem cells and allograft tolerance. AB - Transplantation is the treatment of choice for many diseases that result in organ failure, but its success is limited by organ rejection. Stem cell therapy has emerged in the last years as a promising strategy for the induction of tolerance after organ transplantation. Here we discuss the ability of different stem cell types, in particular mesenchymal stromal cells, neuronal stem/progenitor cells, hematopoietic stem cells and embryonic stem cells, to modulate the immune response and induce peripheral or central tolerance. These stem cells have been studied to explore tolerance induction to several transplanted organs, such as heart, liver and kidney. Different strategies, including approaches to generating tolerance in islet transplantation, are discussed here. PMID- 21554177 TI - The best bone marrow stromal cell for therapy is ... 'yellow'. PMID- 21554178 TI - Everyday hassles and uplifts among women on long-term sick-leave due to stress related disorders. AB - A balance between different experiences of occupations in everyday life is important for well-being. The study aim was to describe hassles and uplifts in everyday occupations among women on long-term sick-leave due to stress-related disorders. The sample consisted of 77 women and experiences were collected by the THU-5 instrument. The statements were analysed using quantitative content analysis. Data were categorized into three domains of hassles concerning oneself, doings, and social and physical context. The same domains occurred among the uplifts. Hassles were mostly generated by disturbing people around the women and by their limited body functions. The women were uplifted by supportive social relationships and by performing relaxing and calming occupations. The study illuminates the strong need for social support among women on sick-leave, as well as their low level of energy, which was an obvious obstacle for performing occupations. It is suggested that, in order to increase well-being in the target group, the occupational therapist should meet their need for occupations that match their current level of energy. The challenge for the client is to avoid remaining in a pattern of low-demand occupations without exceeding her/his capacity and returning to an unhealthy pattern of occupations. PMID- 21554179 TI - Apoptosis in the human periodontal membrane evaluated in primary and permanent teeth. AB - OBJECTIVE: Recent studies revealed a highly innervated layer in close proximity to the root surface in the periodontal membrane of human teeth. Persistence of the epithelial cells of Malassez along root surfaces without resorption has also been demonstrated. It is hypothesized that resorption is connected to apoptosis of the epithelial cells of Malassez. The purpose of this study is to localize cells undergoing apoptosis in the periodontal membrane of human primary and permanent teeth. MATERIALS AND METHODS: Human primary and permanent teeth were examined immunohistochemically for apoptosis and epithelial cells of Malassez in the periodontal membrane. All teeth examined were extracted in connection with treatment. RESULTS: Apoptosis was seen in close proximity to the root surface and within the epithelial cells of Malassez. This pattern of apoptotis is similar in the periodontal membrane in primary and permanent teeth. CONCLUSIONS: The inter relationship between apoptotis and root resorption cannot be concluded from the present study. Apoptosis seen in close proximity to the root surface presumably corresponds to the highly innervated layer of the periodontal membrane. The function of this layer still needs to be elucidated. PMID- 21554180 TI - The cucurbit pathogenic bacterium Acidovorax citrulli requires a polar flagellum for full virulence before and after host-tissue penetration. AB - Acidovorax citrulli causes seedling blight and bacterial fruit blotch of cucurbits. Previous reports demonstrated the contribution of type IV pili (T4P) to A. citrulli virulence and to systemic infection of melon seedlings. Microfluidic flow-chamber assays demonstrated the involvement of T4P in surface adhesion and biofilm formation, whereas polar flagella did not appear to contribute to either of these features. On the other hand, a transposon mutant impaired in the biosynthesis of polar flagella was identified in screens for reduced virulence of an A. citrulli mutant library. Further characterization of polar flagellum mutants confirmed that A. citrulli requires a polar flagellum for full virulence on melon plants. Foliage and stem inoculation experiments revealed that polar flagella contribute to A. citrulli virulence and growth in planta at both pre- and post-host-tissue penetration. Interestingly, light microscope observations revealed that almost all A. citrulli wild-type cells extracted from the xylem sap of stem-inoculated melon seedlings remained motile, supporting the importance of this organelle in virulence and colonization of the host vascular system. We also report a negative effect of polar flagellum impairment on T4P mediated twitching motility of A. citrulli and discuss a possible co-regulation of these two motility machineries in this bacterium. PMID- 21554181 TI - Effect of moderate exercise on IgA levels and lymphocyte count in mouse intestine. AB - The aim of the present study was to determine the effect of moderate exercise on the production and secretion of IgA in mouse duodenum, on lymphocyte levels in the lamina propria, and on gene expression encoding for cytokines that regulate the synthesis of alpha-chain of IgA and the expression of pIgR in the lamina propria. Two groups of young Balb/c mice were fed ad libitum, one sedentary and the other with an exercise program (swimming) for 16 weeks. IgA levels in the duodenum were quantified by ELISA; the number of IgA containing cells as well as B cells, CD4(+) and CD8(+) T cells in the duodenal mucosa was determined by immunohistochemistry; gene expression was analyzed by real-time PCR, and the expression of proteins by Western blotting. Because of physical training, in the duodenum there was a decrease in the number of IgA producing cells, but an increase in the levels of IgA. Additionally, exercise increased the expression of the genes encoding for IL-4, IL-6, IL-10, TNF-alpha and TGF beta, cytokines that regulate the synthesis of IgA and pIgR, the inflammatory response, and the immune response in the intestine. Thus, the increased IgA found in the duodenal lumen is probably due to the increased production of IgA in the LP and the increased transport of the pIgA-pIgR complex across epithelial cells. Possibly the increased S-IgA levels in the bile also contribute to the change in IgA levels. PMID- 21554182 TI - Genetic structure of Xiphinema pachtaicum and X. index populations based on mitochondrial DNA variation. AB - The dagger nematodes Xiphinema pachtaicum and X. index are two of the most widespread and frequently occurring Xiphinema spp. co-infesting vineyards and other crops and natural habitats worldwide. Sexual reproduction is rare in these species. The primary objective of this study was to determine the genetic structure of X. pachtaicum and X. index populations using eight and seven populations, respectively, from different "wine of denomination of origin (D.O.) zones" in Spain and Sardinia (Italy), by studying mitochondrial (cytochrome oxidase c subunit 1 or COI) and nuclear (D2-D3 expansion segments of 28S rDNA) markers. Both Xiphinema spp. showed low intraspecific divergence among COI sequences, ranging from 0.2% (1 base substitution) to 2.3% (10 substitutions) in X. pachtaicum and from 0.2% (1 base substitution) to 0.4% (2 substitutions) in X. index. Population genetic structure was strong for both species. Nevertheless, molecular differences among grapevine-growing areas were not significant, and intrapopulation diversity was very low. It is hypothesized that this genetic homogeneity in the nematode populations reflects their predominant parthenogenetic reproduction mode and low dispersal abilities. Our results also show that X. pachtaicum populations in Spain have possibly been established from two different populations of origin. Results also demonstrated that the two DNA regions studied are suitable diagnostic markers for X. index and X. pachtaicum. PMID- 21554183 TI - Association of a novel DNA virus with the grapevine vein-clearing and vine decline syndrome. AB - A severe vein-clearing and vine decline syndrome has emerged on grapevines (Vitis vinifera) and hybrid grape cultivars in the Midwest region of the United States. The typical symptoms are translucent vein-clearing on young leaves, short internodes and decline of vine vigor. Known viral pathogens of grapevines were not closely associated with the syndrome. To obtain a comprehensive profile of viruses in a diseased grapevine, small RNAs were enriched and two cDNA libraries were constructed from a symptomatic grapevine and a symptomless grapevine, respectively. Deep sequencing of the two cDNA libraries showed that the most abundant viral small RNAs align with the genomes of viruses in the genus Badnavirus, the family Caulimoviridae. Amplification of the viral DNA by polymerase chain reaction allowed the assembly of the whole genome sequence of a grapevine DNA virus, which shared the highest homology with the Badnavirus sequences. This is the first report of a DNA virus in grapevines. The new DNA virus is closely associated with the vein-clearing symptom, and thus has been given a provisional name Grapevine vein clearing virus (GVCV). GVCV was detected in six grapevine cultivars showing vein-clearing and vine decline syndrome in Missouri, Illinois, and Indiana, suggesting its wide distribution in the Midwest region of the United States. Discovery of DNA viruses in grapevines merits further studies on their epidemics and economic impact on grape production worldwide. PMID- 21554184 TI - Combined use of biocontrol agents to manage plant diseases in theory and practice. AB - Effective use of biological control agents (BCAs) is a potentially important component of sustainable agriculture. Recently, there has been an increasing interest among researchers in using combinations of BCAs to exploit potential synergistic effects among them. The methodology for investigating such synergistic effects was reviewed first and published results were then assessed for available evidence for synergy. Correct formulation of hypotheses based on the theoretical definition of independence (Bliss independence or Loewe additivity) and the subsequent and statistical testing for the independence synergistic-antagonistic interactions have rarely been carried out thus far in studies on biocontrol of plant diseases. Thus, caution must be taken when interpreting reported "synergistic" effects without assessing the original publications. Recent theoretical modeling work suggested that disease suppression from combined use of two BCAs was, in general, very similar to that achieved by the more efficacious one, indicating no synergistic but more likely antagonistic interactions. Only in 2% of the total 465 published treatments was there evidence for synergistic effects among BCAs. In the majority of the cases, antagonistic interactions among BCAs were indicated. Thus, both theoretical and experimental studies suggest that, in combined use of BCAs, antagonistic interactions among BCAs are more likely to occur than synergistic interactions. Several research strategies, including formulation of synergy hypotheses in relation to biocontrol mechanisms, are outlined to exploit microbial mixtures for uses in biocontrol of plant diseases. PMID- 21554185 TI - Meta-analysis of yield response of hybrid field corn to foliar fungicides in the U.S. Corn Belt. AB - The use of foliar fungicides on field corn has increased greatly over the past 5 years in the United States in an attempt to increase yields, despite limited evidence that use of the fungicides is consistently profitable. To assess the value of using fungicides in grain corn production, random-effects meta-analyses were performed on results from foliar fungicide experiments conducted during 2002 to 2009 in 14 states across the United States to determine the mean yield response to the fungicides azoxystrobin, pyraclostrobin, propiconazole + trifloxystrobin, and propiconazole + azoxystrobin. For all fungicides, the yield difference between treated and nontreated plots was highly variable among studies. All four fungicides resulted in a significant mean yield increase relative to the nontreated plots (P < 0.05). Mean yield difference was highest for propiconazole + trifloxystrobin (390 kg/ha), followed by propiconazole + azoxystrobin (331 kg/ha) and pyraclostrobin (256 kg/ha), and lowest for azoxystrobin (230 kg/ha). Baseline yield (mean yield in the nontreated plots) had a significant effect on yield for propiconazole + azoxystrobin (P < 0.05), whereas baseline foliar disease severity (mean severity in the nontreated plots) significantly affected the yield response to pyraclostrobin, propiconazole + trifloxystrobin, and propiconazole + azoxystrobin but not to azoxystrobin. Mean yield difference was generally higher in the lowest yield and higher disease severity categories than in the highest yield and lower disease categories. The probability of failing to recover the fungicide application cost (p(loss)) also was estimated for a range of grain corn prices and application costs. At the 10 year average corn grain price of $0.12/kg ($2.97/bushel) and application costs of $40 to 95/ha, p(loss) for disease severity <5% was 0.55 to 0.98 for pyraclostrobin, 0.62 to 0.93 for propiconazole + trifloxystrobin, 0.58 to 0.89 for propiconazole + azoxystrobin, and 0.91 to 0.99 for azoxystrobin. When disease severity was >5%, the corresponding probabilities were 0.36 to 95, 0.25 to 0.69, 0.25 to 0.64, and 0.37 to 0.98 for the four fungicides. In conclusion, the high p(loss) values found in most scenarios suggest that the use of these foliar fungicides is unlikely to be profitable when foliar disease severity is low and yield expectation is high. PMID- 21554186 TI - Advances in plant virus evolution: translating evolutionary insights into better disease management. AB - Recent studies in plant virus evolution are revealing that genetic structure and behavior of virus and viroid populations can explain important pathogenic properties of these agents, such as host resistance breakdown, disease severity, and host shifting, among others. Genetic variation is essential for the survival of organisms. The exploration of how these subcellular parasites generate and maintain a certain frequency of mutations at the intra- and inter-host levels is revealing novel molecular virus-plant interactions. They emphasize the role of host environment in the dynamic genetic composition of virus populations. Functional genomics has identified host factors that are transcriptionally altered after virus infections. The analyses of these data by means of systems biology approaches are uncovering critical plant genes specifically targeted by viruses during host adaptation. Also, a next-generation resequencing approach of a whole virus genome is opening new avenues to study virus recombination and the relationships between intra-host virus composition and pathogenesis. Altogether, the analyzed data indicate that systematic disruption of some specific parameters of evolving virus populations could lead to more efficient ways of disease prevention, eradication, or tolerable virus-plant coexistence. PMID- 21554187 TI - Do patients with motor neuron disease suffer from disorders of taste or smell? AB - Olfactory or gustatory dysfunction has been described in patients with motor neuron disease. This disorder along with other degenerative diseases has been tentatively linked with the olfactory vector hypothesis according to which a toxic agent may enter the organism via the nasal mucosa. In our study we assessed 26 patients diagnosed as suffering from motor neuron disease at various stages and compared them with 26 matched controls using 'Sniffin' Sticks' for smell and taste strips for taste testing. The two groups did not differ with respect to either ability. The smell test correlated with age, but not with the duration of the disease. We concluded that neither olfaction nor gustation seem to be linked to or influenced by the disease, making the causation by a toxin entering the body via the nasal or oral route rather unlikely as well as a degenerative process encompassing sensory pathways. PMID- 21554189 TI - Photomedicine and LLLT Literature Watch. PMID- 21554190 TI - A measurement of the unstirred aqueous boundary layer in a Franz diffusion cell. AB - The unstirred aqueous boundary layer (ABL) thickness was determined for modified Franz diffusion cells using three test compounds--parathion, 4-hexylresorcinol, and 2,4-dinitrochlorobenzene (DNCB). Steady-state fluxes through one, two, and three dialysis membranes in series were achieved in donor-saturated, infinite dose permeation experiments. These results were then used to calculate the total diffusive resistance for each case, as well as an extrapolated zero membrane value which was used in conjunction with an estimate of the aqueous diffusivities to calculate the ABL thickness. The resulting value (mean +/- SE) was 0.070 +/- 0.004 cm. PMID- 21554191 TI - Gene regulation of extracellular matrix remodeling in human bone marrow stem cell seeded tissue-engineered grafts. AB - Tissue-engineered heart valves are prone to early structural deterioration. We hypothesize that cell-scaffold interaction and mechanical deformation results in upregulation of genes related to osteogenic/chondrogenic differentiation and thus changes extracellular matrix (ECM) composition in human bone marrow mesenchymal stem cell (hBMSC)-derived tissue-engineered grafts. hBMSC were expanded and seeded onto poly-glycolic acid/poly-lactic acid scaffold for 14 days. Seeded tissue-engineered constructs (TEC) were subjected to cyclic flexure for 24 h, whereas control TEC was maintained in roller bottles for the same duration. hBMSC, TEC, and mechanically deformed TEC were subjected to gene-array and histological analysis. Expression levels of RNA and/or protein markers related to chondrogenesis (Sox9, MGP, RunX2, Col II, Col X, and Col XI) and osteogenesis (ALPL, BMP2, EDN1, RunX1, and Col I) were increased in TEC compared to unseeded hBMSC. Histological sections of TEC stained positive for Saffranin O, alkaline phosphatase activity, and calcium deposits. The expression levels of the above gene and protein markers further increased in deformed TEC compared to static TEC. Cell-scaffold interactions and mechanical stress results in gene expression suggestive of endochondral-ossification that impact upon ECM composition and may predispose them to eventual calcification. PMID- 21554192 TI - The effect of mesenchymal stromal cell-hyaluronic acid hydrogel constructs on immunophenotype of macrophages. AB - During the past several years, multipotent mesenchymal stromal cells (MSCs) have rapidly moved from in vitro and animal studies into clinical trials as a therapeutic modality potentially applicable to a wide range of disorders. It has been proposed that ex vivo culture-expanded MSCs exert their tissue regeneration potential through their immunomodulatory and anti-inflammatory properties, and paracrine effects more than their ability to differentiate into multiple tissue lineages. Since extracellular matrix (ECM) deposition and tissue support is also one of many physiological roles of MSCs, there is increasing interest in their potential use for tissue engineering, particularly in combination with ECM-based scaffolds such as hyaluronic acid (HA). We investigated the effect of MSCs on immunophenotype of macrophages in the presence of an HA-hydrogel scaffold using a unique 3D coculture system. MSCs were encapsulated in the hydrogel and peripheral blood CD14+ monocyte-derived macrophages plated in direct contact with the MSC gel construct. To determine the immunophenotype of macrophages, we looked at the expression of cell surface markers CD14, CD16, CD206, and human leukocyte antigen (HLA)-DR by flow cytometry. MSCs and macrophages cultured on the HA-hydrogel remained viable and were able to be recovered from the construct. There was a significant difference in the immunophenotype observed between monocyte-derived macrophages cultured on the HA scaffold compared to tissue culture polystyrene. Macrophages cultured on gels with MSCs expressed lower CD16 and HLA-DR with higher expression of CD206, indicating the least inflammatory profile overall, compatible with the immunophenotype of alternatively activated macrophages. Development of macrophages, with this immunophenotype, upon interaction with the MSC-hydrogel constructs may play a potentially significant role in tissue repair when using a cellular-biomaterial therapeutic approach. PMID- 21554196 TI - False positive urine drug screening for tricyclic antidepressants in patients taking quetiapine. PMID- 21554197 TI - Ganglioside GD3 as a raft component in cell death regulation. AB - Subcellular organelles such as mitochondria, endoplasmic reticulum and the Golgi complex are involved in the progression of cell death program. Recent evidence unveils that Fas ligand-mediated apoptosis induces scrambling of mitochondrial and secretory organelles via a global alteration of membrane traffic that is modulated by apical caspases. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides and sphingomyelin, cholesterol and signaling proteins, it has been suggested that they are part of this traffic and can participate in cell remodelling leading to cell death program execution. Although detected in various cell types, the role of lipid rafts in apoptosis has been mostly studied in T cells, where the physiological apoptotic program occurs through CD95/Fas. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation is summarized. We focused on the paradigmatic component of rafts GD3, which can proceed from the cell plasma membrane (and/or from trans Golgi network) to the mitochondria via a microtubule-dependent mechanism. This transport may be regulated by CLIPR-59, a new CLIP-170-related protein, involved in the regulation of microtubule dynamics. Particular attention has been given to mitochondrial raft-like microdomains, which may represent preferential sites where key reactions take place. Indeed, GD3, by interacting with mitochondrial raft-like microdomains, may trigger specific events involved in the apoptogenic program, including mitochondria hyperpolarization and depolarization, fission associated changes, megapore formation and release of apoptogenic factors. These findings introduce an additional task for identifying new molecular target(s) of anti-cancer agents. PMID- 21554198 TI - Alteration of ceramide 1-O-functionalization as a promising approach for cancer therapy. AB - Sphingolipids, which are complex lipidic components of the cell membranes, lie in a key position to modulate the pathways of trans-membrane signaling and allow the cell to adapt to environmental stresses. In malignancies, reduced production of some sphingolipid species able to induce apoptosis such as ceramide and conversely, increased levels of some other metabolites involved in tumor progression and drug resistance of cancer cells, are often described. In this context, the discovery of new chemical entities able to specifically modify ceramide metabolism should offer novel pharmacological tools in cancer therapy. The review dedicates particular attention to the enzymes that modify ceramide at the C1-OH position generating other biologically important sphingolipids in cancer, such as sphingomyelin, ceramide-1-phosphate or glucosylceramide. Findings reported in the literature leading to the development of new chemical entities specifically designed to achieve the above goals have been collected and are discussed. The effects of enzyme inhibitors of sphingomyelin synthase, ceramide kinase and glucosylceramide synthase on cancer cell proliferation, sensitivity to chemotherapeutics, induction of apoptosis or growth of xenografts are presented. PMID- 21554199 TI - Cholesterol, cardiolipin, and mitochondria permeabilisation. AB - Apoptosis is a form of programmed cell death required for the development and for the proper functioning of multicellular organisms. It is defined by a combination of morphological and biochemical modifications that result from the activation of a family of proteases called caspases. Several pathways can lead to caspase activation and they often involve the release of apoptogenic factors normally sequestered in the mitochondrial intermembrane space. Complete release of mitochondrial pro-apoptotic factors ultimately results in cell death, whether in a caspase-dependent or independent manner. A tight control of mitochondrial permeability is therefore essential. Mutations of regulators of the process, such as proteins of the Bcl-2 family, have indeed been reported in many cancers. In addition, the contributions of lipids, both as regulators of protein activities and as components of the pore itself, are starting to be unravelled. Early on, the role of the mitochondria-specific phospholipid cardiolipin as a targeting signal for pro-apoptotic proteins of the Bcl-2 family was discovered. This role was then expanded since it was shown that cardiolipin also supports conformational changes undergone by proteins of the Bcl-2 family, serves as a docking station for additional pro-apoptotic factors, and is essential for the permeabilisation of synthetic liposomes by activated Bax and Bak. More recently, cholesterol, whose level is increased in most cancer cells, was shown to contribute to their resistance to cytotoxic stresses. Reducing cholesterol levels might therefore represent an interesting novel target to sensitize cancer cells to chemotherapeutic agents. PMID- 21554200 TI - Role of stem cells in normal liver and cancer. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world because current treatments, including both surgical and non-surgical ones, cannot effectively cure this disease. Increasing evidence has revealed the importance of cancer stem cells (CSCs) in hepatocarcinogenesis, and the idea of targeting CSCs sheds light on more effective therapeutic strategies for HCC. In this review, normal stem cells and putative CSCs in the liver are briefly introduced. Studies about signaling pathways that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs are also summarized and discussed. PMID- 21554201 TI - Molecular mechanism of liver cancer. AB - Liver cancer, hepatocellular carcinoma (HCC) in particular, is one of the most deadly cancers worldwide, and the incidence of HCC is increasing rapidly in the United States and other developed countries. Epidemiological studies have identified major risk factors for HCC, including infection with hepatitis B and C virus (HBV and HCV), exposure to certain chemicals, high intake of alcohol, as well as metabolic diseases such as obesity and diabetes that are rapidly rising in the US. Although the etiologies for liver carcinogenesis are relatively well defined, the exact mechanism and pathways leading to cancer development are still unclear. Chronic liver injury, followed by inflammation and irregular liver regeneration has been suggested as an important step in hepatocarcinogenesis. Therefore, the identification of key factors that protect the liver from injury and inflammation could provide valuable insight into the development of HCC. In this review, we will summarize the recent findings in HCC studies, mainly focusing on the new molecular link among inflammation, liver repair and HCC. PMID- 21554202 TI - Points of therapeutic intervention along the Wnt signaling pathway in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. However, there is little known about targeted therapeutics for the treatment of this devastating tumor. Among the growth factor signaling cascades deregulated in HCC, evidences suggest that the WNT/Frizzled-mediated signaling pathway plays a key role in the hepatic carcinogenesis. Aberrant activation of the signaling in HCC is mostly due to deregulated expression of the Wnt/beta catenin signaling components. This leads to the activation of the beta catenin/TCF dependent target genes, which controls cell proliferation, cell cycle, apoptosis or motility. It has been shown that disruption of the Wnt/beta catenin signaling cascade displayed anti-cancer properties in HCC. Currently, no therapeutic molecules targeting the WNT pathway are available or under clinical evaluation for the treatment of HCC. This review will discuss the identified potential molecular targets related to the canonical WNT signaling pathway and their potential therapeutic usefulness. PMID- 21554203 TI - microRNA involvement in hepatocellular carcinoma. AB - The role of microRNAs (miRNAs) in human tumorigenesis has been demonstrated by gene profiling and functional studies. In hepatocellular carcinoma (HCC), consistently deregulated miRNAs were identified. Their aberrant expression revealed relations shared with other types of cancer and others unique to HCC, namely the down-regulation of miR-122. Most importantly, functional and molecular studies uncovered mechanisms that linked deregulated miRNAs to cancer-associated pathways, thereby placing their deregulation in a more rational framework. These results improved our knowledge concerning the molecular basis of HCC and helped to increase our understanding about the great clinical potential behind these small molecules. In fact, a number of studies proved that miRNAs may have clinical relevance as bio-pathologic markers for HCC classification, prognostic stratification, early diagnosis or follow-up of patients. Additionally, the demonstration that miRNAs themselves or anti-miRNA oligonucleotides could be successfully used for in vivo modulation of miRNA actions has shown significant potentials in molecularly targeted therapy. In this context, the liver represents an organ of election to test therapeutic possibilities associated with miRNAs. PMID- 21554204 TI - Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma. AB - Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker. PMID- 21554205 TI - Hepatocellular carcinoma detection by gallium scan and subsequent treatment by gallium maltolate: rationale and case study. AB - Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron (Fe(3+)). Because Fe(3+) is needed for ribonucleotide reductase activity--and thus DNA synthesis--gallium can inhibit DNA production and cell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, in vitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activity against HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials, to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominately to serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patient with advanced HCC (20 * 10 cm primary tumor, ascites around liver and spleen, resistant to Nexavar((r)) (sorafenib)), whose cancer was highly gallium-avid in a (67)Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patient had a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor. PMID- 21554206 TI - Targeting cell death and survival receptors in hepatocellular carcinoma. AB - Hepatocarcinoma (HCC) is the fifth most common neoplasia in the world, and the first cause of death by cancer in some areas. The clinical course of HCC patients has improved greatly owing to the use of the oral multikinase inhibitor, Sorafenib. The expression of receptors belonging to the superfamily of tumor necrosis factor receptors (TNF-R), such as TNF-R1, CD95 and TNF-related apoptosis inducing ligand (TRAIL) receptor -1 (TRAIL-R1) and -2 (TRAIL-R2) are altered in patients with HCC, especially those in advanced stages of de-differentiation. The disruption of death receptor (DR)-dependent cell signaling is related to poor survival in patients with HCC. These observations, together with the lack of antitumoral therapy alternatives, have stimulated research on DR-targeted therapies. The increasing research progress in cell death shows the intense crosstalk among DR and cell survival pathways in cancer cells. In consequence, new potential therapeutic strategies involving antibodies or small molecules specifically targeted to DR pathways either in monotherapy or in combination with other therapeutic strategies may be envisaged in the future to treat HCC. PMID- 21554207 TI - Targeting receptor tyrosine kinase pathways in hepatocellular carcinoma. AB - Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of the molecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation, survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuable for treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinical trials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginal and many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effective treatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinase inhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action of these therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overall survival and quality of life in patients with HCC. PMID- 21554209 TI - Gene therapy. Editorial. PMID- 21554208 TI - Role of Class II nuclear receptors in liver carcinogenesis. AB - Nuclear receptors (NRs) are ligand-activated transcription factors that are important to life by regulating a wide variety of physiological and pathological functions. There are three classes of NRs defined by ligands and heterodimer partners. The Class II NRs are involved in a broad range of pathophysiological functions in the liver, including cholesterol and bile acid homeostasis; lipid and glucose metabolism; inflammation; liver regeneration and hepatocellular carcinogenesis. Due to highly complicated molecular mechanisms in the development and progression of hepatocellular carcinoma (HCC), HCC is still one of the most common malignancies in the world. Given the pivotal functions of the Class II NRs in the liver, the roles of these NRs in hepatocellular carcinogenesis are emerging. This review summarizes the roles of Class II NRs in liver carcinogenesis and their potential application in the prevention and treatment of HCC. PMID- 21554210 TI - Crosstalk Signalling Role in Modulation of Drugs Side Effects. AB - Tumorigenesis is regulated by the complex cell-matrix signalling interactions that incorporate feedback mechanisms from constantly evolving microenvironments. Under normal circumstances, these matrix signalling processes together with infiltrating immune cells tightly control the extent of tissue remodelling. They are the key elements of regulated homeostatic repair of local matrix architecture and biological function. In contrast, the pathological tumorigenesis employing similar mechanisms and cellular components to change cellular phenotype promoting proliferation and transformation. However, there is a significant knowledge gap in our understanding about the network integration of different matrix induced signalling processes and their connection to drug side effects. Using epithelial tumorigenesis as a model system, we show that drug actions and pathological conditions are associated with crosstalk signalling mechanisms. These processes functionally integrate microenvironmental cues and generate representative gene expression profiles that are different from those generated by the native ligand driven signalling mechanisms. Particularly in this review, we are focusing on crosstalk signalling processes that are sensitive to transforming growth factor receptor type I (TbRI) inhibitor A83-01 (3-(6-Methyl-2-pyridinyl)-N-phenyl-4-(4 quinolinyl)-1H-pyrazole-1-carbothioamide). This process is affecting inflammatory gene expression, epithelial to mesenchymal transition, migration, proliferation, and changes in metastatic gene expressional patterns. As a result, phenotypic and functional modifications to cells and their immediate microenvironments are unavoidable. Here we demonstrate that future screening strategies for unintended drug side effects from molecular to systemic levels would benefit from future crosstalk signalling analysis. Thorough analysis could be used to forecast the diverse and highly variable gene expression patterns caused by pathological microenvironmental conditions which become apparent only in larger patient populations. PMID- 21554211 TI - Using PK/PD to optimize antibiotic dosing for critically ill patients. AB - Antibiotic prescription for critically ill patients is a complicated process because of the pharmacokinetic differences of this patient population with non critically ill patients and the lack of robust informative studies. This article seeks to review the available literature describing dosing requirements for optimized treatment of critically ill patients and to discuss a framework to rationally address complex cases by outlining the suggested processes for optimal achievement of pharmacokinetic/ pharmacodynamic targets. A variety of papers exist describing the effect of pathophysiology on antibiotic kinetics. In the critically ill patient, dysfunction of almost any organ system can result in significant changes to drug volume of distribution and clearance. Dysfunction of the cardiovascular and renal systems in particular is problematic and can lead to potentially sub-therapeutic antibiotic concentrations in blood and in interstitial fluid. In response to altered pharmacokinetics, dose regimens that adhere to the pharmacodynamics of the antibiotic are essential. In the absence of validated dosing algorithms, therapeutic drug monitoring data and susceptibility data of the infecting pathogen should be inputted into a Bayesian software program that include population pharmacokinetic models to calculate dosing regimens that are personalized for the critically ill patient. PMID- 21554212 TI - Relevance of pharmacokinetic and pharmacodynamic modeling to clinical care of critically ill patients. AB - Efficacious therapy is of utmost importance to save lives and prevent bacterial resistance in critically ill patients. This review summarizes pharmacokinetic (PK) and pharmacodynamic (PD) modeling methods to optimize clinical care of critically ill patients in empiric and individualized therapy. While these methods apply to all therapeutic areas, we focus on antibiotics to highlight important applications, as emergence of resistance is a significant problem. Nonparametric and parametric population PK modeling, multiple-model dosage design, Monte Carlo simulations, and Bayesian adaptive feedback control are the methods of choice to optimize therapy. Population PK can estimate between patient variability and account for potentially increased clearances and large volumes of distribution in critically ill patients. Once patient- specific PK data become available, target concentration intervention and adaptive feedback control algorithms can most precisely achieve target goals such as clinical cure of an infection or resistance prevention in stable and unstable patients with rapidly changing PK parameters. Many bacterial resistance mechanisms cause PK/PD targets for resistance prevention to be usually several-fold higher than targets for near maximal killing. In vitro infection models such as the hollow fiber and one compartment infection models allow one to study antibiotic-induced bacterial killing and emergence of resistance of mono- and combination therapies over clinically relevant treatment durations. Mechanism-based (and empirical) PK/PD modeling can incorporate effects of the immune system and allow one to design innovative dosage regimens and prospective validation studies. Mechanism-based modeling holds great promise to optimize mono- and combination therapy of anti infectives and drugs from other therapeutic areas for critically ill patients. PMID- 21554213 TI - How to measure pharmacokinetics in critically ill patients? AB - There is pressing need to better understand pharmacokinetics in critically ill patients. This will aid clinicians in selecting optimal dosing regimens. Pharmacokinetic studies are difficult in this population due to the heterogeneity of the patients and the practical issues of research involving critically ill patients. Therapeutic drug monitoring is routinely performed to guide dosing for aminoglycoside and glycopeptide antibiotics. Expanding its use to other drug classes could provide new therapeutic advantages. Plasma concentration may not always reflect tissue distribution in critically ill patients. Microdialysis is a technique that can be applied in the Intensive Care Unit to measure tissue concentrations and provide further insights to antimicrobial therapy for critically ill patients. Finally, the application of population pharmacokinetic analysis in studies in critically ill patients may identify factors affecting pharmacokinetics and enhance drug dosing regimens for varied patient groups. PMID- 21554214 TI - The effect of critical illness on drug distribution. AB - The complexity of managing critically ill patients has increased since the early establishment of intensive care units in the 1950s. Despite of the fact that the number of drugs available to clinicians has increased, the understanding of the pharmacokinetics of individual drugs in specific disease states is still a matter of concern. Among the pharmacokinetic processes which may be affected in this patient population, drug distribution is a very important one. Changes in drug distribution may cause inadequate drug exposure at the infection site and consequently influence clinical outcome. Since drug distribution is dependent on a plethora of factors, including the physicochemical characteristics of the drug, we will focus on the most common mechanisms responsible for altered tissue distribution. These include changes in protein binding, fluid shifts, and pH changes. Although less common, alterations in organ perfusion may also play a role, particularly in heart failure patients. Despite great advances in understanding the distribution of antibacterial drugs, further studies are needed to define the consequences of changed drug distribution in critically ill patients on dosing regimens and clinical outcome. PMID- 21554215 TI - ARC--augmented renal clearance. AB - In-hospital and intensive care unit mortality rates for sepsis remain un acceptably high, and have prompted the publication of international guidelines on best practice. Crucial to this is the application of early appropriate antibacterial therapy, in the correct dose. However, antibacterial regimes in this setting have largely been extrapolated from those in healthy volunteers, and fail to consider the unique pathophysiology and treatment provided to this population. As such, augmented renal clearance (ARC) - the enhanced renal elimination of circulating solute - is likely to be one of the more common physiological changes encountered in this setting, although to date remains largely under-appreciated. Significantly this may alter the pharmacokinetics of many routinely prescribed agents in this setting, pre-disposing to subtherapeutic levels or treatment failure. This review paper examines this phenomenon in detail, providing a summary of the likely underlying mechanisms, those patients at greatest risk, and the implications for antibacterial dosing in the critically ill. PMID- 21554216 TI - Dosing of antibiotics in critically ill patients undergoing renal replacement therapy. AB - On September 11, 1945 Maria Schafstaat was the first patient who successfully underwent a dialysis treatment for acute kidney injury (AKI), formerly known as acute renal failure. Since then, the number of patients with AKI is increasing worldwide. Today AKI is generally one feature of a multiple organ dysfunction syndrome (MODS), which develops in response to major surgery, cardiogenic shock or sepsis. Several clinical studies have shown that early and appropriate antibiotic therapy in those patients is of utter importance, yet it remains one of the most difficult challenges to meet. Even in critically ill patients with conserved renal function a myriad of pathophysiological changes, resulting in increased volume of distribution, decreased protein binding and altered hepatic drug clearance, makes appropriate antibiotic dosin difficult. Adequate pharmacotherapy, i.e. dose of anti-infective agens is becoming even more complicated if it has to be tailored to counteract their removal by different modes and intensities of renal replacement therapy. This review summarizes our sparse knowledge about pharmacokinetic studies and dosing recommendations of drugs in patients with AKI undergoing continuous renal replacement therapies (CRRTs) such as continuous venovenous hemofiltration (CVVH) as well as extended dialysis (ED), an increasingly used method to treat patients with AKI in the intensive care setting. We reflect on failure of several large prospective controlled studies to show a survival benefit of higher doses of renal replacement therapy, a finding that might be caused by the fact that we still adhere to dosing guidelines for antibiotics which are at best ineffectual but might also lead to potentially dangerous underdosing of these life saving drugs. Lastly we address possible strategies to overcome the lack of knowledge, the lack of data and the lack of interest in this important area of critical care medicine. Improvement of clinical outcomes and reduction of antibiotic resistance in this patient population will require nephrologist, intensivists and pharmacists to work together. PMID- 21554217 TI - The relevance of drug clearance to antibiotic dosing in critically ill patients. AB - To maximise the effect of an antibiotic it is necessary to pay careful attention to dosing. The maintenance dose is determined by antibiotic clearance which is usually determined in young healthy adults with normal physiology. Antibiotic clearance in critically ill patients may increase or decrease due to altered physiology and the treatments that are administered. Clearance may also vary significantly over time in patients with critical illness. Advancing age and comorbidities, in particular chronic kidney disease, can also decrease antibiotic clearance. Therefore, it is complicated and arguably impossible to suggest generic guidelines for the dosing of antibiotics in critically ill patients. Factors that influence clearance must be identified and accounted for in each patient for a rational approach to dose adjustment of antibiotics in patients with critical illness. The necessary changes can be predicted by understanding pharmacokinetic concepts. It is necessary to quantify organ function in patients at multiple time points because this can be used to estimate antibiotic clearance and guide dose selection. For example, creatinine clearance should be calculated but methods used in ambulatory patients may not apply to patients with critical illness. If possible, therapeutic drug monitoring should be conducted to ensure that antibiotic concentration targets are achieved and also to guide titration of subsequent doses. If blood sampling is carefully planned it may be possible to directly measure antibiotic clearance for dose adjustment. The purpose of this article is to review the concept of clearance and to highlight circumstances where antibiotic clearance may be altered in patients with critical illness. Strategies for dose modification of antibiotics in critically ill patients will be discussed. PMID- 21554218 TI - The relevance of drug volume of distribution in antibiotic dosing. AB - Despite the importance of early an appropriate therapy for the outcomes of severe infections in critically ill patients, there is still little understanding of dose optimization during the most important phase of the treatment, the initial phase. Disease-driven variations in pharmacokinetics and pharmacokinetics/ pharmacodynamics may compromise the therapeutic success of antibiotic therapy. Therefore, dose adjustments that account for these variations are paramount for improving antibiotic use in critically ill patients. Compelling evidence shows significant increases in the Vd of both hydrophilic and lipophilic drugs in critically ill patients as a consequence of patient pathology and from clinical interventions. These increases in the Vd can lead to lower than expected plasma concentrations during the first day of therapy, which may result in sub-optimal achievement of antibiotic pharmacokinetics/pharmacodynamic targets, resulting in inappropriate treatment. Therefore, loading doses of antibiotic during the first day of therapy that account for the predicted increase in the Vd are required. Further research towards the establishment of new dosing regimens that use loading doses to satisfy such increased volumes of distribution is recommended. PMID- 21554219 TI - Physiological changes in the critically ill patient with sepsis. AB - Intensive care medicine deals with the critically ill; these patients usually have multiple organ failure, and complex medical conditions. The mortality in Australia and New Zealand among this population is approximately 16.1%, with approximately 24.2% having existing co-morbidities, and 23.4% of these patients experiencing sepsis or septic shock. Sepsis is a clinical syndrome that traditionally was regarded as a physiological maladaptive response to a foreign pathogen and ranges in disease severity from simple sepsis to septic shock, a life threatening condition, associated with multiple organ failure. Sepsis has profound effects on all systems of the body, and most notably the cardiovascular, renal and hepatic systems. There has been much research into the septic critically ill patient and recent developments in basic pharmacology and physiology has yielded results applicable to clinical practice. Sepsis may induce a state of increased cardiac output, which has significant effects on drug pharmacokinetics and pharmacodynamics. This increased cardiac output increases both renal and hepatic blood flow, and alters rates of antibiotic metabolism, and excretion. There are also alterations in the fluid compartments of the septic critically ill, that results in an altered volume of distribution, and ultimately decreased antibiotic concentrations at their site of action. This article will examine and review in detail the septic critically ill patient, and the effects that sepsis has on physiology and the resulting altered antibiotic pharmacokinetics and pharmacodynamics. Current knowledge suggests that the medical prescriber should be weary of antibiotic dosing in the septic critically ill, and consider alternative dosing regimes that are individualized to the patient in order to maximize efficacy. PMID- 21554220 TI - Pharmacokinetic concepts revisited--basic and applied. AB - Pathophysiological changes are common in critically ill patients, and can alter the time course of drug concentrations following dosing. The latter is termed pharmacokinetics (PK), and describes the relationship between dose administered and drug concentrations in plasma. Thus, modifications in PK necessitate dose adjustment, to optimize drug therapy in critical care. An understanding of basic PK principles is therefore required, to improve dosage guidelines in the population treated. Here, we define the key PK parameters, with specific application to critically ill patients. We then overview the methods used for PK analysis, in both research and in the clinical setting. Traditionally, non compartmental and standard two-stage approaches have been used in small groups of patients with similar demographics and pathophysiology. However, these methods require intensive sampling, and do not explicitly describe inter-individual variability, or errors associated with measurement or sampling. Population PK (POPPK) modelling is advantageous in this regard, and can use both sparse and rich datasets to provide accurate estimates for between-subject variability (BSV). In addition, POPPK can explore patient parameter-covariate relationships, to account for some of the BSV in PK. This information is useful with assisting individualized dosing in the clinic. While the above methods are suitable for research, they are too time-consuming in the clinical setting, and Bayesian approaches have been adopted to optimize dosing. These methods, together with POPPK and appropriate study design are recommended for improved dosing in critical care. PMID- 21554222 TI - Nitric oxide supplementation in postischemic acute renal failure: normotension versus hypertension. AB - Nitric oxide (NO) has been suggested to play a pivotal role in ischemic acute renal failure (ARF) but there are controversies about its role in hypertensive and non hypertensive ischemic kidney. Multiple strategies including administration of exogenous NO donors have been shown to protect the kidney against toxic or ischemic injury, suggesting endothelial dysfunction as impaired NO generation due to ischemia. However, in postischemic kidney, NO derived from inducible nitric oxide synthase (iNOS) has been considered to enhance the tissue damage while iNOS inhibition decreased the tubular damage. It is well known decrease in basal production of NO in essential hypertension and that long lasting hypertension damages medium size and small-size blood vessels, therefore predisposes nephroangiosclerosis patients to ARF. Many studies have shown that long term stimulation of NO release in normotension improves renal haemodymnamics and kidney function in ischemic form of ARF. On the other hand, there are studies that have shown that NO synthesis stimulation has no effect or even worsens tubular damage in postischemic hypertensive kidney. Therefore, it seems likely that NO supplementation plays different role in postischemic renal damage development, beneficial in well preserved normotensive kidney and limited in postischemic hypertensive kidney due to disturbed tubuloglomerular response, vasoreactivity and kidney vascular structure. PMID- 21554223 TI - A review of the ethnopharmacology, phytochemistry and pharmacology of plants of the Maytenus genus. AB - Plants belonging to the genus Maytenus (Celastraceae) are routinely used in folk medicine in Brazil and other countries to treat a variety of illnesses, the most common of which are gastric disorders. Several studies have reported on the importance of these biological effects, and the chemical substances, mostly terpenoids and flavonoid glycosides, responsible for them. This review summarizes the ethnopharmacological, chemical and pharmacological knowledge of plants of the Maytenus genus, with particular emphasis on those growing in Brazil. PMID- 21554224 TI - Serum and pleural fluid N-Terminal-Pro-B-Type natriuretic peptide concentrations in the differential diagnosis of pleural effusions. AB - Currently, new biomarkers like N-Terminal-Pro-B-Type natriuretic peptide (NT proBNP) have been used in the differential diagnosis of pleural effusions. In our study, we aimed to investigate the diagnostic value of NT-proBNP, especially in cardiac originated pleural effusions. Forty-five patients with pleural effusions were included in the study. NT-proBNP levels and biochemical markers involved in the Light's criteria were analyzed in pleural fluid and serums of the patients. Pleural fluid culture, AFB smear, cytology were performed where they were indicated according to the clinical evaluation. In patients, to whom cardiac pathology was considered to be; cardiological evaluation and echocardiography were also done. Thirty-eight pleural effusions were exudative and, 7 were transudative according to the Light's criteria. Final diagnosis were malignant effusion in 13, infection (tuberculosis/pneumonia) in 10, congestive heart failure in 21, and other conditions related with pleural effusion in 1 of the patients. Median (25th to 75th percentiles) NT-proBNP levels of serum and pleural fluid due to congestive heart failure (CHF) were 4747 pg/mL (931-15754) and 4827 pg/mL (1290-12.430) while median NT-proBNP levels of serum and pleural fluid related with non-cardiac reasons were 183 pg/mL (138-444) and 245 pg/mL (187-556) respectively. NT-proBNP levels of serum and pleural fluid were significantly high in CHF (p< 0.001 for both). When four groups were compared serum and pleural fluid NT-proBNP levels were highest in the CHF group which was followed by malignancy, infection and others (p< 0.001 for both). Fourteen of 21 patients who were accepted to have congestive heart failure as the final diagnosis by a cardiological evaluation had an exudative pleural fluid according to the Light's criteria. Serum and pleural fluid NT-proBNP levels were higher in transudates and this reached statistically significance for pleural fluid (p= 0.009). We suggest that measurement of pleural fluid NT-proBNP is a smart approach and pleural fluid NT-proBNP can reflect cardiac origin of effusions better than serum NT-proBNP and Light's criteria. PMID- 21554225 TI - [Pulmonary manifestations of polyvinyl chloride exposure]. AB - There is currently no national data on the effects of polyvinyl chloride (PVC) exposure on pulmonary function. In this study we recruited workers and administrative staff from two PVC plants between July 2008 and July 2009. A questionnaire, pulmonary function tests, carbon monoxide diffusion capacity, and peak flows were recorded. Particulate matter analyses were performed by the Adana Central Laboratory of the Directorate of Occupational Health and Safety. Data were analyzed with SPSS 13.0 software. Nine of the 147 subjects were female. The incidence of a cough was more common in the administrative group. Of the study population, 59.1% were smokers. Tobacco addiction significantly increased cough and dyspnea [OR= 1.10 (1.00-1.20, 95% CI) p= 0.007 and OR= 1.08 (1.02-1.14, 95% CI), p= 0.008, respectively]. Dust exposure was correlated with the incidence of a cough [OR= 0.20 (0.04-0.80, 95% CI) p= 0.008]. The period of work correlated with sputum production [OR= 1.00 (1.00-1.02, 95% CI) p= 0.044]. The FVC% was significantly higher in the administrative group, and FEV1/FVC and DLCO were higher in the exposed group. Tobacco addiction increased the risk of airflow limitation, as evaluated by FEV1/FVC < 70% and FEF25-75 < 50% [OR= 1.15 (1.06 1.25, 95% CI) p= 0.001 and OR= 1.09 (1.02-1.17, 95% CI) p= 0.010, respectively]. Tobacco addiction and increasing duration of work had a negative influence on DLCO in the exposed group (r= -0.270, p= 0.025 and r= -0.210, p= 0.037). In the exposed group PEF variability was significantly greater on workdays, compared with rest days. This study shows that tobacco consumption has a greater affect on the airways than PVC dust exposure. A median of 36 months exposure to PVC dust had no significant impact on pulmonary function parameters, except for DLCO and PEF variability. PMID- 21554226 TI - Did unprogrammed tobacco control efforts over seven years decrease smoking prevalence in the medical school? AB - Medical students will have significant roles in combating against death tool of tobacco. The aim of this study is to evaluate whether any decrease in the smoking prevalence of the medical students over seven years of many tobacco control efforts. A self-administered questionnaire was carried out among 764 of 854 (89.4%) medical students in order to determine the knowledge, attitudes and behaviors towards tobacco use. Chi-square tests, Student's t-test and multiple logistic regression methods were used. Results were compared with the historical control study that was done seven years ago with same methods. 25.9% of the students were smoker (36.6% of males, 16.3% of females), 4.9% was exsmoker and 69.2% was non-smoker. Quit rate was high among males than females (6.8% versus 3.3%, p< 0.05). When compared with historical cohort in 1999, smoking rate decreased only 3.8% for males and 5.5% for females, and quit rates were not higher. Lower curriculum year, and lower knowledge level about the harms of smoking and environmental tobacco smoke in lower grades, living in bachelor homes, easy access to smuggled cigarettes, using non-cigarette tobacco products were main factors for smoking. There was little decline in smoking rates of medical students despite of many local and national tobacco control efforts over seven years. Special attention and organized, programmed efforts are needed in medical schools in Turkey. PMID- 21554227 TI - High level isoniazid resistance correlates with multiple mutation in the katG encoding catalase proxidase of pulmonary tuberculosis isolates from the frontier localities of Iran. AB - The aim of this study was to investigate the significance of multiple-mutations in the katG gene, predominant nucleotide changes and its correlation with high level of resistance to isoniazid in Mycobacterium tuberculosis isolates that were randomly collected from sputa of 42 patients with primary and secondary active pulmonary tuberculosis from different geographic regions of Iran. Drug susceptibility testing was determined using the CDC standard conventional proportional method. DNA extraction, katG gene amplification, and DNA sequencing analysis were performed. Thirty four (80%) isolates were found to have multiple mutations (composed of 2-5 mutations) in the katG gene. Increased number of predominant mutations and nucleotide changes were demonstrated in codons 315 (AGC ->ACC), 316 (GGC-->AGC), 309 (GGT-->GTT) with a higher frequency among patients bearing secondary tuberculosis infection with elevated levels of resistance to isoniazid (MIC >= 5-10 ug/mL). Furthermore, it was demonstrated that the combination of mutations with their predominant nucleotide changes were also observed in codons 315, 316, and 309 indicating higher frequencies of mutations among patients with secondary infection respectively. In this study, 62% (n= 21) of multi-mutated isolates found to have combination of mutations with predominant nucleotide changes in codons 315 (AGC-->ACC), 316 (GGC-->GTT), 309 (GGT-->GGT), and also demonstrated to be more frequent in isolates of patients with secondary infections, bearing higher level of resistance to isoniazid (>= 5-10 ug/mL). PMID- 21554228 TI - Pulmonary tuberculosis in infants less than one year old: implications for early diagnosis. AB - Tuberculosis in older children has been well described; however, its description in infants is very limited. There are a few studies of infants with tuberculosis in the literature. In this study from February 2007 to May 2009, cases of infantile tuberculosis investigated retrospectively. Thirteen patients with pulmonary tuberculosis detected. Mean age of the patients was 168.8 days. The most frequent symptoms were cough in 10 (72.4%) patients, night sweating in five (35.7%) and fever in three (21.4%). Four patients didn't have any symptoms. Physical examinations were normal in 12 patients. Thorax computerized tomography studies of all of the patients were abnormal included the cases with normal chest radiographies. Antituberculosis treatment was well tolerated by all of the patients and all of them improved. Prevention of tuberculosis in infants rest upon the early detection and treatment of tuberculosis of the infant's household members. This study demonstrates that with high index of suspicion and the correct use of chest radiographs and thorax computerized tomography, the disease diagnosed early in infants. Early diagnosis and treatment may prevent dissemination and may reduce mortality, so pediatrician should alert for tuberculosis in infants. PMID- 21554229 TI - Comparison of tuberculin skin testing and QuantiFERON-TB Gold-In Tube test in health care workers. AB - The purpose of this prospective, cross-sectional observational study was to compare the tuberculin skin testing (TST) with QuantiFERON-TB Gold-In Tube (QTF GIT) for the detection of latent tuberculosis infection in healthcare workers (HCWs). The study included 78 volunteers who are HCWs at the same tertiary care teaching hospital for chest diseases and tuberculosis. Participants with active tuberculosis, immunodefficiency or malnutrition were not included. The TST was administered by the Mantoux method. Peptides representing ESAT-6, CFP-10 and TB7 7 were used as TB-specific antigens in the whole-blood Interferon-gamma (IFN-g) assay (QTF-GIT). There was a statistically significant relation between the number of Bacillus Calmette-Guerin (BCG) scars and the diameter of TST (p< 0.01). QTF results according to previous BCG vaccinations did not significantly differ (p> 0.05). There was an intermediate concordance between two tests (k: 0.346). QTF-GIT has a sensitivity of 56.14% (both TST and QTF-GIT are positive), specificity of 90.48% (both TST and QTF-GIT are negative); positive predictive value of 94.12% and negative predictive value of 43.18% and accuracy is 65.38%. There was a statistically significant relation between TST diameter and QTF result (p< 0.01). Latent tuberculosis infection prevalance of our study population was 43% according to QTF-GIT test, 73% according to TST and BCG vaccination rate was 87%. In conclusion, TST is affected by previous BCG vaccinations, QTF-GIT is not. We can recommend QTF-GIT test for the detection of latent tuberculosis infection as an alternative to TST in populations with routine BCG vaccination programme. PMID- 21554230 TI - Polymorphisms in NRAMP1 and MBL2 genes and their relations with tuberculosis in Turkish children. AB - In this study, we aimed to determine genetic susceptibility of children group who are under follow up at outpatient and inpatient clinics or newly diagnosed pediatric tuberculosis according to healthy control group. Patient group consists of 50 cases aged between 0-18 years who are under follow up at outpatient and inpatient clinics or newly diagnosed pediatric tuberculosis between 1996-2009 in Cukurova University, Faculty of Medicine, Department of Pediatrics and the control group consists of 50 healthy cases aged between 0-18 years who have neither chronic nor acute diseases and have no history of tuberculosis contact. Analysis of NRAMP1 (D543N, 3'-UTR and INT4 loci) and MBL (codon 54 and 57) gene polymorphisms carried out in Cukurova University, Faculty of Medicine, Department of Medical Biology and Genetics. In this study comprising in total 50 individuals we did not observe any significant association with microsatellite polymorphisms at the INT4, G543A and 3-UTR loci situated in the NRAMP1 gene (p> 0.005). There was no significant difference of MBL gen frequency polimorphisms of codon 54 and 57 polimorphisms between patient and control group statistically (p> 0.05). We reported that the INT4, G543A and 3-UTR loci microsatellite polymorphisms in the NRAMP1 gene were not associated with tuberculosis. No significant associations were also observed for codons 54 and 57 in the MBL2 gene. These results shed light on the role of NRAMP1 in susceptibility to tuberculosis disease and provide a plausible explanation for NRAMP1 and MBL genetic heterogeneity in tuberculosis susceptibility. PMID- 21554231 TI - Combined transbronchial needle aspiration and PET/CT for mediastinal staging of lung cancer. AB - In this study, we aimed to evaluate the performance of transbronchial needle aspiration (TBNA) combined with positron emission tomography/computed tomography (PET/CT) for the staging of lung cancer. Twenty-five patients having lymphadenopathies greater than 1 cm on thorax CT and maximum standardized uptake value (SUVmax) >= 2.5 on PET/CT were included in this prospective study performed between March 2006 and March 2008. Forty-three lymphnode stations were sampled by using TBNA. Surgical histology, as confirmed by mediastinoscopy, was accepted as the "gold standard". The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of combined TBNA and PET/CT for correct lymph node staging were 67%, 100%, 100%, 76% and 84%; respectively. The initial clinical staging was downstaged after TBNA in 13/19 (69%) patients with adequate TBNA samples, whereas staging was correct in 17/19 (89%) patients assessed by combined TBNA and PET/CT. Staging was completed by TBNA, without mediastinoscopy, in 6/25 (24%) patients. Among the clinical factors that were assessed, only the PET SUVmax was associated with positive TBNA results [odds ratio (OR) 1.27, 95% CI 1.004-1.61, p= 0.046]. A PET SUVmax >= 5 was eleven times more likely in patients with positive TBNA results [OR 10.68, 95% CI 1.91-59.62, p< 0.01]. In conclusion, the combination of TBNA with PET/CT increased the sensitivity of TBNA. Combined TBNA and PET/CT may also allow adequate mediastinal staging of lung cancer in most patients with enlarged lymph nodes, and reduce the need for mediastinoscopy. The SUVmax cut off point for a positive TBNA result was >= 5. PMID- 21554232 TI - [Results of surgical treatment for pulmonary aspergilloma with 26 cases in six years: a single center experience]. AB - Surgery for pulmonary aspergilloma is reputed to be risky. We analyzed our results of the surgical treatment for pulmonary aspergilloma. Between 2003 and 2009, 26 patients underwent thoracotomy for treatment of pulmonary aspergilloma in our center. Results were evaluated retrospectively. There were 5 female and 21 male patients, with a mean age of 44 +/- 11.6 years (28-70). The patients were divided into two groups, group A (simple aspergilloma; n= 8) and group B (complex aspergilloma; n= 18). Major underlying diseases were tuberculosis (61.5%). The most common indication for operation was hemoptysis (57.6%). Of our patients, 23% were complaining of massive hemoptysis or recurrent hemoptysis. Other patients were complaining of mild symptoms and some of them were totally asymptomatic. We performed 15 (57.6%) lobectomies (3 with associated segmentectomies), 8 (30.6%) segmentectomies/wedge resections, 2 (7.6%) pneumonectomies, and 1 (3.8%) cavernoplasty. Postoperative complications occurred in 15 (57.6%) patients. Complications occurred in 72.2% patients of complex aspergilloma, whereas 25% occurred in simple aspergilloma (p= 0.03). Major complications included prolonged air leak, empyema, air space. One patient who underwent lobectomies for complex aspergilloma developed bronchopleural fistula and died of respiratory failure on the 20th postoperative day. Operative mortality was 3.8%. The average postoperative hospital stay was 12.9 days. The mean follow-up period was average 44 months. The actuarial survival at 3 years was 90% and 100% for complex aspergilloma and simple aspergilloma, respectively (p> 0.05). There was two recurrence of disease (8%). But no recurrence of hemoptysis. Low morbidity rate may have been due to the selection of patients with localized pulmonary disease in this study. Surgical resection of asymptomatic or symptomatic pulmonary aspergilloma is effective in preventing recurrence or massive hemoptysis for patients whose condition is fit for pulmonary resection with reasonable mortality, morbidity and survival rates. PMID- 21554233 TI - Multiple mediastinal hydatic cyst: a case report. AB - Hydatid disease is a parasitic infection that is remains endemic in many countries, particularly the Middle East and Central Asia. Mediastinal hydatidosis is very rare (less than 0.1% of all hydatid disease cases) that have been only anecdotally in the literature. To the best of our knowledge only one case of multiple mediastineal hydatid cysts has been reported previously. We report the second cases of multiple mediastineal hydatid cysts and recommend that it can be considered in the differential diagnosis of multiple cystic mediastineal masses in endemic countries. PMID- 21554234 TI - A mass of myxofibrosarcoma in the lung. AB - Fibrosarcoma is a mesenchymal tumor constituted by malignant fibroblasts. Myxofibrosarcoma is one of the fibrosarcoma variants that mostly develops from dermal/subcutaneous tissues. The most common locations are the limbs, with rare occurrences in the chest, head, and neck. Since, to best of our knowledge, there is no such report in English literature, we hereby present a case of lung myxofibrosarcoma. A 47-year-old man who had chest pain for 4 months was admitted to our clinic. The chest X-ray revealed a homogeneous density in the left upper lung. His chest computed tomography (CT) scan showed a solid mass lesion of 52 x 58 mm in size at the apical segment of the left upper lobe. There was tumor invasion at the second and third ribs. CT-guided fine-needle tru-cut lung biopsy was performed. Histopathological evaluation result was high grade myxofibrosarcoma. Surgery was conducted. Myxofibrosarcoma is a surgically curable disease. However, local recurrences occur in 50% to 60% of the cases. Therefore, chemotherapy and/or radiotherapy is the suggested approach following surgery. PMID- 21554235 TI - A case of endobronchial inflammatory pseudotumor invading the mediastinum. AB - A 50-year-old-male was admitted to our hospital in March 2007, complaining of cough and hemoptysis for 3 months. Postero-anterior chest X-ray showed an opacity on right upper zone. Computed tomography of the thorax showed a mass lesion occupying the right upper lobe and superior segment of the lower lobe and invading the mediastinum. Fiberoptic bronchoscopy showed total occlusion of the right upper lobe bronchus by the mass and infiltration of the bronchus intermedius. Bronchoscopic biopsies were nondiagnostic. PET-CT revealed SUVmax of 18.8. Right thoracotomy was performed. Vena cava superior and right pulmonary artery was invaded by the mass. Biopsies were performed. Histopathologic examination demonstrated an inflammatory pseudotumor. Corticosteroid treatment was started. The tumor was clinically and radiologically unresponsive to corticosteroids. He was referred to oncology department for radiotherapy. The patient died on November 2007. PMID- 21554236 TI - [Pulmonary arteriovenous malformation: two sibling cases]. AB - Pulmonary arteriovenous malformations, are abnormal connections between pulmonary arteries and veins. However it can be presented as an isolated single anomaly, also may be multiple when accompanying with autosomal dominant hereditary hemorrhagic telengiectasia (Rendu-Osler-Weber Syndrome; ROWS). In this case report, two patients operated with the diagnosis of multiple pulmonary arteriovenous malformation familial screening done with the possibility of ROWS and pulmonary arteriovenous malformation found in her sister, are presented. PMID- 21554237 TI - A rare cause of interstitial lung disease: Hermansky-Pudlak syndrome. AB - Hermansky-Pudlak syndrome is a rare disease characterized by bleeding diathesis, oculocutaneous albinism and lysosomal ceroid lipofuscin pigment deposits. Pulmonary fibrosis may also accompany with the disease. A 48-year-old male patient with a diagnosis of Hermansky-Pudlak syndrome admitted with dyspnea. A thorax computed tomography revealed bilateral diffuse interlobular septal thickness which was more prominent in the basal segments of lower lobes. Although pirfenidone therapy was planned, clinical deteroriation developed and patient died because of respiratory failure. In conclusion; this report describes a patient with pulmonary fibrosis caused by lung involvement of Hermansky-Pudlak syndrome which is an extremely rare and mortal disease. PMID- 21554238 TI - [Effects of inhaled corticosteroids/long-acting beta-2 agonist fix combinations in COPD]. AB - Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized with progressive air flow limitation, and is expected to be the third leading cause of death until 2030 worldwide. The clinical trials in the last 10 years revealed that fix combinations (inhaled corticosteroids/long-acting beta-2 agonist; ICS/LABA) improve lung functions and quality of life, and reduced symptoms and exacerbation rates in patients with severe and very severe COPD. PMID- 21554239 TI - Forgotten but an important risk factor for pulmonary embolism: ophthalmic surgery. PMID- 21554240 TI - Migration of a fractured totally implantable venous access catheter into the right ventricle. PMID- 21554241 TI - Glycogen synthase kinase-3beta regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src. AB - GSK-3beta (glycogen synthase kinase-3beta), a crucial tau kinase, negatively regulates PP2A (protein phosphatase 2A), the most active tau phosphatase that is suppressed in the brain in AD (Alzheimer's disease). However, the molecular mechanism is not understood. In the present study we found that activation of GSK 3beta stimulates the inhibitory phosphorylation of PP2A at Tyr307 (pY307-PP2A), whereas inhibition of GSK-3beta decreased the level of pY307-PP2A both in vitro and in vivo. GSK-3beta is a serine/threonine kinase that can not phosphorylate tyrosine directly, therefore we measured PTP1B (protein tyrosine phosphatase 1B) and Src (a tyrosine kinase) activities. We found that GSK-3beta can modulate both PTP1B and Src protein levels, but it only inhibits PTP1B activity, with no effect on Src. Furthermore, only knockdown of PTP1B but not Src by siRNA (small interfering RNA) eliminates the effects of GSK-3beta on PP2A. GSK-3beta phosphorylates PTP1B at serine residues, and activation of GSK-3beta reduces the mRNA level of PTP1B. Additionally, we also observed that GSK-3 negatively regulates the protein and mRNA levels of PP2A, and knockdown of CREB (cAMP response-element-binding protein) abolishes the increase in PP2A induced by GSK-3 inhibition. The results of the present study suggest that GSK-3beta inhibits PP2A by increasing the inhibitory Tyr307 phosphorylation and decreasing the expression of PP2A, and the mechanism involves inhibition of PTP1B and CREB. PMID- 21554242 TI - Ubiquitin-mediated internalization of connexin43 is independent of the canonical endocytic tyrosine-sorting signal. AB - Gap junctions are specialized cell-cell contacts that provide direct intercellular communication between eukaryotic cells. The tyrosine-sorting signal (YXXO), present at amino acids 286-289 of Cx43 (connexin43), has been implicated in the internalization of the protein. In recent years, ubiquitination of Cx43 has also been proposed to regulate gap junction intercellular communication; however, the underlying mechanism and molecular players involved remain elusive. In the present study, we demonstrate that ubiquitinated Cx43 is internalized through a mechanism that is independent of the YXXO signal. Indeed, expression of a Cx43-Ub (ubiquitin) chimaera was shown to drive the internalization of a mutant Cx43 in which the YXXO motif was eliminated. Immunofluorescence, cycloheximide chase and cell-surface-protein biotinylation experiments demonstrate that oligomerization of Cx43-Ub into hemichannels containing wild-type Cx43 or mutant Cx43Y286A is sufficient to drive the internalization of the protein. Furthermore, the internalization of Cx43 induced by Cx43-Ub was shown to depend on its interaction with epidermal growth factor receptor substrate 15. PMID- 21554243 TI - Role of sulfatide in vaccinia virus infection. AB - BACKGROUND INFORMATION: Vaccinia virus (VACV) was used as a surrogate of variola virus (genus Orthopoxvirus), the causative agent of smallpox, to study orthopoxvirus infection. VACV infects cells via attachment and fusion of the viral membrane with the host cell membrane. Glycosphingolipids, expressed in multiple organs, are major components of lipid rafts and have been associated with the infectious route of several pathogens. RESULTS: We demonstrate that the VACV-WR (VACV Western-Reserve strain) displays no binding to Cer (ceramide) or to Gal-Cer (galactosylceramide), but binds to a natural sulfated derivative of these molecules: the Sulf (sulfatide) 3' sulfogalactosylceramide. The interaction between Sulf and VACV-WR resulted in a time-dependent inhibition of virus infection. Virus cell attachment was the crucial step inhibited by Sulf. Electron microscopy showed that SUVs (small unilamellar vesicles) enriched in Sulf bound to VACV particles. Both the A27 and L5 viral membrane proteins were shown to interact with Sulf, indicating that they could be the major viral ligands for Sulf. Soluble Sulf was successful in preventing mortality, but not morbidity, in a lethal mouse model infection with VACV-WR. CONCLUSIONS: Together the results suggest that Sulf could play a role as an alternate receptor for VACV-WR and probably other Orthopoxviruses. PMID- 21554244 TI - Chronic HgCl(2) treatment increases vasoconstriction induced by electrical field stimulation: role of adrenergic and nitrergic innervation. AB - In the present study, we have investigated the possible changes in rat mesenteric artery vascular innervation function caused by chronic exposure to low doses of HgCl(2) (mercuric chloride), as well as the mechanisms involved. Rats were divided into two groups: (i) control, and (ii) HgCl(2)-treated rats (30 days; first dose, 4.6 MUg/kg of body weight; subsequent dose, 0.07 MUg.kg-1 of body weight.day-1, intramuscularly). Vasomotor response to EFS (electrical field stimulation), NA (noradrenaline) and the NO donor DEA-NO (diethylamine NONOate) were studied, nNOS (neuronal NO synthase) and phospho-nNOS protein expression were analysed, and NO, O(2)- (superoxide anion) and NA release were also determined. EFS-induced contraction was higher in the HgCl(2)-treated group. Phentolamine (1 MUmol/l) decreased the response to EFS to a greater extent in HgCl(2)-treated rats. HgCl(2) treatment increased vasoconstrictor response to exogenous NA and NA release. L-NAME (N(G)-nitro-L-arginine methyl ester; 0.1 mmol/l) increased the response to EFS in both experimental groups, but the increase was greater in segments from control animals. HgCl(2) treatment decreased NO release and increased O(2)- production. Vasodilator response to DEA NO was lower in HgCl(2)-treated animals. Tempol increased DEA-NO-induced relaxation to a greater extent in HgCl(2)-treated animals. nNOS expression was similar in arteries from both experimental groups, whereas phospho-nNOS was decreased in segments from HgCl(2)-treated animals. HgCl(2) treatment increased vasoconstrictor response to EFS as a result of, in part, reduced NO bioavailability and increased adrenergic function. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease. PMID- 21554245 TI - Hypoxic exercise training promotes antitumour cytotoxicity of natural killer cells in young men. AB - The cytotoxic functions of NKs (natural killer cells) are critical in enabling the immune system to cope efficiently with malignancy. In the present study, we compared how various exercise regimens without/with hypoxia influence phenotypic characteristics of NK subsets and cytotoxicity of NKs to NPCs (nasopharyngeal carcinoma cells). A total of 60 sedentary males were randomly divided into five groups. Each group (n=12) underwent one of five regimens: normoxic (21% O(2)) control (N-C), hypoxic (15% O(2)) control (H-C), normoxic exercise (50% maximal work rate under 21% O(2); N-E), hypoxic relative exercise (50% maximal heart rate reserve under 15% O2; H-RE) or hypoxic absolute exercise (50% maximal work rate under 15% O(2); H-AE) for 30 min/day, 5 days/week for 4 weeks. The results showed that hypoxic exercise regimens increased pulmonary ventilation and tissue oxygen utilization. Moreover, the H-RE regimen resulted in enhanced aerobic fitness at a less intensive training workload in the H-AE regimen. Before each regimen, strenuous exercise elevated NK perforin/granzyme B content and promoted cytotoxicity of NKs to NPCs. However, the percentage of NKs expressing homing (CD11a)/terminally differentiated (CD57)/inhibitory [KLRG1 (killer cell lectin like receptor G1)] molecules that entered the bloodstream from peripheral tissues increased following this exercise. After 4 weeks, both the H-AE and H-RE regimens produced an up-regulated expression of memory (CD45RO)/activating (NKG2D) molecules and was accompanied by a decrease in CD57/KLRG1 levels on NKs at rest and after strenuous exercise. Furthermore, the two regimens increased resting and exercise NK perforin/granzyme B content and NK-induced phosphatidylserine exposure of NPCs. In contrast, no significant change in the phenotypic characteristics of blood NK subsets or NK-induced NPC apoptosis was observed in the N-C, H-C and N-E regimens. Therefore we conclude that 15% O(2) exercise training reduces terminally differentiated NK subsets and up-regulates the expression of activating molecules and cytotoxic granule proteins in NKs, thereby enhancing the capacity of anti-NPC cytotoxicity by NKs. These findings could help to determine effective hypoxic exercise regimens for improving individual aerobic capacity and simultaneously promoting the natural cytotoxicity of NKs. PMID- 21554246 TI - AW551984: a novel regulator of cardiomyogenesis in pluripotent embryonic cells. AB - An understanding of the mechanism that regulates the cardiac differentiation of pluripotent stem cells is necessary for the effective generation and expansion of cardiomyocytes as cell therapy products. In the present study, we have identified genes that modulate the cardiac differentiation of pluripotent embryonic cells. We isolated P19CL6 cell sublines that possess distinct properties in cardiomyogenesis and extracted 24 CMR (cardiomyogenesis-related candidate) genes correlated with cardiomyogenesis using a transcriptome analysis. Knockdown of the CMR genes by RNAi (RNA interference) revealed that 18 genes influence spontaneous contraction or transcript levels of cardiac marker genes in EC (embryonal carcinoma) cells. We also performed knockdown of the CMR genes in mouse ES (embryonic stem) cells and induced in vitro cardiac differentiation. Three CMR genes, AW551984, 2810405K02Rik (RIKEN cDNA 2810405K02 gene) and Cd302 (CD302 antigen), modulated the cardiac differentiation of both EC cells and ES cells. Depletion of AW551984 attenuated the expression of the early cardiac transcription factor Nkx2.5 (NK2 transcription factor related locus 5) without affecting transcript levels of pluripotency and early mesoderm marker genes during ES cell differentiation. Activation of Wnt/beta-catenin signalling enhanced the expression of both AW551984 and Nkx2.5 in ES cells during embryoid body formation. Our findings indicate that AW551984 is a novel regulator of cardiomyogenesis from pluripotent embryonic cells, which links Wnt/beta-catenin signalling to Nkx2.5 expression. PMID- 21554247 TI - Hexokinase II acts through UCP3 to suppress mitochondrial reactive oxygen species production and maintain aerobic respiration. AB - UCP3 (uncoupling protein-3) mitigates mitochondrial ROS (reactive oxygen species) production, but the mechanisms are poorly understood. Previous studies have also examined UCP3 effects, including decreased ROS production, during metabolic states when fatty acid oxidation is high (e.g. a fasting state). However, the role of UCP3 when carbohydrate oxidation is high (e.g. fed state) has remained largely unexplored. In the present study, we show that mitochondrial-bound HK (hexokinase) II curtails oxidative stress and enhances aerobic metabolism of glucose in the fed state in a UCP3-dependent manner. Genetic knockout or inhibition of UCP3 significantly decreased mitochondrial-bound HKII. Furthermore, UCP3 was required for the HKII-mediated decrease in mitochondrial ROS emission. Intriguingly, the UCP3-mediated modulation of mitochondria-associated HKII was only observed in cells cultured under high-glucose conditions. UCP3 was required to maintain high rates of aerobic metabolism in high-glucose-treated cells and in muscle of fed mice. Deficiency in UCP3 resulted in a metabolic shift that favoured anaerobic glycolytic metabolism, increased glucose uptake and increased sensitivity to oxidative challenge. PET (positron emission tomography) of [18F]fluoro-deoxyglucose uptake confirmed these findings in UCP3-knockout and wild-type mice. Collectively, our findings link the anti-oxidative and metabolic functions of UCP3 through a surprising molecular connection with mitochondrial bound HKII. PMID- 21554248 TI - Interleukin enhancer-binding factor 3 functions as a liver receptor homologue-1 co-activator in synergy with the nuclear receptor co-activators PRMT1 and PGC 1alpha. AB - LRH-1 (liver receptor homologue-1), a transcription factor and member of the nuclear receptor superfamily, regulates the expression of its target genes, which are involved in bile acid and cholesterol homoeostasis. However, the molecular mechanisms of transcriptional control by LRH-1 are not completely understood. Previously, we identified Ku80 and Ku70 as LRH-1-binding proteins and reported that they function as co-repressors. In the present study, we identified an additional LRH-1-binding protein, ILF3 (interleukin enhancer-binding factor 3). ILF3 formed a complex with LRH-1 and the other two nuclear receptor co-activators PRMT1 (protein arginine methyltransferase 1) and PGC-1alpha (peroxisome proliferator-activated receptor gamma co-activator-1alpha). We demonstrated that ILF3, PRMT1 and PGC-1alpha were recruited to the promoter region of the LRH-1 regulated SHP (small heterodimer partner) gene, encoding one of the nuclear receptors. ILF3 enhanced SHP gene expression in co-operation with PRMT1 and PGC 1alpha through the C-terminal region of ILF3. In addition, we found that the small interfering RNA-mediated down-regulation of ILF3 expression led to a reduction in the occupancy of PGC-1alpha at the SHP promoter and SHP expression. Taken together, our results suggest that ILF3 functions as a novel LRH-1 co activator by acting synergistically with PRMT1 and PGC-1alpha, thereby promoting LRH-1-dependent gene expression. PMID- 21554249 TI - NMR spectroscopy of 14-3-3zeta reveals a flexible C-terminal extension: differentiation of the chaperone and phosphoserine-binding activities of 14-3 3zeta. AB - Intracellular 14-3-3 proteins bind to many proteins, via a specific phosphoserine motif, regulating diverse cellular tasks including cell signalling and disease progression. The 14-3-3zeta isoform is a molecular chaperone, preventing the stress-induced aggregation of target proteins in a manner comparable with that of the unrelated sHsps (small heat-shock proteins). 1H-NMR spectroscopy revealed the presence of a flexible and unstructured C-terminal extension, 12 amino acids in length, which protrudes from the domain core of 14-3-3zeta and is similar in structure and length to the C-terminal extension of mammalian sHsps. The extension stabilizes 14-3-3zeta, but has no direct role in chaperone action. Lys(49) is an important functional residue within the ligand-binding groove of 14 3-3zeta with K49E 14-3-3zeta exhibiting markedly reduced binding to phosphorylated and non-phosphorylated ligands. The R18 peptide binds to the binding groove of 14-3-3zeta with high affinity and also reduces the interaction of 14-3-3zeta ligands. However, neither the K49E mutation nor the presence of the R18 peptide affected the chaperone activity of 14-3-3zeta, implying that the C terminal extension and binding groove of 14-3-3zeta do not mediate interaction with target proteins during chaperone action. Other region(s) in 14-3-3zeta are most likely to be involved, i.e. the protein's chaperone and phosphoserine binding activities are functionally and structurally separated. PMID- 21554250 TI - Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle. AB - Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20-300 MUM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 MUM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2-10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 degrees C but not 37 degrees C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 MUM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 MUM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state. PMID- 21554251 TI - Remote hindlimb preconditioning and hepatoprotection: NO-table strides against liver ischaemia/reperfusion injury. AB - Hepatic IR (ischaemia/reperfusion) injury is an important clinical problem complicating liver surgery and transplantation. IPC (ischaemic preconditioning) is a strategy whereby brief episodes of IR in an organ can induce an adaptive response to protect against subsequent prolonged IR injury. However, trauma to vessels supplying the target organ is unavoidable using the technique of direct IPC. One amenable strategy would be to apply the protective preconditioning stimulus to an organ distant or remote from the target organ of interest, a technique known as RIPC (remote IPC). In the present issue of Clinical Science, Abu-Amara and co-workers utilize hindlimb RIPC as a novel therapeutic strategy against liver IR injury and investigate the mechanistic contribution of NO to hepatoprotection by administering C-PTIO [2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide potassium salt], an NO scavenger. Their experiments set the stage for more definitive studies to demonstrate a discernible benefit for the utility of RIPC in liver surgery and transplantation. PMID- 21554252 TI - MICB polymorphisms and haplotypes with MICA and HLA alleles in Koreans. AB - Major histocompatibility complex (MHC) class I chain-related gene B (MICB) is located within the human MHC class I region. The location of MICB in the MHC region may imply the presence of linkage disequilibrium with polymorphic MICA and human leukocyte antigen (HLA) loci. MICB is also polymorphic; however, MICB polymorphisms have not been investigated in Koreans. Using sequence-based typing (SBT), we estimated the allelic frequencies of MICB and haplotypes with MICA, HLA B, and HLA-DRB1 at high resolution in a population of 139 unrelated Korean individuals. Eight MICB alleles were identified. The most frequent allele was MICB*005:02/*010 (57.2%), followed by *002 (11.5%), *004 (8.3%), *005:03 (8.3%), and *008 (6.8%). The most common two-locus haplotypes were MICB*005:02/*010 MICA*010 (19.4%), MICB*005:02/*010-DRB1*15:01 (6.5%), and MICB*005:02/*010 B*15:01 (10.4%); the most common three-locus haplotypes were B*15:01-MICA*010 MICB*005:02/*010 (5.8%) and MICA*010-MICB*005:02/*010-DRB1*04:06 (10.4%); and the most common four-locus haplotype was B*15:01-MICA*010-MICB*005:02/*010-DRB1*04:06 (5.8%). This is the first study to provide information about MICB allele frequencies and haplotypes with HLA in Koreans. These study results should help understand mechanisms of disease association between the MICB locus and neighboring loci in Koreans. PMID- 21554253 TI - HLA-DRB1*04:02, DRB1*08:04 and DRB1*14 alleles associated to pemphigus vulgaris in southeastern Brazilian population. PMID- 21554254 TI - EMMPRIN levels in serum of patients with amyotrophic lateral sclerosis. AB - OBJECTIVES: There are evidence that extracellular matrix metalloproteinases (MMPs) may be implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). The extracellular matrix metalloproteinase inducer (EMMPRIN) is said to increase the production of MMPs in cells. The aim of the study was to investigate serum EMMPRIN levels in patients with ALS. MATERIALS AND METHODS: The study included 50 patients with ALS and 50 patients from the control group. Serum EMMPRIN levels were measured using the enzyme-linked immunosorbent method. RESULTS: The study showed that EMMPRIN levels are significantly increased in the serum of the whole group of patients with ALS when compared to the control group and are significantly increased in patients with ALS with severe clinical state compared to patients with mild clinical state (P < 0.05). There was a significant correlation of serum EMMPRIN levels with severity of clinical state of patients with ALS (P < 0.05). CONCLUSION: The results indicate that EMMPRIN is implicated in pathophysiology of ALS and may be the marker of clinical state severity. PMID- 21554255 TI - Ventriculomegaly and balance disturbances in patients with TIA. AB - OBJECTIVES: Dilated ventricles and gait disturbances are common in the elderly, and these are also features of the treatable syndrome idiopathic normal pressure hydrocephalus (INPH). Many studies report an association between hypertension, vascular disease and INPH. The objective of this study was to study the frequency of ventriculomegaly, with or without hydrocephalic symptoms, in patients who had suffered from a transitory ischaemic attack (TIA). METHODS: Gait, Romberg sign, tandem standing and one-leg stance were consecutively evaluated in elderly > 24 h after a TIA. Ventricular size, white matter lesions and atrophy were assessed on computed tomography scans. Exclusion criteria were conditions possibly influencing the balance tests. RESULTS: eventy-six patients with TIA out of 105 were included. Ventriculomegaly [Evans Index (EI) > 0.30] was observed in 19.7% and very large ventricles (EI > 0.33) in 7.9%. Ventriculomegaly was found in 58% of the patients with a previous 'history of balance or gait disturbance', but only in 12% of those without any prior disturbance (chi-square test; P = 0.0009). Three out of 76 patients with TIA (3.9%) fulfilled both radiological and clinical criteria for 'possible INPH'. CONCLUSION: Ventriculomegaly is a common finding in elderly. One out of 20 patients with TIA may suffer from INPH, existing before and independent of the TIA diagnosis. Therefore, patients presenting with ventriculomegaly and gait/balance disturbances not attributable to other causes should be referred to a hydrocephalus centre or a neurologist with special interest in INPH. PMID- 21554256 TI - Guideline on the management of haemophilia in the fetus and neonate. AB - Evidence-based guidelines are presented for the management of haemophilia in the fetus and neonate. This includes information regarding the management of pregnancy and delivery as well as aspects of management during the early neonatal period. Specific issues regarding the mode of delivery and the risk of intra cranial and extra-cranial haemorrhage are discussed. PMID- 21554257 TI - Transition of highly specific microRNA expression patterns in association with discrete maturation stages of human granulopoiesis. PMID- 21554258 TI - Statins are active in acute lymphoblastic leukaemia (ALL): a therapy that may treat ALL and prevent avascular necrosis. PMID- 21554259 TI - The clinical management of tumour lysis syndrome in haematological malignancies. AB - Tumour lysis syndrome (TLS) is caused by the disintegration of malignant cells, usually following the instigation of chemotherapy, although it may already be established at the time of initial presentation in a minority of cases. As a direct consequence of malignant cell breakdown, intracellular ions, proteins, nucleic acids and their metabolites are released into the plasma causing the characteristic metabolic abnormalities of TLS; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia. In many cases the release of large amounts intracellular contents is so abrupt that the normal homeostatic mechanisms are rapidly overwhelmed and without prompt, effective management, the clinical effects of TLS soon become apparent. PMID- 21554260 TI - A steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate high response rates in newly diagnosed multiple myeloma patients. AB - Novel agents have provided a new foundation for multiple myeloma therapies. When combined with other anti-myeloma agents, these compounds significantly enhance clinical efficacy. High-dose steroids are frequently used in anti-myeloma combination regimens; however, the doses employed are often poorly tolerated, especially in patients with concurrent comorbid conditions. We hypothesized that a steroid-independent combination regimen could be developed without significant compromise of efficacy. The availability of such a regimen will be important for patients whose concurrent ailments make them poor candidates for steroid containing anti-myeloma regimens. A phase II single institute, non-randomized clinical trial was conducted to investigate a novel steroid-free three-drug combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), the VDT regimen. Forty-three newly diagnosed multiple myeloma patients requiring treatment were enrolled on this study. The overall response rate and complete response (CR) + near complete response (nCR) rate was 78% and 35%, respectively. Median time to progression was 29.5 months. Fatigue, rash, neuropathy, constipation and infections were the most common side effects. We concluded that VDT is a tolerable and an effective regimen capable of inducing high response rates and can be employed in patients considered to be poor candidates for steroid-based treatment regimens. PMID- 21554261 TI - Unusual nodular bone marrow appearances in a case of myeloid sarcoma. PMID- 21554262 TI - Common genetic variation at 15q25.2 impacts on chronic lymphocytic leukaemia risk. AB - A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk (P(combined) = 1.10 * 10(-7) and 1.30 * 10(-5) respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development. PMID- 21554263 TI - Targeting cell surface beta2 -microglobulin by pentameric IgM antibodies. AB - Monoclonal antibodies (mAbs) specific for human beta(2) -microglobulin (beta(2) M) have been shown to induce tumour cell apoptosis in haematological and solid tumours via recruiting major histocompatibility complex (MHC) class I molecules into and excluding cytokine receptors from the lipid rafts. Based on these findings, we hypothesized that IgM anti-beta(2) M mAbs might have stronger apoptotic effects because of their pentameric structure. Our results showed that, compared with IgG mAbs, IgM anti-beta(2) M mAbs exhibited stronger tumouricidal activity in vitro against different tumour cells, including myeloma, mantle cell lymphoma, and prostate cancer, and in vivo in a human-like xenografted myeloma mouse model without damaging normal tissues. IgM mAb-induced apoptosis is dependent on the pentameric structure of the mAbs. Disrupting pentameric IgM into monomeric IgM significantly reduced their ability to induce cell apoptosis. Monomeric IgM mAbs were less efficient at recruiting MHC class I molecules into and exclusion of cytokine receptors from lipid rafts, and at activating the intrinsic apoptosis cascade. Thus, we developed and validated the efficacy of anti-beta(2) M IgM mAbs that may be utilized in the clinical setting and showed that IgM anti-beta(2) M mAbs may be more potent than IgG mAbs at inducing tumour apoptosis. PMID- 21554264 TI - Advances in the prognostication and management of advanced MDS in children. AB - Advanced myelodysplastic syndrome (MDS) in children includes refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T) according to the paediatric modification of the World Health Organization classification. Clinical features and cytogenetics are essential to make a diagnosis because blast count alone is insufficient to differentiate MDS from acute myeloid leukaemia (AML). Little is known about molecular genetics in paediatric MDS but hypermethylation seem to be frequent. Monosomy 7 is the most common cytogenetic aberration but prognostic neutral whereas those with structural complex karyotype have a very poor outcome. Haematopoietic stem cell transplantation (HSCT) is the treatment of choice and results in cure rates of around 60%. Intensive chemotherapy prior to HSCT provides no survival benefit for children with RAEB and RAEB-T and can generally not be recommended. Intensive chemotherapy before HSCT should be considered in patients with myelodysplasia-related-AML (MDR-AML). PMID- 21554265 TI - 3D position of pericentromeric heterochromatin within the nucleus of a patient with ICF syndrome. AB - ICF (immunodeficiency, centromeric region instability, facial anomalies) syndrome is a rare autosomal recessive disorder characterised by severe immunodeficiency, craniofacial anomalies and chromosome instability. Chromosome analyses from blood samples show a high frequency of decondensation of pericentromeric heterochromatin (PH) and rearrangements involving chromosomes 1 and 16. It is the first and, as far as we know, the only disease associated with a mutation in a DNA methyltransferase gene, DNMT3B, with significant hypomethylation of the classical satellite DNA, the major component of the juxtacentromeric heterochromatin. To better understand the complex links between the hypomethylation of the satellite DNA, the cytogenetic anomalies and the clinical features of ICF syndrome, we performed three-dimensional (3D) FISH on preserved cells from a patient with a suspected ICF phenotype. Analysis of DNMT3B did not reveal any mutation in our patient, making this case an ICF type 2. The results of 3D-FISH showed a statistically significant change in the intranuclear position of PH of chromosome 1 in cells of the patient as compared to normal cells. It is difficult to understand how a defect in the methylation pathway can be responsible for the various symptoms of this condition. From our observations we suggest a mechanistic link between the reorganisation of the nuclear architecture and the altered gene expression. PMID- 21554266 TI - A novel homozygous missense mutation in WNT10B in familial split-hand/foot malformation. AB - Split-hand/foot malformation (SHFM) is a rare limb developmental malformation, characterized by variable degree of median clefts of hands and feet due to the absence of central rays of extremities. To date, six different forms of SHFM have been described. Four of these SHFM1, SHFM3, SHFM4 and SHFM5 show autosomal dominant, SHFM6 autosomal recessive and SHFM2 X-linked pattern of inheritance. In this study a large consanguineous Pakistani family, with autosomal recessive SHFM, appeared in the last two generations, was investigated. In total 15 individuals including 9 males and 6 females were affected with the syndrome. Affected members of the family exhibited SHFM phenotype with involvement of hands and feet. Most of the affected members showed syndactyly/polydactyly in hands and feet, dysplastic hand, aplasia of radial ray of hand and cleft foot. Investigating linkage to known autosomal SHFM loci mapped the family to SHFM6 locus on chromosome 12p11.1-q13.13. Mutation screening of the gene WNT10B revealed a novel sequence variant (c.986C>G, p.Thr329Arg) in all affected individuals who were studied. This is the third mutation reported in gene WNT10B causing autosomal recessive SHFM syndrome. PMID- 21554267 TI - CHD7 mutations causing CHARGE syndrome are predominantly of paternal origin. AB - CHARGE (coloboma, heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, ear anomalies and deafness) syndrome is a congenital malformation syndrome caused by mutations in the CHD7 gene in approximately 2/3 of cases. In the vast majority of cases, CHARGE syndrome is sporadic. There are only a few reports of parent-to-child transmission and somatic or gonadal mosaicism. To determine the parental origin of CHD7 mutations in sporadic CHARGE syndrome, we screened 30 families for informative exonic or intronic polymorphisms located near the detected CHD7 mutation. An informative polymorphism could be identified in 13 out of 30 families. Linkage analysis was performed between the CHD7 mutation and the polymorphism in the child. In 12 out of 13 families, the mutation affected the paternal allele (92.3%). In our cohort, the mean paternal age at birth was 32.92 years. Comparing the age of fathers of an affected CHARGE patient with the paternal age of the German population in general, we could not observe any paternal age effect. Taken together, we show in this study that de novo CHD7 mutations occur predominantly in the male germ line. PMID- 21554268 TI - Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension. AB - BACKGROUND: Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysed exhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PH aetiology. METHODS: Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in 22 patients with PH and 21 healthy controls. Alveolar NO (Calv(NO) ) and bronchial flux (J'aw(NO) ) were calculated using the slope intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH) and PH WHO Groups II-IV, according to the WHO clinical classification of PH. RESULTS: Exhaled NO was reduced at flow-rates in the range of 20-200 mL s(-1) in patients with PAH (n=13) vs. PH WHO Group II-IV (n=9) (P<0.05 all). Patients with PAH had higher Calv(NO) than healthy controls [2.61 (2.23, 3.36) vs. 1.97ppb (1.22, 2.49), P=0.03] and similar to PH WHO Group II-IV (P=0.51). Patients with PAH had lower J'aw(NO) than patients with PH WHO Group II IV or healthy controls [430 (371, 702) vs. 807 (557, 993) or 731pLs(-1) (580, 818), P<0.05 both]. Subjects with PAH were characterized by higher levels of salivary and plasma nitrite than healthy controls (P<0.05 both). CONCLUSIONS: Patients with PAH have lower bronchial NO flux compared to healthy controls and patients with PH WHO Group II-IV along with elevated salivary and plasma nitrite compared to controls. This implies reduced bronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects with PH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in the alveoli. PMID- 21554269 TI - Plasma sodium and mortality risk in patients with myocardial infarction and a low LVEF. AB - BACKGROUND: Hyponatremia is a known prognostic factor for mortality in patients with heart failure but has not been extensively studied in patients with myocardial infarction (MI). This study was, therefore, designed to evaluate whether plasma sodium and hyponatremia (< 135 mM) are associated with mortality risk in patients with MI. MATERIALS AND METHODS: In retrospective analyses using data from the Trandolapril Cardiac Evaluation (TRACE) study--a randomized, double blind, placebo-controlled trial of trandolapril in 1749 patients with MI and left ventricular ejection fraction (LVEF) <= 35%--associations between plasma sodium or hyponatremia and more than 15-year mortality risk were evaluated in multivariate Cox proportional hazard models including traditional clinical confounders before and after additional adjustment for renal function, use of diuretics or both. RESULTS: During the extended follow-up time, 1462 patients died. Both hyponatremia [Hazard ratio: 1.30 (95% CI: 1.13-1.50), P < 0.001] and plasma sodium [Hazard Ratio(pro mM increase in P-Na): 0.98 (95% CI: 0.96-0.99), P = 0.004] were associated with mortality risk, and the adjusted parameter estimates were not affected by additional adjustment for renal function, use of diuretics or both. CONCLUSIONS: Hyponatremia and plasma concentrations of sodium are associated with long-term mortality risk in patients with MI complicated by left ventricular systolic dysfunction. Importantly, these associations are independent of renal function and use of diuretics. Whether the associations between plasma sodium or hyponatremia and long-term mortality risk reflect a causation or merely the severity of the underlying cardiac disease remains to be clarified. PMID- 21554270 TI - Role of type 2 diabetes mellitus in nonalcoholic fatty liver disease. PMID- 21554271 TI - Adverse drug events in U.S. adult ambulatory medical care. AB - OBJECTIVE: To estimate the incidence of adverse drug events (ADEs) associated with health care visits among U.S. adults across all ambulatory settings. DATA SOURCE: We analyzed data from two nationally representative probability sample surveys: the National Ambulatory Medical Care Survey and the National Hospital and Ambulatory Medical Care Survey. From 2005 to 2007, the presence of an ADE was specifically defined, requested, and recorded in these surveys. STUDY DESIGN: Secondary data analysis. PRINCIPAL FINDINGS: An estimated 13.5 million ADE related visits occurred between 2005 and 2007 (0.5 percent of all visits), the large majority (72 percent) occurring in outpatient practice settings, and the remaining in emergency departments. Older patients (age >=65 years) had the highest age-specific ADE rate, 3.8 ADEs per 10,000 persons per year. In adjusted analyses of outpatient visits, there was an increased odds of an ADE-related visit with increased medication burden (odds ratio [OR] for six to eight medications compared with no medications, OR 3.83 [2.20, 6.65]), and increased odds of ADEs associated with primary care visits compared with specialty visits (OR 2.22 [1.70, 2.89]). CONCLUSIONS: Approximately 4.5 million ambulatory visits related to ADEs occur each year, the majority of these in outpatient office practices. A greater focus on ADE prevention and detection is warranted among patients receiving multiple medications in primary care practices. PMID- 21554272 TI - Health behaviors and utilization among users of complementary and alternative medicine for treatment versus health promotion. AB - OBJECTIVE: To compare the characteristics, health behaviors, and health services utilization of U.S. adults who use complementary and alternative medicine (CAM) to treat illness to those who use CAM for health promotion. DATA SOURCE: The 2007 National Health Interview Survey (NHIS). STUDY DESIGN: We compared adult (age >=18 years) NHIS respondents based on whether they used CAM in the prior year to treat an illness (n=973), for health promotion (n=3,281), or for both purposes (n=3,031). We used complex survey design methods to make national estimates and examine respondents' self-reported health status, health behaviors, and conventional health services utilization. PRINCIPAL FINDINGS: Adults who used CAM for health promotion reported significantly better health status and healthier behaviors overall (higher rates of physical activity and lower rates of obesity) than those who used CAM as treatment. While CAM Users in general had higher rates of conventional health services utilization than those who did not use CAM; adults who used CAM as treatment consumed considerably more conventional health services than those who used it for health promotion. CONCLUSION: This study suggests that there are two distinct types of CAM User that must be considered in future health services research and policy decisions. PMID- 21554273 TI - Association between oral malodour and psychological characteristics in subjects with neurotic tendencies complaining of halitosis. AB - OBJECTIVE: To assess the psychosomatically subjective symptoms of subjects with neurotic tendencies complaining of halitosis. DESIGN: Breath malodour was measured in 368 patients using organoleptic test and gas chromatography. Neurotic tendency and subjective symptoms were assessed using the Cornell Medical Index (CMI). RESULTS: Of the 79 subjects who met the criteria for neurotic tendencies according to CMI scores, 58 (73.4%) had oral malodour, whereas 21 (26.6%) did not. Coated tongue, periodontal pocket, and daily drinking were significantly more common in subjects with oral malodour. On the CMI questionnaire, subjects with no oral malodour more frequently responded 'yes' to questions about fatigue and psychological problems in their families. Additionally, many answered that they had perceived their own bad breath. CONCLUSIONS: Difficulties experienced by subjects with neurotic tendencies and oral malodour may manifest primarily in oral conditions, whereas those experienced by individuals with neurotic tendencies and no oral malodour may manifest primarily in psychosomatic symptoms. PMID- 21554274 TI - Macroglossia. AB - Macroglossia is defined as an enlarged tongue and it is usually clinically diagnosed. Pseudomacryglossia concerns a tongue that is of normal size but gives a false impression of being too large in relation to adjacent anatomical structures. The causes of macroglossia are numerous and this is why various classifications have been proposed for this condition. The consequences of macroglossia usually include a possible malfunction of the stomatognathic system, breathing and speech problems, increased mandible size, tooth spacing, diastema and other orthodontic abnormalities. The treatment of macroglossia depends on its aetiology and generally includes correcting the systemic disease underlying the increase in lingual mass, surgical treatment, radiotherapy and treatment of orthodontic abnormalities that might have been caused by the condition. PMID- 21554275 TI - Academic perceptions amongst educators towards eLearning tools in dental education. AB - This paper reports an explorative study about academic educators' perceptions towards learning management systems (LMS) and eLearning tools as used in dental education. Fifty-five educators participated in an online survey which explored their views on eLearning tools within the context of their own professional training background and teaching needs. In general, educators felt that the eLearning LMS (also known as WebCT/Blackboard) was a tool that suited their teaching and learning needs in terms of flexibility, interactivity and accessibility despite a significant level of self-reported lack of competence in the technology. The paper describes current eLearning professional development initiatives in light of these findings. PMID- 21554276 TI - Indices for measuring periodontitis: a literature review. AB - Indices are important tools to measure, quantify and treat periodontitis both in epidemiological and clinical situations and are based on the prevailing understanding of the pathogenesis of periodontal disease. However, there is dearth of literature on collective information of periodontal indices formulated to date. This article collectively describes the evolution and the present concept of formulation of periodontal indices based on the multi-factorial nature of periodontal disease and also provides some direction for future periodontal indices. Periodontal indices have evolved from the simple Russell's index to the current usage of measurement of clinical attachment level in the recording of indices. The use of dichotomous measurements and the Genetic Susceptibility Index are the new additions to the periodontal indices. Nevertheless, an ideal would be an index that will keep pace with the ever changing concept of the pathogenesis of periodontal disease. PMID- 21554277 TI - Determinants of Iranian dentists' behaviour regarding infection control. AB - AIM: To evaluate the determinants of Iranian dentists' behaviour regarding infection control (IC). DESIGN: A cross-sectional questionnaire survey. SETTING: Iranian general dental practitioners (GDP) participating in a national dental congress. METHODS: The GDPs filled in a self-administered questionnaire containing questions regarding their attitudes towards and their behaviour on several aspects of IC. Background factors included GDP's year of birth, gender, and work-related factors. Statistical evaluation employed the Chi-square test, Cronbach alpha, and regression analysis. RESULTS: In total, 479 GDPs returned the questionnaire. Their mean age was 38.6years (SD=9.4) and 53% were men. The vast majority of the GDPs had positive attitudes towards the inquired after IC criteria with no statistical difference based on the GDP's background characteristics. Of all respondents, >70% reported that they inform the laboratory about the infection status of the sent items, disinfect impressions before sending to the laboratory, and wash patients' mouths before working with high-speed or ultrasonic devices. Adherence to all the studied IC criteria was reported by 10% of the respondents; more frequently by younger GDPs and those with fewer experience years (P<0.05). CONCLUSION: Greater emphasis on infection control programmes in dentists' education is called for especially in continuing education. PMID- 21554278 TI - Prevalence of oral abnormalities in a Turkish newborn population. AB - OBJECTIVE: There are a few studies that describe the oral findings in newborn children in various populations but none conducted for a Turkish population. Hence, this study determined the prevalence of intraoral findings in a group of newborns and examined the correlation among these findings with the mother's systemic and gestational medical complications, cigarette consumption during pregnancy and consanguinity between the parents. METHODS: 2,021 full-term, newborn children were examined. Oral cysts, ankyloglossia, attached upper midline frenum and other medical diagnoses at birth were investigated. Medical information for each child and parent was recorded via standard questionnaire. Obtained data was analysed using the Pearson Chi-Square test (P<=0.05). RESULTS: The most common findings were of oral inclusion cysts situated palatally. CONCLUSIONS: There was a statistically significant relationship between the presence of oral inclusion cysts with the congenital diabetes and also insulin treatment and cigarette consumption during pregnancy. Moreover, a significant relationship was found between the presence of oral inclusion cysts and gestational diabetes and with the presence of consanguinity between the parents (P=0.004). PMID- 21554279 TI - Managing dental caries in children in Saudi Arabia. AB - This paper describes oral health among children in Saudi Arabia, the dental health system in the country, and some possible solutions and recommendations to improve the oral health status. PMID- 21554280 TI - Access to dental care in two long-term refugee camps in western Tanzania; programme development and assessment. AB - OBJECTIVE: To analyse the demographics surrounding and the sustainability of a course in Emergency Dental Care and Health Promotion developed and taught by a team of dentists from the United States to refugee camp health-care workers in two long-term refugee camps in Western Tanzania. METHODS: Refugee camp dental patient log books from Mtabila and Nyarugusu camps Kigoma, Tanzania were analysed and demographic data collected on each patient visit from the programme inception in November 2007 until August 2009. Data collection included information relevant to 1961 patient visits. Data were entered into SPSS Statistics 17.0 using the Freq application. OUTCOMES: Patient visit data included demographics involving both the resident camp populations and the surrounding communities. The distribution of patients treated by nationality was: 58% Burundian (Mtabila), 14% Congolese (Nyarugusu), and 28% Tanzanian citizens residing near both camps. Extractions accounted for 95.5% of procedures performed. Recorded incidences of post-operative complications were 1> % of patient visits. Patient visits were steady over time and a referral system was implemented for complex cases. Health promotion sessions were held in both camps. CONCLUSION: This dental programme has been self-sustaining and is providing some access to care where none existed previously. Programmes such as this may be one solution to the access to dental care problem in long-term refugee camps. PMID- 21554281 TI - Nurses must influence governments and policy. PMID- 21554282 TI - Openness and clarity are essential in research reporting. PMID- 21554283 TI - Influencing and persuading: the need to increase government access to nursing policy advice. PMID- 21554287 TI - Music intervention and preoperative anxiety: an integrative review. AB - BACKGROUND: Hospitalized patients and patients scheduled to undergo surgery or invasive medical procedures experience high levels of anxiety. Recently, music intervention has been evaluated for its anxiolytic effects in preoperative patients. AIM: The aim of this integrative review was to illustrate the varying methodological approaches utilized to assess the efficacy of a music intervention in reducing preoperative anxiety in adults. METHODS: A total of 11 articles, meeting the inclusion criteria, were evaluated and included. FINDINGS: Three of the eight (38%) studies, investigating the effect of listening to music on blood pressure, concluded that listening to music lowered blood pressure. Three of seven (43%) studies, investigating the relationship between listening to music and heart rate, illustrated patterns of decreased heart rates. Finally, two of four (50%) studies, investigating relaxing effects of listening to music on breathing, provided evidence of a decreased respiratory rate. CONCLUSION: There was inconsistent evidence regarding music's effectiveness in lowering blood pressure, heart rate and respirations in anxious patients. However, music intervention can still be used by nurses to create a calm, relaxing atmosphere geared towards reducing anxiety in preoperative patients. PMID- 21554288 TI - Emotional distress and health risk behaviours of mothers of United States Marines. AB - AIM: The aim was to explore emotional distress and health risk behaviours of mothers of servicemen. The study was inspired by the first author's clinical practice in primary care among women who reported significant emotional distress surrounding impending deployment of their sons. BACKGROUND: Thousands of US service members have been deployed in the current wars. The potentially profound effects of deployment on emotional distress of military spouses and children have been documented; however, mothers of servicemen have not been studied. METHODS: This was an exploratory descriptive study to determine self-reported levels of emotional distress and health risk behaviours in the mothers of deployed male US Marines compared with mothers of male Marines not currently deployed. Mothers were accessed via a voluntary online support organization. RESULTS: Mothers of deployed sons reported significantly higher levels of emotional distress and more health risk behaviours compared with mothers of sons not deployed. Many of the mothers in both groups reported high levels of emotional distress. DISCUSSION: As primary care providers, nurses should be alert to the high levels of emotional distress and health risk behaviours among all patients. This exploratory study highlights these dimensions in mothers of servicemen. CONCLUSIONS: This study is the first of mothers of sons serving in the military. While the focus is on mothers of sons serving in the US military, their experience is likely not unique. Mothers of military service members all over the world send their children off to war and wait for their safe return. PMID- 21554289 TI - A qualitative content analysis of nurse-patient communication in Iranian nursing. AB - BACKGROUND: Communication is the source of patients' health promotion, and nurses cannot do their duties without communicating with patients. Nurses with good communication skills have a great role in alleviating the stressful identity of hospitalization for both patients and their families. AIM: To explore cultural and contextual factors influencing nurse-patient communication according to lived experiences of Iranian nurses and patients. METHODS: The participants in this qualitative study consisted of eight bachelor's degree nurses and nine patients hospitalized in surgical and medical wards of a referral teaching hospital in Tehran, Iran. Data were gathered through unstructured and semi-structured interviews as well as observations. The data were analysed using a content analysis approach. FINDINGS: The data analysis revealed the following theme that encompassed nurse-patient communication in Iranian nursing: 'a patient-centred attitude in the shadow of mechanistic structure'. This theme consisted of three categories: (1) communication as the essence of nursing care, (2) reactive communication and (3) difficulties of nurse-patient communication. CONCLUSION: In spite of the nurses' and patients' belief in the importance of communication, in practice each party's role in communication leaves much to be desired. This is because of some structural and socio-cultural factors that hinder effective communication. More attention should be paid by policy makers to remove factors that hinder the nurse-patient communication process. PMID- 21554290 TI - Nursing students' immunisation status and knowledge about viral hepatitis in Turkey: a multi-centre cross-sectional study. AB - BACKGROUND: The aims of this multi-centre cross-sectional survey were to detect Turkish nursing students' level of knowledge on viral hepatitis, to evaluate their rates of exposure to blood and to find out their hepatitis A (HAV), hepatitis B (HBV) vaccination status. METHODS: This multi-centre cross-sectional study was conducted in 14 nursing schools located in the seven geographical regions of Turkey. A questionnaire composed of 47 questions on socio-demographic factors, level of knowledge on HAV, HBV, hepatitis C (HCV) immunisation status, exposure history and attitudes was applied to the study group. RESULTS: A total of 1491 third- and fourth-year nursing students participated with an 89% response rate. The mean age of the participating students was 21.4 +/- 1.3. Their mean knowledge score was 23.7 +/- 4.6 (71/100) and was significantly higher in fourth year students than third-year students. There were significant differences in mean scores among nursing schools. Among the participants, 85.3% had received HBV vaccine and 9.1% had received HAV vaccine. The percentage of students who signify themselves at increased risk of acquiring viral hepatitis was 97.3%. Of the students, 28.1% had sustained a needle-stick injury and 5.4% had experienced conjunctival exposure to blood. CONCLUSIONS: Curriculum differences among nursing schools have a significant effect on nursing students' level of knowledge. For this reason, nursing schools should organize HBV immunisation programmes for their students to increase vaccination coverage. PMID- 21554291 TI - Commentary: the importance of education and vaccination in reducing the risk of hepatitis infection among nursing students. AB - BACKGROUND: Healthcare workers are at risk of contracting blood-borne viral infection during contact with blood and body fluids. Nursing students may be at particular risk because of their inexperience. Adoption of suitable precautions, hepatitis B vaccination and appropriate post-exposure prophylaxis will significantly reduce the risk of infection. AIM: This commentary puts into context the findings of a study by Yamazhan et al. who explored nursing students' knowledge on hepatitis together with their immunization status. EVALUATION: Knowledge of hepatitis, its mode of transmission and the risks of infection following adverse exposure to blood and body fluids are essential to ensure safe practice. This paper identifies that nursing students' knowledge of hepatitis is moderate only and varies between universities. However, the uptake of hepatitis B vaccination among the sample was high, suggesting a high commitment to reducing the risk of this infection by the universities and clinical placements. IMPLICATIONS: This paper highlights the need for a standardized education package to be developed and delivered by all universities in Turkey to ensure that nursing students have a sound knowledge of hepatitis and other blood-borne infections. Vaccination programmes must continue to ensure that nursing students are protected from hepatitis B. PMID- 21554292 TI - Intercultural education of nurses and health professionals in Europe (IENE). AB - AIMS: The study aimed to explore the perceived learning and teaching needs of students and practitioners of health-care professions in relation to preparation for working in another European country and/or in a multicultural environment. The participating countries were: Belgium, Bulgaria, Germany, Romania and the UK. METHODS: Questionnaires, consisting of open questions, were completed by a total of 118 participants. Data analysis adopted both a priori and inductive approaches. The predetermined constructs of cultural awareness, cultural knowledge, cultural sensitivity and cultural competence were used to structure suggestions for theoretical input and practical activities and experiences. Inductive analysis revealed other emergent themes that underpin all four of these constructs. RESULTS: Practical experiences form a fundamental part of preparation for labour mobility and/or for practice within a multicultural environment. However, health-care practitioners need to be adequately prepared for such experiences and value the opportunity to learn about culture, to explore values and beliefs, and to practise intercultural skills within the safe environment of an educational establishment, facilitated by skilled teachers. PMID- 21554293 TI - A framework to develop a clinical learning culture in health facilities: ideas from the literature. AB - BACKGROUND: Internationally, there is an increase in demand to educate nurses within the clinical practice environment. Clinical practice settings that encourage teaching and learning during episodes of care delivery can be powerful in educating both the existing nursing workforce and nursing students. AIM: This paper presents a framework, informed by the literature, that identifies the key factors that are needed to encourage the interactions fundamental to learning in clinical practice. KEY CONCEPTS: Learning occurs when nurses demonstrate good practice, share their knowledge through conversations and discussions, and also provide feedback to learners, such as students and novices. These types of interactions occur when positive leadership practices encourage trust and openness between staff; when the management team provides sessions for staff to learn how to interact with learners, and also when partnerships provide support and guidance around learning in the workplace. APPLICATION OF CONCEPTS: This framework presents how the concepts of leadership, management and partnership interact to create and sustain learning environments. The feedback from proposed measurement tools can provide valuable information about the positive and negative aspects of these concepts in the clinical learning environment. Analysis of the subscales can assist in identifying appropriate recommended strategies outlined in the framework to guide nurses in improving the recognized deficits in the relationship between the concepts. CONCLUSION: Leadership, management and partnerships are pivotal for the creation and maintenance of positive learning environments. Diagnostic measurement tools can provide specific information about weaknesses across these areas. This knowledge can guide future initiatives. PMID- 21554294 TI - The effect of a peer-mentoring strategy on student nurse stress reduction in clinical practice. AB - BACKGROUND: That nursing students suffer high levels of stress during clinical practice is a common topic in nursing education, but there are some effective strategies for dealing with it. PURPOSE: The purpose of this study is to examine the effects that a peer mentoring program has on student nurses' stress levels during clinical practice. METHODS: A quasi-experimental design was conducted. Forty-nine junior level nursing students (n = 17 in the experimental group; n = 32 in the control group) were enrolled in the same medical-surgical nursing class. Mentors were recruited from students who had received medical-surgical experience before entering university. A 6-point perceived Stress Scale for the nursing students' questionnaire was used to evaluate the stress level. RESULTS: Stress from 'lack of professional knowledge and skills' was the highest score before clinical practice in the experimental (3.78) and control (3.57) group, and also was the highest score after clinical practice in the control group (3.44). Stress from 'assignments and workload' was the highest score after clinical practice in experimental group (3.25). Wilcoxon matched paired signed ranks test revealed that there are no significant differences in stress scores between the two groups. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Study findings reveal that there are various advantages and disadvantages to implementing peer mentoring programs. The clinical teacher needs to provide suitable support and encouragement to the mentor and mentee students during this program. These results might provide information that can be used in improving clinical internship experience for the students. PMID- 21554295 TI - Perceptions of nursing students' parents regarding the profession and their college. AB - BACKGROUND: To ensure client satisfaction, it is important for all educational institutions to identify the characteristics of their clients and to consider their expectations and demands through quality studies. AIM: The study aims to identify the perceptions of parents of nursing students regarding the nursing profession and the related educational institution. METHODS: The parents of all students attending the nursing school of a public Turkish university were included in the study. Following permission from the university management, questionnaires developed by the researchers in light of the related literature were sent to 474 parents via mail, and 133 completed questionnaires (28% response rate) were analysed statistically. FINDINGS: Mothers of nursing students were mostly <=45 years of age, primary school graduates and housewives, while fathers were >=46 years of age, at least secondary school graduates, old-age pensioners or had an independent business. In general, the responding fathers and mothers preferred not to get involved in their children's choice of profession, perceiving nursing as a helpful and sacred profession. Therefore, they also recommended nursing to others and had no problems with the idea of male nurses. CONCLUSION: Study findings demonstrated that the parents had positive attitudes towards the nursing profession and were satisfied with the nursing college. PMID- 21554296 TI - 21st century nursing practice in Ghana: challenges and opportunities. AB - AIM: This article is intended to stimulate critical thinking and generate fruitful discussion on nursing practice in Ghana as experienced by the authors. Its rationale is to promote exchange of ideas and creative partnerships to ensure that right decisions are made in preparing competent, adaptable and resourceful nurses who can contribute to health for all in the 21st century. THE PROBLEM: The challenges of nursing education, practice and migration in Ghana seem grim. There is inadequate capacity of training institutions, low staff morale, poor distribution and serious workforce shortages. METHODS: Government reports and policy documents on nursing were sourced from official websites and reviewed and discussed in the context of the international scholarly published literature. OPPORTUNITIES: The authors note that despite the severe crises, a number of opportunities such as improved home-based training, international nursing education partnerships and welfare and human resource development could foster effective nurse retention and managed migration. CONCLUSIONS: To address the issues with nursing health service delivery and nursing shortages in Ghana requires all stakeholders to move beyond the traditional stereotypes and be flexible and forward-looking. Needed policy options include expansion of local nursing education and training capacity, collaborative training opportunities, improving the welfare and retention rates of current staff and international exchange of nurse resources that is mutually beneficial to both source and sink countries. PMID- 21554297 TI - New Zealand general practice nurses' roles in mental health care. AB - AIM: To examine the roles of nurses in general practice interdisciplinary teams caring for people with mild to moderate mental health conditions. BACKGROUND: Supporting mental health and well-being is an important aspect of primary care. Until now nurses in general practice settings have had variable roles in providing mental health care. The New Zealand Primary Mental Health Initiatives are 26 government-funded, time-limited projects using different service delivery models. METHODS: An analysis was undertaken of a qualitative data set of interviews, which included commentary about nurses mental health work collected from the different project stakeholders throughout a 29-month external evaluation. FINDINGS: Two main groups of roles for nurses within the general practice interdisciplinary team were identified: specialist mental health nurses working in newly created roles and practice nurses working in existing roles. Barriers exist to the development of the latter roles. CONCLUSIONS: Mental health care is a key role in general practice as this is where people frequently present. Internationally, nurses represent a large workforce with the potential to provide effective mental health care. This study found that attitudinal, structural and professional barriers are restricting New Zealand practice nurse role development in the care of those with mild to moderate mental health conditions. There is potential to develop their role within a structured pathway by workforce development and recognition of the value of interdisciplinary care. Given the shortage of mental health professionals this will be an important aspect of the improvement of primary mental health care. PMID- 21554298 TI - Nursing personnel's perceptions of the organizational climate in public and private hospitals in Spain. AB - BACKGROUND: Organizational climate is considered one of the most significant determinants of individual and group behaviour in institutions. The International Council of Nurses has launched a campaign to improve professional recognition, support for personal development, safety and health at work. AIM: To analyse nursing personnel's organizational climate perceptions using the Work Environment Scale (WES) in two categories of hospitals. METHODS: A cross-sectional survey was undertaken in public and private hospitals. Two sampling approaches were used. At the Public Hospital, the sample was randomly selected (n = 297, 168 nurses and 129 other nursing personnel). At the Private Hospitals, a convenience sampling method was used (n = 66, 14 nurses and 52 other nursing personnel). The study used descriptive and inferential statistic analyses to explain the nursing personnel perception of organizational climate and to explore variations between nurses and other nursing personnel in both categories of hospitals. RESULTS: Sixty per cent and seventy per cent of WES subscales yielded scores below the midpoint for the perception of work environment in public and private hospitals, respectively. Mean scores for both categories were similar, except for the subscales of Pressure and Control that were higher in Private Hospitals. In the Public Hospital, nurses scored significantly lower than other nursing personnel in Involvement, Innovation and Comfort. CONCLUSIONS: Based on these findings, it is suggested that nurse managers should introduce strategies to set conditions for a better work environment in public and private hospitals. PMID- 21554299 TI - Conflict management in public hospitals: the Cyprus case. AB - BACKGROUND: Conflict among health-care personnel has been identified as an issue within health-care settings around the world. AIM: To investigate the existence and management of conflict among health-care personnel in public hospitals in Cyprus; to assess the factors leading to conflict among staff members; to evaluate the consequences of conflict arising; and to consider the management strategies. METHODS: A self-administered questionnaire was completed by a random sample of 1037 health-care professionals in all (seven) state-run hospitals in Cyprus in 2008. RESULTS: Mean age of respondents was 41 years, and 75% were female. Sixty-four per cent of respondents reported that they had never been informed about conflict management strategies, with physicians being the least informed as the relative percentage was 79.8% (chi(2) = 33, P < 0.001). Sixty per cent of health-care professionals reported conflict at work with other health care personnel one to five times per week, and 37% of the respondents stated that they devote 90 min (mean value) from work during their shift in conflict resolution, meaning that managing conflicts may absorb 19% of working time daily. The majority of respondents agreed that organizational problems and communication gaps were the main issues creating conflict. Avoidance and collaboration were the preferable strategies for conflict resolution, used by 36.6% and 37.5% of the respondents, respectively. CONCLUSION: Better communication, fair management practices and clear job descriptions and expectations may be needed in order to facilitate change and reverse the negative atmosphere that exists. Further education in conflict management for physicians, nurses and their managers may also be needed. PMID- 21554300 TI - The relationship between management safety commitment and patient safety culture. AB - AIM: The study aims to explore the relationship between management safety commitment and patient safety culture using data from a Chinese hospital. BACKGROUND: Developing a positive patient safety culture has been suggested as an important strategy to improve the quality of health services and patient safety. Management safety commitment has been identified as key to establishing a culture of safety. However, little empirical evidence could be found in the literature to substantiate the relationship between management safety commitment and patient safety culture. Even less is known about the relationship in a Chinese hospital setting. METHODS: The study used a correlational research methodology with a cross-sectional survey design. A total of 248 registered nurses, including 20 nurse managers and 228 staff nurses, were surveyed using self-administered questionnaires. Both descriptive and inferential statistics were used to explore the relationship between management safety commitment and patient safety culture. FINDINGS: The mean score of safety commitment was 8.38 on a 0-10 visual analogue scale. The mean score of patient safety culture was 148.66. Staff nurses scored patient safety culture significantly lower than those of nurse managers (F = 18.88, P < 0.01). In addition, management safety commitment was significantly related to patient safety culture (r = 0.46, P < 0.01) and was an important predictor of patient safety culture (F = 65.29, P < 0.01). CONCLUSIONS: The findings provide significant empirical evidence that management safety commitment is associated with the culture of patient safety. Thus, to build a positive safety culture, managers need to visibly commit to patient safety and be a role model to ensure patient safety. PMID- 21554301 TI - Hospital nurses' work environment, quality of care provided and career plans. AB - BACKGROUND: In several European countries, the availability of qualified nurses is insufficient to meet current healthcare requirements. Nurses are highly dissatisfied with the rising demands of the healthcare environment and increasingly considering leaving their jobs. AIM: The study aims to investigate the relationships between the characteristics of hospital nurses' work environment and the quality of care provided, and furthermore to examine Dutch nurses' career plans. METHODS: A cross-sectional, questionnaire survey of registered nurses (n = 334) working in the academic and district hospitals was conducted in 2005/2006. Previously validated questionnaires translated into the participants' language were used. Factor and regression analysis were used for data analysis. RESULTS: Overall, nurses rated their work environment rather favourably. Five work environment characteristics were identified: support for professional development, adequate staffing, nursing competence, supportive management and teamwork. Significant relationships were found between nurses' perceptions of their work environment characteristics and quality of care provided and nurses' career plans. When work environment characteristics were evaluated to be better, nurse-assessed quality of care also increased and intentions to leave current job decreased linearly. CONCLUSIONS: Study findings suggest that nurses' perceptions of their work environment are important for nurse outcomes in hospital settings. Further research is needed to explore the predictive ability of the work environment for nurse, patient and organizational outcomes in hospitals. PMID- 21554302 TI - Internal and external environmental factors affecting the performance of hospital based home nursing care. AB - BACKGROUND: Numerous studies on HNC services have been carried out by signifying their needs, efficiency and effectiveness. However, no study has ever been performed to determine the critical factors associated with HNC's positive results despite the deluge of positive studies on the service. METHODS: This study included all of the 89 training hospitals that were practising HNC service in Korea as of November 2006. The input factors affecting the performance were classified as either internal or external environmental factors. This analysis was conducted to understand the impact that the corresponding factors had on performance. Data were analysed by using multiple linear regressions. RESULTS: The internal and external environment variables affected the performance of HNC based on univariate analysis. The meaningful variables were internal environmental factors. Specifically, managerial resource (the number of operating beds and the outpatient/inpatient ratio) were meaningful when the multiple linear regression analysis was performed. Indeed, the importance of organizational culture (the passion of HNC nurses) was significant. CONCLUSION: This study, considering the limited market size of Korea, illustrates that the critical factor for the development of hospital-led HNC lies with internal environmental factors rather than external ones. Among the internal environmental factors, the hospitals' managerial resource-related factors (specifically, the passion of nurses) were the most important contributing element. PMID- 21554303 TI - Making it real: a hands-on approach to teaching research. AB - AIM: The purpose of this paper was to report on the delivery of a series of seminars in Sarawak, East Malaysia using a unique hands-on approach to the teaching of skills in research and evidence-based health care. These seminars proved to be a meaningful and memorable experience for both the facilitators and participants. BACKGROUND: The international push for the delivery of evidence based health care has resulted in a growing need for the teaching of skills in the conduct and application of research. Nurses and other health-care professionals recognize that they have a responsibility to contribute to and maintain an evidence base for practice, yet are often stymied by a lack of professional development opportunities. CONCLUSION: The knowledge necessary to understand research, along with skills in the conduct of research, can be made accessible to health-care professionals in diverse locations. The experience reported in this paper demonstrates that opportunities exist to provide education about research and evidence-based practice in an engaging, active and meaningful way. PMID- 21554304 TI - Practitioner review: clinical applications of attachment theory and research for infants and young children. PMID- 21554305 TI - Treated prevalence of and mental health services received by children and adolescents in 42 low-and-middle-income countries. AB - BACKGROUND: Little is known about the treated prevalence and services received by children and adolescents in low- and middle-income countries (LAMICs). The purpose of this study is to describe the characteristics and capacity of mental health services for children and adolescents in 42 LAMICs. METHODS: The World Health Organization Assessment Instrument for Mental Health Systems (WHO-AIMS), a 155-indicator instrument developed to assess key components of mental health service systems, was used to describe mental health services in 13 low, 24 lower middle, and 5 upper-middle-income countries. Child and adolescent service indicators used in the analysis were drawn from Domains 2 (mental health services), 4 (human resources), and 5 (links with other sectors) of the WHO-AIMS instrument. RESULTS: The median one-year treated prevalence for children and adolescents is 159 per 100,000 population compared to a treated prevalence of 664 per 100,000 for the adult population. Children and adolescents make up 12% of the patient population in mental health outpatient facilities and less than 6% in all other types of mental health facilities. Less than 1% of beds in inpatient facilities are reserved for children and adolescents. Training provided for mental health professionals on child and adolescent mental health is minimal, with less than 1% receiving refresher training. Most countries (76%) organize educational campaigns on child and adolescent mental health. CONCLUSIONS: Mental health services for children and adolescents in low- and middle-income countries are extremely scarce and greatly limit access to appropriate care. Scaling up of services resources will be necessary in order to meet the objectives of the WHO Mental Health Gap Action (mhGAP) program which identifies increased services for the treatment of child mental disorders as a priority. PMID- 21554306 TI - Field capability of dogs to locate individual human teeth. AB - Avulsed teeth can be difficult if not impossible to recover in the outdoor environment, yet are important for victim identification. This study assessed dog teams as a resource to locate human teeth in a field setting and related performance in training with field capability. Standardized, objective training data were recorded and analyzed followed by double-blind capability trials. In the double-blind trials, 10 teeth were placed in each of six (10 m(2)) plots. Search time per plot ranged from 27 to 50 min, and the proportion of teeth found by the teams varied between 0.20 and 0.79. Using 0.45 m as a distance criterion for a "find," the proportion of false positives ranged between 0.07 and 0.75. Results show that dog teams are capable of recovering individual human teeth in the field setting with high precision although capability varies. Training records support a team's expected field performance. Additional studies are needed. PMID- 21554307 TI - On using gait in forensic biometrics. AB - Given the continuing advances in gait biometrics, it appears prudent to investigate the translation of these techniques for forensic use. We address the question as to the confidence that might be given between any two such measurements. We use the locations of ankle, knee, and hip to derive a measure of the match between walking subjects in image sequences. The Instantaneous Posture Match algorithm, using Harr templates, kinematics, and anthropomorphic knowledge is used to determine their location. This is demonstrated using real CCTV recorded at Gatwick International Airport, laboratory images from the multiview CASIA-B data set, and an example of real scene of crime video. To access the measurement confidence, we study the mean intra- and inter-match scores as a function of database size. These measures converge to constant and separate values, indicating that the match measure derived from individual comparisons is considerably smaller than the average match measure from a population. PMID- 21554308 TI - Congenital tetragametic blood chimerism explains a case of questionable paternity. AB - Human chimerism is the presence of >= 2 cell populations in one person that contain genetic material from more than one zygote. Chimerism may be either acquired by transfusion or transplantation of donor cells, or congenital arising from embryo fusion or dizygotic twin-twin transfusion. We encountered a 4-year old boy with developmental hip dysplasia whose preoperative (serologic) blood group was AB, but whose red cell agglutination was atypical ("mixed field") and caused us to study the patient's parents' ABO blood groups. Parental blood groups (AB and O) suggested possible nonparentage. An alternative explanation of the findings was that the child was chimeric or mosaic. Molecular cloning and genotyping of his ABO locus in leukocytes revealed two heterozygous genotypes: A102/O01 and B101/O01. Other loci, each of which possessed three distinct alleles, unambiguously showed transmission of two alleles from either the child's mother (e.g., HLA-A) or two alleles from the child's father (e.g., D8S1179). Findings indicate that the child is a tetragametic chimera. PMID- 21554309 TI - The myth of virginity: the case of a Franco-Belgian serial killer. AB - This article provides an in-depth description of the case of Michel Fourniret (MF), a French serial killer who, with his wife Monique Olivier (MO), confessed to kidnapping, raping, and murdering at least nine girls during the 1980s and 1990s. Using information from writers, witnesses, trial experts, and regarding current forensic literature, we utilize this case to discuss sexual homicide from both the forensic and neuropsychiatric perspectives. Interview, psychometric, and forensic data from the trial were used to explain and shed light on MF's and MO's personalities and psychosexual proclivities. In the final section, we propose and discuss several theories and specific areas of potential exploration that, in light of the murder couple case story, may prove fruitful in the study of violent attachment and murder pacts. PMID- 21554310 TI - Suicide by gabapentin overdose. AB - Gabapentin is an antiepileptic drug that is prescribed for both FDA-approved and multiple off-label conditions, and has a relatively safe side-effect profile. Rare cases of overdose-related adverse effects have been reported in the literature. Described herein are the circumstances and autopsy findings of a 62 year-old woman with a history of depression, whose death was caused by intentional ingestion of excess gabapentin. The postmortem peripheral blood gabapentin concentration as determined by high-performance liquid chromatography/tandem mass spectroscopy was 88 MUg/mL. Previously reported cases of individuals surviving gabapentin overdoses are discussed and compared with this case. Based on a review of the available literature, this appears to be the first published report of a death due solely to gabapentin toxicity. PMID- 21554311 TI - Death related to aortic coarctation in a young female during sexual intercourse. AB - Coarctation of the aorta (CA) is diagnosed mainly in pediatric patients, and therapy is conservative if asymptomatic, but surgical treatment is required if advanced arterial hypertension is present. Moderate to severe forms contraindicate any type of physical activity requiring cardiac effort. Here, we describe the first documented death of an apparently healthy 35-year-old woman because of cardiac tamponade by rupture of an aortic aneurysm, possibly related to congenital CA, prolonged use of oxymetazoline hydrochloride, and physical and/or emotional stress during sexual activity. Our patient was asymptomatic for classical CA symptoms. The patient's breathing difficulties likely in hindsight were due not so much to nasal congestion, but rather to an ineffective oxygenation of the blood from the abnormal heart. In an attempt to treat the "nasal disease," the patient ingested chronic and excessive doses of decongestants, aggravating her fatal disease. The danger of inhaling large doses of nasal decongestants without an appropriate medical indication is highlighted here. PMID- 21554312 TI - Changes in the morphology and presumptive chemistry of impact and pooled bloodstain patterns by Lucilia sericata (Meigen) (Diptera: Calliphoridae). AB - Bloodstain pattern analysis can be critical to accurate crime scene reconstruction. However, bloodstain patterns can be altered in the presence of insects and can confound crime scene reconstruction. To address this problem, we conducted a series of controlled laboratory experiments to investigate the effect of Lucilia sericata (Meigen) on impact bloodstains and pooled bloodstains in association with three combinations of common surfaces (linoleum/painted drywall, wood floor/wallpaper, and carpet/wood paneling). L. sericata fed from the pooled bloodstains and added insect stains through regurgitation and defecation of consumed blood. L. sericata formed defecatory trails of insect stains that indicated directionality. Defecatory stains fluoresced when viewed at 465 nm with an orange filter. These observations differed from Calliphora vicina insect stains because feeding on blood spatter was not observed and trails of insect stains were formed by L. sericata. The fluorescence of defecatory stains can be used as a method to detect insect stains and discriminate them from real bloodstains. PMID- 21554313 TI - Does a draft really influence postmortem body cooling?. AB - Estimation of the time of death (TOD) is a very important task of forensic pathologist, and measurement of body temperature is a method deemed to be most precise during the initial postmortem period. The study aimed at verification of the significance of airflow present in the room where a corpse is found on body cooling process and hence on determination of the TOD. The experiment was performed in pigs during which the postmortem temperature of the eye, muscles, and rectum was recorded--in still air and with generated draft in the room. The results showed that the moderate airflow present in the experimental conditions did not significantly affect the course of cooling of the investigated body sites. Despite moderate wind generated in the room, the air movement close to pigs' bodies was actually minimal. This allowed to conclude that to evaluate the TOD most precisely, one should first have reliable data on the actual velocity of air in the direct vicinity of the body rather than relying on subjective sensation of the draft and using various unnecessary corrective coefficients for TOD calculation. PMID- 21554314 TI - Utilizing a magnetic locator to search for buried firearms and miscellaneous weapons at a controlled research site. AB - Forensic personnel generally use basic all-metal detectors for weapon searches because of their ease of use and cost efficiency. For ferromagnetic targets, an alternative easy to use and low-cost geophysical tool is a magnetic locator. The following study was designed to demonstrate the effectiveness of a common, commercially available magnetic locator in forensic weapon searches by determining the maximum depth of detection for 32 metallic forensic targets and testing the effects of metallic composition on detection. Maximum depth of detection was determined for 16 decommissioned street-level firearms, six pieces of assorted scrap metals, and 10 blunt or bladed weapons by burying each target at 5-cm intervals until the weapons were no longer detected. As expected, only ferromagnetic items were detected; weapons containing both ferromagnetic and nonferromagnetic components were generally detected to shallower depths. Overall, the magnetic locator can be a useful addition to weapon searches involving buried ferromagnetic weapons. PMID- 21554315 TI - A case of factitious pedophilia. AB - Factitious disorder involves feigning, exaggerating, or self-inducing physical and/or psychological ailments with the goal of assuming the "sick" or "patient" role. In turn, the sick role entitles the factitious disorder patient to care, nurturance, and protection; it also exempts one from usual responsibilities. In this paper, we present the first reported case of factitious pedophilia. Although it seems counterintuitive, this middle-aged man has falsely claimed or exaggerated sexual desire for minors ostensibly to remain in a state hospital; indeed, he has remained in the same inpatient facility for more than 20 years as a result of his deceptions. At times, his reports have included disconfirmed claims of bizarre accidents and other physical travails. This case enlarges the literature on factitious psychological disorders and shows that some individuals may falsify paraphilic behaviors, although clearly minimization of these behaviors remains more common. PMID- 21554318 TI - Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motoneuronal disease which occurs in sporadic or familial forms, clinically indistinguishable. About 15% of familial ALS cases are linked to mutations of the superoxide dismutase 1 (SOD1) gene that may induce misfolding in the coded protein, exerting neurotoxicity to motoneurons. However, other cell types might be target of SOD1 toxicity, because muscle-restricted expression of mutant SOD1 correlates with muscle atrophy and motoneurons death. We analysed the molecular behaviour of mutant SOD1 in motoneuronal NSC34 and muscle C2C12 cells. We found that misfolded mutant SOD1 clearance is much more efficient in muscle C2C12 than in motoneuronal NSC34 cells. Mutant SOD1 forms aggregates and impairs the proteasome only in motoneuronal NSC34 cells. Interestingly, NSC34 cells expressing mutant SOD1 are more sensitive to a superoxide-induced oxidative stress. Moreover, in muscle C2C12 cells mutant SOD1 remains soluble even when proteasome is inhibited with MG132. The higher mutant SOD1 clearance in muscle cells correlates with a more efficient proteasome activity, combined with a robust autophagy activation. Therefore, muscle cells seem to better manage misfolded SOD1 species, not because of an intrinsic property of the mutant protein, but in function of the cell environment, indicating also that the SOD1 toxicity at muscle level may not directly depend on its aggregation rate. PMID- 21554319 TI - beta-N-oxalyl-L-alpha,beta-diaminopropionic acid regulates mitogen-activated protein kinase signaling by down-regulation of phosphatidylethanolamine-binding protein 1. AB - beta-N-Oxalyl-L-alpha,beta-diaminopropionic acid (l-ODAP) an alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist activates protein kinase C in white leghorn chick brain. The current study focuses on the protein kinase C downstream signaling targets associated with L-ODAP excitotoxicity in SK-N-MC human neuroblastoma cells and white leghorn male chick (Gallus domesticus) brain extracts. L-ODAP treatment in SK-N-MC cells (1.5 mM) and chicks (0.5 mg/g body weight) results in a decreased expression and increased phosphorylation of phosphatidylehthanolamine-binding protein 1 (PEBP1) up to 4 h which however, returns to normal by 8 h. D-ODAP, the non-toxic enantiomer however, did not affect PEBP1 levels in either chick brain or SK-N-MC cells. Decreased PEBP1 expression correlated with subsequent activation of Raf-1, MEK and ERK signaling components of the mitogen-activated protein kinase cascade and nuclear translocation of hypoxia inducible factor-1alpha (HIF-1alpha) in chick brain nuclear extracts and SK-N-MC cells. SK-N-MC cells over-expressing PEBP1 inhibited nuclear translocation of HIF-1alpha when treated with l-ODAP, indicating that down-regulation of PEBP1 is responsible for HIF-1alpha stabilization and nuclear localization. Excitotoxicity of L-ODAP may thus be the result of phosphorylation and down-regulation of PEBP1, a crucial signaling protein regulating diverse signaling cascades. L-ODAP induced convulsions and seizures in chicks could be the result of a hypoxic insult to brain. PMID- 21554320 TI - rho1 GABAC receptors are expressed in fibrous and cartilaginous layers of chick sclera and located on sclera fibroblasts and chondrocytes. AB - rho(1) GABA(C) receptor antagonists inhibit myopia in chick but the site of this effect is not known. The sclera ultimately determines the shape and size of the globe and thus an untested possibility is that GABA agents have a scleral mechanism. Whether rho(1) GABA(C) receptors are expressed and located in chick sclera is unknown. Real-time PCR, western blot and immunohistochemistry were used to determine whether rho1 GABA(C) receptors are expressed and located in chick fibrous and cartilaginous sclera. Both layers of the chick sclera were positive for rho1 GABA(C) receptor mRNA (PCR) and protein (western blot) expression and labeling was observed in both fibroblasts and chondrocytes of the fibrous and cartilaginous layers (immunohistochemistry). These investigations clearly show that chick sclera possesses rho(1) GABA(C) receptors. The sclera is thus a potential previously unrecognized site for activity of rho(1) GABA(C) agents. PMID- 21554321 TI - Forced-exercise delays neuropathic pain in experimental diabetes: effects on voltage-activated calcium channels. AB - Physical exercise produces a variety of psychophysical effects, including altered pain perception. Elevated levels of centrally produced endorphins or endocannabinoids are implicated as mediators of exercise-induced analgesia. The effect of exercise on the development and persistence of disease-associated acute/chronic pain remains unclear. In this study, we quantified the physiological consequence of forced-exercise on the development of diabetes associated neuropathic pain. Euglycemic control or streptozotocin (STZ)-induced diabetic adult male rats were subdivided into sedentary or forced-exercised (2-10 weeks, treadmill) subgroups and assessed for changes in tactile responsiveness. Two weeks following STZ-treatment, sedentary rats developed a marked and sustained hypersensitivity to von Frey tactile stimulation. By comparison, STZ treated diabetic rats undergoing forced-exercise exhibited a 4-week delay in the onset of tactile hypersensitivity that was independent of glucose control. Exercise-facilitated analgesia in diabetic rats was reversed, in a dose-dependent manner, by naloxone. Small-diameter (< 30 MUm) DRG neurons harvested from STZ treated tactile hypersensitive diabetic rats exhibited an enhanced (2.5-fold) rightward (depolarizing) shift in peak high-voltage activated (HVA) Ca(2+) current density with a concomitant appearance of a low-voltage activated (LVA) Ca(2+) current component. LVA Ca(2+) currents present in DRG neurons from hypersensitive diabetic rats exhibited a marked depolarizing shift in steady state inactivation. Forced-exercise attenuated diabetes-associated changes in HVA Ca(2+) current density while preventing the depolarizing shift in steady-state inactivation of LVA Ca(2+) currents. Forced-exercise markedly delays the onset of diabetes-associated neuropathic pain, in part, by attenuating associated changes in HVA and LVA Ca(2+) channel function within small-diameter DRG neurons possibly by altering opioidergic tone. PMID- 21554322 TI - It is still not for the old iron: adjuvant effects of carbonyl iron in experimental autoimmune encephalomyelitis induction. AB - Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis. Dark Agouti rats immunized with spinal cord homogenate (SCH) and carbonyl iron (CI), as an adjuvant, develop severe hyperacute form of EAE. They succumb to EAE earlier and have higher clinical scores and lethality rate in comparison to counterparts immunized with SCH + complete Freund's adjuvant. There is no difference in the number of cells or in histological presentation of the CNS infiltrates of rats immunized with the two adjuvants. However, there are more granulocytes, NK and NKT cells, and less CD4(+) T cells in the spinal cord infiltrates of SCH + CI-immunized animals. Nitric oxide (NO)-generating enzyme inducible NO synthase have higher expression in spinal cord of SCH + CI-immunized rats, and this corresponds to more intensive nitrotyrosine formation in the CNS tissue of these rats. Abundant infiltration of granulocytes and NK cells into the CNS and excessive generation of peroxynitrite within the CNS of SCH + CI immunized rats might account for the severe neurological deficits induced by immunization with CI. These factors should be closely examined in the fulminant forms of multiple sclerosis and acute disseminated encephalomyelitis, as they could represent a promising targets for therapy. PMID- 21554323 TI - Neuroprotective effects of granulocyte-colony stimulating factor in a novel transgenic mouse model of SCA17. AB - Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited disorder characterized by degeneration of spinocerebellar tracts and selected brainstem neurons owing to the expansion of a CAG repeat of the human TATA binding protein (hTBP) gene. To gain insight into the pathogenesis of this hTBP mutation, we generated transgenic mice with the mutant hTBP gene driven by the Purkinje specific protein (Pcp2/L7) gene promoter. Mice with the expanded hTBP allele developed ataxia within 2-5 months. Behavioral analysis of L7-hTBP transgenic mice showed reduced fall latency in a rotarod assay. Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1. The L7-hTBP transgenic mice were thus confirmed to recapitulate the SCA17 phenotype and were used as a disease model to explore the potential of granulocyte-colony stimulating factor in SCA17 treatment. Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits. These data indicate that the expression of the mutant hTBP in Purkinje cells is sufficient to produce cell degeneration and an ataxia phenotype, and constitutes a good model for better analysis of the neurodegeneration in SCA17. PMID- 21554324 TI - Detection of N-acetyl methionine in human and murine brain and neuronal and glial derived cell lines. AB - Despite the fact that N-acetyl methionine (NAM) supplementation has long been reported as a bioavailable source of methionine in humans, and known to reduce liver toxicity after acetaminophen overdose, its cellular endogenous presence has never been investigated. We demonstrate for the first time that NAM is present in both human and mouse tissues and cells in culture. A wide variety of cultured cells, including a number of brain derived cell types, as well as mouse and human brain tissue all have clearly detectable levels of NAM. Methionine is rapidly acetylated to form NAM in cultured human oligodendroglioma cells with an initial rate of 0.44 +/- 0.064 atom percent excess per minute. The presence of measurable quantities of NAM in brain cells in combination with its rapid formation point to a potential physiological role for N-acetylated methionine in the brain. Aminoacylase 1 is responsible for metabolism of NAM to methionine and acetate. Deficiencies in aminoacylase 1 have been linked to a variety of neurological disorders; however, it is unclear whether and how the brain is affected by this defect. The reported presence of NAM in the human brain may provide an invaluable key to discovering the link between aminoacylase 1 mutations and neurological problems. PMID- 21554325 TI - Quantitative trait loci analysis reveals a correlation between the ratio of sucrose/raffinose family oligosaccharides and seed vigour in Medicago truncatula. AB - Seed vigour is important for successful establishment and high yield, especially under suboptimal environmental conditions. In legumes, raffinose oligosaccharide family (RFO) sugars have been proposed as an easily available energy reserve for seedling establishment. In this study, we investigated whether the composition or amount of soluble sugars (sucrose and RFO) is part of the genetic determinants of seed vigour of Medicago truncatula using two recombinant inbred line (RIL) populations. Quantitative trait loci (QTL) mapping for germination rate, hypocotyl and radicle growth under water deficit and nutritional stress, seed weight and soluble sugar content was performed using RIL populations LR1 and LR4. Seven of the 12 chromosomal regions containing QTL for germination rate or post germinative radicle growth under optimal or stress conditions co-located with Suc/RFO QTL. A significant negative correlation was also found between seed vigour traits and Suc/RFO. In addition, one QTL that explained 80% of the variation in the ratio stachyose/verbascose co-located with a stachyose synthase gene whose expression profile in the parental lines could explain the variation in oligosaccharide composition. The correlation and co-location of Suc/RFO ratio with germination and radicle growth QTL suggest that an increased Suc/RFO ratio in seeds of M. truncatula might negatively affect seed vigour. PMID- 21554326 TI - Comparative physiology and transcriptional networks underlying the heat shock response in Populus trichocarpa, Arabidopsis thaliana and Glycine max. AB - The heat shock response continues to be layered with additional complexity as interactions and crosstalk among heat shock proteins (HSPs), the reactive oxygen network and hormonal signalling are discovered. However, comparative analyses exploring variation in each of these processes among species remain relatively unexplored. In controlled environment experiments, photosynthetic response curves were conducted from 22 to 42 degrees C and indicated that temperature optimum of light-saturated photosynthesis was greater for Glycine max relative to Arabidopsis thaliana or Populus trichocarpa. Transcript profiles were taken at defined states along the temperature response curves, and inferred pathway analysis revealed species-specific variation in the abiotic stress and the minor carbohydrate raffinose/galactinol pathways. A weighted gene co-expression network approach was used to group individual genes into network modules linking biochemical measures of the antioxidant system to leaf-level photosynthesis among P. trichocarpa, G. max and A. thaliana. Network-enabled results revealed an expansion in the G. max HSP17 protein family and divergence in the regulation of the antioxidant and heat shock modules relative to P. trichocarpa and A. thaliana. These results indicate that although the heat shock response is highly conserved, there is considerable species-specific variation in its regulation. PMID- 21554327 TI - Revealing complexity and specificity in the activation of lipase-mediated oxylipin biosynthesis: a specific role of the Nicotiana attenuata GLA1 lipase in the activation of jasmonic acid biosynthesis in leaves and roots. AB - The activation of enzymatic oxylipin biosynthesis upon wounding, herbivory and pathogen attack depends on the biochemical activation of lipases that make polyunsaturated fatty acids (PUFAs) available to lipoxygenases (LOXs). The identity and number of the lipases involved in this process remain controversial and they probably differ among plant species. Analysis of transgenic Nicotiana attenuata plants (ir-gla1) stably reduced in the expression of the NaGLA1 gene showed that this plastidial glycerolipase is a major supplier of trienoic fatty acids for jasmonic acid (JA) biosynthesis in leaves and roots after wounding and simulated herbivory, but not during infection with the oomycete Phytophthora parasitica (var. nicotianae). NaGLA1 was not essential for the developmental control of JA biosynthesis in flowers and for the biosynthesis of C(6) volatiles by the hydroperoxide lyase (HPL) pathway; however, it affected the metabolism of divinyl ethers (DVEs) early during infection with P. parasitica (var. nicotianae) and the accumulation of NaDES1 and NaLOX1 mRNAs. Profiling of lysolipids by LC MS/MS was consistent with a rapid activation of NaGLA1 and indicated that this lipase utilizes different lipid classes as substrates. The results revealed the complexity and specificity of the regulation of lipase-mediated oxylipin biosynthesis, highlighting the existence of pathway- and stimulus-specific lipases. PMID- 21554328 TI - Oxidation-reduction signalling components in regulatory pathways of state transitions and photosystem stoichiometry adjustment in chloroplasts. AB - State transitions and photosystem stoichiometry adjustment are two oxidation reduction (redox)-regulated acclimatory responses in photosynthesis. State transitions are short-term adaptations that, in chloroplasts, involve reversible post-translational modification by phosphorylation of light-harvesting complex II (LHC II). Photosystem stoichiometry adjustments are long-term responses involving transcriptional regulation of reaction centre genes. Both responses are initiated by changes in light quality and are regulated by the redox state of plastoquinone (PQ). The LHC II kinase involved in the state 2 transition is a serine/threonine kinase known as STT7 in Chlamydomonas, and as STN7 in Arabidopsis. The phospho LHC II phosphatase that produces the state 1 transition is a PP2C-type protein phosphatase currently termed both TAP38 and PPH1. In plants and algae, photosystem stoichiometry adjustment is governed by a modified two-component sensor kinase of cyanobacterial origin - chloroplast sensor kinase (CSK). CSK is a sensor of the PQ redox state. Chloroplast sigma factor 1 (SIG1) and plastid transcription kinase (PTK) are the functional partners of CSK in chloroplast gene regulation. We suggest a signalling pathway for photosystem stoichiometry adjustment. The signalling pathways of state transitions and photosystem stoichiometry adjustments are proposed to be distinct, with the two pathways sensing PQ redox state independently of each other. PMID- 21554329 TI - Estimation of canopy average mesophyll conductance using delta(13) C of phloem contents. AB - Conductance to CO(2) inside leaves, known as mesophyll conductance (g(m)), imposes large limitations on photosynthesis. Because g(m) is difficult to quantify, it is often neglected in calculations of (13)C photosynthetic discrimination. The 'soluble sugar method' estimates g(m) via differences between observed photosynthetic discrimination, calculated from the delta(13)C of soluble sugars, and discrimination when g(m) is infinite. We expand upon this approach and calculate a photosynthesis-weighted average for canopy mesophyll conductance ((c) g(m)) using delta(13)C of stem phloem contents. We measured gas exchange at three canopy positions and collected stem phloem contents in mature trees of three conifer species (Pseudotsuga menziesii, Thuja plicata and Larix occidentalis). We generated species-specific and seasonally variable estimates of (c)g(m) . We found that (c)g(m) was significantly different among species (0.41, 0.22 and 0.09 mol m(-2) s(-1) for Larix, Pseudotsuga and Thuja, respectively), but was similar throughout the season. Ignoring respiratory and photorespiratory fractionations ((c)Delta(ef)) resulted in ~30% underestimation of (c)g(m) in Larix and Pseudotsuga, but was innocuous in Thuja. Substantial errors (~1-40/00) in photosynthetic discrimination calculations were introduced by neglecting (c)g(m) and (c)Delta(ef) . Our method is easy to apply and cost-effective, captures species variation and would have captured seasonal variation had it existed. The method provides an average canopy value, which makes it suitable for parameterization of canopy-scale models of photosynthesis, even in tall trees. PMID- 21554330 TI - Different serum cytokine levels in chronic vs. acute Anisakis simplex sensitization-associated urticaria. AB - The knowledge on immune mechanisms of chronic urticaria (CU) at the cytokine level is widely scarce. We compared pro- and anti-inflammatory as well as Th1- and Th2-associated serum cytokine levels in two phenotypes of CU: associated with (CU+) and without (CU-) sensitization against Anisakis simplex, a ubiquitous fish parasite, that has been associated with acute urticaria in gastro-allergic anisakiasis (GAA) and with CU+. Thirteen CU+ and 19 CU- patients were compared with 13 GAA patients and 15 control subjects for cytokines, measured by cytometric bead array. Urticaria activity score was positively correlated with IL 6 in CU-. Serum levels of IL-10 were lower in CU+ and CU- with respect to the control group. Median IFN-gamma was lower in all urticaria groups. Patients with previous parasitism by A. simplex displayed higher TGF-beta levels than subjects without previous parasitism. The main finding was lower levels of IL-17 in CU+ with respect to GAA or controls, with a further tendency to even lower levels in CU-. Different urticaria phenotypes are associated with distinct serum cytokine levels. PMID- 21554331 TI - Obesity surgery and the management of excess: exploring the body multiple. AB - Drawing on ethnographic data gathered through observations and interviews at a surgical weight management clinic in a large hospital, this article argues that while the core values governing the provision of obesity surgery (obesity = ill health; obesity surgery = weight loss; weight loss = improved health and cost savings) can be seen as governing the clinical encounter, the singularity of these collective equations reflects neither the complexity of the patient experience of obesity surgery nor the extent to which the 'war on obesity' itself does not adhere strictly to those principles. Drawing on Annemarie Mol's concept of the body multiple, and focusing on three different forms of excess (excess weight, excess consumption and excess skin) that emerged in the course of the study, this article argues that the rationalised singularity of obesity that is enacted in the obesity surgery clinic risks obscuring the uncertainties inherent to those practices and the moral judgements and values that are ultimately inextricable from them. PMID- 21554332 TI - The association between the SLC6A3 VNTR 9-repeat allele and alcoholism-a meta analysis. AB - BACKGROUND: Dopamine transporter gene (SLC6A3) represents a promising candidate involved in the development of alcoholism. This study aimed to explore the association between the 9-repeat allele (A9) of a 40-bp variable number tandem repeat (VNTR) polymorphism in the 3' un-translated region (3' UTR) of the SLC6A3 gene and alcoholism. METHODS: The SLC6A3 VNTR was genotyped by PCR in unrelated Mexican Americans including 337 controls and 365 alcoholics. Pearson's chi-square test or Fisher's exact test was used to compare the genotype and allele distribution. Meta-analyses were performed for population-based case-control association studies of the SLC6A3 VNTR polymorphism with alcoholism. Data were analyzed under random effect models with the Comprehensive Meta-analysis (v.2) statistical software package. RESULTS: In Mexican Americans, no significant difference was found in allele and genotype distribution between controls and alcoholics or between controls and alcoholics with alcohol withdrawal seizure (AWS) or delirium tremens (DT) (unadjusted p > 0.05). A total of 13 research articles were included in the meta-analyses. No significant difference of the SLC6A3 VNTR A9 was noted between controls and alcoholics at the genotypic and allelic level when all ethnic populations, only Caucasian populations, or only Asian populations were considered (p > 0.05). Significant associations were observed between SLC6A3 VNTR A9 and alcoholics with AWS or DT at the genotypic as well as allelic level when all ethnic populations or only Caucasian populations were considered (p < 0.05, OR 1.5-2.1). CONCLUSIONS: Meta-analyses suggest a possible association between the SLC6A3 VNTR A9 and alcoholic subgroup with AWS or DT. PMID- 21554333 TI - Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis. AB - BACKGROUND: Microphthalmia (reduced eye size), generally accompanied by vision defects, is a hallmark of fetal alcohol spectrum disorder (FASD) in humans. In zebrafish, embryonic ethanol exposure over the time of retinal neurogenesis also results in microphthalmia. This microphthalmia is in part the consequence of reduced retinal cell differentiation, including photoreceptors. Here we pursue 2 signaling pathways implicated in other aspects of FASD pathogenesis: retinoic acid (RA) and Sonic hedgehog (Shh). METHODS: We evaluated markers for RA and Shh signaling within the eyes of embryos treated with ethanol during the period of retinal neurogenesis. We also performed rescue experiments using administration of exogenous RA and microinjection of cholesterol, which augments Shh signaling. RESULTS: Using sequential or co-treatments, RA did not rescue ethanol-induced microphthalmia at any concentration tested. In addition, RA itself caused microphthalmia, although the underlying mechanisms were distinct from those of ethanol. Interestingly, RA treatment appeared to recover photoreceptor differentiation in a concentration-dependent manner. This may be an independent effect of exogenous RA, as ethanol treatment alone did not alter RA signaling in the eye. Cholesterol injection also did not rescue ethanol-induced microphthalmia at any concentration tested, and ethanol treatments did not alter expression of shh, or of ptc-2, which is normally regulated by Shh signaling. CONCLUSIONS: Together these findings indicate that, during the time of retinal neurogenesis, effects of ethanol on eye development are likely independent of the RA and Shh signaling pathways. These studies suggest that FASD intervention strategies based upon augmentation of RA or Shh signaling may not prevent ethanol-induced microphthalmia. PMID- 21554334 TI - Association of moderate alcohol use and binge drinking during pregnancy with neonatal health. AB - BACKGROUND: Heavy drinking and smoking during pregnancy are known to have a negative impact on the unborn child. However, the impact of low-to-moderate alcohol consumption and binge drinking has been debated recently. The aim of this study was to examine the relationship of moderate prenatal drinking and binge drinking with birthweight, being small for gestational age (SGA) at birth, preterm birth, and neonatal asphyxia. METHODS: Moderate alcohol drinking, binge drinking, and several possible confounders were assessed in 1,258 pregnant women; information on neonatal health was obtained at birth. RESULTS: Results indicate that 30.8% of the women drank at low levels (<2 glasses/wk), 7.9% drank moderately (2 to 4 glasses/wk), and 0.9% showed higher levels of drinking (5 glasses/wk); 4.7% reported binge drinking (defined as 3 glasses/occasion). 6.4% of the children were SGA (<10th percentile of birthweight adjusted for gestational age), 4.6% were preterm (<37th week of gestation), and 13.0% showed asphyxia (arterial cord pH <7.10 and/or arterial cord lactate >6.35 mmol and/or Apgar score <7 at 5 minutes). When controlling for maternal age, citizenship, occupational status, parity, smoking, use of prescription/over-the-counter drugs, illicit drug use, and child gender moderate drinking was related to lower birthweight (p < 0.01), and moderate drinking and binge drinking were associated with neonatal asphyxia at trend level (p = 0.06 and p = 0.09). Moderate drinking and binge drinking were not related to length of gestation. CONCLUSIONS: In contrast to recent reviews in the field, our results assume that moderate drinking and binge drinking are risk factors for neonatal health. PMID- 21554335 TI - Artificial sweeteners, caffeine, and alcohol intoxication in bar patrons. AB - BACKGROUND: Previous laboratory research on alcohol absorption has found that substitution of artificially sweetened alcohol mixers for sucrose-based mixers has a marked effect on the rate of gastric emptying, resulting in elevated blood alcohol concentrations. Studies conducted in natural drinking settings, such as bars, have indicated that caffeine ingestion while drinking is associated with higher levels of intoxication. To our knowledge, research has not examined the effects of alcohol mixers that contain both an artificial sweetener and caffeine, that is, diet cola. Therefore, we assessed the event-specific association between diet cola consumption and alcohol intoxication in bar patrons. We sought to determine whether putative increases in blood alcohol, produced by accelerated gastric emptying following diet cola consumption, as identified in the laboratory, also appear in a natural setting associated with impaired driving. METHODS: We conducted a secondary analysis of data from 2 nighttime field studies that collected anonymous information from 413 randomly selected bar patrons in 2008 and 2010. Data sets were merged and recoded to distinguish between energy drink, regular cola, diet cola, and noncaffeinated alcohol mixers. RESULTS: Caffeinated alcohol mixers were consumed by 33.9% of the patrons. Cola caffeinated mixed drinks were much more popular than those mixed with energy drinks. A large majority of regular cola-caffeinated mixed drink consumers were men (75%), whereas diet cola-caffeinated mixed drink consumers were more likely to be women (57%). After adjusting for the number of drinks consumed and other potential confounders, number of diet cola mixed drinks had a significant association with patron intoxication (beta = 0.233, p < 0.0001). Number of drinks mixed with regular (sucrose-sweetened) cola and energy drinks did not have significant associations with intoxication (p > 0.05). CONCLUSIONS: Caffeine's effect on intoxication may be most pronounced when mixers are artificially sweetened, that is, lack sucrose which slows the rate of gastric emptying of alcohol. Risks associated with on-premise drinking may be reduced by greater attention given to types of mixers, particularly diet colas. PMID- 21554336 TI - Response to Bell, et al. [The remarkably high prevalence of epilepsy and seizure history in fetal alcohol spectrum disorders. Alcohol Clin Exp Res 34:1084-1089.]. PMID- 21554337 TI - In remembrance: G. Alan Marlatt. PMID- 21554338 TI - Commentary: will analyzing the epigenome yield cohesive principles of ethanol teratology? AB - This commentary discusses the impact of the manuscript by Zhou et al., titled "Alcohol Alters DNA Methylation Patterns and Inhibits Neural Stem Cell Differentiation," published in the April 2011 issue of Alcoholism: Clinical and Experimental Research (volume 35, issue 4, pages 1-12). In this manuscript, the authors present intriguing evidence from a genome scale analysis of promoter DNA methylation patterns in a class of neural crest stem cells associated with dorsal root ganglia, showing that ethanol essentially prevents epigenetic programming associated with neural stem cell differentiation. This manuscript presents several interesting and novel pieces of data and raises important questions for future research. The implications of these data for our understanding of the etiology of fetal alcohol spectrum disorders are discussed. PMID- 21554339 TI - Potential application of the nisin Z preparation of Lactococcus lactis W8 in preservation of milk. AB - AIMS: The aim of the study is to evaluate the effectiveness of the preparation of nisin Z from Lactococcus lactis W8-fermented milk in controlling the growth of spoilage bacteria in pasteurized milk. METHODS AND RESULTS: Spoilage bacteria isolated from pasteurized milk at 8 and 15 degrees C were identified as Enterococcus italicus, Enterococcus mundtii, Enterococcus faecalis, Bacillus thuringiensis, Bacillus cereus, Lactobacillus paracasei, Acinetobacter sp., Pseudomonas fluorescens and Enterobacter aerogenes. These bacteria were found to have the ability to survive pasteurization temperature. Except Enterobacter aerogenes, the spoilage bacteria were sensitive to the nisin Z preparation of the L. lactis W8. Addition of the nisin Z preparation to either the skim milk or fat milk inoculated with each of the spoilage bacteria reduced the initial counts (about 5 log CFU ml-1) to an undetectable level within 8-20 h. The nisin Z preparation extended the shelf life of milk to 2 months under refrigeration. CONCLUSIONS: The nisin Z preparation from L. lactis W8-fermented milk was found to be effective as a backup preservative to counteract postpasteurization contamination in milk. SIGNIFICANCE AND IMPACT OF THE STUDY: A rapid inhibition of spoilage bacteria in pasteurized skim and fat milk with the nisin Z preparation of L. lactis W8 is more significant in comparison with the commercially available nisin (nisin A). The nisin Z preparation can be used instead of commercial nisin, which is not effective in fat milk. PMID- 21554340 TI - Characterization and comparison of microbial community of different typical Chinese liquor Daqus by PCR-DGGE. AB - AIMS: To identify and compare microbiota in Chinese liquor Daqu, which were produced in the different regions using different production process. METHODS AND RESULTS: The DNA exacted from Daqu samples was used as a template for PCR with universal primers of 16S rRNA, 26S rRNA and 18S rRNA, respectively. The amplicons were analysed using denaturing gradient gel electrophoresis (DGGE). It was observed that the bacterial DGGE profile indicated high diversity and predominance of lactic acid bacteria. The results showed that Saccharomycopsis fibuligera and Pichia anomal were dominant yeast species and that several non Saccharomyces yeasts including Hanseniaspora guilliermondii, Debaryomyces hansenii, Issatchenkia orientalis and Trichosporon asahii were also detected. As for fungal DGGE, Aspergillus oryzae and Absidia blakesleeana were the most common species amongst different samples. Based on the DGGE analysis, a few differences in community structure were found between Daqu samples. CONCLUSIONS: A variety of bacteria, yeast and moulds were identified in Daqu samples, in addition to the present knowledge obtained mainly through the traditional culture-dependent methods. Moreover, production temperature played a more decisive role on the formation of micro-organism composition in Daqu than geographical region. SIGNIFICANCE AND IMPACT OF THE STUDY: PCR-DGGE technique was used in this study to fully observe and asses all microbial community (including bacteria, yeast and mould) in Chinese liquor Daqu for the first time and proved to be effective in profiling Daqu microbial diversity. PMID- 21554341 TI - Demonstration of viable but nonculturable Vibrio cholerae O1 in fresh water environment of India using ciprofloxacin DFA-DVC method. AB - AIM: To demonstrate the presence of culturable and nonculturable viable pathogenic Vibrio cholerae O1 in fresh water environments of a cholera-endemic region in India. METHODS AND RESULTS: Conventional culture and ciprofloxacin DFA DVC were utilized to investigate the existence of V. cholerae O1. We isolated pathogenic culturable V. cholerae O1 from water samples collected from cholera affected areas. No culturable V. cholerae O1 was isolated from water and plankton samples from natural fresh water bodies. Ciprofloxacin was used for DFA-DVC as V. cholerae O1 are 100% resistant to nalidixic acid in our region. The viable but nonculturable O1 cells were demonstrated in 2.21 and 40.69% samples from natural water bodies and cholera-affected areas, respectively. CONCLUSION: Vibrio cholerae O1 VBNC could be demonstrated using modified DFA-DVC technique. Ciprofloxacin is preferable to nalidixic acid for DVC in view of existing high level resistance to nalidixic acid in cholera-endemic areas. SIGNIFICANCE AND IMPACT OF THE STUDY: We endorse that for public health surveillance, cholera outbreak investigation and disease control water samples in addition to culture should be tested for V. cholerae using DFA-DVC. PMID- 21554342 TI - Xylitol production from a mutant strain of Candida tropicalis. AB - AIMS: To characterize the kinetics of growth, sugar uptake and xylitol production in batch and fed-batch cultures for a xylitol assimilation-deficient strain of Candida tropicalis isolated via chemical mutagenesis. METHODS AND RESULTS: Chemical mutagenesis using nitrosoguanidine led to the isolation of the xylitol assimilation deficient strain C. tropicalis SS2. Shake-flask fermentations with this mutant showed a sixfold higher xylitol yield than the parent strain in medium containing 25 g l-1 glucose and 25 g l-1 xylose. With 20 g l-1 glycerol, replacing glucose for cell growth, and various concentrations of xylose, the studies indicated that the mutant strain resulted in xylitol yields from xylose close to theoretical. Under fully aerobic conditions, fed-batch fermentation with repeated addition of glycerol and xylose resulted in 3.3 g l-1 h-1 xylitol volumetric productivity with the final concentration of 220 g l-1 and overall yield of 0.93 g g-1 xylitol. CONCLUSIONS: The xylitol assimilation-deficient mutant isolated in this study showed the potential for high xylitol yield and volumetric productivity under aerobic conditions. In the evaluation of glycerol as an alternative low-cost nonfermentable carbon source, high biomass and xylitol yields under aerobic conditions were achieved; however, the increase in initial xylose concentrations resulted in a reduction in biomass yield based on glycerol consumption. This may be a consequence of the role of an active transport system in the yeast requiring increasing energy for xylose uptake and possible xylitol secretion, with little or no energy available from xylose metabolism. SIGNIFICANCE AND IMPACT OF THE STUDY: The study confirms the advantage of using a xylitol assimilation-deficient yeast under aerobic conditions for xylitol production with glycerol as a primary carbon source. It illustrates the potential of using the xylose stream in a biomass-based bio-refinery for the production of xylitol with further cost reductions resulting from using glycerol for yeast growth and energy production. PMID- 21554343 TI - Lactobacillus pentosus strain b240 suppresses pneumonia induced by Streptococcus pneumoniae in mice. AB - AIMS: Oral administration of probiotics has been known to improve inflammatory responses against infectious diseases. Here, we describe the inhibitory effect of oral intake of heat-killed Lactobacillus pentosus strain b240 (b240) on pneumococcal pneumonia in a murine experimental model. METHOD AND RESULTS: The mice treated with oral b240 for 21 days before Streptococcus pneumoniae infection exhibited prolonged survival time and less body weight loss, compared with saline treated control mice. Mild pneumonia with significantly reduced secretion of inflammatory cytokines/chemokines according to related mitogen-activated protein kinase signalling molecules (phosphorylated c-Jun N-terminal kinase) was found in b240-treated mice, whereas severe pneumonia with hypercytokinemia was evident in control mice. Prominent reduction in the number of pneumococci and elevated expression of Toll-like receptor 2 and 4 in the lung tissues was concomitantly noted in b240-treated mice. CONCLUSIONS: These findings indicate that b240 has inhibitory effects on pneumococcal pneumonia induced by Strep. pneumoniae infection and improves inflammatory tissue responses, resulting in reduced damages to the respiratory tissues. SIGNIFICANCE AND IMPACT OF THE STUDY: These results demonstrate that oral administration of b240 might protect host animals from Strep. pneumoniae infection by augmentation of innate immune response. PMID- 21554344 TI - Evaluation of the selective and differential ET medium for detection of Edwardsiella tarda in aquaculture systems. AB - AIMS: Edwardsiella tarda is an important pathogen in aquaculture where it can cause serious losses. A rapid detection of it is vital to minimize the mortalities caused by this disease, and in this work, the effectiveness of the selective differential Edw. tarda medium (ET) was evaluated for the diagnosis of edwardsiellosis as well as for its possible use in epidemiological studies. METHODS AND RESULTS: ET medium was evaluated in parallel with the commercial Salmonella-Shigella agar (SS), which is usually employed for the selective isolation of enteric bacilli. Moreover, two general media (TSA-1 and MA) were employed as a control. The results obtained showed that ET is distinctly selective for the isolation of Edw. tarda, allowing its recovery from mixed cultures and natural samples as a unique species. In contrast, although colonies of Edw. tarda could be clearly distinguishable in SS because of the appearance of a characteristic black centre, other enteric and nonenteric bacterial species were also able to grow on this medium. CONCLUSIONS: We recommend ET agar as an useful medium for the primary isolation of Edw. tarda from aquaculture samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The results obtained support ET medium as the most appropriate to develop epidemiological studies of edwardsiellosis in aquaculture and permits an earlier diagnosis of this important disease. PMID- 21554345 TI - Population structure in Indian sheep ascertained using microsatellite information. AB - This study attempts to provide a comprehensive insight into the prevailing genetic status of Indian sheep breeds using microsatellite markers. Seventeen Indian sheep breeds from 3 agroecological zones were analysed using a panel of 25 microsatellite markers. All of the sheep breeds investigated were genetically diverse, as evident from the high allele (>6) and gene (>0.6) diversity values. The gene diversity values for all breeds ranged from 0.621 to 0.780. The within population heterozygote deficit (F(IS)) varied from -0.098 to 0.234, reflecting significant levels for 12 of the 17 breeds investigated. The average genetic differentiation between all breeds (F(ST)) was 11.1%, revealing moderate discrimination between the indigenous sheep breeds. The genetic distance and principal component analysis revealed a separation of sheep breeds based on geographical propinquity. The Bayesian clustering approach suggested poor breed differentiation in the north-western arid and semi-arid region when compared to the breeds from the eastern and southern peninsular regions. The observed results mirror the divergent management strategies in the different agroecological regions, lack of specific selection policies, and intermixing of breeds in close proximity. Immediate steps to curb the intermixing and erosion of breed purity for some of these breeds need to be implemented, for example, by introducing measures like making proven rams available and ensuring their frequent exchange between flocks. The data generated here provides valuable information about the genetic structure of the 17 Indian sheep breeds and this can be used for designating priorities for their conservation. PMID- 21554346 TI - Mapping of fertility traits in Finnish Ayrshire by genome-wide association analysis. AB - A whole-genome scan using single marker association was used to detect chromosome regions associated with seven female fertility traits in Finnish Ayrshire dairy cattle. The phenotypic data consisted of de-regressed estimated breeding values for 340 bulls which were estimated using a single trait model. Genotypes were obtained with the Illumina BovineSNP50 panel and a total of 35 630 informative, high-quality single nucleotide polymorphism (SNP) markers were used. The association analysis was performed using a mixed-model approach which fitted a fixed effect for each SNP and a random polygenic effect. We detected eleven genome-wide significant associations on eight different chromosomes. With at least chromosome-wise significance after Bonferroni correction, sixteen SNPs on nine chromosomes showed significant associations with one or more fertility traits. The results confirmed quantitative trait loci on three chromosomes (1, 2 and 20) for fertility traits previously reported for the same breed and one on chromosome four previously detected in Holstein cattle. PMID- 21554347 TI - Bovine lactoferrin (LTF) gene promoter haplotypes have different basal transcriptional activities. AB - Genetic polymorphisms present in the bovine lactoferrin (LTF) gene promoter have the potential to affect milk lactoferrin concentrations. The objectives were: (1) to identify, in silico, SNPs in the promoter region of the LTF gene that could affect transcription factor binding activity, (2) to investigate the effects of these SNPs in vitro by measuring promoter transcriptional activities of different bovine LTF promoter haplotypes and (3) to investigate the genetic association between LTF promoter SNPs and milk lactoferrin concentration. Haplotypes were deduced from sequencing of the 2.2-kb bovine LTF promoter in 78 unrelated animals. In silico analysis of the 2.2-kb promoter revealed two major haplotypes (BtLTF_H1a and BtLTF_H2a) that differed at 10 SNP loci that affect transcription factors of both a constitutive (at -28, -1702) and an inducible (at -131, -270, 586, -2047, -2077, -2122, -2140 and -2151) nature. The basal promoter transcriptional activity of BtLTF_H1a was 1.44-fold higher than that of BtLTF_H2a in mammary epithelial cells. Cows with the BtLTF_H1a haplotype had increased lactoferrin protein concentration in milk at various time points over the lactation curves, compared to herdmates with the BtLTF_H2a haplotype. The SNPs c. 28A>C, c.-131T>C, c.-156A>G, c.-270T>C, c.-586C>T, c.-1702A>G, c.-1953G>A, c. 2047A>G, c.-2077A>G, c.-2122C>T, c.-2140A>G and c.-2151G>A were associated (P < 0.001) with milk lactoferrin content in 372 Holstein-Friesian cows. The identification of bovine LTF promoter haplotypes with different basal transcriptional activities in vitro that are associated with lactoferrin levels in milk in vivo may facilitate the identification of designer dairy herds for increased lactoferrin content in milk. PMID- 21554348 TI - Validation of a paternally imprinted QTL affecting pH24h distinct from PRKAG3 on SSC15. AB - We previously performed a genome scan in a White Duroc * Erhualian F(2) population and identified a QTL on SSC15 with strong effect on pH24h in M. Longissimus dorsi and M. Semimembranous muscle tissue. At that time, the mode of inheritance of this QTL was not clarified, and it was also unclear whether the observed QTL effect was completely or partially caused by mutations in the PRKAG3 gene, which is the only major gene on SSC15 so far known to influence pH24h. In this study, effects of the PRKAG3 gene on meat quality traits were estimated by association analyses. Two substitutions in PRKAG3, p.Ile199Val (p.I199V) and p.Thr30Asn (p.T30N), were found to be segregating in the F(2) population and to significantly affect pH24h and total glycogen in meat, respectively. However, we excluded PRKAG3 as a causative gene for the detected QTL based on the following reasons: (i) the gene was located outside of the QTL confidence interval; (ii) when the PRKAG3 substitution was included as a fixed effect in the QTL model, the F-ratio for the QTL increased rather than decreased; (iii) favourable alleles for pH24h at the QTL and at the PRKAG3 p.I199V locus originated from Erhualian and White Duroc founders, respectively; (iv) more importantly, this QTL showed exclusive maternal expression, differing from the Mendelian expression of PRKAG3. In conclusion, this study is the first to report a maternally-expressed QTL for pH24h on SSC15, which is distinct from PRKAG3. PMID- 21554349 TI - A linkage map of sheep chromosome X (OARX) aligned to human chromosome X (HSAX). AB - We have constructed a genetic linkage map of the sheep X chromosome (OARX) containing 22 new gene loci from across the human X chromosome (HSAX). The female OARX linkage map has a total length of 152.6 cM with average gene spacing of 5.5 cM. Comparison with HSAX confirms one previously reported major breakpoint and inversion, and other minor rearrangements between OARX and HSAX. Comparison of the linkage map with sheep sequence data OAR 1.0 reveals a different arrangement of markers on the q arm, which may more accurately reflect the genuine arrangement of this region. PMID- 21554350 TI - Molecular characterization of the human ABO blood group orthologus system in pigs. AB - The selection and use of animals with blood group 0 in the process of transplanting pig organs or tissues into humans can positively contribute to the control of acute immune rejection due to differences in blood groups. Exon specific PCRs for the porcine blood group A transferase gene against genomic DNA from either blood group A or 0 animals resulted in the amplification failure of the A0 blood group gene exon 8 from blood group 0 animals. To characterize the genetic abnormality in the genome of blood group 0 animals, we screened bacterial artificial chromosome (BAC) clones from a Korean native pig BAC library which had the blood group 0 allele, and carried out shotgun sequencing. The analysis showed that the 0 allele has a large deletion between exon 7 of the A0 blood group gene and the neighbouring SURF6. We also showed that the ABO blood group antigens in humans and the A0 blood group antigens in pigs are coded by mutations within the orthologous glycosyltransferase gene. In addition, we developed a multiplex genotyping method for the porcine A0 blood group gene. PMID- 21554351 TI - Association between molecular markers for beef tenderness and growth traits in Argentinian angus cattle. AB - Molecular markers for beef tenderness are classic examples of the contribution of genome technology to animal breeding through marker-assisted selection (MAS). Markers on the MU-calpain (CAPN1) and calpastatin (CAST) genes have been extensively evaluated for their association with tenderness. However, little is known about their potential effect on other economically important traits. In this work, the association of molecular markers for beef tenderness with growth traits was evaluated in Angus cattle of Argentina. Expected progeny differences were extracted from the 2008 Angus Sire Summary of Argentina. Information corresponding to 268 influential bulls that had been genotyped for two markers in CAPN1 and two markers in CAST was provided by the Argentine Angus Association. Genotype probabilities were assigned, by segregation analysis, to those bulls in the Sire Summary that had no marker information. Expected progeny differences of 1365 sires were regressed on the number of alleles favouring tenderness at each locus. There was a significant effect of markers on expected progeny differences of birth weight, weaning weight (direct), weight at 18 months and rib eye area. In general, there was a negative effect of alleles favouring tenderness on growth traits. These correlated responses should be taken into account when molecular markers are used in selection schemes that aim to improve beef tenderness. PMID- 21554352 TI - Evaluation of SNPs in the chicken HMGA2 gene as markers for body weight gain. AB - A QTL affecting body weight in chickens has been mapped to GGA1, between the markers GCT0006 and MCW0106. The gene HMGA2, which was previously identified as a candidate gene for determining body height in humans and mice, is also conspicuously close to the MCW0106 marker in chickens. Subsequently, 14 SNP markers of HMGA2 were genotyped in CAU chicken resource populations, and the associations between body weight and those SNP markers that displayed polymorphisms were analysed. Three SNPs (rs13849241, rs15231472 and rs13849381) were found to be significantly correlated with body weight in chickens (P < 0.05). Furthermore, haplotypes constructed based on these three SNPs were also discovered to be associated with body weight in chickens at the ages of 6, 7, 9 and 12 weeks. These results suggest that the chicken HMGA2 gene is indeed involved in body weight gain. PMID- 21554353 TI - Dynein light chain 1 (LC8) sequence is highly conserved between pig species. PMID- 21554354 TI - Five novel KIT mutations in horses with white coat colour phenotypes. PMID- 21554355 TI - Novel polymorphisms in the myostatin gene and their association with growth traits in a variety of bay scallop, Argopecten irradians. PMID- 21554356 TI - Identification of polymorphisms in the rabbit (Oryctolagus cuniculus) myostatin (MSTN) gene and association analysis with finishing weight in a commercial rabbit population. PMID- 21554357 TI - The systemic inflammatory response syndrome and sequential organ failure assessment scores are effective triage markers following paracetamol (acetaminophen) overdose. AB - BACKGROUND: The systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores are widely used as prognostic markers in critical care settings and could improve triage of high-risk paracetamol (acetaminophen) overdose patients. AIM: To evaluate the prognostic accuracy of the SIRS and SOFA scores following single time point paracetamol overdose. METHODS: Analysis of 100 single time point paracetamol overdoses admitted to a tertiary liver centre, with subsequent prospective validation of identified thresholds. Individual laboratory samples were correlated with the corresponding clinical parameters in relation to time post-overdose, and the daily SOFA and SIRS scores calculated. RESULTS: A total of 74 (74%) patients developed the SIRS, which occurred significantly earlier in patients who died (n=21) compared with spontaneous survivors (n=53, P=0.05). The SIRS occurred in 70 (70%) patients by 96h post-overdose, with a 30% mortality rate; compared with 0% mortality in the 30 non-SIRS patients (P=0.001). Median SOFA scores were significantly higher in nonsurvivors at 48 (P=0.009), 72 (P<0.001), and 96h (P<0.001). A SOFA score >7 during the first 96h post-overdose predicted death/transplantation with a sensitivity of 95.0 (95% CI 78.5-99.1) and specificity of 70.5 (95% CI 66.3 71.6). A validation cohort of 38 single time point paracetamol overdoses confirmed the extremely high negative predictive value of both the SIRS and SOFA thresholds. CONCLUSIONS: The absence of either a SOFA score >7 or a SIRS response during the first 96 h following paracetamol overdose could improve triage and reduce transfers of lower risk patients to tertiary liver centres. PMID- 21554358 TI - Direct colloid osmometry in healthy New World camelids. AB - BACKGROUND: Direct colloid osmometry provides an objective assessment of the oncotic effects of crystalloid or colloidal fluid therapy, which is especially useful in monitoring fluid therapy of critically ill camelids due to their tendency toward nonspecific hypoproteinemia with increased risk of developing edema and ascites. OBJECTIVES: The aims of this study were to measure colloid osmotic pressure (COP) of alpacas and llamas, determine its correlation with concentrations of total protein (TP) and total solids (TS), as well as both albumin (A) and globulin (G) concentrations in the same model (A+G), and evaluate the effects of sample type and storage conditions on COP. METHODS: Blood was collected from clinically healthy alpacas (n=23) and llamas (n=22) into heparin tubes. COP of fresh whole blood (COP(FB) ) and plasma (COP(FP) ) was determined using a membrane osmometer. For 20 alpacas, COP of refrigerated whole blood (COP(RB) ) and frozen plasma (COP(FrP) ) was also measured. Correlations between COP(FB) and TS, TP, and A+G concentrations were assessed by simple and multiple regression analysis to model potential predictors. RESULTS: Median COP(FB) from alpacas (24.6 mmHg, range 19.3-28.1) was not significantly different from that of llamas (25.3 mmHg, range 22.5-33.7). Sample type or storage conditions did not affect COP. Measured COP had a strong positive linear correlation with TS, TP, and A+G concentrations in alpacas (r(2) =.7, .74, and .88, respectively). In llamas, COP correlated best with TS concentration (r(2) =.59), whereas correlation with TP and A+G concentrations was poor (r(2) =.19 and .25, respectively). CONCLUSION: COP can be measured using heparinized whole blood or plasma, either fresh or stored. Direct measurement is recommended whenever quantitative knowledge of COP is required in clinical or research setting. Further studies are needed to verify if the poor association of COP with TP found in this study can be generalized to llamas. PMID- 21554359 TI - Evaluation of a portable glucose meter for use in cattle and sheep. AB - BACKGROUND: In farm animal practice, determination of blood glucose concentration under field conditions is often necessary. OBJECTIVE: As there is no portable glucose meter device developed for use in farm animals, the analytical accuracy of a portable glucometer designed for people was evaluated for its use in cattle and sheep. METHODS: Blood samples from 90 cattle and 101 sheep were used in the study. Glucose concentration was determined in whole blood immediately after blood collection from the jugular vein with the One Touch Vita portable glucometer and in serum with an enzymatic colorimetric method. The agreement between methods was assessed by Passing and Bablok regression analysis. The precision and the accuracy of the measurements were determined using the concordance correlation coefficient. RESULTS: There was a strong linear relationship between the glucose values obtained using the portable glucometer and those obtained by the bench method in both cattle and sheep. Precision was 95% for cattle and 88% for sheep, whereas accuracy was 92% and 99%, respectively. The mean glucose values obtained using the portable glucometer were significantly lower by 8.3% in cattle and 3.2% in sheep than those determined by the bench method. CONCLUSION: The One Touch Vita portable glucometer can be used in clinical practice to determine blood glucose concentrations in cattle and sheep, but reference intervals (RI) must be corrected to allow for negative bias. Based on these equations the RI for blood glucose in cattle and sheep using the portable glucometer were corrected to 1.84-4.17 and 2.41-4.35 mmol/L, respectively. PMID- 21554360 TI - Agarose gel serum protein electrophoresis in cats with and without lymphoma and preliminary results of tandem mass fingerprinting analysis. AB - BACKGROUND: Serum electrophoretic profiles in cats are poorly characterized with respect to the proteins that comprise the globulin fractions, and interpretation of the electrophoretograms is routinely done in the absence of information about identity of the proteins found within each fraction. OBJECTIVES: The aims of this study were to compare protein fractions separated by serum protein electrophoresis (SPE) in healthy cats and in cats with lymphoma and to confirm some component proteins in the major fractions following SPE using tandem mass fingerprinting analysis (TMFA). METHODS: Total protein concentration was measured and agarose gel SPE performed on serum from 14 healthy cats and 14 cats with lymphoma. The absolute protein concentration within each fraction was compared between the 2 groups. Bands corresponding to the SPE fractions were excised from the gels of 2 control cats and 1 cat with lymphoma and analyzed by liquid chromatography coupled to mass spectrometry. Results were compared with sequences in the National Center for Biotechnology Information protein database. RESULTS: Median albumin concentrations were significantly decreased and median beta globulin concentrations were significantly increased in cats with lymphoma. Narrow electrophoretic spikes were present in the beta/gamma-globulin fraction in 3 cats with lymphoma. Following TMFA, multiple proteins were identified in each fraction, and their mobility agreed with results from previous studies generated using alternative techniques. Inter-alpha (globulin) inhibitor 4 was identified in feline serum for the first time. CONCLUSIONS: Cats with lymphoma had lower albumin and higher beta-globulin concentrations than did healthy cats. Despite limitations of one-dimensional agarose gel SPE, TMFA provided preliminary data to confirm the protein components of the various fractions. PMID- 21554361 TI - Frequency of dog erythrocyte antigen 1.1 expression in dogs from Portugal. AB - BACKGROUND: Dog erythrocyte antigen (DEA) 1.1 is the antigen considered most responsible for severe hemolysis owing to incompatible blood transfusions in previously sensitized dogs. Few reports describe the frequency of DEA 1.1 expression in European dogs, and there are no reports in dogs from Portugal. OBJECTIVE: The aims of this study were to identify the frequency of DEA 1.1 expression in Portuguese dogs, to examine the relationship between phenotypic traits and expression of this blood group, and to assess the risk of transfusing blood that is not typed or cross-matched. METHODS: Expression of DEA 1.1 was determined in 274 dogs using a migration gel test. Weight, sex, breed, and hair length and color were recorded for each dog. Results were analyzed by descriptive statistical analysis, probabilistic analysis, and chi(2)-tests. RESULTS: Of 274 dogs, 56.9% were DEA 1.1-positive and 43.1% were DEA 1.1-negative. All Boxers, German Shepherds, and Dobermans were DEA 1.1-negative, whereas all Saint Bernards, 88.9% of Golden Retrievers, 88.2% of Rottweilers, and 61.4% of mixed breed dogs were DEA 1.1-positive. A significant relationship between DEA 1.1 expression and phenotypic traits was not found. The probability of sensitization of recipient dogs following first-time transfusion with blood that was not typed or cross-matched was 24.5%; the probability of an acute hemolytic reaction following a second transfusion with blood from any other donor in the absence of pretransfusion compatibility testing was 6%. CONCLUSION: The frequency of DEA 1.1 expression in dogs in Portugal is high, and there is a potential risk of sensitization following transfusion with blood that is not typed or cross matched. Breed-related frequencies may help predict DEA 1.1-positivity, but the best practice is to type and cross-match blood before transfusion. PMID- 21554362 TI - One-stage prothrombin time, activated partial thromboplastin time, thrombin time, fibrin degradation product concentration, and antithrombin activity in healthy adult alpacas. AB - BACKGROUND: Alpacas are increasingly presented to veterinarians for evaluation and care. Reports of alpaca reference intervals for one-stage prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), concentration of fibrin degradation products (FDP), and antithrombin (AT) activities are scarce or nonexistent. OBJECTIVE: The aim of this study was to determine values for blood coagulation times (PT, aPTT, and TT), FDP concentrations, and AT activities in healthy adult alpacas. METHODS: Of blood samples collected from 35 clinically healthy adult alpacas via jugular venipuncture and placed into sodium citrate and FDP tubes, 29 samples were assayable for coagulation testing. PT, aPTT, and TT were determined by physical (mechanical) clot detection; AT activity was determined using a thrombin-specific chromogenic substrate end-point assay; and FDP concentrations were determined by the slide agglutination method. RESULTS: Median values and ranges (minimum maximum) were determined for PT (8.7 seconds, 6.6-11.2 seconds), aPTT (17.3 seconds, 11.9-22.5 seconds), TT (10.2 seconds, 5.4-16.0 seconds), and AT activity (123.3%, 104.8-144.2%). The mean concentration of FDP was <8 MUg/mL. CONCLUSION: These values for coagulation times, FDP concentration, and AT activity will provide a useful starting point in the diagnostic evaluation of ill adult alpacas. PMID- 21554363 TI - Secondary renal tubular acidosis in a Hereford calf. AB - A 3-month-old Hereford heifer calf was presented for lethargy. Blood gas analysis and plasma biochemical testing revealed severe metabolic acidosis, azotemia, hyponatremia, hyperchloremia, and normal anion gap. Results of a urinalysis were consistent with acute tubular necrosis with inadequate acidification of urine based on the degree of acidemia. Salmonella enterica serovar agona was cultured from both urine and feces. The calf was treated with intravenous polyionic fluids, bicarbonate, and antimicrobials. Acidosis and azotemia resolved, and 4 months following initial presentation the heifer was clinically normal. PMID- 21554364 TI - Evaluation of modified Wright-staining of dried urinary sediment as a method for accurate detection of bacteriuria in cats. AB - BACKGROUND: Urinary sediment examination and quantitative urinary culture results are frequently discordant. OBJECTIVES: The aims of this study were to compare accuracy of light microscopic examination of wet-mounted unstained (wet unstained) and air-dried modified Wright-stained (dry-stained) sedimented preparations of urine with results of quantitative aerobic bacterial culture for detection and characterization of bacteriuria in cats. In addition, the presence of pyuria detected by urinalysis and potential risk factors were assessed. METHODS: A blinded prospective study was conducted on 472 urinary samples collected from 410 cats by cystocentesis. The age and sex of each cat were recorded. Complete urinalyses were performed and included quantification of WBCs. Quantity and morphology of bacteria in each specimen were determined by light microscopic examination of wet-unstained (performed by certified medical technologists) and dry-stained (performed by a veterinary clinical pathologist) sedimented preparations of urine and compared with results of quantitative bacterial cultures. RESULTS: Of 472 urinary specimens, 29 were positive for bacteriuria by culture and considered true positives and 443 were considered true negatives. Compared with these results, examination of wet-unstained and dry stained urines had sensitivities of 75.9% and 82.8%, specificities of 56.7% and 98.7%, and test efficiencies of 57.8% and 97.7%, respectively. Positive likelihood ratios were 1.8 and 63.7 and negative likelihood ratios were 0.42 and 0.17 for wet-unstained and dry-stained examinations, respectively. Compared with 29 culture-positive samples, the wet-unstained method had morphologic concordance and misclassification rates of 37.9% and 62.1%, respectively, whereas the dry stained method had morphologic concordance and misclassification rates of 65.5% and 34.5%, respectively. Only 34% of samples with bacteriuria had pyuria. Frequency of bacteriuria was not significantly different based on age and sex of the cats, but there was a tendency for increased frequency in female cats and in cats >10 years old. CONCLUSIONS: Staining dried urinary sediment with a modified Wright-stain significantly improved sensitivity, specificity, and test efficiency of microscopic detection and classification of bacteriuria compared with the wet unstained method. Pyuria should not be a criterion for determining the presence or absence of bacteriuria. PMID- 21554365 TI - Prior probability (the pretest best guess) affects predictive values of diagnostic tests. AB - Authors who publish evaluations of dichotomous (yes/no) diagnostic tests often include the predictive values of their test at a single prior probability (eg, the prevalence of the target disease within the evaluation data set). The objectives of this technical note are to demonstrate why single-probability predictive values are misleading and to show a better way to display positive predictive values (PPV) and negative predictive values (NPV) for a newly evaluated test. Secondly, this technical note will show readers how to calculate predictive values from only sensitivity and specificity for any desired prior probability. As prior probability increases from 0% to 100%, PPV increases from 0% to 100%, but NPV goes in the opposite direction (drops from 100% to 0%). Because prior probabilities vary so greatly across situations, predictive values should be provided in publications for the full range of potential prior probabilities (if provided at all). This is easily done with a 2-curve graph displaying the predictive values (y-axis) against the prior probability (x-axis). PMID- 21554366 TI - What is your diagnosis? Pale yellowish digestive gland and watery tissues in Mediterranean mussels. PMID- 21554367 TI - What is your diagnosis? Blood smear from a dog. PMID- 21554368 TI - P2Y12 receptor gene mutation associated with postoperative hemorrhage in a Greater Swiss Mountain dog. AB - A novel hereditary disorder of platelets was identified across 5 generations of a family of Greater Swiss Mountain dogs. The first dog identified with the mutation bled excessively following routine ovariohysterectomy and required multiple transfusions. Coagulation screening assays, platelet counts, and von Willebrand factor antigen activity were within reference intervals. Flow cytometric studies indicated that platelets from the affected dog expressed normal levels of glycoproteins IIb and IIIa and responded to 2 platelet-activating agents, convulxin and platelet-activating factor, but not to ADP. Based on DNA studies, a 3 base-pair deletion predicted to result in elimination of a serine from the extracellular domain was identified in the gene encoding P2Y12, an ADP receptor protein located on platelet membranes. Flow cytometric analysis of platelets and studies of DNA performed concurrently on 2 unrelated Greater Swiss Mountain dogs were unremarkable. The mutation was subsequently identified in the sire, the maternal grand-dam, a maternal great grandparent, a paternal great grandparent, and a great-great grandparent. The sire was homozygous, but had not yet been identified as having a hemostatic disorder; the other 4 dogs were carriers. This is the first report of a mutation in the gene encoding the ADP receptor P2Y12 in a domestic animal. P2Y12 is the same receptor targeted by ticlopidine and clopidogrel, platelet inhibitors used in lieu of aspirin in people at risk for cardiovascular disease; thus, spontaneous bleeding is not expected unless there are other contributing factors. This disorder is particularly troublesome because spontaneous hemorrhage is absent to mild in affected dogs; however, following routine surgical procedures or trauma, excessive bleeding could occur and have possible fatal consequences. PMID- 21554369 TI - Oil Red O-positive lipid in peritoneal fluid from a horse with a rectal tear. AB - A 4-year-old Quarter Horse mare was presented to the Texas A&M University Veterinary Medical Teaching Hospital for evaluation of a rectal tear. On initial evaluation, rectal palpation and colonoscopy revealed a grade IIIb rectal tear. Analysis of peritoneal fluid revealed a modified transudate. Preliminary supportive care included fluid therapy and mineral oil administration via nasogastric tube. Approximately 48 hours after presentation, a second abdominocentesis was performed, and cytologic examination of the fluid revealed a marked suppurative exudate. Round clear nonrefractile material observed within neutrophils and macrophages and in the background stained bright pink to red with Oil Red O, confirming the material as lipid, likely from leakage of mineral oil through the rectal tear. The condition of the mare deteriorated and euthanasia was elected due to the poor prognosis. At necropsy, gross and histologic findings included peritoneal effusion and a full-thickness rectal tear with transmural necrotizing pyogranulomatous colitis and fibrinous peritonitis. To the authors' knowledge, this is the first reported case of Oil Red O-positive lipid vacuoles in the peritoneal fluid of a horse from presumed leakage of mineral oil through a transmural rectal perforation. The frequency of this occurrence in horses is unknown, but it is important for cytopathologists to be familiar with the appearance and significance of lipid-type droplets in phagocytic cells in cytologic fluid analysis specimens. PMID- 21554370 TI - May-Hegglin anomaly in a dog. AB - An 8-year-old female spayed Pug dog was presented for evaluation of cutaneous lesions occurring secondary to immunosuppressive treatment of presumed immune mediated thrombocytopenia. Abnormal hematologic findings included persistent thrombocytopenia, macrothrombocytes, and variably shaped, often fusiform, blue cytoplasmic inclusions in neutrophils. May-Hegglin anomaly (MHA) was suspected based on the morphologic appearance of platelets and neutrophils. Examination of cells by transmission electron microscopy revealed normal platelet ultrastructure; neutrophil inclusions had features similar to those reported for inclusions in human MHA. Neutrophil function was within normal limits based on flow cytometric analysis. Thrombelastography indicated a prolonged clotting time (r), and PlateletMapping showed a lack of response to 2 MUM ADP compared with a moderate response in the control dog. Immunocytochemical staining of blood smears using 2 commercially available antibodies against MYH9 protein (nonmuscle myosin heavy chain II) yielded negative results. However, genomic DNA sequencing analysis of the dog's MYH9 gene identified a single point mutation, resulting in substitution of lysine for glutamine at the 1841 amino acid position; this mutation is identical to one identified in people with MHA. To our knowledge, this is the first report of an MYH9 mutation in the dog. MHA-associated macrothrombocytopenia may be mistaken for immune-mediated thrombocytopenia. PMID- 21554371 TI - Anaplasmosis in two dogs in France and molecular and phylogenetic characterization of Anaplasma phagocytophilum. AB - Two dogs in France were diagnosed with Anaplasma phagocytophilum infection by real-time PCR. The most remarkable hematologic and biochemical findings were severe thrombocytopenia, mild neutrophilia, morulae in neutrophils, and increased serum concentration of the alpha2-globulin fraction detected by agarose gel electrophoresis of serum proteins. Using sequencing of the partial 16S rRNA and ankA genes, molecular characterization of the A. phagocytophilum strains showed that the organisms from both dogs were identical to the European strains isolated from horses and people. Based on phylogenetic analysis, the ankA gene was more discriminating than the 16S rRNA gene in distinguishing the majority of European and American strains of A. phagocytophilum infecting people and animals. Three isolates of A. phagocytophilum, 1 from Spain (cow) and 2 from Norway (sheep and deer), were external to the European and American clades. PMID- 21554372 TI - What is your diagnosis? Discrepancy between Sysmex XT-2000iV reticulocyte count and polychromasia. PMID- 21554373 TI - Corticotrophin-releasing hormone and desmopressin tests in the differential diagnosis between Cushing's disease and pseudo-Cushing state: a comparative study. AB - BACKGROUND: We recently proposed a new and effective way of interpreting human corticotrophin-releasing hormone (hCRH) and desmopressin (DDAVP) tests, for the differential diagnosis between Cushing's disease (CD) and pseudo-Cushing state (PC), based on the simultaneous analysis of ACTH and cortisol. OBJECTIVE: The study had the aims of comparing the diagnostic performance of the two tests and determining whether carrying out both tests was more beneficial than carrying out only one. PATIENTS AND MEASUREMENTS: We studied 30 CD, 18 PC and 12 control (CT) subjects: in these patients, hCRH test, DDAVP test, 24-h urinary free cortisol, serum cortisol after overnight 1-mg dexamethasone suppression test and serum cortisol circadian rhythm were performed. RESULTS: The hCRH test and the DDAVP test showed an identical and excellent diagnostic performance (sensitivity 96.6% and specificity 100% for both tests); moreover, the hCRH and DDAVP tests showed almost perfect diagnostic agreement (kappa = 0.93; P < 0.05) with a significantly higher number of concordant diagnoses (58 cases of 60) than those resulting from all other possible combinations among the studied tests. Interestingly, there were no subjects in whom both hCRH and DDAVP tests gave a simultaneous misdiagnosis. CONCLUSIONS: Our study indicates that the hCRH and DDAVP tests have similar diagnostic performance and present excellent agreement, without giving simultaneous misdiagnosis in any subject. Because of these characteristics, the use of both tests offers the physician a valuable tool for those cases of hypercortisolism which are difficult to interpret. PMID- 21554374 TI - Might the association between gamma-glutamyltransferase and arterial stiffness be mediated by iron overload? PMID- 21554375 TI - The cost-effectiveness of supportive periodontal care: a global perspective. AB - AIM: To evaluate the cost-effectiveness of supportive periodontal care (SPC) provided in generalist and periodontal specialist practices under publicly subsidized or private dental care. MATERIAL AND METHODS: SPC cost data and the costs of replacing teeth were synthesized with estimates of the effectiveness of SPC in preventing attachment and tooth loss and adjusted for differences in clinician's time. Incremental cost-effectiveness ratios were calculated for both outcomes assuming a time horizon of 30 years. RESULTS: SPC in specialist periodontal practice provides improved outcomes but at higher costs than SPC provided by publicly subsidized or private systems. SPC in specialist periodontal practice is usually more cost-effective than in private dental practice. For private dental practices in Spain, United Kingdom and Australia, specialist SPC is cost-effective at modest values of attachment loss averted. Variation in the threshold arises primarily from clinician's time. CONCLUSION: SPC in specialist periodontal practice represents good value for money for patients (publicly subsidized or private) in the United Kingdom and Australia and in Spain if they place relatively modest values on avoiding attachment loss. For patients in Ireland, Germany, Japan and the United State, a higher valuation on avoiding attachment loss is needed to justify SPC in private or specialist practices. PMID- 21554376 TI - Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice. AB - 1. Uncoupling of nitric oxide synthase (NOS) has been implicated in the pathogenesis of left ventricular (LV) dysfunction in diabetes mellitus. In the present study, we investigated the role of NOS uncoupling in oxidative/nitrosative stress and LV dysfunction in the diabetic mouse heart. 2. Diabetes was induced in wild-type (WT), endothelial (e) NOS knockout (eNOS(-/-)), inducible (i) NOS knockout (iNOS(-/-)) and neuronal (n) NOS knockout (nNOS(-/-)) mice by streptozotocin (STZ) treatment. 3. In the diabetic heart, iNOS, but not eNOS or nNOS, expression was increased. Levels of malondialdehyde (MDA), 4 hydroxy-noneal (HNE) and nitrotyrosine (NT), as markers of oxidative/nitrosative stress, were increased in the diabetic mouse heart, but the increase in oxidative/nitrosative stress was significantly repressed in the iNOS(-/-) diabetic mouse heart. Levels of nitrite and nitrate (NO(x)), as an index of nitric oxide, bioavailability were significantly decreased in the iNOS(-/-) diabetic mouse heart. 4. Oral administration of sepiapterin (10 mg/kg per day), a precursor of tetrahydrobiopterin (BH(4)), significantly increased BH(4) and the BH(4)/BH(2) ratio in diabetic mouse heart. Similarly, sepiapterin inhibited the formation of HNE, MDA and NT in diabetic hearts from all three genotypes, but the increase in NO(x) following sepiapterin treatment was significantly attenuated in the iNOS(-/-) diabetic mouse heart. Percentage fractional shortening (FS), evaluated by echocardiography, decreased significantly in all genotypes of diabetic mice. Sepiapterin significantly increased percentage FS in diabetic mice, except in iNOS(-/-) mice. 5. These results suggest that sepiapterin inhibits uncoupling of NOS and improves LV function presumably by increasing iNOS derived nitric oxide in the diabetic heart. PMID- 21554377 TI - At the moment of practice. PMID- 21554379 TI - The discursive practices of nurse practitioner legislation in Australia. AB - AIM: The aim of this paper was to examine the nurse practitioner legislative framework in Australia from a critical social theory perspective. BACKGROUND: National regulation for nurses and midwives has superseded all previous state legislation with effect from July 2010. The aim of this change was to streamline regulation processes across all health professionals requiring regulation, in order to eliminate diverse state-based regulatory policies that were identified as hindering transferability of the workforce across Australia. This paper explores the changes with reference to nurse practitioners. Since their introduction to Australia different legislative practices between states have presented difficult endorsement procedures which have affected employment. DATA SOURCES: Information for the paper is drawn from a doctoral study which examined the politics of advancing nursing in Australia, with particular reference to the discourses of nurse practitioners. This is augmented by more recent legislative documents and policies, as well as media reports, to examine the process of change in legislation and the unfolding discourses on employment and practice. IMPLICATIONS TO NURSING: Nurse practitioner endorsement may be more complicated, defeating the original premise of transferability of a skilled workforce across state jurisdictions. CONCLUSION: This paper exposes the influence that powerful discourses can have on a major change to professional practice. PMID- 21554380 TI - spyder, a new method for in silico design and assessment of 16S rRNA gene primers for molecular microbial ecology. AB - Molecular microbial ecology studies are heavily reliant on 'Universal' 16S rRNA gene primers for elucidating microbial community structure and composition, and yet primer design and optimization is often overlooked. Primers that exhibit minor biases due to primer-template mismatches can substantially alter the pool of amplicons from a community DNA sample, resulting in inaccurate conclusions. As a result, it is important that primers are critically evaluated against the most comprehensive data sets available before commencing molecular microbial community studies. We present a user-friendly, multi-platform (e.g. Windows, Linux, Mac) method named spyder for the in silico design and assessment of 16S rRNA gene primers. The method utilizes the Ribosomal Database Project's Probe Match feature coupled with a compact program (available at http://people.uleth.ca/~selibl/Spyder/Spyder.html) that aligns and identifies mismatches between primers and templates. To demonstrate the value of spyder, we assessed commonly used 'Universal' and phyla-specific primers and identified primer modifications that improved the coverage of target organisms by 5-42% as well as removed excessive degeneracies. PMID- 21554381 TI - LytR-CpsA-Psr proteins in Staphylococcus aureus display partial functional redundancy and the deletion of all three severely impairs septum placement and cell separation. AB - Staphylococcus aureus contains three members of the LytR-CpsA-Psr (LCP) family of membrane proteins: MsrR, SA0908 and SA2103. The characterization of single-, double- and triple-deletion mutants revealed distinct phenotypes for each of the three proteins. MsrR was involved in cell separation and septum formation and influenced beta-lactam resistance; SA0908 protected cells from autolysis; and SA2103, although displaying no apparent phenotype by itself, enhanced the properties of msrR and sa0908 mutants when deleted. The deletion of sa0908 and sa2103 also further attenuated the virulence of msrR mutants in a nematode killing assay. The severely defective growth phenotype of the triple mutant revealed that LytR-CpsA-Psr proteins are essential for optimal cell division in S. aureus. Growth could be rescued to varying degrees by any one of the three proteins, indicating some functional redundancy within members of this protein family. However, differing phenotypic characteristics of all single and double mutants and complemented triple mutants indicated that each protein played a distinct role(s) and contributed differently to phenotypes influencing cell separation, autolysis, cell surface properties and virulence. PMID- 21554382 TI - Effectiveness of different cleaning agents on the adherence of Candida albicans to acrylic denture base resin. AB - OBJECTIVE: To evaluate the ability of three alkaline peroxide-type (Polident, Efferdent, Fittydent) and two mouth rinse cleaning agents (CloSYSII and Corsodyl) to inhibit Candida albicans on acrylic denture base resin. BACKGROUND: Appropriate routine cleaning of dentures is necessary to prevent denture stomatitis and maintenance of healthy supporting tissues. MATERIALS AND METHODS: A total of 180 acrylic resin specimens (10 * 10 * 2 mm) were prepared and divided into six groups. Candida albicans was incubated on Sabouraud dextrose agar (SDA) at 37 degrees C for 48 h. After dilution, a final yeast suspension of approximately 10(6) C. albicans per millimetre was prepared. Ten acrylic resin specimens for each group were placed in a sterile Petri dish covered with 20 ml of fungal suspension and incubated at 37 degrees C for 90 min. Then, the specimens were immersed in 40 ml of the test solution at 37 degrees C for 15, 30 and 60 min. Fungal cells adhering to acrylic resin surfaces were fixed in formaldehyde and counted microscopically. RESULTS: Mouth rinses showed the highest removal activity for all the treatment times and completely eliminated the adherence of C. albicans. CONCLUSIONS: The use of mouth rinse may be a suitable method for cleaning dentures. PMID- 21554383 TI - Pachyonychia congenita with laryngeal obstruction. AB - Pachyonychia congenita is a rare genodermatosis that can affect the larynx. Laryngeal obstruction is very unusual with only a few cases reported. A 2-year old girl presented with typical clinical features of pachyonychia congenita shortly after birth. At age 9 months, following an upper respiratory infection, she developed stridor and hoarseness and was found to have severe laryngeal obstruction, which was felt to be secondary to pachyonychia congenita based on direct laryngoscopy and laryngeal biopsy. Leukokeratosis of her larynx was treated with CO(2) laser on three occasions, with improvement in her respiratory distress after each treatment. This report is the first case of pachyonychia congenita with laryngeal obstruction in which the gene mutation has been established (a deletional mutation in K6a), confirming that laryngeal obstruction can occur in PC-1. PMID- 21554384 TI - Gianotti-Crosti syndrome after H1N1-influenza vaccine. AB - Papular acrodermatitis of childhood, or Gianotti-Crosti syndrome, is a symmetric papular or papulovesicular acral exanthem associated with several infectious agents and immunizations. We present a case of Gianotti-Crosti syndrome appearing shortly after H1N1-influenza vaccination. This has not been previously reported to our knowledge. PMID- 21554385 TI - Intraventricular muscular septal defect: a possible result of spontaneous closure of interventricular communication. PMID- 21554386 TI - Perceptions of community trust and safety - consequences for children's well being in rural and urban contexts. AB - AIM: To explore the associations between subjective well-being and perceptions of community trust and safety amongst children in rural and urban areas. METHODS: The study used self-reported data from the 2001/2002 Swedish cross-national WHO study Health Behaviour in School-aged Children. The sample consisted of 3852 children aged 11-15 years, living in different residential areas. Bivariate analyses and multivariate logistic regression were performed. RESULTS: The results indicated that a greater proportion of children in urban areas perceived low community trust and safety, compared with children in rural areas. Further, the multivariate analysis revealed that perceived community trust and safety significantly impacts upon children's subjective well-being in both rural and urban contexts. CONCLUSION: Children's perceptions of trust and safety have different magnitudes in urban and rural areas. The associations of perceptions of community trust and safety for children's subjective well-being are relevant in both urban and rural areas. As perceptions of low trust and safety in the community seem to be related to low subjective well-being, efforts to encourage community trust and safety should be included amongst the key priorities in community health promotion. PMID- 21554387 TI - Suicide mortality trends in young people aged 15 to 19 years in Lithuania. AB - AIM: This paper considers the suicide mortality trends from 1990-2009 in young people aged 15 to 19 years in Lithuania. METHODS: Suicide and injury mortality data, plus mortality data from all causes, were used to compare the trend lines. RESULTS: Suicide mortality rate in young people aged 15-19 years and in all population showed a rising trend from 1990, and then a decreasing trend from 2002 year. This trend was significant exclusively in boys. When comparing suicide deaths as a percentage of injury deaths and of all deaths in the age group 15-19 years, rising trends for boys were evident, whilst in girls, there was no evidence of change. CONCLUSIONS: In Lithuania, from early 1990s, the frequency of suicide increased amongst adults and young people aged 15-19 years. After 2002, a decrease in deaths by suicide was observed both for the whole population and for young people aged 15-19 years. The rise and fall was obvious for boys. The reasons for different trends may have been influenced by the political and socioeconomic instability in the 1990-2002 period, and the socioeconomic stability, together with active preventive measures, from 2002. Although the consumption of modern Selective serotonin reuptake inhibitors (SSRIs) increased during the same time, suicide mortality was again high during the economic crisis in 2008-2009. PMID- 21554388 TI - Alternative cannulation strategy for pediatric ECMO. AB - Vascular access in children who require extracorporeal membrane oxygenation (ECMO) support can be a challenging endeavor particularly in those who have undergone prior median sternotomies or interventional procedures. We present an alternative cannulation strategy that can be utilized in pediatric patients requiring ECMO that involves utilization of the iliac vein via a retroperitoneal approach. PMID- 21554389 TI - Adhesive strips versus subcuticular suture for mediansternotomy wound closure. AB - BACKGROUND AND AIM: This prospective randomized study was undertaken to compare the use of the 3MTM Steri-StripTM S Surgical Skin closure system with a running absorbable subcuticular suture technique for skin closure following a mediansternotomy for cardiac surgical procedures. METHODS: Thirty-six patients undergoing a mediansternotomy for a cardiac surgical procedure were prospectively randomized to either Steri-Strip S or subcuticular suture for wound closure. The wounds were evaluated on postoperative days 7 and 21 for erythema, edema, pain, cosmesis, and the time taken to close the incision. RESULTS: Skin closure with Steri-Strip S was faster (5.33 +/- 1.32 minutes steri-strips vs. 6.07 +/- 0.91 sutures; p = 0.06) and resulted in significantly less erythema and edema, but no difference in pain or cosmesis after seven days. Following 21 days, there was no difference in pain, edema, or cosmesis between the groups. However, patients receiving steri-strips continue to have less erythema. CONCLUSIONS: Both Steri Strip S and absorbable sutures are effective techniques for skin closure following a mediansternotomy incision for cardiac surgical procedures. Steri Strip S can decrease the amount of erythema, but results in no significant difference in pain, cosmesis, or edema compared to the traditional subcuticular wound closure technique. PMID- 21554390 TI - Aortobronchial fistula presenting 14 years following ligation of a patent ductus arteriosus. AB - Aortobronchial fistula (ABF) presenting as massive hemoptysis is a rapidly fatal process that is extremely difficult to diagnose and manage. ABF following ligation of patent ductus arteriosus (PDA) is extremely rare. We now report a case of an ABF developing 14 years after ligation of a PDA. PMID- 21554391 TI - Acute bioprosthetic mitral valve stenosis in a patient with HITS. AB - Acute thrombosis involving the left atrium and a bioprosthetic valve during the early postoperative period is an extremely rare complication of heparin-induced thrombocytopenia syndrome (HITS). We present a patient with early bioprosthetic mitral valve stenosis complicated by HITS in a patient with severe mitral regurgitation, atrial fibrillation, and severe left ventricular dysfunction. PMID- 21554392 TI - Use of extracorporeal membrane lung assist device (Novalung) in H1N1 patients. AB - We present three patients with severe respiratory failure secondary to H1N1 influenza type A pneumonitis, in whom hypercapnia and respiratory acidosis were not controlled by the conventional mechanical lung ventilation or high-frequency oscillatory ventilation. Use of a pumpless arteriovenous extracorporeal carbon dioxide removal device (NovalungTM, Inspiration Healthcare Ltd, Leicester, UK) resulted in reduced carbon dioxide levels, improved pH, and a reduction in inspiratory pressures, allowing for a less-harmful ventilator strategy. These cases demonstrate that the Novalung is a safe and effective device to use in patients with H1N1 pneumonitis refractory to the conventional therapy and may be an alternative to extracorporeal membrane oxygenation (ECMO) in selected cases. PMID- 21554393 TI - Surgical infection prophylaxis for left ventricular assist device implantation. AB - BACKGROUND: Antimicrobial prophylaxis is commonly administered to patients undergoing left ventricular assist device (LVAD) surgeries to prevent infectious complications. However, optimal surgical infection prophylaxis (SIP) for LVAD surgeries is not well defined. METHODS: We conducted an electronic survey to characterize LVAD SIP used at different centers performing LVAD implantation. RESULTS: Responses were received from 23 of 85 centers (27%). Of 21 centers that provided usable data about their LVAD SIP regimens for nonpenicillin allergic patients, 42.9% reported using a four-drug regimen (three antibiotics plus fluconazole), 23.8% reported using a three-drug regimen (three antibiotics or two antibiotics plus fluconazole), 23.8% reported using a regimen of two antibiotics, and 9.5% reported using vancomycin alone. A similar pattern was observed among SIP regimens for penicillin-allergic patients. Criteria for discontinuation of SIP and use of decolonization strategies also varied widely across centers. CONCLUSIONS: Our results demonstrate wide variability in LVAD SIP regimens and underscore the lack of consensus regarding best practice. PMID- 21554394 TI - Extra-anatomic aorto-femoral graft for acute limb ischemia after type a aortic dissection repair. AB - We report an alternative approach to revascularization of the leg in a patient with acute type A aortic dissection, where other options were not feasible. An aorto-femoral extra-anatomic conduit was used to salvage the leg after major aortic surgery where further surgery or endovascular grafting would have lead to increased morbidity. PMID- 21554395 TI - Carotid stenting in high-risk patients: early and late outcomes. AB - PURPOSE: Some patients with severe carotid stenosis have anatomical or clinical comorbidities that place them at high risk for carotid endarterectomy (CEA). The early and late outcomes after carotid artery stenting (CAS) were evaluated in patients at high risk for CEA. METHODS: Between 2002 and 2009, 186 patients were enrolled in a high-risk CAS institutional registry. The primary outcome was major adverse cardiac and cerberovascular events (MACCEs) at 30 days, including death, stroke, and myocardial infarction. Secondary outcomes were technical, procedural, and clinical success; nonstroke neurological events; and death and ipsilateral stroke at 5 years. RESULTS: Twenty-five patients (13.2%) were symptomatic. Thirty day MACCE occurred in 2.6%, including death in 1 (0.5%), stroke in 3 (1.6%), and myocardial infraction in 1 (0.5%) patient. Strokes were nonfatal in 3 (1.6%), major in 2 (1.1%), and minor in 1 (0.5%) patients. Other neurological events included transient ischemic attack in 9 (4.7%) and retinal artery occlusion in 2 (1.1%) patients. After stroke, 2 patients had complete resolution of neurological deficit within 30 days, and 1 patient had improvement in neurological deficit. By Kaplan--Meier analysis, all-cause mortality was 47.5% and ipsilateral stroke was 4.5% at 5 years. CONCLUSIONS: In patients who are high risk for CEA, CAS can be performed with low MACCE at 30 days and ipsilateral stroke at 5 years. However, nearly half of these patients die within 5 years from causes unrelated to stroke. PMID- 21554396 TI - Patient attitudes toward CDC high infectious risk donor kidney transplantation: inferences from focus groups. AB - INTRODUCTION: Deceased donors are considered high infectious risk donors (IRDs) based on criteria thought to be associated with risk of HIV transmission. Significant variation exists in provider willingness to utilize IRD kidneys. Little is known about how patients view these organs. Our aim was to explore patient attitudes toward IRDs and IRD kidney transplantation. METHODS: Patients were recruited from a single-center deceased donor waitlist. Focus groups stratified by age and race were conducted to ascertain patient attitudes toward IRD kidney transplantation. Transcripts were examined using standard qualitative methods. RESULTS: Patients considered IRD kidneys most appropriate for patients at high risk of death or with poor quality of life on dialysis. Patients felt unprepared to receive organ offers, especially from IRDs. They desired information about IRD behaviors, kidney quality, and probability of undetected infection. Patients weighed the opinion of their nephrologist most heavily when deciding about organ offers. A brief education session about donor screening resulted in increased willingness to consider IRD kidneys. CONCLUSIONS: Lack of preparedness contributes to patient apprehension toward IRD organs. Ongoing transplant education seems necessary. The non-transplant nephrologist seems to be the most trusted source of information. PMID- 21554397 TI - Over 500 pancreas transplants by a single team in Sao Paulo, Brazil. AB - Pancreas transplantation (PT) remains a developing practice in Latin America. From 1996 to 2009, 506 PTs were performed by our team in the following categories: simultaneous pancreas-kidney (SPK), simultaneous deceased donor pancreas and living-donor kidney (SPLK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). Enteric drainage was preferred for SPK and bladder drainage for solitary PT or SPLK. Immunosuppression was with tacrolimus, mycophenolate mofetil, and steroids, and anti-lymphocytic drugs were used to induce solitary PT and SPLK. The series includes 254 SPK, 60 SPLK, 94 PAK, and 98 PTA. The one-yr patient survivals were 82% for SPK, 90% for SPLK, 95% for PTA, and 93% for PAK. The one-yr pancreas graft survivals were 70% for SPK, 86% for SPLK, 86% for PAK, and 77% for PTA. The one-yr kidney graft survivals were 77.5% for SPK and 89% for SPLK. This represents the largest reported PT series in Latin America. Results comparable to those of developed countries were achieved, with the exception of the SPK category. This has led our program to prioritize solitary PT and SPLK. PMID- 21554398 TI - The role and future challenges for recombinant growth hormone therapy to promote growth in children after renal transplantation. AB - Chronic kidney disease can severely impair linear growth in children. For many children, growth improves after renal transplantation, but for some, growth velocity remains low and for others, catch-up growth is insufficient to compensate for the deficit imparted by renal disease in the preceding years. Inadequate final adult height after renal transplant is multifactorial and can adversely affect the quality of life (QOL), psychosocial development and long term prospects for these children as they grow into adulthood. Growth failure after renal transplant requires thorough evaluation and its management in renal transplant recipients can involve improved nutritional intake, correction of metabolic acidosis, treatment of secondary hyperparathyroidism, steroid-sparing immunosuppression and/or use of recombinant human growth hormone (rGH). Treatment with rGH after renal transplant has been evaluated by a limited number of clinical trials suggesting efficacy and safety for this treatment strategy. Several important clinical questions regarding rGH use in children post-renal transplant remain unanswered. PMID- 21554399 TI - Pancreas transplantation considering the spectrum of body mass indices. AB - BACKGROUND: In kidney, liver, heart, and lung transplantation, extremes of body mass index (BMI) have been reported to influence post-operative outcomes and even survival. Given the limited data in pancreas transplantation, we sought to elucidate the influence of BMI on outcomes. METHODS: We reviewed 139 consecutive pancreas transplants performed at our institution and divided them into four categories based on BMI: underweight (<=18.5 kg/m(2)), normal (18.6-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), and obese (>=30 kg/m(2)). Parameters analyzed included post-operative complications, early graft loss, one-yr acute rejection rate (AR), non-surgical infections, and survival. RESULTS: Demographic data were similar between the groups. Compared with normal, only obese patients trended toward more post-operative complications (p = 0.06). Underweight and obese patients had significantly more post-operative infectious complications than normal (p = 0.0005 and p = 0.03, respectively). Obese patients had more complications requiring percutaneous drainage compared with normal (p = 0.03). Overweight and obese patients had significantly more complications requiring re laparotomy (p = 0.03 and p = 0.048, respectively). Early graft loss, AR, non surgical infections, and patient and graft survival rates were not different between normal and underweight, overweight, or obese patients (p > 0.05). CONCLUSIONS: Extremes of BMI were associated with increased morbidity. Donors and recipients should be carefully selected to maximize potential for successful outcomes. PMID- 21554400 TI - Direct pressure measurement in the hepatic artery during liver transplantation: can it prevent the "steal" syndrome? AB - Splenic artery "steal" syndrome after orthotopic liver transplantation (OLT) is an important cause of graft dysfunction. Direct pressure measurement in the hepatic (HA) and radial artery (RA) may identify patients at risk allowing its prevention. This observational study compared radial and hepatic mean arterial pressures (MAP) measured during 100 OLTs performed in 99 recipients, in whom the HA was considered suitable for the anastomosis. A difference of >=5 mmHg between the radial and hepatic MAP was arbitrarily chosen as the criterion for inflow modulation. Seven patients fulfilled this criterion showing a MAP gradient that was significantly different compared to the others (-10.8+/-3.3 vs. 2.6+/-5.0; p<0.0001). They underwent splenic artery ligation (n=5), arcuate ligament division (n=1) and aortohepatic bypass grafting (n=1) that all resulted in immediate normalization of the arterial inflow pressure to the graft. The splenic artery "steal" syndrome occurred in one patient (day 2 after OLT) in whom the mean HA pressure normalized during OLT following arcuate ligament division, suggesting pathology within the graft as the most likely etiology. Our results indicate that radial MAP can reflect the hepatic MAP during OLT. If a substantial pressure gradient is found, it can be corrected by intraoperative splenic artery ligation or arcuate ligament division. PMID- 21554401 TI - The impact of two different doses of chelating therapy (deferasirox) on echocardiographic tissue Doppler indices in patients with thalassemia major. AB - BACKGROUND: Chelating therapy in transfusion-dependent patients with beta thalassemia major (beta-TM) is mandatory to reduce the toxic effect of iron on the myocardium. AIM: To evaluate the impact of low and high dose of oral chelating therapy (deferasirox) on pulsed and tissue echocardiographic indices in patients with beta-TM. METHODS: This interventional study conducted on patients with transfusion-dependent beta-TM (n=38) on deferasirox 20 mg/kg/d medication, group (DFX-20) for at least 6 months, followed by administration of a higher dose of deferasirox, 40 mg/kg/d, group (DFX-40) for another 6 months. Pulsed and tissue Doppler echocardiography carried out at the beginning and at the end of treatment interval (6 months) for both groups, with monthly blood analysis of serum ferritin, alanine transaminase, hemoglobin, and creatinine. An age-matched control group of 38 patients was evaluated for echo Doppler blood analysis. RESULTS: Patients of group DXF-40 compared with group DFX-20, the tissue Doppler echocardiogram showed lower E/Em ratio (16.01 +/- 2.85 vs. 19.68 +/- 2.81, P<0.05), higher systolic wave velocity (Sm) (5.87 +/- 1.40 vs. 4.80 +/- 1.20, P<0.05), and higher early diastolic wave (Em) velocity (4.25 +/- 1.70 vs. 3.50 +/ 1.80, P<0.05), respectively. Patients in group DFX-20, compared with control group, had M-Mode echo with thicker left ventricle (LV) septal wall (P<0.001) and posterior wall (P<0.01), higher left ventricle end diastolic diameter index (P<0.05). The pulsed Doppler echocardiogram showed a higher LV transmitral E wave velocity (P<0.05), higher E/A ratio (P<0.01), and the duration of deceleration time was significantly shorter (P<0.01). There were no significant changes observed in the left ventricle ejection fraction percentage (LVEF%) or fractional shortening between both treatment groups. Serum ferritin was significantly lower in DFX-40 group compared with DFX-20 beta-TM group (338). There was a significant positive correlation between the serum ferritin and the E/Em ratio (r=0.31, P<0.001). The tricuspid valve velocity was significantly higher in beta-TM patients compared with the control group (P<0.05). CONCLUSION: The increment of oral deferasirox as chelating therapy in beta-TM patients to 40 mg/kg/d over 6 months duration showed a significant increments of systolic and diastolic tissue Doppler velocities with a significant reduction of E/Em ratio in comparison with 20 mg/kg/d. There were no changes of LVEF. A longer duration of follow-up may be justified in such group of patients. PMID- 21554402 TI - Extra-nodal non-Hodgkin-lymphoma with an acneiform eruption: folliculotropic mycosis fungoides. PMID- 21554403 TI - Differential expression of toll-like receptor mRNAs in recurrent aphthous ulceration. AB - BACKGROUND: Toll-like receptors (TLR) are membrane proteins that recognize conserved molecules derived from bacterial, viral, fungal or host tissues. They are responsible for promoting the production of cytokines and chemokines, increasing the expression of costimulatory molecules and influencing the T Helper response (Th) toward either a Th1 or Th2 profile, thereby modulating the regulatory T cell response and controlling the integrity of the epithelial barrier. The key factors responsible for increased susceptibility to recurrent aphthous ulceration (RAU) are unclear, and because TLRs are involved in both immune regulation and control of the epithelial barrier, a deficiency in TLR activity is likely to cause increased susceptibility. METHODS: We investigated the gene expression of TLRs one through 10 in tissue samples and peripheral blood mononuclear cells (PBMC) of RAU patients in comparison to healthy controls using real-time quantitative reverse transcription PCR. RESULTS: The analysis of mRNA expression levels in oral lesion showed significant (P < 0.01) overexpression of the TLR2 (~6-fold) gene and decreased expression of the TLR3 (~5-fold) and TLR5 (~6-fold) genes in comparison with healthy oral mucosa. The analysis of mRNA expression in PBMC indicated a down-regulation of TLR5 gene expression in the cells from RAU patients (P < 0.05; ~2-fold). CONCLUSION: Our results support the hypothesis that a subset of RAU patients has fewer TLR expression that have been tentatively implicated in anti-inflammatory effects. This derangement of TLR gene expression may cause an overlay exuberant inflammation reaction in situations where normal individuals are resistant. PMID- 21554404 TI - Resorption of deproteinized bovine bone mineral in a porcine calvaria augmentation model. AB - OBJECTIVES: The original aim of the study was to determine the osteoconductive capacity of deproteinized bovine bone mineral (DBBM) of different particle sizes underneath acrylic hemispheres in vivo. However, the model failed and allowed us to report on the resorption of DBBM. MATERIAL AND METHODS: Acrylic hemispheres were filled with and without a DBBM at a small particle size of 125-250 MUm and at the regular particle size of 250-1000 MUm. The hemispheres were positioned on the calvaria of eight minipigs. Histological and histomorphometric analysis was performed after 12 weeks. RESULTS: We found that the acrylic hemispheres were displaced and a dense fibrous capsule sequestered the augmented area. Histology showed severe resorption activity and the presence of multinucleated cells on the surface of DBBM particles in areas adjacent to the fibrous capsule. Histomorphometric analysis revealed that only less than half of the originally augmented area, which was approximately 30 mm(2) , remained after 12 weeks. The amount of residual DBBM (median 0.9 and 3.49 mm(2)) and bone (median 7.22 and 7.51 mm(2)) in the augmented area was similar in the small and the regular particle size group. CONCLUSION: The model represents a pathologic situation of excess resorption of DBBM and bone in an augmented area. The underlying cellular mechanisms remain to be uncovered. PMID- 21554405 TI - Annotation of sheep keratin intermediate filament genes and their patterns of expression. AB - Keratin IF (KRT) and keratin-associated protein genes encode the majority of wool and hair proteins. We have identified cDNA sequences representing nine novel sheep KRT genes, increasing the known active genes from eight to 17, a number comparable to that in the human. However, the absence of KRT37 in the type I family and the discovery of type II KRT87 in sheep exemplify species-specific compositional differences in hair KRT genes. Phylogenetic analysis of hair KRT genes within type I and type II families in the sheep, cattle and human genomes revealed a high degree of consistency in their sequence conservation and grouping. However, there were differences in the fibre compartmentalisation and keratinisation zones for the expression of six ovine KRT genes compared with their human orthologs. Transcripts of three genes (KRT40, KRT82 and KRT84) were only present in the fibre cuticle. KRT32, KRT35 and KRT85 were expressed in both the cuticle and the fibre cortex. The remaining 11 genes (KRT31, KRT33A, KRT33B, KRT34, KRT36, KRT38-39, KRT81, KRT83 and KRT86-87) were expressed only in the cortex. Species-specific differences in the expressed keratin gene sets, their relative expression levels and compartmentalisation are discussed in the context of their underlying roles in wool and hair developmental programmes and the distinctive characteristics of the fibres produced. PMID- 21554406 TI - The cactus effect: an alternative to the lupin effect for increasing ovulation rate in sheep reared in semi-arid regions? AB - The present study evaluated the effects of supplementation with cactus cladodes on follicular dynamics and ovulatory response of sheep reared in semi-arid areas. A total of 76 ewes were distributed into two equal groups supplemented with either concentrated feed or cactus cladodes. After 30 days of supplementation, no differences were found between feeding regimens on the final live weight (LW; 41.5 +/- 0.6 and 42.1 +/- 0.7 kg in the Concentrate and Cactus groups respectively) and body condition score (BCS; 1.8 +/- 0.3 and 1.8 +/- 0.4 for Concentrate and Cactus group respectively). Moreover, no differences were found between the initial and the final values of both LW and BCS; thus, there were no effects of supplementation on any of both parameters. Analysis of follicular population showed that, during the follicular phase induced by ram effect, the number of follicles reaching ovulatory size increased in both groups. However, the number was always higher in Cactus ewes and, at oestrus, Cactus ewes had 1.6 +/- 0.2 and Concentrate sheep had 1.2 +/- 0.2 large follicles (p < 0.05). Thereafter, ovulation rate was affected by duration of supplementation; being higher in sheep fed with cactus for 6-10 days (1.7 +/- 0.1) than in ewes supplied with cactus for more than 11 days (1.3 +/- 0.1; p < 0.05), in sheep fed with concentrate for 6-10 days (1.2 +/- 0.1; p < 0.01) and even than in individuals subjected to classical flushing with concentrate (1.3 +/- 0.1; p < 0.05). PMID- 21554407 TI - Effect of beta-glucosidase on the meat quality and digestibility in broilers. AB - This study investigated the effects of supplementary beta-glucosidase on the carcass composition, meat quality, weight of digestive organ and apparent digestibility in male broilers. Two hundred and forty male, 1-day avine broiler chicks were randomly allocated into four treatment groups and fed with corn-soya bean meal supplemented with 0 (control), 0.6, 1.2 and 1.8 U/g of beta-glucosidase respectively. The results showed that there were no significant differences (p > 0.05) among groups in carcass composition (percentages of eviscerated yield, half eviscerated yield, muscle yield of breast and leg). However, adding 0.6 U/g beta glucosidase to the diet not only altered the meat quality by decreasing the drip loss ratio (p < 0.05) and relative lightness (L*) value (p < 0.01), increasing relative redness (a*) value (p < 0.01), but also significantly decreased the pancreas to body weight ratio (p < 0.05), however, with little effect on liver, proventriculus and gizzard to body weight ratio (p > 0.05). The length and width of duodenum villus were not affected by the addition of beta-glucosidase, but the coefficients of total tract apparent digestibility of protein and fat increased by 9.02% (p < 0.05) and 7.40% (p < 0.01) respectively; the parameters of ash were not affected by beta-glucosidase addition (p < 0.05). This study provided valuable information for evaluation of the effect of supplementary beta glucosidase on the meat quality and digestibility of broilers. PMID- 21554408 TI - Composition and use of puppy milk replacers in German Shepherd puppies in the Netherlands. AB - Enostosis or eosinophilic panosteitis is a common disease in young growing large breed dogs, such as the German Shepherd, and the risk of developing the disease by 3-4 months of age is increased by a high calcium intake. The aim of the study was to investigate whether German Shepherd puppies raised on milk replacers receive more calcium and/or vitamin D than their requirements in the pre-weaning period and thus are at increased risk of developing skeletal diseases. To this end, we surveyed German Shepherd breeders in the Netherlands about the use of puppy milk replacers (PMR). The metabolizable energy, calcium, phosphorus and vitamin D content of the eight most used PMR were compared with that of bitch milk, as reported in the literature. The protein and fat content of most PMR were somewhat lower (range 24.4-33.2 g per 100 g on dmb and 18.3-37.5 g per 100 g on dmb respectively) compared with bitch milk (31.9 and 40.2 g on dmb respectively). The vitamin D content of one of the PMR samples was sevenfold the level recommended by the NRC (Nutrient Requirements of Dogs and Cats, National Academy Press, 2006) and threefold the average level of bitch milk. The clinical relevance of this high amount is questionable, as bitch milk contains mainly 25 hydroxy-vitamin D [3843 MUg (96.1 IU) per 100 g on dmb] and only limited amounts of vitamin D [524 MUg (13.3 IU) per 100 g on dmb], as was determined in this study. Dutch German Shepherd breeders tended to overfeed their puppies. We calculated that misguided use of PMR can increase the risk of excessive calcium, phosphorus and possibly vitamin D intake during a vulnerable period, potentially giving rise to bone and cartilage problems later in life. PMID- 21554409 TI - Animal breeding in India: a time for reflection, and action. PMID- 21554410 TI - MIM: an indirect method to assess inbreeding and coancestry in large incomplete pedigrees of selected dairy cattle. AB - In real data, inbreeding is usually underestimated because of missing pedigree information. A method adapted to the dairy cattle situation is presented to approximate inbreeding when the stored population pedigree is incomplete. Missing parents in incomplete pedigrees were given a dummy identification and assigned to groups (up to nine for a given birth date of progeny). These groups were linked to contemporary reference groups with known parents. An explicit model considered that polygenic breeding values in a censored group were centred on a function of the average breeding value in the corresponding reference group and deviated independently. Inbreeding coefficients were obtained progressively over birth dates starting from founders. For each date considered, the parameters pertaining to its groups were computed using the parameters already obtained from groups belonging to the previous dates. The updating algorithms were given in detail. An indirect method was implemented to expedite mass computations of the relationship coefficients involved (MIM). MIM was compared to Van Raden's (VR) method using simulated populations with 20 overlapping generations and different rates of missing sires and dams. In the situation of random matings, the average inbreeding coefficients by date obtained by MIM were close to true values, whereas they were strongly underestimated by VR. In the situation of assortative matings, MIM gave average inbreeding coefficients moderately underestimated, whereas those of VR's method were still strongly underestimated. The main conclusion of this study adapted to the situation of dairy cattle with incomplete pedigrees was that corrections for inbreeding and coancestry coefficients are more efficient with an explicit appropriate genetic model than without. PMID- 21554411 TI - Udder health and female fertility traits are favourably correlated and support each other in multi-trait evaluations. AB - Genetic parameters were estimated for protein yield (PY), clinical mastitis (CM), somatic cell score, number of inseminations (NI) and days from calving to first insemination (CFI) in first-parity Swedish Red cows by series of tri-variate linear animal models. The heritability of PY was moderate (0.34 +/- 0.004), and the heritabilities of the functional traits were all low (0.014 +/- 0.001-0.14 +/ 0.004). The genetic correlation between CM and CFI (0.38 +/- 0.05) was stronger than the correlation between CM and NI (0.05 +/- 0.06), perhaps because CM and CFI usually are observed in early lactation when the cow is likely to be in negative energy balance, whereas NI generally is recorded when the cow is not in negative energy balance any more. The genetic correlation between NI and CFI was very close to zero (-0.002 +/- 0.05), indicating that these two fertility traits have different genetic backgrounds. All genetic correlations between PY and the functional traits were moderate and unfavourable, ranging from 0.22 +/- 0.02 to 0.47 +/- 0.03. In addition, the effect of including genetic and phenotypic correlations between the trait groups milk production, udder health and female fertility on the accuracy of the selection index was quantified for a heifer, a cow and a proven bull. The difference between the accuracy obtained by multi trait and single-trait evaluations was largest for the cow (0.012) and small for the heifer and the bull (0.006 and 0.004) because the phenotype of the cow for one trait could assist in predicting the Mendelian sampling term for a correlated trait. PMID- 21554412 TI - Gene expression patterns in the ventral tegmental area relate to oestrus behaviour in high-producing dairy cows. AB - Reduced oestrus behaviour expression or its absence (silent oestrus) results in subfertility in high-producing dairy cows. Insight into the genomic regulation of oestrus behaviour is likely to help alleviate reproduction problems. Here, gene expression was recorded in the ventral tegmental area (VTA) of high milk production dairy cows differing in the degree of showing oestrus behaviour (H - highly expressing versus L - lowly expressing), which was then analysed. Genes regulating cell morphology and adhesion or coding for immunoglobulin G (IgG) chains were differentially expressed in VTA between cows around day 0 and 12 of the oestrus cycle, but only in cows that earlier in life tended to show high levels of oestrus behaviour (H0 versus H12). The comparisons between H and L groups of cows also revealed differential expression of several genes (e.g. those of the IgG family or encoding for pro-melanin-concentrating hormone). However, any significant changes in VTA genes expression were detected in the comparison of L0 versus L12 cows. Altogether, the genes expression profile in VTA of cows highly expressing oestrus behaviour changes together with phases of the oestrus cycle, while in case of cows expressing oestrus behaviour lowly it remains stable. This supports the existence of genomic regulation by centrally expressed genes on the expression of oestrus behaviour in dairy cows. PMID- 21554413 TI - Consequences of elimination of the Rendement Napole allele from Danish Hampshire. AB - An elimination programme was carried out to remove the dominant Rendement Napole mutation (RN(-) ) from Danish Hampshire pigs. We reasoned that during and after the elimination of the RN(-) allele, genetic gain of production traits decreased while rate of inbreeding in the population increased compared to the period prior to elimination. The hypothesis was tested by estimating the genetic gain in seven production traits and measuring the rate of inbreeding in the population prior to and during the elimination period. Genetic gain was reduced for quantitative traits daily gain(30-100 kg) and feed conversion ratio, while gain for ultimate pH, lean meat percentage and slaughter loss were increased slightly. There were no changes in genetic gain for daily gain(birth-30 kg) and conformation. RN polymorphism affected several of the quantitative traits. The RN(-) mutation had a dominant effect on the traits daily gain(birth-30 kg) , daily gain(30-100 kg) , slaughter loss, lean meat percentage and ultimate-pH. It exhibited overdominance for feed conversion ratio and additive effect for conformation. Rate of inbreeding decreased during the elimination of RN(-) . Our findings indicate that the consequences of the elimination programme were not as serious as were feared and that a carefully designed preselection strategy may avoid unacceptable loss of genetic gain and excessive loss of genetic variation. PMID- 21554414 TI - Genetic characterization of the Blonde d'Aquitaine cattle breed using microsatellite markers and relationship with three other French cattle populations. AB - This study was conducted to evaluate the genetic diversity of Blonde d'Aquitaine, a well-muscled native French beef breed, and to understand the relationships between Blonde d'Aquitaine, Limousin and Salers. We also compared these three beef breeds to the Holstein dairy breed. For this purpose, a set of 16 microsatellite markers were investigated. The obtained results show that Blonde d'Aquitaine has a high level of genetic diversity. Our study shows also that the French beef breeds have genetic differentiation among them, with approximately 9% of the total variation owing to breed differences. Our results show also that Blonde d'Aquitaine and Salers populations are genetically more similar to each other than to the Limousin. PMID- 21554415 TI - Genetic diversity and conservation of South African indigenous chicken populations. AB - In this study, we compare the level and distribution of genetic variation between South African conserved and village chicken populations using microsatellite markers. In addition, diversity in South African chickens was compared to that of a reference data set consisting of other African and purebred commercial lines. Three chicken populations Venda, Ovambo and Eastern Cape and four conserved flocks of the Venda, Ovambo, Naked Neck and Potchefstroom Koekoek from the Poultry Breeding Resource Unit of the Agricultural Research Council were genotyped at 29 autosomal microsatellite loci. All markers were polymorphic. Village chicken populations were more diverse than conservation flocks. structure software was used to cluster individuals to a predefined number of 2 <= K <= 6 clusters. The most probable clustering was found at K = 5 (95% identical runs). At this level of differentiation, the four conservation flocks separated as four independent clusters, while the three village chicken populations together formed another cluster. Thus, cluster analysis indicated a clear subdivision of each of the conservation flocks that were different from the three village chicken populations. The contribution of each South African chicken populations to the total diversity of the chickens studied was determined by calculating the optimal core set contributions based on Marker estimated kinship. Safe set analysis was carried out using bootstrapped kinship values calculated to relate the added genetic diversity of seven South African chicken populations to a set of reference populations consisting of other African and purebred commercial broiler and layer chickens. In both core set and the safe set analyses, village chicken populations scored slightly higher to the reference set compared to conservation flocks. Overall, the present study demonstrated that the conservation flocks of South African chickens displayed considerable genetic variability that is different from that of the assumed founder populations (village chickens). PMID- 21554416 TI - Genetic analyses of elbow and hip dysplasia in the German shepherd dog. AB - Results from radiographic screening for canine hip dysplasia (CHD) and elbow dysplasia (CED) of 48 367 German shepherd dogs born in 2001-07 were used for the population genetic analyses. Available information included CHD scores for 47 730 dogs, CED scores for 28 011 dogs and detailed veterinary diagnoses of primary ED lesions for a subsample of 18 899 dogs. Quasi-continuous traits were CHD, CED and cases of CED without radiographically visible primary lesion (CED-ARTH). Binary coding was used for fragmented medial coronoid process of the ulna (FCP), borderline findings and mild to severe signs of dysplasia in hip and elbow joints. Genetic parameters were estimated in univariate threshold and multivariate linear and mixed linear-threshold models using Gibbs sampling. Correlations between univariately predicted breeding values (BV) indicated genetic differences between borderline and affected disease status for both CHD (r(BV) = 0.5) and CED (r(BV) = 0.3). Multivariate genetic analyses with separate consideration of borderline findings revealed moderate heritabilities of 0.2-0.3 for the quasi-continuous traits with positive additive genetic correlation of 0.3 between CHD and both CED and CED-ARTH. For FCP, heritability of 0.6 and additive genetic correlations of +0.1 to CHD and -0.1 to CED-ARTH were estimated. Results supported the relevant genetic determination of CHD and CED, argued for both diseases against interpretation of borderline findings as healthy and implied genetic heterogeneity of CED. Accordingly, future breeding strategies to reduce the prevalences of CHD and CED in the German shepherd dog should be most efficient when based on BV from multivariate genetic evaluation for CHD, CED-ARTH and FCP with use of the whole scale of categories for classification of CHD and CED. PMID- 21554417 TI - Symmetry of hip dysplasia traits in the German Shepherd Dog in Australia. AB - Canine hip dysplasia (CHD) is a common and debilitating developmental condition of the canine coxofemoral (hip) joint, exhibiting a multifactorial pattern of inheritance. British Veterinary Association hip traits (BVAHTs) are nine radiographic features of hips used in several countries to ordinally score both the right and left hip of potential breeding candidates to assess their suitability for breeding. The objective of this study was to examine some aspects of the relationship between contralateral scores for each BVAHT in a cohort of 13 124 Australian-registered German Shepherd Dogs. Goodman and Kruskal gamma coefficients of 0.48-0.95 and correlation coefficients of 0.50-0.74 demonstrate that the association between right and left hip scores varies between moderate and strong for BVAHTs. Principal component analysis of scores detected a sizeable left-versus-right effect, a finding supported by symmetry and quasi-symmetry analyses which found that seven of the nine BVAHTs display significant marginal asymmetry. Dogs showing asymmetry for one BVAHT are significantly more likely to display asymmetry at other BVAHTs. When asymmetry is expressed as a binary trait (either symmetrical or asymmetrical), it displays low to moderate heritability. Estimates of genetic correlations between right and left scores are very high for all BVAHTs (>0.945), suggesting right and left scores for each BVAHT are largely determined by the same set of genes. The marginal asymmetries are therefore more likely to be of environmental and non-additive genetic origin. In breeding programmes for CHD, we recommend that scores from both hips be used to estimate breeding values, with a term for side-of-hip included in the model to account for score variation owing to asymmetry. PMID- 21554418 TI - Activation of the human complement system by pigmented and hypopigmented mycelia of the fungus Fonsecaea pedrosoi. AB - The action of the complement system on pigmented and hypopigmented mycelia of the fungus Fonsecaea pedrosoi, the major aetiological pathogen of the chromoblastomycosis is herein discussed. Fungi were grown in medium Czapeck-Dox at 37 degrees C, for 14 days, without shaking to obtain pigmented mycelium. To obtain hypopigmented mycelium, the fungus was grown at the same conditions, but in the dark and with low oxygenation. Activation was measured by complement consumption and enzyme-linked immunosorbent assay. We also observed by immunofluorescence the deposition of C3, C4 fragments and C9 on the surface of the different forms studied. The results indicate that both forms were able to activate the complement system mainly by the alternative pathway. Pigmented mycelia had the highest consumption results, indicating that the pigment, melanin, may have influence in activation. PMID- 21554419 TI - Case-control study of statin prevention of mould infections. AB - Invasive mould infections (IMI) are associated with significant morbidity and mortality. In vitro studies have demonstrated that hydroxymethylglutaryl-CoA (HMG CoA) reductase inhibitors (statins) have activity against several pathogenic moulds including Zygomycetes and Aspergillus spp. The aim of our study was to determine if statin use is a preventive factor for the development of IMI. This was a retrospective case-control study of 10 United States Veterans Affairs Medical Centers that comprise the Veterans Integrated Service Network (VISN) 16. Cases with IMI and controls were identified from 2001 to 2008. Controls were matched by age, facility, history of transplantation, presence of chronic steroid use and presence of human immunodeficiency virus infection (HIV). Two hundred and thirty-eight patients were included. Independent variables associated with the development of IMI were history of solid malignant tumours (OR 2.63, 1.41-4.87) and hypertension (OR 2.29, 1.13-4.68). Statin use within 3 months of index date was not an independent variable for prevention or development of IMI. No level of exposure to a statin drug appeared to influence the development of infection. This retrospective case-control study suggests that despite evidence of in vitro activity, statins may not decrease risk of IMI. Prospective, controlled trials may be necessary to investigate any potential clinical benefit. PMID- 21554420 TI - Mycological survey of activated sludge in MBRs. AB - The objective of this research was to conduct a survey of fungi in activated sludge plants with membrane bioreactors (MBRs). Thirty-six samples of both aerobic and anoxic activated sludge were taken from two plants with MBRs treating domestic wastewater. Over a period of 8 months, two samples from each plant were taken per month. The samples were prepared for count and identification of fungi. The obtained data show that 61 species belonging to 30 genera were identified from activated sludge samples, under aerobic conditions (27 genera and 54 species) and anoxic conditions (21 genera and 39 species), by culturing at 30 degrees C for 15 days. In aerobic activated sludge samples, the prevalence of Geotrichum candidum was 100% followed by Fusarium (72.2%), yeast (61.1%), Aspergillus (50.0%), Penicillium (50.0%) and Trichoderma (41.6%), while in anoxic activated sludge, G. candidum (94.4%), Fusarium (91.6%), Aspergillus (77.7%), yeast (63.8%), Penicillium (50.0%) and Trichoderma (50.0%) species were the most prevalent. In addition, the other genera found included Chaetomum, Chrysosporium, Cladosporium, Doratomyces, Gibberella, Gliocladium, Gymnoascus, Mucor, Paecilomyces, Phialophora, Rhizopus, Scopulariopsis, Stachybotrys, Stemphylium and others. The results indicate that aerobic and anoxic activated sludge provides a suitable habitat for the growth and sporulation of different groups of fungi, both saprophytic and pathogenic. PMID- 21554421 TI - Antifungal treatment strategies in patients with haematological diseases or cancer: from prophylaxis to empirical, pre-emptive and targeted therapy. AB - Immunocompromised patients have a high risk for invasive fungal diseases (IFDs). These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Empirical treatment is regarded as the standard of care for granulocytopenic patients who remain febrile despite broad-spectrum antibiotics. However, this strategy can bear a risk of overtreatment and subsequently induce toxicities and unnecessary treatment costs. Pre-emptive antifungal therapy is now increasingly used to close the time gap between delayed initiation for proven disease and empirical treatment for anticipated infection without further laboratory or radiological evidence of fungal disease. Currently, some new non invasive microbiological and laboratory methods, like the Aspergillus galactomannan sandwich-enzyme immunoassay (Aspergillus GM-ELISA), 1,3-beta-D glucan assay or PCR techniques have been developed for a better diagnosis and determination of target patients. The current diagnostic approaches to fungal infections and the role of the revised definitions for invasive fungal infections, now IFDs, will be discussed in this review as well as old and emerging approaches to empirical, pre-emptive and targeted antifungal therapies in patients with haemato-oncological malignancies. PMID- 21554422 TI - Disseminated erythema multiforme-like reaction triggered by tinea unguium. PMID- 21554423 TI - Current issues in the clinical management of invasive candida infections--the AGIHO, DMykG, OGMM and PEG web-based survey and expert consensus conference 2009. AB - The objectives of this study were to identify unsolved issues in the management of invasive candidiasis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG e.V.) asked other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of fungal infections. Based on these contributions, a digital web-based questionnaire of 12 questions on Candida infections was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG e.V. in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on treatment indications, choice of antifungals for clinical situations, handling of central venous catheters, duration of treatment and role of susceptibility testing. Opinions diverged on: initial treatment of haemodynamically stable neutropenic and haemodynamically unstable non-neutropenic patients, step down to oral treatment and the differential role of the echinocandins. These questions were presented for discussion at the expert consensus conference. In three of four questions, consensus was achieved. A two-step approach - web-based survey plus classical panel discussion - allows to capture expeditiously the opinions of a large and diverse group of individuals, to identify controversial issues and to resolve them in a personal, interactive setting. Thus, expert consensus was achieved on nine of 12 important questions on how to treat invasive candidiasis. PMID- 21554424 TI - Achievements and challenges in composite tissue allotransplantation. AB - Overall, more than 60 hand/forearm/arm transplantations and 16 face transplantations have been performed in the past 12 years. In the European experience summarized here, three grafts have been lost in response to a vascular thrombosis (n = 1), rejection and incompliance with immunosuppression (n = 1) and death (n = 1). The overall functional and esthetic outcome is very satisfactory, but serious side effects and complications related to immunosuppression are challenges hindering progress in this field. The high levels of immunosuppression, skin rejection, nerve regeneration, donor legislation and the acceptance level need to be addressed to promote growth of this promising new field in transplantation and reconstructive surgery. PMID- 21554425 TI - From Ryle's tube to PEG and beyond; a personal journey. PMID- 21554426 TI - Nutritional practices in full-day-care pre-schools. AB - BACKGROUND: Full-day-care pre-schools contribute significantly to the nutritional intake and acquisition of dietary habits of the pre-school child. The present study investigated nutritional practices in full-day-care pre-schools in Dublin, Ireland, aiming to determine the nutritional support that pre-school managers deem necessary, thereby facilitating the amelioration of existing pre-school nutritional training and practices. METHODS: A telephone questionnaire completed by pre-school managers (n=54) examined pre-school dietary practices, food provision and the association between these and pre-school size, nutritional training attendance, possession of the Food and Nutrition Guidelines for Pre school Services and having a healthy eating policy. Nutritional training needs were also investigated. RESULTS: Twenty-five pre-schools provided all food for attending children; parents were sole providers in six. Thirty-four pre-schools had a written healthy eating policy. Attendance at nutritional training was reported by 40. Possession of the Guidelines (n=40) did not consistently result in their use. Poor parental and staff involvement in policy and menu development was cited. Although the delayed introduction of iron-containing foods and a feeding beaker in infants was clearly evident, inappropriate beverages and snacks were served to children aged 1-5 years in 43 and 37 pre-schools, respectively. Training priorities cited by managers included parental education and the provision of information regarding menu planning and healthy food choices. CONCLUSIONS: Nutritional training should advocate whole staff familiarity with and use of current guidelines, in addition to encouraging nutritional policy development and enforcement. Parental education is warranted. Dietary education should focus specifically on appropriate weaning practices, healthy beverage and snack provision and menu planning. PMID- 21554429 TI - Ventral premotor cortex neuronal activity matches perceptual decisions. AB - The relationship between neuronal activity and psychophysical judgments is central to understanding the brain mechanisms responsible for perceptual decisions. The ventral premotor cortex is known to be involved in representing different components of the decision-making process. In this cortical area, however, neither the neuronal ability to discriminate nor the trial-to-trial relationship between neuronal activity and behavior have been studied during visual decision-making. We recorded from single neurons while monkeys reported a decision based on the comparison of the orientation of two lines shown sequentially and separated by a delay. Analyses based on signal detection theory provided both the behavioral and neuronal sensitivities (d') and the coherence between behavioral and neuronal choices. To determine the temporal evolution of neuronal sensitivity and of coherence, the optimal size and position of the encoding windows were assessed. For a subset of neurons from the premotor ventral cortex, neuronal sensitivity was close to behavioral sensitivity and the trial-to trial coherence between the neuronal and behavioral choices was close to 100%. By comparing these results with those obtained in a motor control task we ruled out the possibility of this activity being explained by the motor component of the task. These results suggest that activity in the ventral premotor cortex explains behavioral performance and predicts trial-to-trial subject choices. PMID- 21554431 TI - Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor alpha. AB - Palmitoylethanolamide (PEA) regulates many pathophysiological processes in the central nervous system, including pain perception, convulsions and neurotoxicity, and increasing evidence points to its neuroprotective action. In the present study, we report that PEA, acting as a ligand of peroxisome-proliferator activated receptor (PPAR)-alpha, might regulate neurosteroidogenesis in astrocytes, which, similar to other glial cells and neurones, have the enzymatic machinery for neurosteroid de novo synthesis. Accordingly, we used the C6 glioma cell line and primary murine astrocytes. In the mitochondrial fraction from cells stimulated with PEA, we demonstrated an increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 enzyme (P450scc) expression, both comprising proteins considered to be involved in crucial steps of neurosteroid formation. The effects of PEA were completely blunted by GW6471, a selective PPAR alpha antagonist, or by PPAR-alpha silencing by RNA interference. Accordingly, allopregnanolone (ALLO) levels were increased in supernatant of PEA-treated astrocytes, as revealed by gas chromatography-mass spectrometry, and this effect was inhibited by GW6471. Moreover, PEA showed a protective effect, reducing malondialdehyde formation in cells treated with l-buthionine-(S,R)-sulfoximine, a glutathione depletor and, interestingly, the effect of PEA was partially inhibited by finasteride, a 5alpha-reductase inhibitor. A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis. The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-alpha in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions. PMID- 21554430 TI - Anabolic androgenic steroid abuse: multiple mechanisms of regulation of GABAergic synapses in neuroendocrine control regions of the rodent forebrain. AB - Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone originally developed for clinical purposes but are now predominantly taken at suprapharmacological levels as drugs of abuse. To date, almost 100 different AAS compounds that vary in metabolic fate and physiological effects have been designed and synthesised. Although they are administered for their ability to enhance muscle mass and performance, untoward side effects of AAS use include changes in reproductive and sexual behaviours. Specifically, AAS, depending on the type of compound administered, can delay or advance pubertal onset, lead to irregular oestrous cyclicity, diminish male and female sexual behaviours, and accelerate reproductive senescence. Numerous brains regions and neurotransmitter signalling systems are involved in the generation of these behaviours, and are potential targets for both chronic and acute actions of the AAS. However, critical to all of these behaviours is neurotransmission mediated by GABA(A) receptors within a nexus of interconnected forebrain regions that includes the medial preoptic area, the anteroventral periventricular nucleus and the arcuate nucleus of the hypothalamus. We review how exposure to AAS alters GABAergic transmission and neural activity within these forebrain regions, taking advantage of in vitro systems and both wild-type and genetically altered mouse strains, aiming to better understand how these synthetic steroids affect the neural systems that underlie the regulation of reproduction and the expression of sexual behaviours. PMID- 21554432 TI - Inhibition of maternal behaviour by central infusion of corticotrophin-releasing hormone in marmoset monkeys. AB - Stress can inhibit maternal behaviour and increase rates of child abuse in humans and other animals; however, the neuroendocrine mechanisms are not known. To determine whether corticotrophin-releasing hormone (CRH) plays a role in stress induced disruption of maternal behaviour in primates, we characterised the effects of acute i.c.v. infusions of CRH on maternal and abusive behaviour in common marmoset monkeys (Callithrix jacchus). Nulliparous females were implanted with indwelling i.c.v. guide cannulae before conception. Between 18 and 58 days after the birth of her first infants, each female underwent a series of i.c.v. infusions of human CRH (0, 2, 8 and 25 MUg) in 8 MUl of artificial cerebrospinal fluid. In the 70 min after infusion, marmosets were tested with one of their infants, first in their home cage and, subsequently, in an unfamiliar cage in which the infant was confined in a transparent box on the cage floor. In the home cage, the highest dose of CRH significantly reduced the amount of time that mothers spent carrying their infants, as compared to vehicle alone, although it did not reliably affect aggression toward the infant or other behaviours. In the confined-infant test, the highest dose of CRH significantly reduced the amount of time that mothers spent on the cage floor, increased mothers' vocalisation rates, and tended to reduce their activity levels and time spent in proximity to their infant. Twenty-five micrograms of CRH also elicited significant elevations in plasma adrenocorticotrophic hormone and cortisol concentrations compared to vehicle. These results indicate that i.c.v.-administered CRH reduces maternal behaviour in marmoset mothers, in both familiar and unfamiliar environments, but does not increase infant abuse. PMID- 21554433 TI - Insulin but not leptin protects olfactory mucosa from apoptosis. AB - The mammalian olfactory mucosa (OM) is continually renewed throughout life. Owing to their position in the nasal cavity, OM cells are exposed to multiple insults, including high levels of odourants that can induce their death. OM regeneration is therefore essential to maintain olfactory function, and requires the tight control of both cell death and proliferation. Apoptosis has been implicated in OM cell death. Olfaction is one of the senses involved in food intake and depends on individual nutritional status. We have previously reported the influence of hormones related to nutritional status on odour perception and have shown that the OM is a target of insulin and leptin, two hormones known for their anti apoptotic properties. In the present study, we investigated the potential anti apoptotic effect of these metabolic hormones on OM cells. Both Odora cells (an olfactive cell line) and OM cells treated with etoposide, a p53 activity inducer, exhibited mitochondrial-dependent apoptosis that was inhibited by the pan-caspase inhibitor zVAD-fmk. Insulin, but not leptin, impaired this apoptotic effect. Insulin addition to the culture medium reduced p53 phosphorylation, caspase-3 and caspase-9 cleavage, and caspase-3 enzymatic activity induced by etoposide. The apoptotic wave observed in the OM after interruption of the neuronal connections between the OM and the olfactory bulb by bulbectomy was impaired by intranasal insulin treatment. These findings suggest that insulin may be involved in OM cellular dynamics, through endocrine and/or paracrine-autocrine effects of circulating or local insulin, respectively. PMID- 21554434 TI - The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH) promoter activity in GH3 cells. AB - Somatic mutations in the GNAS1 gene, encoding the alpha-subunit of the heterotrimeric stimulatory G protein (Galphas), occur in approximately 40% of growth hormone (GH)-secreting pituitary tumours. By altering the adenylate cyclase-cAMP-protein kinase A pathway, they unequivocally give somatotroph cells a growth advantage. Hence, the pathogenesis of somatotropinomas could be linked to anomalies in receptors coupled to the cAMP second-messenger cascade. Among them, the glucose-dependent insulinotropic polypeptide receptor (GIPR) is already known to play a primary role in the impaired cAMP-dependent cortisol secretion in patients affected by food-dependent Cushing's syndrome. In the present study, 43 somatotropinomas and 12 normal pituitary glands were investigated for GIPR expression by quantitative reverse transcriptase-polymerase chain reaction, western blotting and immunohistochemistry. Tumoural specimens were also evaluated for GNAS1 mutational status. The effect of GIPR overexpression on cAMP levels and GH transcription was evaluated in an in vitro model of somatotropinomas, the GH secreting pituitary cell line GH3. GIPR was expressed at higher levels compared to normal pituitaries in 13 GNAS1 mutation-negative somatotropinomas. GIP stimulated adenylyl cyclase and GH-promoter activity in GIPR-transfected GH3 cells, confirming a correct coupling of GIPR to Galphas. In a proportion of acromegalic patients, GIPR overexpression appeared to be associated with a paradoxical increase in GH after an oral glucose tolerance test. Whether GIPR overexpression in acromegalic patients may be associated with this paradoxical response or more generally involved in the pathogenesis of acromegaly, as suggested by the mutually exclusive high GIPR levels and GNAS1 mutations, remains an open question. PMID- 21554435 TI - Selenium status and blood lipids: the cardiovascular risk in Young Finns study. AB - BACKGROUND: Concern has been recently raised about possible adverse cardio metabolic effects of high selenium status, such as increased risks of diabetes and hyperlipidaemia. However, most of the evidence comes from selenium-replete populations such as that of the United States. OBJECTIVES: To examine cross sectional and longitudinal associations of serum selenium with cardiovascular risk factors in Finland where selenium levels were amongst the lowest in the world until the early 1980s before the implementation of a nationwide selenium fertilization programme. METHODS: Serum selenium was measured in 1235 young Finns aged 3-18 years at baseline in 1980 (prefertilization) and in a subgroup (N = 262) at the 6-year follow-up (1986, postfertilization). During the 27-year follow up, serum lipids, blood pressure, body mass index and smoking were assessed five times (1980, 1983, 1986, 2001 and 2007). RESULTS: Mean (+/-SD) serum selenium concentrations were 74.3 +/- 14.0 ng mL(-1) in 1980 and 106.6 +/- 12.5 ng mL(-1) in 1986 (average increase 32.3 ng mL(-1); 95% CI: 30.3 to 34.3, P < 0.0001). In univariate and multivariable cross-sectional models in 1980 and 1986, increased serum selenium levels were consistently associated with increased total, HDL and Low-density lipoprotein (LDL) cholesterol. However, the average longitudinal changes in lipids were -0.20 mmol L(-1) (95% CI: -0.30 to -0.10, P < 0.0001) for total cholesterol, 0.06 mmol L(-1) (95% CI: 0.03 to 0.10, P < 0.0001) for HDL cholesterol, and -0.23 mmol L(-1) (95% CI: -0.31 to -0.14, P < 0.0001) for LDL cholesterol. Selenium measured in 1986 was not associated with lipids assessed in 2001 and 2007. CONCLUSIONS: Cross-sectional findings from the Young Finns study corroborate positive associations of selenium status with serum lipids. However, longitudinal evidence does not support the causality of this link. PMID- 21554436 TI - Hundred years of allergen immunotherapy. AB - Allergic rhinitis was almost unknown until the early 19th century, but within 100 years it was described as a modern epidemic. Pollen was identified as the likely cause of hayfever and although the nature and mechanisms of the sensitivity remained obscure, it was speculated that hayfever might be caused by a toxin in pollen. Vaccination schedules were developed to treat this, but later it became clear that an antibody was responsible. The first clinical trials of specific immunotherapy (SIT) were published in 1911 and 1914 and were followed by several similar papers from the United States. The use of skin prick tests and new allergen extraction techniques accelerated the development of SIT, which became a widespread practice, especially in the United States. Formal controlled clinical trials were reported in 1953 (United Kingdom) and in 1965 (United States). Since then, many controlled clinical trials have confirmed the efficacy of SIT, and although some concerns have arisen around safety, SIT remains a valid option for treating allergic disease. Recent developments include the introduction of sublingual immunotherapy, and clinical trials of recombinant and peptide vaccines. Future developments should increase efficacy and safety, but the biggest challenge to the wider use of SIT is probably economic, as patients and healthcare providers become increasingly critical of all forms of allergy treatments. PMID- 21554437 TI - Epithelial-mesenchymal transition in renal fibrosis - evidence for and against. AB - Epithelial to mesenchymal transition (EMT) is a well established biological process in metazoan embryological development. Over the past 15 years, investigators have sought to establish whether EMT also occurs in renal epithelial cells, following kidney injury, and to show that the mesenchymal cells formed could give rise to myofibroblasts which populate the renal interstitium, causing fibrosis within it. There is no doubt that proximal tubular epithelial cells (PTECs) can undergo EMT in vitro in response to TGFbeta-1 and other inflammatory stimuli. Moreover, the results of experiments with animal models of renal fibrosis and examination of biopsies from patients with chronic kidney disease have lent support to the hypothesis that EMT occurs in vivo. This review discusses some of the key evidence underlying that idea and summarises recent advances in understanding the molecular mechanism underlying the process. Early experiments using mice which were genetically engineered to mark PTECs with the LacZ gene to trace their fate following kidney injury provided evidence supporting the occurrence of EMT. Recently, however, cell lineage tracking experiments using the red fluorescent protein (RFP) as a high-resolution marker for cells of renal epithelial origin did not replicate this result; the interstitial space following kidney injury was devoid of RFP expressing cells, leading the investigators to reject the renal EMT hypothesis. PMID- 21554438 TI - The global and essential linkage of pharmacy practice and public health. PMID- 21554439 TI - Development, validation and application of a patient satisfaction scale for a community pharmacy medicines-management service. AB - OBJECTIVE: To develop, validate and apply a scale to measure patient satisfaction in a randomised controlled trial of community pharmacy service. METHODS: Published scales were reviewed to inform development of the patient satisfaction scale. Questionnaires were sent to patients in the control (n=500) and intervention (n=941) groups of a randomised controlled trial of community pharmacy-led management of coronary heart disease at baseline and 12-month follow up. Any underlying main factors were assessed with exploratory factor analysis. Reliability and construct validity were tested. The 15-item scale was used to compare patient satisfaction across arms with their most recent pharmacy visit. RESULTS: Response rates were 92% (461/500) for control and 96% (903/941) for intervention groups at baseline and 85% control (399/472) and intervention (810/941) at follow-up. At baseline satisfaction was very similar in the intervention and control groups (median scores of 42). At follow-up mean satisfaction had significantly improved for the intervention compared with the control (median scores of 46 compared with 43; P<0.01); intervention females were more likely to be satisfied with the service than males (49 compared with 44; P<0.01). Three main factors explained the majority of the data variance. Cronbach's alpha was 0.7-0.9 for both groups over time for all factors and total scale. An increase in the overall satisfaction corresponding to a decrease in subjects wanting that particular service to be provided during their next visit indicated construct validity of the scale. CONCLUSION: A new scale of patient satisfaction with community pharmacy services was developed and shown to be reliable and valid. Its application showed increased satisfaction in the intervention group receiving a new pharmacy service. PMID- 21554440 TI - Non-prescription medicines and Australian community pharmacy interventions: rates and clinical significance. AB - OBJECTIVE: To quantify pharmacy intervention rates for non-prescription medications (pharmacist-only and pharmacy medicines), to document the clinical significance of these interventions and to determine the adverse health consequences and subsequent health care avoided as a result of the interventions. METHODS: Non-prescription medicines interventions undertaken by community pharmacy staff were recorded in two field studies: a study of all Australian pharmacies to determine incidence rates for low-incidence, highly significant interventions, and a study of a sample of pharmacies to collect data on all non prescription interventions. Recorded interventions were assessed by a clinical panel for clinical significance, potential adverse health consequence avoided, probability and likely duration of the adverse health consequence. KEY FINDINGS: The rate of professional intervention that occurs in Australia for pharmacist only and pharmacy medicines is 5.66 per 1000 unit sales (95% confidence interval 4.79-6.64). Rates of intervention varied by clinical significance. When considering health care avoided, the main impact of the interventions was avoidance of urgent general practitioner (GP) visits, followed by avoidance of regular GP visits and accident and emergency treatment. The most common adverse health consequences avoided were exacerbations of an existing condition (e.g. hypertension, asthma) and adverse drug effects. CONCLUSIONS: This study demonstrates the way in which community pharmacy encourages appropriate non prescription medicine use and prevents harm through intervening at the point of supply. It was estimated that Australian pharmacies perform 485912 interventions per annum when dealing with non-prescription medicines, with 101324 per annum being interventions that avert emergency medical attention or serious harm, or which are potentially life saving. PMID- 21554441 TI - Demographic risk factors affecting emergency room visits caused by benzodiazepine poisoning in Kansas City, Missouri, from 2001 to 2007. AB - OBJECTIVE: The study objective was to identify demographic risk factors associated with emergency room visits caused by benzodiazepine poisoning. METHODS: A retrospective study was conducted utilizing Missouri Hospital Discharge Data for Kansas City, Missouri, USA, for 2001-2007. The data included patients' demographics such as racial group, age, sex, health insurance status and annual income. Emergency room visits due to benzodiazepine poisoning were identified by ICD-9 code 969.4. The frequencies of patient visits were calculated according to categories of each demographic variable. Chi-square tests were used to assess the difference of emergency room visits among categories of each demographic variable. A multiple logistic regression analysis was performed, where the outcome variable was emergency room visits due to benzodiazepine poisoning (yes/no), and the independent variables were the demographic variables. KEY FINDINGS: Of 1317566 emergency room visits over the 7-year period, 562 were due to benzodiazepine poisoning. Seventy-seven per cent of these visits were made by patients who were white, of whom 53% were 30-49years old, 56% were female, 74% had health insurance and 44% lived in zip codes with median family incomes of $40000-59999. Chi-square tests were significant for racial group, age and annual income (P<0.01). In the logistic regression white patients were 73% more likely than black patients to have emergency room visits caused by benzodiazepine poisoning (P<0.01), with an odds ratio (95% confidence interval) of 5.63 (4.33 7.30). Compared with those aged 0-19 years, the odds ratio for patients aged 30 39 to have such visits was 2.73 (2.09-3.57), and the odds ratio for patients aged 40-49 was 2.84 (2.17-3.71). CONCLUSIONS: White patients and patients aged 30 49years were at higher risk for emergency room visits due to benzodiazepine poisoning. Health interventions such as medication review by pharmacists may reduce the risk of benzodiazepine poisoning for these patients. PMID- 21554442 TI - Provision of advice on alcohol use in community pharmacy: a cross-sectional survey of pharmacists' practice, knowledge, views and confidence. AB - OBJECTIVE: Community pharmacists are well placed to provide advice to clients on public health issues such as alcohol use. The aim of the study was to characterise community pharmacists' current level of activity and views on providing such advice in Scotland. METHOD: A postal questionnaire survey, covering provision of advice, knowledge and views on alcohol issues, was sent to all community pharmacies in Scotland (n=1098). KEY FINDINGS: The response rate was 45% (497/1098). Knowledge of recommended alcohol-intake limits was high (79 and 84% correct for male and female limits, respectively), but few respondents (5%) currently advised clients on alcohol consumption once a week or more and 29% had never done so. Around a quarter were confident in explaining alcohol limits, binge drinking and confidentiality issues, but about 40% lacked confidence in screening and providing a brief intervention on alcohol. Respondents expressed mixed views on the appropriateness of pharmacist involvement in discussing alcohol use with clients. Attitudes to harmful or hazardous drinkers varied: some 20% of respondents felt uncomfortable with this group, whereas another 20% felt they could work with this group as well as with any other. CONCLUSION: Community pharmacists in Scotland provide little advice on alcohol use, have a reasonable knowledge of recommended limits but lack the knowledge and confidence to provide a brief intervention. Implementation of a brief alcohol intervention in community pharmacy, therefore, would need to be underpinned by an appropriate training programme. Such a programme needs to provide factual knowledge but must also address pharmacists' attitudes to clients and promote confidence in service delivery. PMID- 21554443 TI - Pharmacy student perceptions of public health service roles and responsibilities. AB - BACKGROUND: There is increasing emphasis on pharmacists' assuming responsibility for public health promotion and delivery with formal expansion of public health activities in their practice. A number of pharmacy school accreditation bodies now incorporate public health competencies within expected professional training outcomes. The objective of this study was to characterize pharmacy student perceptions towards pharmacist public health services roles and responsibilities. METHODS: All undergraduate students at the College of Pharmacy at Qatar University were surveyed 1 week following a student-led breast cancer awareness event. A questionnaire was devised from a literature review and comprised of 10 questions assessing pharmacy student motivations, perceptions and anticipated comfort with various pharmacist-conducted public health activities. RESULTS: Ninety-four per cent of students responded, most having participated in the breast cancer awareness event. They generally felt pharmacist participation in such health promotions would enhance the profession's profile among patients (75.1%) and colleagues (89.6%), but recognized that other health professionals may be unfamiliar with certain pharmacist activities in this regard. Students considered knowledge of disease aetiology and diagnosis necessary for pharmacists (97.9%), as well as the obligation to offer non-pharmacological patient counselling (73.8%). Many (61.7%) anticipated comfort in communicating potentially culturally sensitive health matters both to patients in their own practice site or as a spokesperson to the general public. CONCLUSION: Undergraduate pharmacy students in our College of Pharmacy expressed favourable attitudes towards public health roles of pharmacists. Early enthusiasm for participation in public health activities is valuable for building communication skills, promoting leadership and potentially influencing practising pharmacists. PMID- 21554444 TI - Knowledge, attitude and practices of Qatari patients with type 2 diabetes mellitus. AB - OBJECTIVES: Patient compliance with their medications and their ability for self management in type 2 diabetes mellitus (T2DM) is a growing cause of concern to healthcare providers. Knowledge about diabetes, attitude towards the condition and time management with respect to the condition (practice), collectively known as KAP, are known to affect compliance and play an important part in diabetes management. We aimed to describe the knowledge, attitude, practice and psychological status of adult Qatari patients with T2DM, and to explore the interaction between these and other patient-related factors which could impact on the ability of the patients to manage their diabetes and to achieve desirable health outcomes. METHODS: A questionnaire (the Diabetes Habits and Beliefs Questionnaire, DHBQ) was used to investigate the level and relationship between knowledge, attitude, general practice and psychological status of patients with T2DM. The data was collected in face-to-face interviews with patients visiting the diabetic clinic at a tertiary hospital in Qatar during the period January 2008 to March 2009. KEY FINDINGS: There were significant differences in attitude and knowledge between educational levels. Knowledge and attitude were highly correlated and the psychological status of the patient was positively associated with both knowledge and attitude. There was generally poor practice of regularly inspecting feet to detect signs of neuropathy, taking medication in relation to meals, modifying doses when necessary and setting goals for therapy. CONCLUSIONS: The data provided can assist pharmacists and other healthcare practitioners in tailoring educational programmes aimed at improving diabetes control. PMID- 21554445 TI - What do community pharmacists think about undertaking screening and brief interventions with problem drinkers? Results of a qualitative study in New Zealand and England. AB - OBJECTIVE: Problem drinking is an increasing concern to many governments worldwide including those of England and New Zealand. Screening and brief intervention (SBI) is effective at reducing alcohol consumption and preventing escalation of hazardous drinking patterns into harmful drinking or dependence. Community pharmacy has been suggested as a potential site from which to provide readily accessible SBI services. This paper explores the views of 40 pharmacists on the prospect of providing SBI for alcohol health promotion purposes, focusing particularly upon potential barriers and incentives to provision of these services. The aim was to explore the views of community pharmacists toward the development of SBI for risky drinkers through semi-structured interviews. METHODS: Qualitative, tape-recorded interviews conducted with 22 English pharmacists and 18 New Zealand pharmacists. Data collection continued until theme saturation occurred. Transcribed interviews were thematically analysed. KEY FINDINGS: Pharmacists considered there was a place for alcohol health promotion in community pharmacy. However, not all participants were positive about this potential new role and some expressed apprehension about implementing SBI services due to concerns about offending or alienating customers. Other barriers included lack of experience and confidence, problems faced with other health promotion initiatives, time, privacy and remuneration. Other pharmacists were more positive, seeing potential in terms of remaining competitive. Facilitators included a public health campaign to raise awareness of problem drinking, having appropriate screening tools available and training for pharmacists. CONCLUSION: There appears to be potential for alcohol SBI services in community pharmacy, and interventions designed to reduce barriers and enhance incentivisation need to be implemented and evaluated. PMID- 21554446 TI - A public-health approach to site-specific formulary management: addressing deficient drug supplies in Malawi. AB - OBJECTIVES: Maintaining a well-stocked dispensary at a private non-profit clinic in a developing country can often be challenging due to limited financial and human resources. Organizations face frequent drug shortages, excesses of unnecessary medications and potentially inappropriate international donations. To promote adherence to international recommendations and enable targeted requests for international drug donations, this paper describes a process using a public health approach to create a site-specific pharmacy formulary in a resource-poor setting using the World Health Organization's (WHO) Model List of Essential Medicines ('Model List'). METHODS: The study site was a Malawian-run non-profit private clinic serving over 3000 people annually. The organization focuses on providing community support for orphans from the HIV/AIDS crisis in sub-Saharan Africa. While using the Model List as a backbone, we incorporated the clinic's drug inventory, patient needs, clinician prescribing patterns, and the country's national drug list into the final formulary. After analyzing site-specific factors, we determined which WHO Model List therapeutic classes were necessary for the clinic to address in the final formulary. KEY FINDINGS: Of the drug products currently available in the inventory, 65.6% were expired, 29.8% of which were international donations. After removing expired medications from the inventory, seven Model List priority categories remained unaddressed by the clinic's initial inventory. Based on the results of a structured needs assessment, 54 products were selected for the final simplified formulary. CONCLUSIONS: Conscious selection of pharmaceuticals, resulting in a systematic formulary for drug distribution management, is critical so that a clinic can focus on procuring and prescribing the most needed medications. This selection process using the WHO Model List and a public-health approach to drug management could serve as a private clinic model for pharmaceutical optimization and targeted international drug donations in sub-Saharan Africa and other resource limited settings. PMID- 21554447 TI - Local and global volunteer opportunities for pharmacists to contribute to public health. AB - There are many local and global volunteer opportunities for pharmacists to contribute to public health initiatives that help promote health, prevent disease and improve access to care. This article provides perspective and guidance for pharmacists and student pharmacists who desire to take part in volunteer initiatives related to local and global public health needs. The case examples provided are limited to activities that occurred strictly in a volunteer capacity. Pharmacists serving in a volunteer capacity have an opportunity to broaden their depth of practice and patient care responsibilities. Their skills sets and knowledge can be applied in a variety of public health settings to help meet the health care needs of the communities and patients they serve. Emergency response and caring for the underserved are recurring themes within the volunteer opportunities afforded to pharmacists. Examples include, but are not limited to, the US Medical Reserve Corps, health departments, health centres and clinics, medical service trips and disaster relief. Regardless of setting, the volunteer pharmacist will need to consider scope of practice limitations and certain legal protections. An array of volunteer opportunities exists for pharmacists and student pharmacists in the public health arena. Participating in these events allows pharmacists to expand their practice experiences while contributing to public health needs and outreach. PMID- 21554448 TI - The expanding public health threat of obesity and overweight. AB - Obesity and overweight is a continuing public health crisis. This health threat respects no boundaries or economic strata, and is a pervasive universal threat with short- and long-term negative sequelae associated. Pharmacists and other health professionals need to structure interventions from individual patient and population-based standpoints. Documentation of effects of programmes needs to be disseminated and incorporated into educational, research and practice-based efforts. PMID- 21554449 TI - PIPKs are essential for rhizoid elongation and caulonemal cell development in the moss Physcomitrella patens. AB - PtdIns-4,5-bisphosphate is a lipid messenger of eukaryotic cells that plays a critical role in processes such as cytoskeleton organization, intracellular vesicular trafficking, secretion, cell motility, regulation of ion channels and nuclear signalling pathways. The enzymes responsible for the synthesis of PtdIns(4,5)P2 are phosphatidylinositol phosphate kinases (PIPKs). The moss Physcomitrella patens contains two PIPKs, PpPIPK1 and PpPIPK2. To study their physiological role, both genes were disrupted by targeted homologous recombination and as a result mutant plants with lower PtdIns(4,5)P2 levels were obtained. A strong phenotype for pipk1, but not for pipk2 single knockout lines, was obtained. The pipk1 knockout lines were impaired in rhizoid and caulonemal cell elongation, whereas pipk1-2 double knockout lines showed dramatic defects in protonemal and gametophore morphology manifested by the absence of rapidly elongating caulonemal cells in the protonemal tissue, leafy gametophores with very short rhizoids, and loss of sporophyte production. pipk1 complemented by overexpression of PpPIPK1 fully restored the wild-type phenotype whereas overexpression of the inactive PpPIPK1E885A did not. Overexpression of PpPIPK2 in the pipk1-2 double knockout did not restore the wild-type phenotype demonstrating that PpPIPK1 and PpPIPK2 are not functionally redundant. In vivo imaging of the cytoskeleton network revealed that the shortened caulonemal cells in the pipk1 mutants was the result of the absence of the apicobasal gradient of cortical F actin cables normally observed in wild-type caulonemal cells. Our data indicate that both PpPIPKs play a crucial role in the development of the moss P. patens, and particularly in the regulation of tip growth. PMID- 21554450 TI - PHOSPHATIDYLSERINE SYNTHASE1 is required for microspore development in Arabidopsis thaliana. AB - Phosphatidylserine (PS) has many important biological roles, but little is known about its role in plants, partly because of its low abundance. We show here that PS is enriched in Arabidopsis floral tissues and that genetic disruption of PS biosynthesis decreased heterozygote fertility due to inhibition of pollen maturation. At1g15110, designated PSS1, encodes a base-exchange-type PS synthase. Escherichia coli cells expressing PSS1 accumulated PS in the presence of l-serine at 23 degrees C. Promoter-GUS assays showed PSS1 expression in developing anther pollen and tapetum. A few seeds with pss1-1 and pss1-2 knockout alleles escaped embryonic lethality but developed into sterile dwarf mutant plants. These plants contained no PS, verifying that PSS1 is essential for PS biosynthesis. Reciprocal crossing revealed reduced pss1 transmission via male gametophytes, predicting a rate of 61.6%pss1-1 pollen defects in PSS1/pss1-1 plants. Alexander's staining of inseparable qrt1-1 PSS1/pss1-1 quartets revealed a rate of 42% having three or four dead pollen grains, suggesting sporophytic pss1-1 cell death effects. Analysis with the nuclear stain 4',6-diamidino-2-phenylindole (DAPI) showed that all tetrads from PSS1/pss1-1 anthers retain their nuclei, whereas unicellular microspores were sometimes anucleate. Transgenic Arabidopsis expressing a GFP LactC2 construct that binds PS revealed vesicular staining in tetrads and bicellular microspores and nuclear membrane staining in unicellular microspores. Hence, distribution and/or transport of PS across membranes were dynamically regulated in pollen microspores. However, among unicellular microspores from PSS1/pss1-2 GFP-LactC2 plants, all anucleate microspores showed little GFP-LactC2 fluorescence, suggesting that pss1-2 microspores are more sensitive to sporophytic defects or show partial gametophytic defects. PMID- 21554451 TI - Phylogenetic variation in glycosidases and glycanases acting on plant cell wall polysaccharides, and the detection of transglycosidase and trans-beta-xylanase activities. AB - Wall polysaccharide chemistry varies phylogenetically, suggesting a need for variation in wall enzymes. Although plants possess the genes for numerous putative enzymes acting on wall carbohydrates, the activities of the encoded proteins often remain conjectural. To explore phylogenetic differences in demonstrable enzyme activities, we extracted proteins from 57 rapidly growing plant organs with three extractants, and assayed their ability to act on six oligosaccharides 'modelling' selected cell-wall polysaccharides. Based on reaction products, we successfully distinguished exo- and endo-hydrolases and found high taxonomic variation in all hydrolases screened: beta-D-xylosidase, endo-(1->4)-beta-D-xylanase, beta-D-mannosidase, endo-(1->4)-beta-D-mannanase, alpha-D-xylosidase, beta-D-galactosidase, alpha-L-arabinosidase and alpha-L fucosidase. The results, as GHATAbase, a searchable compendium in Excel format, also provide a compilation for selecting rich sources of enzymes acting on wall carbohydrates. Four of the hydrolases were accompanied, sometimes exceeded, by transglycosylase activities, generating products larger than the substrate. For example, during beta-xylosidase assays on (1->4)-beta-D-xylohexaose (Xyl6), Marchantia, Selaginella and Equisetum extracts gave negligible free xylose but approximately equimolar Xyl5 and Xyl7, indicating trans-beta-xylosidase activity, also found in onion, cereals, legumes and rape. The yield of Xyl9 often exceeded that of Xyl7-8, indicating that beta-xylanase was accompanied by an endotransglycosylase activity, here called trans-beta-xylanase, catalysing the reaction 2Xyl6 -> Xyl3 + Xyl9. Similar evidence also revealed trans-alpha xylosidase, trans-alpha-arabinosidase and trans-alpha-arabinanase activities acting on xyloglucan oligosaccharides and (1->5)-alpha-L-arabino oligosaccharides. In conclusion, diverse plants differ dramatically in extractable enzymes acting on wall carbohydrate, reflecting differences in wall polysaccharide composition. Besides glycosidase and glycanase activities, five new transglycosylase activities were detected. We propose that such activities function in the assembly and re-structuring of the wall matrix. PMID- 21554452 TI - The biosynthesis of Caryophyllaceae-like cyclic peptides in Saponaria vaccaria L. from DNA-encoded precursors. AB - Cyclic peptides (CPs) are produced in a very wide range of taxa. Their biosynthesis generally involves either non-ribosomal peptide synthases or ribosome-dependent production of precursor peptides. Plants within the Caryophyllaceae and certain other families produce CPs which generally consist of 5-9 proteinogenic amino acids. The biological roles for these CPs in the plant are not very clear, but many of them have activity in mammalian systems. There is currently very little known about the biosynthesis of CPs in the Caryophyllaceae. A collection of expressed sequence tags from developing seeds of Saponaria vaccaria was investigated for information about CP biosynthesis. This revealed genes that appeared to encode CP precursors which are subsequently cyclized to mature CPs. This was tested and confirmed by the expression of a cDNA encoding a putative precursor of the CP segetalin A in transformed S. vaccaria roots. Similarly, extracts of developing S. vaccaria seeds were shown to catalyze the production of segetalin A from the same putative (synthetic) precursor. Moreover, the presence in S. vaccaria seeds of two segetalins, J [cyclo(FGTHGLPAP)] and K [cyclo(GRVKA)], which was predicted by sequence analysis, was confirmed by liquid chromatography/mass spectrometry. Sequence analysis also predicts the presence of similar CP precursor genes in Dianthus caryophyllus and Citrus spp. The data support the ribosome-dependent biosynthesis of Caryophyllaceae-like CPs in the Caryophyllaceae and Rutaceae. PMID- 21554453 TI - Large-scale detection of rare variants via pooled multiplexed next-generation sequencing: towards next-generation Ecotilling. AB - Common variants, such as those identified by genome-wide association scans, explain only a small proportion of trait variation. Growing evidence suggests that rare functional variants, which are usually missed by genome-wide association scans, play an important role in determining the phenotype. We used pooled multiplexed next-generation sequencing and a customized analysis workflow to detect mutations in five candidate genes for lignin biosynthesis in 768 pooled Populus nigra accessions. We identified a total of 36 non-synonymous single nucleotide polymorphisms, one of which causes a premature stop codon. The most common variant was estimated to be present in 672 of the 1536 tested chromosomes, while the rarest was estimated to occur only once in 1536 chromosomes. Comparison with individual Sanger sequencing in a selected sub-sample confirmed that variants are identified with high sensitivity and specificity, and that the variant frequency was estimated accurately. This proposed method for identification of rare polymorphisms allows accurate detection of variation in many individuals, and is cost-effective compared to individual sequencing. PMID- 21554454 TI - Additive inheritance of histone modifications in Arabidopsis thaliana intra specific hybrids. AB - Plant genomes are earmarked with defined patterns of chromatin marks. Little is known about the stability of these epigenomes when related, but distinct genomes are brought together by intra-species hybridization. Arabidopsis thaliana accessions and their reciprocal hybrids were used as a model system to investigate the dynamics of histone modification patterns. The genome-wide distribution of histone modifications H3K4me2 and H3K27me3 in the inbred parental accessions Col-0, C24 and Cvi and their hybrid offspring was compared by chromatin immunoprecipitation in combination with genome tiling array hybridization. The analysis revealed that, in addition to DNA sequence polymorphisms, chromatin modification variations exist among accessions of A. thaliana. The range of these variations was higher for H3K27me3 (typically a repressive mark) than for H3K4me2 (typically an active mark). H3K4me2 and H3K27me3 were rather stable in response to intra-species hybridization, with mainly additive inheritance in hybrid offspring. In conclusion, intra-species hybridization does not result in gross changes to chromatin modifications. PMID- 21554455 TI - Role of tomato BRANCHED1-like genes in the control of shoot branching. AB - In angiosperms, shoot branching greatly determines overall plant architecture and affects fundamental aspects of plant life. Branching patterns are determined by genetic pathways conserved widely across angiosperms. In Arabidopsis thaliana (Brassicaceae, Rosidae) BRANCHED1 (BRC1) plays a central role in this process, acting locally to arrest axillary bud growth. In tomato (Solanum lycopersicum, Solanaceae, Asteridae) we have identified two BRC1-like paralogues, SlBRC1a and SlBRC1b. These genes are expressed in arrested axillary buds and both are down regulated upon bud activation, although SlBRC1a is transcribed at much lower levels than SlBRC1b. Alternative splicing of SlBRC1a renders two transcripts that encode two BRC1-like proteins with different C-t domains due to a 3'-terminal frameshift. The phenotype of loss-of-function lines suggests that SlBRC1b has retained the ancestral role of BRC1 in shoot branch suppression. We have isolated the BRC1a and BRC1b genes of other Solanum species and have studied their evolution rates across the lineages. These studies indicate that, after duplication of an ancestral BRC1-like gene, BRC1b genes continued to evolve under a strong purifying selection that was consistent with the conserved function of SlBRC1b in shoot branching control. In contrast, the coding sequences of Solanum BRC1a genes have evolved at a higher evolution rate. Branch-site tests indicate that this difference does not reflect relaxation but rather positive selective pressure for adaptation. PMID- 21554456 TI - Wheat flowering repressor VRN2 and promoter CO2 compete for interactions with NUCLEAR FACTOR-Y complexes. AB - The transition from vegetative to reproductive development in the temperate cereals is mainly regulated by seasonal cues including vernalization (determined mainly by VRN1 and VRN2 genes) and photoperiod (determined mainly by PPD1 and CO2 genes). The wheat VRN3 gene, which is similar to Arabidopsis FT, plays a central role in the integration of the competing signals from these two pathways. Under long days, VRN3 transcription is down-regulated by VRN2, a unique flowering repressor in cereals, and up-regulated by CO2. Overexpression of VRN3 overcomes VRN2 repression and promotes VRN1 transcription and flowering initiation. Using yeast two- and three-hybrid assays we show here that the CCT domains present in VRN2 and CO2 proteins interact with the same subset of eight NF-Y proteins, and that these CCT proteins compete with NF-YA for interactions with NF-YB proteins. We have confirmed all these interactions in vitro, and the interactions between VRN2 and two of the three NF-YB proteins were further confirmed in planta. In addition, we show that mutations in the CCT domain of VRN2 that eliminate the vernalization requirement in winter wheat also reduce the strength of the interactions between VRN2 and NF-Y proteins, and the ability of VRN2 to compete with CO2. Taken together, our results suggest that the interactions between CCT and NF-Y proteins play an important role in the integration of the vernalization and photoperiod seasonal signals, and provide a flexible combinatorial system to integrate multiple developmental and environmental signals in the regulation of flowering initiation in the temperate cereals. PMID- 21554457 TI - Biolistic co-transformation of the nuclear and plastid genomes. AB - Particle gun-mediated (so-called 'biolistic') transformation represents a universal genetic transformation technology that is widely applied in nearly all groups of organisms. The mechanism of how accelerated DNA-coated particles, after their entry into the cell, deliver the foreign DNA to the target compartment is not known. Here we have studied this process in plants by performing co transformation experiments with vectors targeted to two different cellular compartments, the nucleus and the plastids (chloroplasts). We find that coating of particles with both plastid and nuclear transformation vectors can result in co-transformation of chloroplasts and the nucleus. In contrast, mixing of particles coated individually with the vectors does not produce co-transformed plants. Our data suggest that a single DNA-coated particle can transform more than one compartment of the plant cell, opening up the possibility to generate doubly transgenic plants in one step. Importantly, co-transformation can also be obtained in the absence of selection, thus providing a method to produce marker free transgenic genomes. In addition, our findings raise the possibility of occasional inadvertent co-transformation of two genomes and, therefore, have important implications for the molecular characterization and regulation of transgenic plants. PMID- 21554458 TI - Pseudomonas syringae colonizes distant tissues in Nicotiana benthamiana through xylem vessels. AB - The ability to move from the primary infection site and colonize distant tissue in the leaf is an important property of bacterial plant pathogens, yet this aspect has hardly been investigated for model pathogens. Here we show that GFP expressing Pseudomonas syringae pv. syringae DC3000 that lacks the HopQ1-1 effector (PtoDC3000DeltahQ) has a strong capacity to colonize distant leaf tissue from wound-inoculated sites in N. benthamiana. Distant colonization occurs within 1 week after toothpick inoculation and is characterized by distant colonies in the apoplast along the vasculature. Distant colonization is blocked by the non host resistance response triggered by HopQ1-1 in an SGT1-dependent manner and is associated with an explosive growth of the bacterial population, and displays robust growth differences between compatible and incompatible interactions. Scanning electron microscopy revealed that PtoDC3000DeltahQ bacteria are present in xylem vessels, indicating that they use the xylem to move through the leaf blade. Distant colonization does not require flagellin-mediated motility, and is common for P. syringae pathovars that represent different phylogroups. PMID- 21554459 TI - Editorial: Credibility and impact: two sides of the same coin. PMID- 21554460 TI - Decompression sickness in hyperbaric nurses: retrospective analysis of 4500 treatments. PMID- 21554461 TI - Commentary on Shields L (2010) Models of care: questioning family-centred care. Journal of Clinical Nursing 19, 2629-2638. PMID- 21554462 TI - Commentary on Shields L (2010) Questioning family-centred care. Journal of Clinical Nursing 19, 2629-2638. PMID- 21554463 TI - Commentary on Chen WT & Han M (2010) Knowledge, attitudes, perceived vulnerability of Chinese nurses and their preferences for caring for HIV-positive individuals: a cross-sectional survey. Journal of Clinical Nursing 19, 3227-3234. PMID- 21554464 TI - Variability of human upper airway collapsibility during sleep and the influence of body posture and sleep stage. AB - The critical pressure at which the pharynx collapses (Pcrit) is an objective measurement of upper airway collapsibility, an important pathogenetic factor in obstructive sleep apnoea. This study examined the inherent variability of passive Pcrit measurement during sleep and evaluated the effects of sleep stage and body posture on Pcrit. Repeated measurements of Pcrit were assessed in 23 individuals (15 male) with diagnosed obstructive sleep apnoea throughout a single overnight sleep study. Body posture and sleep stage were unrestricted. Applied upper airway pressure was repetitively reduced to obtain multiple measurements of Pcrit. In 20 subjects multiple measurements of Pcrit were obtained. The overall coefficient of repeatability for Pcrit measurement was 4.1 cm H2O. Considering only the lateral posture, the coefficient was 4.8 cm H2O. It was 3.3 cm H2O in the supine posture. Pcrit decreased from the supine to lateral posture [supine mean 2.5 cm H2O, 95% confidence interval (CI) 1.4-3.6; lateral mean 0.3 cm H2O, 95% CI -0.8-1.4, P = 0.007] but did not vary with sleep stage (P = 0.91). This study has shown that the overall coefficient of repeatability was 4.1 cm H2O, implying that the minimum detectable difference, with 95% probability, between two repeated Pcrit measurements in an individual is 4.1 cm H2O. Such variability in overnight measures of Pcrit indicates that a single unqualified value of Pcrit cannot be used to characterize an individual's overall collapsibility during sleep. When within-subject variability is accounted for, change in body posture from supine to lateral significantly decreases passive pharyngeal collapsibility. PMID- 21554465 TI - Out-of-area provision for adults with intellectual disabilities and challenging behaviour in England: policy perspectives and clinical reality. AB - BACKGROUND: The use of out-of-area placements to meet the needs of individuals with intellectual disabilities and challenging behaviour has been increasing in the UK. Such placements claim a large proportion of service budget expenditure; therefore, it is important to consider whether they offer the best-quality care. This paper reports on current evidence relating to such placements and uses a scoping review across five London boroughs to illustrate key issues on provider characteristics and aspects of good practice. METHODS: We conducted a literature review to identify papers that describe out-of-area placements and carried out a postal survey of 54 service providers that delivered services to service users from five London boroughs. RESULTS: Individuals with intellectual disability and challenging behaviour are more likely to be placed out-of-area in services of variable quality and a minority may underperform. Our empirical data suggest that the private sector that is the main accommodation provider is most likely to underperform on meeting standards of care. CONCLUSION: Overall, the majority of out-of-area providers appear to supply a good standard of care but there are many factors that continue to hinder the local treatment of individuals who present with challenging behaviour. There is an imperative to identify poorly performing providers as well as exploring ways in which service users, out-of-area, can be supported effectively. PMID- 21554466 TI - Defendants with intellectual disabilities and mental health diagnoses: faring in a mental health court. AB - BACKGROUND: Begun in the late 1990s, mental health courts are specialty criminal courts developed to address the needs of persons with mental illness. METHODS: As many persons with intellectual disabilities (IDs) may overlap in the mental health court system, we used mental health court records to examine the phenomenology and outcomes of 224 defendants with and without co-occurring IDs in the mental health court. This study had two goals: (1) to examine the prevalence of defendants with IDs in the court and (2) to compare defendants with dual diagnoses with defendants with lone mental health disorders. RESULTS: Approximately 11% of defendants in the mental health court also had IDs. Compared with individuals with mental health disorders alone, individuals with dual diagnoses were more likely to be younger, male, African-American and less well educated; these defendants were also more likely to show externalising, 'turning against-others' symptoms, less likely to show internalising, 'turning-against self' symptoms. Defendants with IDs (vs. those without) more often received behavioural, vocational rehabilitation and other services, although the two groups did not differ on most outcome variables. CONCLUSION: Directions for future research are discussed. PMID- 21554467 TI - Mental health aspects of autistic spectrum disorders in children. AB - BACKGROUND: Previous studies have reported variable and at times opposite findings on comorbid psychiatric problems in children with autistic spectrum disorders (ASD). AIMS: This study aimed to examine patterns of comorbid psychiatric problems in children with ASD and their parents compared with IQ matched controls and their parents. METHODS: Behavioural/emotional problems were evaluated in a sample of children with ASD [a diagnosis of ASD was given if they met criteria for ASD on both of the ADI-R (Autism Diagnostic Interview-Revised) and ADOS (Autism Diagnostic Observational Schedule)] and an age and IQ matched control group using the Child Behavior Checklist (CBCL/6-18). Parental psychological distress for both groups was evaluated with the Brief Symptom Inventory (BSI). RESULTS: There were 59 (88%) boys and 8 (12%) girls in the ASD group. Similarly, 57 (85%) of the control group were male and 10 (15%) were female. The groups did not differ significantly on mean age, mean IQ scores, gender and parents mean age. Results of the CBCL/6-18 revealed that the majority of parents reported their child with ASD as having either internalising (clinical range: 47.8%; borderline range: 16.4%) or externalising problems (clinical range: 10.4%; borderline range: 20.9%). In the control group more parents reported their children having externalising (clinical range: 46.3%; borderline range: 16.4%) than internalising problems (clinical range: 35.8%; borderline range: 11.9%). Almost a half of the ASD group met CBCL DSM criteria for clinically significant attention deficit hyperactivity disorder (44.78%) and anxiety (46.2%) problems. Based on the Brief Symptom Inventory Global Severity Index 22.4% of fathers and 23.8% of mothers of ASD children produced scores that were indicative of possible psychopathology. CONCLUSIONS: High rates of clinically significant psychiatric problems were detected in ASD children, with anxiety and attention deficit hyperactivity disorder being the most frequently detected syndromes. PMID- 21554468 TI - Identifying the barriers and facilitators to participation in physical activity for children with Down syndrome. AB - BACKGROUND: Many children with Down syndrome do not undertake the recommended amount of daily physical activity. The aim of this study was to explore the barriers and facilitators to physical activity for this group. METHODS: Eighteen in-depth interviews were conducted with 20 parents (16 mothers, 4 fathers) of children with Down syndrome aged between 2 and 17 years to examine what factors facilitate physical activity and what factors are barriers to activity for their children. The participants were recruited through a community disability organisation that advocates for people with Down syndrome and their families. Interviews were recorded, transcribed and independently coded and analysed by two researchers using thematic analysis. RESULTS: Four themes on facilitators of physical activity were identified: (1) the positive role of the family; (2) opportunity for social interaction with peers; (3) structured accessible programmes that make adaptations for children with Down syndrome; and (4) children who were determined to succeed and physically skilled. Four themes on the barriers to physical activity were also identified: (1) characteristics commonly associated with Down syndrome; (2) competing family responsibilities; (3) reduced physical or behavioural skills; and (4) a lack of accessible programmes. CONCLUSIONS: The results highlight the important role of families in determining how much physical activity children with Down syndrome undertake and the effect that common characteristics associated with Down syndrome can have on maintaining an active lifestyle. Future research needs to concentrate on successful methods of encouraging physical activity, such as ensuring social interaction is part of the activity, and eliminating barriers to physical activity such as the a lack of appropriate programmes for children with Down syndrome. Implementing these strategies may encourage children with Down syndrome to participate more frequently in a physically active lifestyle. PMID- 21554469 TI - Featural versus configural face processing in a rare genetic disorder: Williams syndrome. AB - BACKGROUND: Williams syndrome (WMS) is a rare genetic disorder with an estimated prevalence of 1 in 20 000 live births. Among other characteristics, WMS has a distinctive cognitive profile with spared face processing and language skills that contrasts with impairment in the cognitive domains of spatial cognition, problem solving and planning. It remains unclear whether individuals with WMS process faces using a featural strategy that focuses on features or a configural strategy that takes into consideration the contour of a face and spatial relations between features. METHODS: To investigate face processing in WMS, the tasks specifically probe unfamiliar face matching by using a design that includes manipulations in face presentation (thatcherised and non-thatcherised), face orientation (upright and inverted) and face valence (happy and neutral expression) in a match-to-target face recognition design. The sample consisted of 20 participants with WMS, 10 participants with non-specific developmental delay (IQ-matched) and 10 normal control participants (chronological age-matched). RESULTS: Similar to normal controls, WMS performed best when faces were presented upright. The results show while the WMS group did not perform as well as their typically developing counterparts, they did significantly better than the IQ matched developmentally delayed group. WMS did not show an accuracy advantage for inverted faces commonly understood as an index for featural face processing, nor did they perform better on thatcherised inverted face conditions whereby featural processing is forced. Furthermore, no accuracy advantage was observed for positively valenced (happy) faces in the WMS group. CONCLUSION: These results are consistent with previous work showing a configural face processing approach in WMS, a strategy that is also utilised by normal controls. PMID- 21554470 TI - Mental health: knowledge, attitudes and training of professionals on dual diagnosis of intellectual disability and psychiatric disorder. AB - BACKGROUND: Dual diagnosis (DD) refers to the coexistence of intellectual disability and psychiatric disorder. In order to provide individuals with DD with adequate care, it is essential for mental health workers to have adequate knowledge and positive attitudes. These may be achieved through proper training. AIMS: To summarise the available literature examining the knowledge, attitudes and training of psychiatrists and other professional caregivers in regard to serving people with DD. METHODS: A search strategy was developed to find manuscripts published in English since 1995. RESULTS: Twenty-seven studies on knowledge, attitudes and training in the field of DD were identified and reviewed in this paper. CONCLUSION: The findings of this review stress the need to improve the knowledge, competence and attitudes of practitioners within the DD field via training and practice opportunities. In light of this review, recommendations for improving training opportunities and for conducting future research are made. PMID- 21554471 TI - Brain plasticity over the metamorphic boundary: carry-over effect of larval environment on froglet brain development. AB - Brain development shows high plasticity in response to environmental heterogeneity. However, it is unknown how environmental variation during development may affect brain architecture across life history switch points in species with complex life cycles. Previously, we showed that predation and competition affect brain development in common frog (Rana temporaria) tadpoles. Here, we studied whether larval environment had carry-over effects in brains of metamorphs. Tadpoles grown at high density had large optic tecta at metamorphosis, whereas tadpoles grown under predation risk had small diencephala. We found that larval density had a carry-over effect on froglet optic tectum size, whereas the effect of larval predation risk had vanished by metamorphosis. We discuss the possibility that the observed changes may be adaptive, reflecting the needs of an organism in given environmental and developmental contexts. PMID- 21554473 TI - Comparison of radiography and ultrasonography for diagnosing small-intestinal mechanical obstruction in vomiting dogs. AB - A cross-sectional study was performed on acutely vomiting dogs to compare the accuracy of radiography and ultrasonography for the diagnosis of small-intestinal mechanical obstruction and to describe several radiographic and ultrasonographic signs to identify their contribution to the final diagnosis. The sample population consisted of 82 adult dogs and small-intestinal obstruction by foreign body was confirmed in 27/82 (33%) dogs by surgery or necropsy. Radiography produced a definitive result (obstructed or not obstructed) in 58/82 (70%) of dogs; ultrasonography produced a definitive result in 80/82 (97%) of dogs. On radiographs, a diagnosis of obstruction was based on detection of segmental small intestinal dilatation, plication, or detection of a foreign body. Approximately 30% (8/27) of obstructed dogs did not have radiographic signs of segmental small intestinal dilatation, of which 50% (4/8) were due to linear foreign bodies. The ultrasonographic diagnosis of small-intestinal obstruction was based on detection of an obstructive lesion, sonographic signs of plication or segmental, small intestinal dilatation. The ultrasonographic presence or absence of moderate-to severe intestinal diameter enlargement (due to lumen dilatation) of the jejunum (>1.5 cm) was a useful discriminatory finding and, when present, should prompt a thorough search for a cause of small-intestinal obstruction. In conclusion, both abdominal radiography and abdominal ultrasonography are accurate for diagnosing small-intestinal obstruction in vomiting dogs and either may be used depending on availability and examiner choice. Abdominal ultrasonography had greater accuracy, fewer equivocal results and provided greater diagnostic confidence compared with radiography. PMID- 21554474 TI - Radiographic characterization of the os penis in the cat. AB - The os penis in the cat has not been described radiographically, as compared with the dog. However, a small linear bony radiopacity is sometimes detected in the perineal area of male cats. We hypothesized that the feline os penis might be visible on survey radiographs of the pelvis, and we aimed to investigate the frequency of its visualization using analog and computed radiography (CR) system. One hundred radiographs of the pelvis of 99 male cats were reviewed retrospectively (50 were obtained with a CR system and 50 with an analog system). Age, breed, neutering status, and reason for presentation were recorded, as well as the visualization of the os penis. An os penis was detected in 19/50 (38%) cats with CR and in eight of 50 (16%) cats with analog radiography; this difference was statistically significant. With CR, the median age of cats with a visible os penis was significantly higher than in cats where the os penis was not seen. In one cat with a visible os penis examined with CR and analog radiography, the os penis was only visible on CR images. The penile tissues were examined histopathologically in one cat and well-differentiated bone was found but there were no pathologic findings detected in surrounding tissues. Thus, the os penis can be detected on radiographs of cats and this should not be mistaken for a pathologic finding such as urolithiasis or dystrophic mineralization. PMID- 21554475 TI - Magnetic resonance anatomy of the carpus of the horse described from images acquired from low-field and high-field magnets. AB - Cadaver carpi of 30 mature horses with no history of carpal or proximal metacarpal pain were examined using low-field (0.27 T) and high-field (1.5 T) magnetic resonance imaging (MRI). Normal MRI anatomy in transverse, sagittal, and dorsal plane images was determined by comparison with anatomical specimens and standard texts. Subchondral bone and cortical bone thickness measurements were obtained from standardised sites. There was variable subchondral bone thickness in the radius and carpal bones; subchondral bone thickness was consistently larger at dorsal compared with palmar sites in the proximal row of carpal bones. The endosteal surface of the subchondral bone was smooth. The shape of the ulnar carpal bone was variable and one or more small osseous fragments were identified palmar to the bone in 5/30 limbs. There was no evidence to suggest that these were pathological fractures or avulsions of the lateral palmar intercarpal ligament. The amount of muscle tissue in the superficial and deep digital flexor tendons in the proximal aspect of the carpus varied, but none was present at the level of the middle carpal joint and distally. Several structures could be evaluated that cannot be imaged using radiography, ultrasonography, or arthroscopy, including the transverse intercarpal ligaments, the radiocarpal ligament, the short palmar carpal ligaments, and the carpometacarpal ligaments. Anatomical variations not previously described were identified, including the layers of the medial aspect of the carpal fascia. Knowledge of the variation in MRI appearance of the carpus of nonlame horses is helpful for interpretation of MR images of lame horses. PMID- 21554476 TI - Contrast-enhanced portal magnetic resonance angiography in dogs with suspected congenital portal vascular anomalies. AB - Contrast-enhanced multiphase magnetic resonance angiography (CE-MRA) was used in 17 dogs with a suspected congenital portal vascular anomaly. Portal vascular anomalies were identified in 16 of the 17 dogs. Eleven had a single intrahepatic portocaval shunt (two central divisional, three right divisional, and six left divisional), one dog had a double intrahepatic portocaval shunt, one dog had a hepatic arteriovenous malformation, one dog had a complex intrahepatic porto caval shunt. Two dogs had an extrahepatic portosystemic shunt and no shunt was identified in one dog. Total imaging time was <10 min and image quality was good to excellent in all dogs. Portal CE-MRA is a feasible, fast and non invasive technique to diagnose portal vascular anomalies in dogs, with a large field-of view and good anatomic depiction of the abnormal vessels. Based on these results, CE-MRA is an efficient imaging technique for the diagnosis of portal vascular anomalies in dogs. PMID- 21554477 TI - Thoracic computed tomography findings in dogs experimentally infected with Angiostrongylus vasorum. AB - To characterize the computed tomography (CT) features of thoracic lesions caused by infection with Angiostrongylus vasorum, pre- and postcontrast CT was performed in six experimentally infected Beagles 13 weeks postinoculation and in four of these 9 weeks postchemotherapy. Findings were compared with survey radiographs and necropsy findings. A multicentric bronchoalveolar pattern more pronounced at the lung periphery was present radiographically. On CT, the predominant abnormality underlying this alveolar pattern was multiple large nodules merging to areas of consolidation, and containing air bronchograms of varying extent. These nodular changes corresponded to histopathologic granulomata, consisting mainly of macrophages, multinucleated giant cells, and lymphocytes that had accumulated around larvae and eggs. Morphologically, no bronchial changes were observed on CT or histologically. Quantitatively, however, on CT there was evidence of bronchial thickening at 13 weeks postinoculation and mild very peripheral bronchiectasia 9 weeks postchemotherapy. Regional lymph nodes were enlarged after infection, and smaller after treatment. On postcontrast CT, several suspicious intraluminal filling defects suggestive of thrombosis were found; however, the tortuosity of some pulmonary arteries seen radiographically was not present in CT images. After treatment, the consolidations and large nodules had almost completely disappeared. A remaining radiographic interstitial pattern was characterized on CT as ground-glass opacifications, subpleural interstitial thickening, subpleural lines, and interface signs. These interstitial changes reflected fibrosis as documented histopathologically. CT allowed very detailed and accurate characterization of pulmonary parenchymal lesions, bronchi, and lymphnodes and closely reflected histopathological changes. PMID- 21554478 TI - Ultrasound-guided mesenteric lymph node iohexol injection for thoracic duct computed tomographic lymphography in cats. AB - Computed tomographic (CT) lymphography was performed in cats using percutaneous ultrasound-guided injection of contrast medium into a mesenteric lymph node. The thoracic duct and its branches were clearly delineated in CT images of seven cats studied. The thoracic duct was characterized by anatomic variation and appeared as single or multiple branches. The thoracic duct and the cisterna chyli were identified along the ventral or left ventral aspect of the vertebrae from the level of the cranial lumbar to the caudal cervical vertebrae. The thoracic duct was identified in the central caudal mediastinum, deviated to the left in the cranial mediastinum, and finally moved toward the venous system. Small volumes of extranodal contrast medium leakage were identified in all cats. After injection, the mesenteric lymph nodes were cytologically normal. Ultrasound-guided CT lymphography via percutaneous mesenteric lymph node injection appears safe and effective in cats. PMID- 21554479 TI - Imaging diagnosis-synovial myxoma of lumbar vertebrae articular process joint. AB - Magnetic resonance (MR) imaging and histopathology were used to diagnose an articular process synovial myxoma in a dog. On MR images, the tumor was characterized by distortion of the left L1-L2 articular process, widening of the articular process joint, and the presence of a mass contiguous with the synovium of the articular process that displaced the spinal cord. The tumor was T2 hyperintense, T1-hypointense, relative to muscle, and had mild contrast enhancement. The MR features of articular process synovial myxoma may be distinct from other diseases of the articular process joint. PMID- 21554480 TI - Imaging diagnosis-magnetic resonance imaging pulsatility artifact in the canine cervical spine. AB - Pulsatile venous flow in the internal vertebral venous plexus of the cervical spine can lead to vertical, linear T2-hyperintensities in the spinal cord at the cranial aspect of C3 and C4 in transverse T2-weighted images in large breed dogs that are not accompanied by ghosting. The artifact is more conspicuous in pre- and postcontrast transverse T1-weighted images and is accompanied by ghosting in that sequence, typical of a pulsatility artifact. A flow-related artifact was confirmed as the cause for this appearance by noting its absence after either exchange of phase and frequency encoding direction or by flow compensation. Care should be exercised to avoid misdiagnosing this pulsatility artifact seen in transverse T2-weighted images of the midcervical spine in large dogs as an intramedullary lesion when T1-images or phase-swap images are not available to confirm its artifactual origin. PMID- 21554481 TI - Safety and correlation of test results of combined ultrasound-guided fine-needle aspiration and needle core biopsy of the canine spleen. AB - The safety and diagnostic value of combined splenic fine-needle aspiration (FNA) and needle core biopsy (NCB) is unknown. Forty-one dogs with splenic lesions were studied prospectively. Safety was assessed in 38 dogs and no complications were encountered. Initially, clinical and anatomic pathologists reviewed each FNA and NCB sample, respectively, without knowledge of the other's results. Diagnoses were categorized as neoplastic, benign, inflammatory, normal, or nondiagnostic. The level of agreement between sampling methods was categorized as complete, partial, disagreement, or not available. Test correlation was performed in 40 dogs. Nondiagnostic results occurred in 5/40 NCB (12.5%) and no FNA samples. Neoplasia was diagnosed in 17/40 dogs (42.5%), benign changes in 20/40 dogs (50%), inflammatory disorders in 0/40 dogs, and normal 2/40 dogs (5%). One of the 40 dogs (2.5%) had a diagnosis that was equivocal for neoplasia on both tests and therefore was not categorized. Of the 35 dogs that had diagnostic samples, cytopathologic and histopathologic diagnoses agreed completely in 18/35 dogs (51.4%), partially in 3/35 dogs (8.6%), and were in disagreement in 14/35 dogs (40.0%). Pathologists collaboratively reviewed diagnoses that were in disagreement or partial agreement and altered their individual diagnoses in 6/17 dogs (35.3%) to be within partial or complete agreement, respectively. Percutaneous FNA and NCB can be performed safely in dogs with sonographic splenic changes. Results suggest that adding NCB to FNA provides complementary information in dogs with suspected splenic neoplasia. This combined protocol may improve detection of splenic neoplasia and provide neoplastic subclassification. PMID- 21554482 TI - Abdominal ultrasonographic findings in dogs naturally infected with babesiosis. AB - Canine babesiosis is a tick-borne disease with a worldwide distribution that can involve multiple organs and result in a wide variety of clinical manifestations. Our goal was to describe the sonographic changes occurring in 72 dogs naturally infected with babesiosis. Seven healthy Beagle dogs were used as a control group. The most common finding in all dogs was splenomegaly with a diffuse heterogenic parenchyma and generally reduced echogenicity. Diffuse hypoechoic hepatomegaly and bilaterally increased cortical echogenicity of the renal parenchyma were found more frequently in severe uncomplicated and complicated babesiosis groups. Mean renal resistive index and pulsatility index (PI) values were 0.66/1.35, 0.73/1.91, and 0.71/1.73 for mild uncomplicated, severe uncomplicated, and complicated babesiosis groups, respectively. A markedly increased PI for complicated and severe uncomplicated groups correlated with anemia and severity of renal damage. Ultrasonography can be an adjunct for diagnosis and monitoring canine babesiosis and its systemic complications. The detection of diffuse heterogeneous splenomegaly can support the diagnosis of Babesia infection, because of the high prevalence of this lesion in these patients. PMID- 21554483 TI - Ultrasonography of intestinal mast cell tumors in the cat. AB - The sonographic features of intestinal mast cell tumors (MCT) were reviewed in 14 cats. The mean age was 13.4 +/- 2.5 years. There were 16 focal intestinal tumors and one diffuse submucosal infiltrate. The most common pattern was focal, hypoechoic wall thickening that was noncircumferential and eccentric (9/16 tumors) or circumferential, asymmetric, and eccentric (5/16 tumors). Nine of the cats had lesions in the jejunum or duodenum, four were at the ileocecocolic junction, and one cat had a colonic mass. Six MCTs had altered but not loss of wall layering, and the most commonly affected layer on ultrasound examination was the muscularis propria. Nine cats had enlarged abdominal lymph nodes, and seven were due to metastatic disease. Metastatic disease was not routinely detected by ultrasound in the liver (1/4 cats) or the spleen (0/3 cats). Concurrent small cell (T cell) lymphoma was present in four of 14 cats (29%). PMID- 21554472 TI - French brain tumor database: 5-year histological results on 25 756 cases. AB - This work aimed to prospectively record all primary central nervous system tumor (PCNST) cases in France, for which histological diagnosis is available. The objectives were to (i) create a national registry and a network to perform epidemiological studies; (ii) implement clinical and basic research protocols; and (iii) harmonize the health care of patients affected by PCNST. For 5 years, 25 756 cases of newly diagnosed and histologically confirmed PCNST have been recorded. Histological diagnoses included glioma (48.9%), all other neuroepithelial tumors (5%), meningioma (28.8%), nerve sheath tumors (8.4%), lymphoma (3.2%) and others (5.7%). Cryopreservation was reported for 6018 PCNST specimens. Tumor resections (R) were performed in 78% cases, while biopsies accounted for 22%. Median age (MA), sex, percentage R and number of cryopreserved tumors were detailed for each histology; for example, out of 6053 glioblastomas (MA 63 years, male 59.4%, R 62%, 1611 were cryopreserved), and out of 37 atypical teratoid/rhabdoid tumors (MA 2 years, male 56.8%, R 94%, 17 were cryopreserved). This database or databank dedicated to PCNST cases contains detailed data on clinical, histological and other characteristics, such as the inclusion of data on cryopreserved specimens that are not available in other European registries. Therefore, this is a valuable resource that can be used for planning future epidemiological and clinical research. PMID- 21554484 TI - Ultrasonographic characterization of feline ileocecocolic abnormalities. AB - The clinical signs of 29 cats with ultrasonographic abnormalities at the ileocecocolic junction were reviewed. Twenty-eight cats had gastrointestinal signs, with acute vomiting and diarrhea being most prevalent. Eighteen of 29 cats had enlarged cecal lymph nodes. Focal hyperechoic mesenteric fat was noted in 18 of 29 cats, and mild focal fluid accumulation was seen in seven of 29 cats. Six cats had a round cecum, and eight cats had cecal content. The cecal wall was thickened in 19 cats, and the ileal wall was mildly thickened in six cats. Three cats had changes involving the ascending colon adjacent to the ileocecocolic junction. Fourteen cats had no ultrasonographic evidence of changes in the remainder of the gastrointestinal tract, and 13 of these 14 cats were symptomatic for gastrointestinal disease. Four cats with resolution of the ultrasonographic changes also had resolution of clinical signs. These results suggest that ultrasonographic abnormalities at the level of the ileocecocolic junction in cats are clinically significant and are seen in cats with acute vomiting or diarrhea. Fine-needle aspirates and biopsies of the ileocecocolic area had a low diagnostic yield. When no other gastrointestinal abnormalities are detected, we therefore recommend follow-up ultrasound examinations of these patients. PMID- 21554485 TI - Static and dynamic (18) FDG-PET in normal hispaniolan Amazon parrots (Amazona ventralis). AB - Positron emission tomography (PET) is often used to stage and monitor human cancer and has recently been used in a similar fashion in veterinary medicine. The most commonly used radiopharmaceutical is 2-Deoxy-2-[(18) F]-Fluoro-d-glucose ((18) F-FDG), which is concentrated and trapped within cells that use glucose as their energy substrate. We characterized the normal distribution of (18) F-FDG in 10 healthy Hispaniolan Amazon parrots (Amazona ventralis) by performing whole body PET scans at steady state, 60min after injection. Significant variability was found in the intestinal activity. Avian species are known to reflux fluid and electrolytes from their cloaca into their colon. To evaluate reflux as the cause of variability in intestinal distribution of (18) F-FDG, dynamic PET scans were performed on the coelomic cavity of six Hispaniolan Amazon parrots from time 0 to 60min postinjection of radiotracer. Reflux of radioactive material from the cloaca into the colon occurred in all birds to varying degrees and occurred before 60min. To evaluate the intestinal tract of clinical avian patients, dynamic scans must be performed starting immediately after injection so that increased radioactivity due to metabolism or hypermetabolic lesions such as cancer can be differentiated from increased radioactivity due to reflux of fluid from the cloaca. PMID- 21554488 TI - Ocular blood flow analysis detects microvascular abnormalities in impaired glucose tolerance. AB - OBJECTIVE: Waveform analysis has been used to assess vascular resistance and predict cardiovascular events. We aimed to identify microvascular abnormalities in patients with IGT using ocular waveform analysis. The effects of pioglitazone were also assessed. METHODS: Forty patients with IGT and 24 controls were studied. Doppler velocity recordings were obtained from the central retinal, ophthalmic, and common carotid arteries, and sampled at 200 Hz. A discrete wavelet-based analysis method was employed to quantify waveforms. The RI was also determined. Patients with IGT were randomized to pioglitazone or placebo, and measurements were repeated after 12-week treatment. RESULTS: In the ocular waveforms, significant differences in power spectra were observed in frequency band 4 (corresponding to frequencies between 6.25 and 12.50 Hz) between groups (p < 0.05). No differences in RI occurred. No association was observed between waveform parameters and fasting glucose or insulin resistance. Pioglitazone had no effect on waveform structure, despite significantly reducing insulin resistance, fasting glucose, and triglycerides (p < 0.05). CONCLUSIONS: Analysis of ocular Doppler flow waveforms using the discrete wavelet transform identified microvascular abnormalities that were not apparent using RI. Pioglitazone improved glucose, insulin sensitivity, and triglycerides without influencing the contour of the waveforms. PMID- 21554489 TI - Are all ICUs the same? AB - The ability to compare intensive care units (ICUs) and determine whether they provide the same level of care with regard to efficacy, efficiency, and quality is a cornerstone of understanding critical care and improving the quality of that care. Without collecting high-quality data, adjusted for severity of illness and analyzed in a comparative fashion, it would not be possible to describe best practices objectively, to identify which ICUs are doing a good job or to learn from those units that are. This review article discusses how and why ICUs are compared. Particular attention is focused on the severity of illness scores, standardized mortality, and comparative reporting. A data collecting network, Virtual Pediatric Systems, limited liability corporation (VPS, LLC), designed for the purposes of determining where differences in critical care can be identified and the value that this adds in improving quality is discussed. Finally, results from this large data sharing collaborative describing the practice of pediatric critical care are included for the purpose of pediatric intensive care units practice benchmarks. PMID- 21554490 TI - Desire for perioperative information and parental ethnicity. AB - OBJECTIVES: To examine the role of ethnicity, language, and socioeconomic variables in parental desire for information regarding children's surgery. AIM: To compare anesthetic and surgical information desired between English- and Spanish-speaking White and Hispanic mothers of children undergoing outpatient surgery. BACKGROUND: Parents report wanting to receive detailed information regarding children's preoperative care; however, variables such as parent ethnicity and language spoken have not been accounted for in understanding desire for information. METHODS/MATERIALS: One hundred and eighty-one mothers of children undergoing outpatient surgery, elective surgery, and general anesthesia were recruited and categorized into one of three groups: English-speaking White (ESW, n=79), English-speaking Hispanic (ESH, n = 63), and Spanish-speaking Hispanic (SSH, n = 39). In addition to providing demographic questionnaire, mothers completed the Parental Desire for Information (PDI) questionnaire, a 14 item measure of surgery and anesthesia-related statements. RESULTS: Overall, mothers desired receiving information about the majority of the items on the PDI. As compared to ESW mothers, SSH mothers and ESH mothers were overrepresented in the 'have a right to know' response option, with significant differences existing in items concerning alternative methods of anesthesia, details of needles used, and location of PACU and OR. CONCLUSIONS: Anesthesiologists should tailor the provision of preoperative information based on ethnicity and language of mothers involved. Ethnic and language differences shown in this study may exist in other populations as well. PMID- 21554491 TI - Sumoylation of eukaryotic elongation factor 2 is vital for protein stability and anti-apoptotic activity in lung adenocarcinoma cells. AB - By screening mouse monoclonal antibody libraries for Kelch repeats, we serendipitously identified monoclonal antibodies to eukaryotic elongation factor 2 (eEF2). Interestingly, eEF2 was highly expressed in lung adenocarcinoma (LADC), but not in the neighboring non-tumor lung tissue. Normally, eEF2 is involved in the peptidyl-tRNA translocation during protein synthesis. Overexpression of eEF2 would implicate an association with disease progression of LADC. In the present study, we investigated the prognostic significance of eEF2 in patients with LADC. Expression of eEF2 was detected by immunoblotting, immunohistochemistry and confocal immunofluorescence microscopy. Our results show that patients with high eEF2 expression had a significantly higher incidence of early tumor recurrence (67.8%vs 18.2%, P = 0.016), and a significantly worse prognosis (P < 0.001). In an in vitro study, silencing of eEF2 expression increased mitochondrial elongation, cellular autophagy and cisplatin sensitivity. Moreover, eEF2 was sumoylated in LADC cells, and eEF2 sumoylation correlated with drug resistance. These results suggest that eEF2 is an anti-apoptotic marker in LADC. However, biological function and involvement of eEF2 in the disease progression of LADC require further studies. PMID- 21554493 TI - Contribution of ultrasound in the assessment of nerve diseases. AB - BACKGROUND AND PURPOSE: Recently, ultrasound (US) has been used to assess the peripheral nervous system; however, there is no real study about its possible significant role in routine practice. Our study aims to assess the contribution of US as a routine tool in a neurophysiological laboratory. METHODS: The study assesses 130 patients who presented clinical suspicion of peripheral nerve diseases, excluding motor neuron disease, radiculopathy, hereditary and acquired polyneuropathy. All patients were clinically, neurophysiologically and sonographically assessed in the same session by the same neurologist/neurophysiologist. To avoid interpretation bias, two independent and blinded clinicians, different than the examiners performing electrodiagnosis and US, reviewed clinical, neurophysiological and US findings (also data about follow up, when available) and classified the contribution of US as follows: Contributive (US had influence on the diagnostic and therapeutic strategies), Confirming (US confirmed the clinical and neurophysiological diagnosis), Non Confirming (US findings were normal) and Incorrect (US findings led to incorrect diagnosis). RESULTS: US impacted, namely modified the diagnostic and therapeutic path in 42.3% of cases (55 patients); US had a confirmatory role in 40% (52 patients); US did not confirm clinical and neurophysiological diagnosis in 17.7% (23 cases); no incorrect US findings were observed. CONCLUSION: US complements neurophysiological assessment even in routine practice, and this confirms the increasing interest in US for a multidimensional evaluation of peripheral nerve system diseases. PMID- 21554494 TI - Aphasia in border-zone infarcts has a specific initial pattern and good long-term prognosis. AB - BACKGROUND: While border-zone infarcts (BZI) account for about 10% of strokes, studies on related aphasia are infrequent. The aim of this work was to redefine specifically their early clinical pattern and evolution. METHODS: We prospectively studied consecutive patients referred to our stroke unit within a 2 year period. Cases of aphasia in right-handed patients associated with a MRI confirmed left-sided hemispheric BZI were included. These patients had a standardized language examination in the first 48 h, at discharge from stroke unit and between 6 and 18 months later. RESULTS: Eight patients were included. Three had anterior (MCA/ACA), two posterior (MCA/PCA), two both anterior and posterior, and one bilateral BZI. All our patients initially presented transcortical mixed aphasia, characterized by comprehension and naming difficulties associated with preserved repetition. In all patients, aphasia rapidly improved. It fully recovered within a few days in three patients. Initial improvement was marked, although incomplete in the five remaining patients: their aphasias specifically evolved according to the stroke location toward transcortical motor aphasia for the three patients with anterior BZI and transcortical sensory aphasia for the two patients with posterior BZI. All patients made a full language recovery within 18 months after stroke. CONCLUSIONS: We report a specific aphasic pattern associated with hemispheric BZI, including an excellent long-term outcome. These findings appear relevant to (i) clinically suspect BZI and (ii) plan rehabilitation and inform the patient and his family of likelihood of full language recovery. PMID- 21554495 TI - Psychogenic amnesia and self-identity: a multimodal functional investigation. AB - BACKGROUND: Patients with psychogenic amnesia generally suffer from episodic memory deficits associated with an impairment of self-identity. While the first is generally attributed to limbic dysfunction, the latter might be related to posterior parietal cortex. METHODS AND RESULTS: In a patient with acute repetitive psychogenic amnesia, three different functional investigations (fMRI, electrical-neuroimaging, PET) during both resting-state and a behavioural paradigm testing 'time-travel' showed left posterior parietal activation, unlike in 12 control subjects. CONCLUSION: Impairment of self-identity and episodic memory in psychogenic amnesia may be associated with functional alterations of left posterior parietal cortex. PMID- 21554496 TI - Inhibition of peripheral blood natural killer cell cytotoxicity in patients with myasthenia gravis treated with plasmapheresis. AB - BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disorder that may involve natural killer (NK) cells. Although NK cells are part of the innate immune system, they also influence adaptive immune responses. Double-filtration plasmapheresis (DFP) is an effective therapy for MG crisis. Thus, we examined the effects of DFP on the cytotoxicity of NK cells. METHODS: A total of 20 patients with MG and 16 healthy controls were recruited for the study. Ficoll-Paque isolated peripheral blood mononuclear cells (PBMCs) and K562 cells were used as the effector and target cells, respectively. NK cell cytotoxicity was analyzed using flow cytometry immediately before and after DFP and upon course completion. RESULTS: Double-filtration plasmapheresis treatment decreased significantly the NK cell cytotoxicity in patients with MG, especially in good responders, those who were positive for acetylcholine receptor (AChR) antibodies, and those receiving immunosuppressants. CONCLUSIONS: The decrease in NK cell cytotoxicity after DFP and the decline of AChR antibody titer were observed in good responders indicating that this could benefit patients with MG. PMID- 21554497 TI - Optimizing the risk estimation after a transient ischaemic attack - the ABCDE? score. AB - BACKGROUND AND PURPOSE: The risk of stroke after a transient ischaemic attack (TIA) can be predicted by scores incorporating age, blood pressure, clinical features, duration (ABCD-score), and diabetes (ABCD2-score). However, some patients have strokes despite a low predicted risk according to these scores. We designed the ABCDE+ score by adding the variables 'etiology' and ischaemic lesion visible on diffusion-weighted imaging (DWI) -'DWI-positivity'- to the ABCD-score. We hypothesized that this refinement increases the predictability of recurrent ischaemic events. METHODS: We performed a prospective cohort study amongst all consecutive TIA patients in a university hospital emergency department. Area under the computed receiver-operating curves (AUCs) were used to compare the predictive values of the scores with regard to the outcome stroke or recurrent TIA within 90 days. RESULTS: Amongst 248 patients, 33 (13.3%, 95%-CI 9.3-18.2%) had a stroke (n = 13) or a recurrent TIA (n = 20). Patients with recurrent ischaemic events more often had large-artery atherosclerosis as the cause for TIA (46% vs. 14%, P < 0.001) and positive DWI (61% vs. 35%; P = 0.01) compared with patients without recurrent events. Patients with and those without events did not differ with regard to age, clinical symptoms, duration, blood pressure, risk factors, and stroke preventive treatment. The comparison of AUCs [95%CI] showed superiority of the ABCDE+ score (0.67[0.55-0.75]) compared to the ABCD(2) -score (0.48[0.37-0.58]; P = 0.04) and a trend toward superiority compared to the ABCD score (0.50[0.40-0.61]; P = 0.07). CONCLUSION: In TIA patients, the addition of the variables 'etiology' and 'DWI-positivity' to the ABCD-score seems to enhance the predictability of subsequent cerebral ischaemic events. PMID- 21554498 TI - Dopaminergic genes modulate response inhibition in alcohol abusing adults. AB - Compulsion in alcohol use disorders (AUD) has been attributed to impairment in response inhibition. Because genes that regulate dopamine (DA) have been implicated not only for risk for AUD but also for impulsivity based on behavioral studies, we set out to examine the underlying neural mechanisms associated with these effects. We collected functional magnetic resonance imaging images on 53 heavy drinking but otherwise healthy adults while performing the Go/NoGo task. We predicted that genetic variants previously reported in the literature to be associated with substance abuse, specifically the DRD2 rs1799732 and DRD4 VNTR, will modulate neural processes underlying response inhibition. Our results showed differential neural response for the DRD4 VNTR during successful inhibition in the inferior frontal gyrus (IFG) (cluster-corrected P<0.05, z=1.9). Similarly, DRD2 rs1799732 groups were significantly different in the precuneus and cingulate gyrus during successful response inhibition (cluster-corrected P<0.05, z=1.9). These findings provide further evidence for the role of DAergic genes in modulating neural response in areas that underlie response inhibition and self monitoring processes. Variants within these genes appear to influence processes related to impulsive behavior, which may increase one's risk for alcohol abuse and dependence. PMID- 21554499 TI - Essential roles of Xenopus TRF2 in telomere end protection and replication. AB - TRF1 and TRF2 are double-stranded (ds) telomere DNA-binding proteins and the core members of shelterin, a complex that provides the structural and functional basis of telomere functions. We have reported that unlike mammalian TRF1 that constitutively binds to chromatin, Xenopus TRF1 (xTRF1) associates with mitotic chromatin but dissociates from interphase chromatin reconstituted in Xenopus egg extracts. This finding raised the possibility that xTRF1 and Xenopus TRF2 (xTRF2) contribute to telomere functions in a manner different from mammalian TRF1 and TRF2. Here, we focused on the role of xTRF2. We prepared chromatin reconstituted in egg extracts immunodepleted for xTRF2. Compared to mock-depleted nuclei, DNA damage response at telomeres was activated, and bulk DNAs were poorly replicated in xTRF2-depleted nuclei. The replication defect was rescued by inactivating ATR through the addition of anti-ATR neutralizing antibody, suggesting that ATR plays a role in the defect. Interestingly, the bulk DNA replication defect, but not the DNA damage response at telomeres, was rescued by supplementing the xTRF2-depleted extracts with recombinant xTRF2 (rTRF2). We propose that xTRF2 is required for both efficient replication of bulk DNA and protection from the activation of the DNA damage checkpoints pathway, and that those two functions are mechanistically separable. PMID- 21554500 TI - Mitotic kinase Aurora-B is regulated by SUMO-2/3 conjugation/deconjugation during mitosis. AB - The small ubiquitin-related modifier (SUMO) system of higher eukaryotes plays important roles in normal cell division, especially in chromosome segregation. However, only a few mitotic SUMO substrates have been identified in mammals. Here, we show that the mitotic kinase Aurora-B can be modified by SUMO. The E3 SUMO-protein ligase PIAS3 [protein inhibitor of activated STAT (signal transducer and activator of transcription)] dramatically enhanced poly-SUMO-2/3 conjugation of Aurora-B, whereas the SUMO-specific isopeptidase SENP2 (Sentrin/SUMO-specific protease) specifically deconjugated SUMO from Aurora-B. The Lys-202 residue on human Aurora-B was preferentially modified by SUMO, and enhancement of SUMOylation in cells facilitated Aurora-B autophosphorylation, which is essential for its activation. Conversely, SENP2-mediated deSUMOylation of Aurora-B down regulated its autophosphorylation in cells and also impaired its re-activation in Aurora inhibitor VX-680-treated mitotic cells. Poly-SUMO-2 conjugation of Aurora B occurred during the M phase of the cell cycle, and both SUMO-2 and PIAS3 were localized adjacent to Aurora-B in the kinetochores in early mitosis. Based on these results, we propose that Aurora-B is a novel mitotic SUMO substrate and that its kinase activity is fine-tuned by the SUMO system. PMID- 21554501 TI - Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction. AB - Cap'n'Collar (CNC) proteins heterodimerize with small Maf proteins and regulate the transcription of various genes. Small Maf-deficient mice develop severe neurodegeneration, and it remains unclear whether CNC proteins are involved in this process. In this study, we examined the contribution of Nrf1, one of the CNC proteins, to neuronal homeostasis in vivo. As Nrf1 gene knockout mice are embryonic lethal, we developed a central nervous system (CNS)-specific Nrf1 knockout (CKO) mouse line using mice bearing an Nrf1(flox) allele and Nestin-Cre allele. At birth, the CKO mice appeared indistinguishable from control mice, but thereafter they showed progressive motor ataxia and severe weight loss. All Nrf1 CKO mice died within 3 weeks. These phenotypes are similar to those reported in small Maf-deficient mice, suggesting the presence of collaboration between Nrf1 and small Maf proteins. We also found aberrant accumulation of polyubiquitinated proteins in various CNS regions and apparent neuronal loss in the hippocampus of Nrf1 CKO mice. An oxidative stress marker was accumulated in the spinal cords of the mice, but the expression patterns of oxidative stress response genes regulated by Nrf2 did not change substantially. These results show that Nrf1 sustains the CNS homeostasis through regulating target genes distinct from those regulated by Nrf2. PMID- 21554502 TI - Murine cerebral malaria: histopathology and ICAM 1 immunohistochemistry of the inner ear. AB - OBJECTIVE: To evaluate the pathophysiologic changes in the inner ear during the course of severe cerebral malaria in an established animal model, C57 BL/6J mice. METHODS: This study aims to examine the hearing threshold, the histological changes and ICAM-1 expression in the murine cochlea. RESULTS: Four of seven mice showed an expected hearing loss of 20 dB or more. The light microscopy of the inner ear did not show any morphologic alterations. The immunohistochemical analysis for ICAM-1 showed intensive staining in the stria vascularis of sick animals and hardly any reaction in healthy controls. CONCLUSION: The up regulation of ICAM-1 in the stria vascularis - generating the endocochlear potential - suggests its involvement in plasmodial infection. PMID- 21554503 TI - Phages of Pseudomonas aeruginosa: response to environmental factors and in vitro ability to inhibit bacterial growth and biofilm formation. AB - AIMS: To examine effects of various environmental factors on adsorption and inactivation of Pseudomonas aeruginosa-specific phages: delta (family Podoviridae), J-1, sigma-1 and 001A (family Siphoviridae) and their ability to inhibit bacterial growth and biofilm formation. METHODS AND RESULTS: The phages examined in the study were clonally different, as revealed by RFLP. The temperature in the range 7-44 degrees C had no influence on the adsorption of Podoviridae, but did affect Siphoviridae adsorption, particularly 001A. All phages were significantly stable at pH 5-9, and phages delta and 001A even at pH 3. Most of the examined carbohydrates and exopolysaccharides of the original host efficiently inactivated phage delta, while phages sigma-1 and J-1 were inactivated considerably only by the amino acid alanine. Silver nitrate efficiently inactivated all the phages, while Siphoviridae were more resistant to povidone-iodine. Serum of nonimmunized rats had no influence on phage inactivation and adsorption. Only phage delta showed ability to effectively inhibit in vitro bacterial growth and biofilm formation. CONCLUSIONS: The examined environmental parameters can significantly influence the adsorption and viability of Ps. aeruginosa-specific phages. The phage delta is a good candidate for biocontrol of Ps. aeruginosa. SIGNIFICANCE AND IMPACT OF THE STUDY: The study provides important data on Ps. aeruginosa-specific phage adsorption, inactivation and in vitro lytic efficacy. PMID- 21554504 TI - Pseudomonas sp. M174 inhibits the fish pathogen Flavobacterium psychrophilum. AB - AIMS: To study the antagonic affect of probiotic Pseudomonas M174 on the fish pathogen Flavobacterium psychrophilum. METHODS AND RESULTS: The ability of Pseudomonas M174 to inhibit the growth of Fl. psychrophilum was examined in iron sufficient and -deficient media. Possible siderophore production was also investigated. Antagonistic activity was confirmed in disease challenge experiments using a rainbow trout (Oncorhynchus mykiss) model. Adhesion of Pseudomonas M174 to fish surfaces and its ability to stimulate innate immunity was also investigated in vivo. Pseudomonas M174 antagonized Fl. psychrophilum and produced siderophores in vitro. In challenge experiments with Fl. psychrophilum, fish fed with Pseudomonas M174 had lower levels of mortalities than the controls. It was possible to find Pseudomonas M174 in the intestinal content of these fish after feeding and bathing with the probiotic, but probiotic was obtained from the gills only after feeding. Respiratory burst activity was also found to be enhanced in the M174 fed fish. CONCLUSIONS: These results suggest that M174 is a potential probiotic against Fl. psychrophilum and has several modes of action. SIGNIFICANCE AND IMPACT OF THE STUDY: Probiotics are a promising alternative to the use of antibiotics in aquaculture and could be a more sustainable disease control method. PMID- 21554505 TI - Proposal of autoimmune hepatitis presenting with acute hepatitis, severe hepatitis and acute liver failure. PMID- 21554506 TI - In situ measurement of the electrical potential across the lysosomal membrane using FRET. AB - The progressive acidification of the endocytic pathway is generated by H(+) pumping of electrogenic vacuolar-type ATPases (V-ATPases) on the endosomal/lysosomal membrane. The determinants of pH during endosome maturation are not completely understood, but the permeability to ions that neutralize the electrogenic effect of the V-ATPase has been proposed to play a central role. If counter-ion conductance becomes limiting, the generation of a large membrane potential would dominate the proton-motive force (pmf), diminishing the pH gradient proportionally. Validation of this notion requires direct measurement of the electrical potential that develops across the endosomal/lysosomal membrane. To date, the measurement of lysosomal membrane potential (psi(phi) ) in situ has been hampered by the inability to access endosomes by electrophysiological means and the fact that individual organelles cannot be discerned when using potentiometric fluorescent dyes. Here, we describe a noninvasive procedure to estimate psi(phi) in intact cells, based on fluorescence resonance energy transfer (FRET). At steady state, psi(phi) averaged 19 mV (lumen positive) and was only partially dissipated by inhibition of the V-ATPase with concanamycin A (CcA). psi(phi) was considerably increased by alkalinization of the lysosome lumen by NH(4) Cl, implying that at steady state the V-ATPase operates at submaximal rates and that the contribution of psi(phi) to pmf is relatively small. Our method should enable systematic studies of endosomal/lysosomal potential. PMID- 21554507 TI - Rab27a targeting to melanosomes requires nucleotide exchange but not effector binding. AB - Rab GTPases are important determinants of organelle identity and regulators of vesicular transport pathways. Consequently, each Rab occupies a highly specific subcellular localization. However, the precise mechanisms governing Rab targeting remain unclear. Guanine nucleotide exchange factors (GEFs), putative membrane resident targeting factors and effector binding have all been implicated as critical regulators of Rab targeting. Here, we address these issues using Rab27a targeting to melanosomes as a model system. Rab27a regulates motility of lysosome related organelles and secretory granules. Its effectors have been characterized extensively, and we have identified Rab3GEP as the non-redundant Rab27a GEF in melanocytes (Figueiredo AC et al. Rab3GEP is the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes. J Biol Chem 2008;283:23209-23216). Using Rab27a mutants that show impaired binding to representatives of all four Rab27a effector subgroups, we present evidence that effector binding is not essential for targeting of Rab27a to melanosomes. In contrast, we observed that knockdown of Rab3GEP resulted in mis-targeting of Rab27a, suggesting that Rab3GEP activity is required for correct targeting of Rab27a. However, the identification of Rab27a mutants that undergo efficient GDP/GTP exchange in the presence of Rab3GEP in vitro but are mis-targeted in a cellular context indicates that nucleotide loading is not the sole determinant of subcellular targeting of Rab27a. Our data support a model in which exchange activity, but not effector binding, represents one essential factor that contributes to membrane targeting of Rab proteins. PMID- 21554508 TI - Cysteine ubiquitination of PTS1 receptor Pex5p regulates Pex5p recycling. AB - Pex5p is the cytosolic receptor for peroxisome matrix proteins with peroxisome targeting signal (PTS) type 1 and shuttles between the cytosol and peroxisomes. Here, we show that Pex5p is ubiquitinated at the conserved cysteine(11) in a manner sensitive to dithiothreitol, in a form associated with peroxisomes. Pex5p with a mutation of the cysteine(11) to alanine, termed Pex5p-C11A, abrogates peroxisomal import of PTS1 and PTS2 proteins in wild-type cells. Pex5p-C11A is imported into peroxisomes but not exported, resulting in its accumulation in peroxisomes. These results suggest an essential role of the cysteine residue in the export of Pex5p. Furthermore, domain mapping indicates that N-terminal 158 amino-acid region of Pex5p-C11A, termed 158-CA, is sufficient for such dominant negative activity by binding to membrane peroxin Pex14p via its two pentapeptide WXXXF/Y motifs. Stable expression of either Pex5p-C11A or 158-CA likewise inhibits the wild-type Pex5p import into peroxisomes, strongly suggesting that Pex5p-C11A exerts the dominant-negative effect at the translocation step via Pex14p. Taken together, these findings show that the cysteine(11) of Pex5p is indispensable for two distinct steps, its import and export. The Pex5p-C11A would be a useful tool for gaining a mechanistic insight into the matrix protein import into peroxisomes. PMID- 21554509 TI - The RabGAP proteins Gyp5p and Gyl1p recruit the BAR domain protein Rvs167p for polarized exocytosis. AB - The Rab GTPase-activating proteins (GAP) Gyp5p and Gyl1p are involved in the control of polarized exocytosis at the small-bud stage in Saccharomyces cerevisiae. Both Gyp5p and Gyl1p interact with the N-Bin1/Amphiphysin/Rvs167 (BAR) domain protein Rvs167p, but the biological function of this interaction is unclear. We show here that Gyp5p and Gyl1p recruit Rvs167p to the small-bud tip, where it plays a role in polarized exocytosis. In gyp5Deltagyl1Delta cells, Rvs167p is not correctly localized to the small-bud tip. Both P473L mutation in the SH3 domain of Rvs167p and deletion of the proline-rich regions of Gyp5p and Gyl1p disrupt the interaction of Rvs167p with Gyp5p and Gyl1p and impair the localization of Rvs167p to the tips of small buds. We provide evidence for the accumulation of secretory vesicles in small buds of rvs167Delta cells and for defective Bgl2p secretion in rvs167Delta cultures enriched in small-budded cells at 13 degrees C, implicating Rvs167p in polarized exocytosis. Moreover, both the accumulation of secretory vesicles in Rvs167p P473L cells cultured at 13 degrees C and secretion defects in cells producing Gyp5p and Gyl1p without proline-rich regions strongly suggest that the function of Rvs167p in exocytosis depends on its ability to interact with Gyp5p and Gyl1p. PMID- 21554510 TI - Reference values for the Timed Up and Go test in healthy Japanese elderly people: determination using the methodology of meta-analysis. AB - AIM: The purpose of this study was to determine the reference value for the Timed Up and Go test (TUG) in healthy Japanese elderly people using the methodology of meta-analysis, and to determine the value for different measurement protocols. METHODS: Relevant research articles were identified from electronic databases: MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Igaku-cyuouzasshi. The search was conducted from January 1991 to June 2010, and the terms "timed up and go" and "elderly" were used in combination in the search. Furthermore, the searches were limited to articles involving Japanese healthy elderly people aged 60years and older. Weighted means of TUG were calculated by a fixed effect model and a random effect model to estimate reference values. Furthermore, the 95% confidence interval (CI) for the weighted mean of TUG was also estimated. RESULTS: Twelve studies fulfilled the inclusion criteria: eight provided data for maximum effort, and five provided data related to usual pace. When weighted means of TUG were estimated by the fixed effect model, there was significant heterogeneity. Therefore, a random effect model was used for re estimation. As a result, the weighted mean of TUG with maximum effort was 6.60s (95% CI=6.18-7.02s), and that at usual pace was 8.86s (95% CI=7.99-9.72s). CONCLUSION: The reference values of TUG in Japanese healthy elderly people calculated in this study are certainly shorter than in African-Americans and Caucasians. The reference values of TUG estimated by our study appear to be specific for healthy, elderly, Japanese people. PMID- 21554511 TI - Neutral communities may lead to decreasing diversity-disturbance relationships: insights from a generic simulation model. AB - Many attempts have been made to confirm or reject the unimodal relationship between disturbance and diversity stated by the intermediate disturbance hypothesis (IDH). However, the reasons why the predictions of the IDH apply or fail in particular systems are not always obvious. Here, we use a spatially explicit, individual-based community model that simulates species coexistence in a landscape subjected to disturbances to compare diversity-disturbance curves of communities with different coexistence mechanisms: neutrality, trade-off mechanism and intraspecific density dependence. We show that the shape of diversity-disturbance curves differs considerably depending on the type of coexistence mechanism assumed: (1) Neutral communities generally show decreasing diversity-disturbance curves with maximum diversity at zero disturbance rates contradicting the IDH, whereas trade-off communities generally show unimodal relationships confirming the IDH and (2) density-dependent mechanisms do increase the diversity of both neutral and trade-off communities. Finally, we discuss how these mechanisms determine diversity in disturbed landscapes. PMID- 21554512 TI - Toward an integration of evolutionary biology and ecosystem science. AB - At present, the disciplines of evolutionary biology and ecosystem science are weakly integrated. As a result, we have a poor understanding of how the ecological and evolutionary processes that create, maintain, and change biological diversity affect the flux of energy and materials in global biogeochemical cycles. The goal of this article was to review several research fields at the interfaces between ecosystem science, community ecology and evolutionary biology, and suggest new ways to integrate evolutionary biology and ecosystem science. In particular, we focus on how phenotypic evolution by natural selection can influence ecosystem functions by affecting processes at the environmental, population and community scale of ecosystem organization. We develop an eco-evolutionary model to illustrate linkages between evolutionary change (e.g. phenotypic evolution of producer), ecological interactions (e.g. consumer grazing) and ecosystem processes (e.g. nutrient cycling). We conclude by proposing experiments to test the ecosystem consequences of evolutionary changes. PMID- 21554513 TI - Bioavailability of soil organic matter and microbial community dynamics upon permafrost thaw. AB - Amplified Arctic warming could thaw 25% of the permafrost area by 2100, exposing vast amounts of currently fixed organic carbon to microbially mediated decomposition and release of greenhouse gasses through soil organic matter (SOM) respiration. We performed time-series incubation experiments with Holocene permafrost soils at 4 degrees C for up to 11 days to determine changes in exoenzyme activities (EEAs) (i.e. phosphatase, beta-glucosidase, aminopeptidase) as a measure for the bioavailability of SOM in response to permafrost thaw. We also profiled SSU rRNA transcripts to follow the qualitative and quantitative changes in viable prokaryotes and eukaryotes during incubation. EEA, amount of rRNA transcripts and microbial community structures differed substantially between the various soil intervals in response to thaw: after 11 days of incubation, the active layer became slightly depleted in C and P and harboured bacterial phyla indicative of more oligotrophic conditions (Acidobacteria). A fast response in phosphatase and beta-glucosidase upon thaw, and a predominance of active copiotrophic Bacteroidetes, showed that the upper permafrost plate serves as storage of easily degradable carbon derived from the overlying thawed active layer during summer. EEA profiles and microbial community dynamics furthermore suggest that the deeper and older permafrost intervals mainly contain recalcitrant SOM, and that extracellular soil-bound exoenzymes play a role in the initial cleavage of biopolymers, which could kick-start microbial growth upon thaw. Basidiomycetous fungi and Candidate Subdivision OP5 bacteria were the first to respond in freshly thawed deeper permafrost intervals, and might play an important role in the decomposition of recalcitrant SOM to release more labile substrates to support the major bacterial phyla (beta-Proteobacteria, Actinobacteria, Firmicutes), which predominated thereafter. PMID- 21554514 TI - Bacillus cereus responses to acid stress. AB - Coping with acid environments is one of the prerequisites for the soil saprophytic and human pathogenic lifestyle of Bacillus cereus. This minireview highlights novel insights in the responses displayed by vegetative cells and germinating spores of B. cereus upon exposure to low pH as well as organic acids, including acetic acid, lactic acid and sorbic acid. Insights regarding the possible acid-inflicted damage, physiological responses and protective mechanisms have been compiled based on single cell fluorescence microscopy, flow cytometry and transcriptome analyses. PMID- 21554515 TI - Drivers of bacterial diversity dynamics in permeable carbonate and silicate coral reef sands from the Red Sea. AB - Permeable sediments and associated microbial communities play a fundamental role in nutrient recycling within coral reef ecosystems by ensuring high levels of primary production in oligotrophic environments. A previous study on organic matter degradation within biogenic carbonate and terrigenous silicate reef sands in the Red Sea suggested that observed sand-specific differences in microbial activity could be caused by variations in microbial biomass and diversity. Here, we tested this hypothesis by comparing bacterial abundance and community structure in both sand types, and by further exploring the structuring effects of time (season) and space (sediment depth, in/out-reef). Changes in bacterial community structure, as determined via automated ribosomal intergenic spacer analysis (ARISA), were primarily driven by sand mineralogy at specific seasons, sediment depths and reef locations. By coupling ARISA with 16S-ITS rRNA sequencing, we detected significant community shifts already at the bacterial class level, with Proteobacteria (Gamma-, Delta-, Alpha-) and Actinobacteria being prominent members of the highly diverse communities. Overall, our findings suggest that reef sand-associated bacterial communities vary substantially with sand type. Especially in synergy with environmental variation over time and space, mineralogical differences seem to play a central role in maintaining high levels of bacterial community heterogeneity. The local co-occurrence of carbonate and silicate sands may thus significantly increase the availability of microbial niches within a single coral reef ecosystem. PMID- 21554516 TI - Key two-component regulatory systems that control biofilm formation in Pseudomonas aeruginosa. AB - Biofilm formation in P. aeruginosa is a highly regulated process that proceeds through a number of distinct stages. This development is controlled by a wide range of factors, of which two-component systems (TCSs) play a key role. In this review, we focus on some of the TCSs that regulate the switch from a motile to a sessile bacterial lifestyle, either via the production of extracellular appendages or by the production of exopolysaccharides. Extracellular appendages, such as flagella, type IV pili and Cup fimbriae are often involved in the initial attachment of bacteria to a surface. In P. aeruginosa, many of these surface structures are regulated by TCSs, and some systems regulate more than one type of appendage. Furthermore, the production of exopolysaccharides, such as Pel and Psl, is required for P. aeruginosa biofilm formation. The regulation of Pel and Psl is post-transcriptionally repressed by RsmA, the activity of which is controlled by a complex regulatory system involving several sensor kinases and accessory components. Furthermore, the Rsm system is a major control system that inversely regulates factors involved in motility and acute infection on one hand, and factors involved in biofilm formation and chronic infection on the other hand. Finally, a series of TCSs has recently been discovered that regulates biofilm development in a stage-specific manner. Taken together, these complex regulatory networks allow the bacterium to respond appropriately to diverse environmental stimuli, and increased knowledge of their mechanisms and signals could be of great importance in the design of novel antibacterial strategies. PMID- 21554517 TI - Microbial growth on the edge of desiccation. AB - The availability of water, which can be expressed in terms of water activity (a(w)), is one of the most important determinants for microbial homeostasis and growth on surface to air interfaces. Here we show, using an environmental control chamber containing a precisely controlled temperature/a(w) gradient in combination with a mathematical approach, that the environmental a(w) growth limit of a microorganism can be lower than its intracellular a(w) limit. This internal limit represents the point at which microbial cells cannot lower their internal a(w) any further in response to low external a(w) values without interfering with essential intracellular processes. To grow at external a(w) values below their internal limit, microbes need to generate more water metabolically than they lose to their environment. This internal a(w) limit can be calculated by measuring the a(w) growth limit of an organism at different water vapour diffusivities using barometric pressure as a variable. Fascinating morphological changes, such as rope-like superstructures formed by B. subtilis, are furthermore observed in response to low external a(w) values in particular around the calculated intracellular a(w) limit. The intracellular a(w) limit of an organism is a decisive parameter for water limitation-induced adaptations in cellular hydrophilicity and morphogenesis. PMID- 21554518 TI - Changes in viral and bacterial communities during the ice-melting season in the coastal Arctic (Kongsfjorden, Ny-Alesund). AB - Microbial communities in Arctic coastal waters experience dramatic changes in environmental conditions during the spring to summer transition period, potentially leading to major variations in the relationship between viral and prokaryotic communities. To document these variations, a number of physico chemical and biological parameters were determined during the ice-melting season in the coastal Arctic (Kongsfjorden, Ny-Alesund, Spitsbergen). The bacterial and viral abundance increased during the spring to summer transition period, probably associated to the increase in temperature and the development of a phytoplankton bloom. The increase in viral abundance was less pronounced than the increase in prokaryotic abundance; consequently, the viral to prokaryotic abundance ratio decreased. The bacterial and viral communities were stratified as determined by Automated Ribosomal Intergenic Spacer Analysis and Randomly Amplified Polymorphic DNA-PCR respectively. Both the bacterial and viral communities were characterized by a relatively low number of operational taxonomic units (OTUs). Despite the apparent low complexity of the bacterial and viral communities, the link between these two communities was weak over the melting season, as suggested by the different trends of prokaryotic and viral abundance during the sampling period. This weak relationship between the two communities might be explained by UV radiation and suspended particles differently affecting the viruses and prokaryotes in the coastal Arctic during this period. Based on our results, we conclude that the viral and bacterial communities in the Arctic were strongly affected by the variability of the environmental conditions during the transition period between spring and summer. PMID- 21554519 TI - Cyclic diguanylate turnover mediated by the sole GGDEF/EAL response regulator in Pseudomonas putida: its role in the rhizosphere and an analysis of its target processes. AB - GGDEF and EAL/HD-GYP protein domains are responsible for the synthesis and hydrolysis of the bacterial secondary messenger cyclic diguanylate (c-di-GMP) through their diguanylate cyclase and phosphodiesterase activities, respectively. Forty-three genes in Pseudomonas putida KT2440 are putatively involved in the turnover of c-di-GMP. Of them only rup4959 (locus PP4959) encodes a GGDEF/EAL response regulator, which was identified in a genome wide analysis as preferentially induced while this bacterium colonizes roots and adjacent soil areas (the rhizosphere). By using fusions to reporter genes it was confirmed that the rup4959 promoter is active in the rhizosphere and inducible by corn plant root exudates and microaerobiosis. Transcription of rup4959 was strictly dependent on the alternative transcriptional factor sigma(S) . The inactivation of the rup4959-4957 operon altered the expression of 22 genes in the rhizosphere and had a negative effect upon oligopeptide utilization and biofilm formation. In multicopy or when overexpressed, rup4959 enhanced adhesin LapA-dependent biofilm formation, the development of wrinkly colony morphology, and increased Calcofluor stainable exopolysaccharides (EPS). Under these conditions the inhibition of swarming motility was total and plant root tip colonization considerably less efficient, whereas swimming was partially diminished. This pleiotropic phenotype, which correlated with an increase in the global level of c-di-GMP, was not acquired with increased levels of Rup4959 catalytic mutant at GGDEF as a proof of this response regulator exhibiting diguanylate cyclase activity. A screen for mutants in putative targets of c-di-GMP led to the identification of a surface polysaccharide specific to KT2440, which is encoded by the genes cluster PP3133 PP3141, as essential for phenotypes associated with increased c-di-GMP. Cellulose and alginate were discarded as the overproduced EPS, and lipopolysaccharide (LPS) core and O-antigen were found to be essential for the development of wrinkly colony morphology. PMID- 21554520 TI - Effects of saxagliptin on beta-cell stimulation and insulin secretion in patients with type 2 diabetes. AB - AIM: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on beta-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. METHODS: Patients in this randomized, parallel-group, double-blind, placebo controlled study were drug-naive, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. RESULTS: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). CONCLUSIONS: DPP-4 inhibition with saxagliptin improves pancreatic beta-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the beta-cell is warranted. PMID- 21554521 TI - Comparison of insulins detemir and glargine: effects on glucose disposal, hepatic glucose release and the central nervous system. AB - AIMS: The effects of insulins detemir (Det) and glargine (Glar) on endogenous glucose production (EGP) and net hepatic glucose output (NHGO) were compared. METHODS: Arteriovenous difference and tracer ([3-(3) H]glucose) techniques were employed during a two-step hyperinsulinemic euglycaemic clamp in conscious dogs (6 groups, n = 5-6/group). After equilibration and basal sampling (0-120 min), somatostatin was infused and basal glucagon was replaced intraportally. Det or Glar was infused via portal vein (Po), peripheral vein (IV), or bilateral carotid and vertebral arteries (H) at 0.1 and 0.3 mU/kg/min (low Insulin; Glar vs. Det, respectively, 120-420 min) and 4* the low insulin rate (high insulin; 420-540 min). RESULTS: NHGO and EGP were suppressed and glucose R(d) and infusion rate were stimulated similarly by Det and Glar at both Low and high insulin with each infusion route. Non-esterified fatty acid (NEFA) concentrations during low insulin were 202 +/- 37 versus 323 +/- 75 uM in DetPo and GlarPo (p < 0.05) and 125 +/- 39 versus 263 +/- 48 uM in DetIV and GlarIV, respectively (p < 0.05). In DetH versus GlarH, pAkt/Akt (1.7 +/- 0.2 vs. 1.0 +/- 0.2) and pSTAT3/STAT3 (1.4 +/- 0.2 vs. 1.0 +/- 0.1) were significantly increased in the liver but not in the hypothalamus. CONCLUSIONS: Det and Glar have similar net effects on acute regulation of hepatic glucose metabolism in vivo regardless of delivery route. Portal and IV detemir delivery reduces circulating NEFA to a greater extent than glargine, and head detemir infusion enhances molecular signalling in the liver. These findings indicate a need for further examination of Det's central and hepatic effects. PMID- 21554522 TI - Lentiviral vector-mediated knockdown of SOCS3 in the hypothalamus protects against the development of diet-induced obesity in rats. AB - AIM: Leptin resistance is a feature of most cases of obesity in both humans and rodents. The suppressor of cytokine signalling 3 (SOCS3) is a negative-feedback regulator of leptin signalling involved in leptin resistance; therefore, the suppression of SOCS3 is a potential therapy for leptin resistance in obesity. In the studies, we investigated whether hypothalamic silencing of SOCS3 would attenuate diet-induced obesity in rats. METHODS: First we established hypothalamic SOCS3-deficient rats through lentiviral vector (LV)-mediated RNA interference (RNAi) technique, then provided a high-fat diet or a chow diet to the rats. After 8 weeks of the diet, the serum leptin and insulin concentrations were measured by RIA, and the gene expressions of SOCS3 and the long form of leptin receptor in hypothalamus were detected by a real time RT-PCR. The leptin induced Stat3 activation was examined by Western blot. RESULTS: The RNAi protocol specifically knocked down the expression of SOCS3 mRNA by 50% approximately. The rats treated with LV-SOCS3-shRNA exhibited enhanced leptin-induced Stat3 activation, decreased body weight gain and improved metabolic parameters when exposed to a high-fat diet. CONCLUSION: Our results provide evidence that the rats treated with hypothalamic SOCS3 silencing are significantly protected against the development of diet-induced obesity and SOCS3 is a potential target molecule for therapeutic intervention of obesity. PMID- 21554523 TI - Dissociated incretin hormone response to protein versus fat ingestion in obese subjects. AB - Protein elicits a stronger early (30 min) glucose-dependent insulinotropic polypeptide (GIP) response than fat ingestion in lean individuals, with no difference in glucagon-like peptide-1 (GLP-1). We assessed the incretin hormone response to protein versus fat ingestion in obesity. Equicaloric (8 kcal/kg) fat (olive oil) or protein (whey protein) was ingested by non-diabetic obese male volunteers [body mass index (BMI) >30 kg/m(2) ; n = 12] and plasma GIP and GLP-1 were determined. We found no difference in the early GIP or GLP-1 responses to fat versus protein. However, the total 300-min GIP response was greater after fat than after protein ingestion (20.3 +/- 3.9 vs. 10.0 +/- 2.8 nmol/l * min; p = 0.026), whereas the 300-min GLP-1 responses were the same. Thus, in obesity, protein and fat ingestion elicit similar early (30 min) incretin hormone responses, whereas 300-min GIP secretion is more pronounced after fat than protein ingestion. PMID- 21554524 TI - Adherence to antiretroviral therapy: factors independently associated with reported difficulty taking antiretroviral therapy in a national sample of HIV positive Australians. AB - OBJECTIVES: Given the importance of adherence to combination antiretroviral therapy (cART) for the reduced morbidity and improved mortality of people living with HIV infection (PLWH), we set out to determine which of a number of previously investigated personal, socioeconomic, treatment-related and disease related factors were independently associated with self-reported difficulty taking antiretroviral therapy (ART) in an Australian sample of PLWH. METHODS: Using data from a national cross-sectional survey of 1106 PLWH, we conducted bivariate and multivariable analyses to assess the association of over 70 previously investigated factors with self-reported difficulty taking ART. Factors that maintained an association with reported difficulty taking ART at the level of alpha=0.05 in the multivariable logistic regression analysis were considered to be independently associated with reported difficulty taking ART. RESULTS: A total of 867 (78.4%) survey respondents were taking antiretroviral medication at the time of completing the HIV Futures 6 survey. Overall, 39.1% of these respondents reported difficulty taking ART. Factors found to be independently associated with reported difficulty taking ART included younger age, alcohol and party drug use, poor or fair self-reported health, diagnosis of a mental health condition, living in a regional centre, taking more than one ART dose per day, experiencing physical adverse events or health service discrimination, certain types of ART regimen and specific attitudes towards ART and HIV. CONCLUSIONS: Thirteen previously investigated factors were found to be independently associated with reported difficulty taking ART, reaffirming the dynamic nature of adherence behaviour and the ongoing importance of addressing adherence behaviour in the clinical management of PLWH. PMID- 21554525 TI - Mineral density and bone remodelling markers in patients with calcium lithiasis. AB - What's known on the subject? and What does the study add? Hypercalciuria is related with bone mineral density loss. This study demonstrates the relationship between recurrent calcium nephrolithiasis and bone mineral density loss and their correlation with bone markers. OBJECTIVES: * To show that a relationship exists between the loss of bone mineral density (BMD) and calcium renal lithiasis and that bone remodelling markers correlate with changes in BMD. * It is possible that many cases hypercalciuria are related to the increase of bone turnover and the predominance of bone resorption phenomena. PATIENTS AND METHODS: * The present study comprised a transversal investigation in three groups: group O, without lithiasis; group A, with a single episode of lithiasis; and group B, with relapsed calcium renal lithiasis. * An analysis was made of body mass index; abdominal X-ray and/or urography and renal ultrasonography; osteocalcin and beta crosslaps bone markers; calcium and citrate concentrations in the urine; and femur and spinal column bone densitometry. * The results were analyzed by analysis of variance and Pearson's correlation coefficient. RESULTS: * Patients with relapsed calcium renal lithiasis present a greater BMD loss than those in the O or A groups. * Densitometry: T-score femur -0.2 group O, -0.5 group A, -1.2 group B (P= 0.001); T-score column -0.6 group O, -0.6 group A, -1.3 group B (P= 0.05). * A statistically significant negative correlation exists between values of beta-crosslaps and T-score femur (R=-0.251; P= 0.009) and T-score column (R= 0.324; P= 0.001); thus, a higher concentration of beta-crosslaps was accompanied by a lower value of the T-score and a greater loss of BMD. * A positive relationship is observed between beta-crosslaps and osteocalcin (R= 0.611; P < 0.001) and between calciuria and cocient beta-crosslaps/osteocalcin (R= 0.303; P= 0.001). CONCLUSIONS: * A statistically significant relationship is shown between the loss of BMD and relapsed calcium renal lithiasis. * Determination of bone remodelling markers (i.e. osteocalcin and beta-crosslaps) facilitates the diagnosis of osteopaenia/osteoporosis in these patients. PMID- 21554526 TI - Safety and feasibility of the prostatic urethral lift: a novel, minimally invasive treatment for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). AB - OBJECTIVES: * To investigate the Prostatic Urethral Lift (PUL) procedure, a novel, minimally invasive treatment for symptomatic benign prostatic hyperplasia (BPH), which aims to mechanically open the prostatic urethra without ablation or resection. * To demonstrate the safety and feasibility of this procedure and to make an initial assessment of effectiveness. PATIENTS AND METHODS: * The PULprocedure was performed on 19 men in Australia. * Small suture-based implants were implanted transurethrally under cystoscopic visualisation to separate encroaching lateral prostatic lobes. * Patients were evaluated at 2 weeks and 3, 6, and 12 months after PUL. RESULTS: * All cases were successfully completed with no serious or unexpected adverse events (AEs). * Between two and five sutures were delivered in each patient and the prostatic urethral lumen was visually increased in all patients. * Reported postoperative AEs were typically mild and transient and included dysuria and haematuria. * Follow-up cystoscopy at 6 months in a subset of patients showed no calcification. Histological findings from two of three patients who progressed to transurethral resection of the prostate for return of symptoms showed no evidence of inflammation related to the implanted materials. * The mean International Prostate Symptom Score was reduced by 37% at 2 weeks and 39% at 1 year after PUL as compared with baseline. CONCLUSIONS: * We demonstrated in this initial experience that the PUL procedure is safe and feasible. * The safety profile of the PUL procedure appears favourable; most patients reported sustained symptom relief to 12 months with minimal morbidity * PUL therefore warrants further study as a new option for the many patients who seek an alternative to current therapies. PMID- 21554527 TI - The suburethral tension adjustable sling (REMEEX system) in the treatment of female urinary incontinence due to 'true' intrinsic sphincter deficiency: results after 5 years of mean follow-up. AB - OBJECTIVE: * To retrospectively report the objective and subjective outcomes of suburethral tension adjustable sling (Remeex system) implantation for stress urinary incontinence (SUI) caused by 'true' intrinsic sphincter deficiency (ISD) with fixed urethra. PATIENTS AND METHODS: * Thirty female patients with severe SUI, mainly because of iatrogenic ISD, underwent Remeex system positioning between May 2002 and July 2008 (mean follow-up 60.6 months, range 22-96 months). * Before surgery, patients were evaluated by physical examination, translabial ultrasonography, flexible cystoscopy, urodynamics, 1-hour pad test and compilation of a quality-of-life questionnaire. * Postoperatively, based on the physical examination and pad test, patients were stratified into three groups: (i) Cured: perfectly dry patients at stress test, pad weight 0-1 g; (ii) Improved: patients with mild to moderate incontinence, pad weight 2-50 g; and (iii) Failed: unchanged or worsened patients, pad weight >50 g. RESULTS: * At the final follow-up visit, 26 (86.0%) patients were cured, 2 (7.0%) were improved and 2 (7.0%) had failed. * In particular, the total mean pad weight decreased to 33.2 +/- 15.6 (71%) and the total mean questionnaire score significantly increased to 86.9 +/- 6.7 (74.0%). * Sling tension readjustment was needed during follow-up in two patients (7%). * Among the complications, persistent urinary retention (10%), seroma formation (3%) and de novo urgency (7%) were easily treated. CONCLUSION: * The Remeex system produced remarkable 5-year results with a low complication rate. These outcomes have also been confirmed in a worse prognosis patient group as reported in the present study. PMID- 21554528 TI - GhHmgB3 deficiency deregulates proliferation and differentiation of cells during somatic embryogenesis in cotton. AB - The proteins of high-mobility group box (HmgB) family were involved in the regulation of transcription and other DNA-dependent processes. To investigate the function of HmgB proteins during cotton somatic embryogenesis (SE), four Gossypium hirsutum HmgB genes were characterized. The gene GhHmgB3 preferentially expressed in embryonic tissues and was studied in detail. RNA interference and over-expression was used to regulate the expression of GhHmgB3 during cotton SE by transforming both hypocotyl and embryogenic calli (ECs) via Agrobacterium tumefaciens. The GhHmgB3-deficient somatic cells of hypocotyls dedifferentiated more vigorously than the control cells, but they failed to differentiate to ECs. In another case, the proliferation and differentiation of GhHmgB3-deficient ECs were significantly improved, but failed to form plantlets. Over-expression of GhHmgB3 had no significant differences in callus initiation and differentiation compared with the control cell lines. The different expression genes between the control and GhHmgB3-deficient ECs were identified by Solexa sequencing technology. The bioinformatics analysis and experimental verification revealed series of abnormal mechanism associated with beta-catenin signalling. These results in response to the down-regulation of GhHmgB3 revealed series of beta catenin-related mechanisms might be responsible for the deregulation of proliferation and differentiation of cells in cotton SE. PMID- 21554529 TI - Metabolic engineering of soybean affords improved phytosterol seed traits. AB - Different combinations of three rate-limiting enzymes in phytosterol biosynthesis, the Arabidopsis thaliana hydroxyl methylglutaryl CoA1 (HMGR1) catalytic subunit linked to either constitutive or seed-specific beta-conglycinin promoter, and the Glycine max sterol methyltransferase1 (SMT1) and sterol methyltransferase2-2 (SMT2-2) genes, under the control of seed-specific Glycinin 1 and Beta-phaseolin promoters, respectively, were engineered in soybean plants. Mature seeds of transgenic plants displayed modest increases in total sterol content, which points towards a tight control of phytosterol biosynthesis. However, in contrast to wild-type seeds that accumulated about 35% of the total sterol in the form of intermediates, in the engineered seeds driven by a seed specific promoter, metabolic flux was directed to Delta(5) -24-alkyl sterol formation (99% of total sterol). The engineered effect of end-product sterol (sitosterol, campesterol, and stigmasterol) over-production in soybean seeds resulted in an approximately 30% increase in overall sitosterol synthesis, a desirable trait for oilseeds and human health. In contradistinction, increased accumulation of cycloartenol and 24(28)-methylencylartanol (55% of the total sterol) was detected in plants harbouring the constitutive t-HMGR1 gene, consistent with the previous studies. Our results support the possibility that metabolic flux of the phytosterol family pathway is differentially regulated in leaves and seeds. PMID- 21554530 TI - Biomedical Ti-Mo alloys with surface machined and modified by laser beam: biomechanical, histological, and histometric analysis in rabbits. AB - PURPOSE: In vivo bone response was assessed by removal torque, hystological and histometrical analysis on a recently developed biomedical Ti-15Mo alloy, after surface modification by laser beam irradiation, installed in the tibia of rabbits. MATERIALS AND METHODS: A total of 32 wide cylindrical Ti-15Mo dental implants were obtained (10mm * 3.75mm). The implants were divided into two groups: 1) control samples (Machined surface - MS) and 2) implants with their surface modified by Laser beam-irradiation (Test samples - LS). Six implants of each surface were used for removal torque test and 10 of each surface for histological and histometrical analysis. The implants were placed in the tibial metaphyses of rabbits. RESULTS: Average removal torque was 51.5Ncm to MS and >90Ncm to LS. Bone-to-implant-contact percentage was significantly higher for LS implants both in the cortical and marrow regions. CONCLUSIONS: The present study demonstrated that laser treated Ti-15Mo alloys are promising materials for biomedical application. PMID- 21554531 TI - Analysis of new bone formation induced by periosteal distraction in a rat calvarium model. AB - BACKGROUND: A controlled, gradual distraction of the periosteum is expected to result in the formation of new bone. PURPOSE: This study was designed to estimate the possibility of new bone formation by periosteal distraction in a rat calvarium model. MATERIAL AND METHODS: Sixteen animals were subjected to a 7-day latency period and distraction rate at 0.4 mm/24 hours for 10 days. Two experimental groups with seven rats each were killed at 10 and 20 days of consolidation period and analyzed by means of microcomputed tomography, histologically and histomorphometry. RESULTS: In the central regions underneath the disk device, signs of both bone apposition and bone resorption were observed. Peripheral to the disc, new bone was consistently observed. This new bone was up to two and three times thicker than the original bone after a 10- and 20-day consolidation period, respectively. Signs of ongoing woven bone formation indicated that the stimulus for new bone formation was still present. There were no statistically significant differences regarding bone density, bone volume, and total bone height between the two groups. CONCLUSION: The periosteal distraction model in the rat calvarium can stimulate the formation of considerable amounts of new bone. PMID- 21554532 TI - One-year results of a clinical and radiological prospective multicenter study on NEOSS(r) dental implants. AB - BACKGROUND: NEOSS(r) (Neoss Ltd., Harrogate, UK) dental implant system was introduced on the clinical arena in 2003. It is important that novel implant systems are systematically evaluated in a multicenter setting. PURPOSE: The aim of this study was to follow a large number of consecutively treated patients, with NEOSS dental implant system, both clinically and radiographically. The current report constitutes the 1-year data of a planned 5-year study. MATERIALS AND METHODS: The study included a total of 177 patients treated with 590 NEOSS implants at 13 clinics in Sweden. The material was composed of 72 males and 105 females treated for single, partial, and total edentulism. Clinical, radiographic, and subjective evaluations were performed. RESULTS: Out of 590 implants, 13 early failures have been reported, corresponding to a 1-year cumulative survival rate (CSR) of 97.8%. Evaluation of function and esthetics at the 1-year visit resulted in 100% success for function and 98% success for the esthetic outcome. The mean marginal bone loss was 0.6 mm (SD 1.1) after 1 year in clinical function. No adverse effects of the NEOSS dental implants were reported, and complications were few and similar to those reported for implant treatment in general. CONCLUSION: The CSR in the present study was 97.8%. No adverse effects of the NEOSS implants were reported, and complications during the study period were few and similar to those reported to for other well-documented implants system. Based on the present data, we conclude that NEOSS dental implant is a safe and predictable implant system. However, the high number of dropouts in the radiological evaluation must be considered when interpreting the data. PMID- 21554533 TI - Relaxin promotes growth and maturation of mouse neonatal cardiomyocytes in vitro: clues for cardiac regeneration. AB - The demonstration that the adult heart contains myocardial progenitor cells which can be recruited in an attempt to replace the injured myocardium has sparkled interest towards novel molecules capable of improving the differentiation of these cells. In this context, the peptide hormone relaxin (RLX), recently validated as a cardiovascular hormone, is a promising candidate. This study was designed to test the hypothesis that RLX may promote the growth and maturation of mouse neonatal immature cardiomyocytes in primary culture. The cultures were studied at 2, 12, 24 and 48 hrs after the addition of human recombinant H2 RLX (100 ng/ml), the main circulating form of the hormone, or plain medium by combining molecular biology, morphology and electrophysiology. RLX modulated cell proliferation, promoting it at 2 and 12 hrs and inhibiting it at 24 hrs; RLX also induced the expression of both cardiac-specific transcription factors (GATA-4 and Nkx2-5) and cardiac-specific structural genes (connexin 43, troponin T and HCN4 ion channel) at both the mRNA and protein level. Consistently, RLX induced the appearance of ultrastructural and electrophysiological signs of functionally competent, mature cardiomyocytes. In conclusion, this study provides novel circumstantial evidence that RLX specifically acts on immature cardiomyocytes by promoting their proliferation and maturation. This notion suggests that RLX, for which the heart is both a source and target organ, may be an endogenous regulator of cardiac morphogenesis during pre-natal life and could participate in heart regeneration and repair, both as endogenous myocardium-derived factor and exogenous cardiotropic drug, during adult life. PMID- 21554534 TI - Anxiety and fear in a cross of C57BL/6J and DBA/2J mice: mapping overlapping and independent QTL for related traits. AB - Anxiety, like other psychiatric disorders, is a complex neurobehavioral trait, making identification of causal genes difficult. In this study, we examined anxiety-like behavior and fear conditioning (FC) in an F(2) intercross of C57BL/6J and DBA/2J mice. We identified numerous quantitative trait loci (QTL) influencing anxiety-like behavior in both open field (OF) and FC tests. Many of these QTL were mapped back to the same chromosomal regions, regardless of behavior or test. For example, highly significant overlapping QTL on chromosome 1 were found in all FC measures as well as in center time measures in the OF. Other QTL exhibited strong temporal profiles over testing, highlighting dynamic relationship between genotype, test and changes in behavior. Next, we implemented a factor analysis design to account for the correlated nature of the behaviors measured. OF and FC behaviors loaded onto four main factors representing both anxiety and fear behaviors. Using multiple QTL modeling, we calculated the percentage variance in anxiety and fear explained by multiple QTL using both additive and interactive terms. Quantitative trait loci modeling resulted in a broad description of the genetic architecture underlying anxiety and fear accounting for 14-37% of trait variance. Factor analysis and multiple QTL modeling showed both unique and shared QTL for anxiety and fear; suggesting a partially overlapping genetic architecture for these two different models of anxiety. PMID- 21554535 TI - Sensitivity to rewarding or aversive effects of methamphetamine determines methamphetamine intake. AB - Amphetamines have rewarding and aversive effects. Relative sensitivity to these effects may be a better predictor of vulnerability to addiction than sensitivity to one of these effects alone. We tested this hypothesis in a dose-response study in a second replicate set of mouse lines selectively bred for high vs. low methamphetamine (MA) drinking (MADR). Replicate 2 high (MAHDR-2) and low (MALDR 2) MA drinking mice were bred based on MA consumption in a two-bottle choice procedure and examined for novel tastant drinking. Sensitivities to the rewarding and aversive effects of several doses of MA (0.5, 2 and 4 mg/kg) were measured using a place conditioning procedure. After conditioning, mice were tested in a drug-free and then drug-present state for time spent in the saline- and MA-paired contexts. Similar to the first set of MADR lines, by the end of selection, MAHDR 2 mice consumed about 6 mg MA/kg/18 h, compared to nearly no MA in MALDR-2 mice, but had similar taste preference ratios. MAHDR-2 mice exhibited place preference in both the drug-free and drug-present tests, and no significant place aversion. In contrast, MALDR-2 mice exhibited no place preference or aversion during the drug-free test, but robust place aversion in the drug-present test. These data extend our preliminary findings from the first set of MADR lines and support the hypothesis that the combination of greater sensitivity to the rewarding effects of MA and insensitivity to the aversive effects of MA is genetically associated with heightened risk for MA consumption. PMID- 21554536 TI - Exacerbation of atopic dermatitis upon alkaline skin care. PMID- 21554537 TI - Abscisic acid receptors: past, present and future. AB - Jin-Gui Chen (Corresponding author) Abscisic acid (ABA) is the key plant stress hormone. Consistent with the earlier studies in support of the presence of both membrane- and cytoplasm-localized ABA receptors, recent studies have identified multiple ABA receptors located in various subcellular locations. These include a chloroplast envelope-localized receptor (the H subunit of Chloroplast Mg(2+) chelatase/ABA Receptor), two plasma membrane-localized receptors (G-protein Coupled Receptor 2 and GPCR-type G proteins), and one cytosol/nucleus-localized Pyrabactin Resistant (PYR)/PYR-Like (PYL)/Regulatory Component of ABA Receptor 1 (RCAR). Although the downstream molecular events for most of the identified ABA receptors are currently unknown, one of them, PYR/PYL/RCAR was found to directly bind and regulate the activity of a long-known central regulator of ABA signaling, the A-group protein phosphatase 2C (PP2C). Together with the Sucrose Non-fermentation Kinase Subfamily 2 (SnRK2s) protein kinases, a central signaling complex (ABA-PYR-PP2Cs-SnRK2s) that is responsible for ABA signal perception and transduction is supported by abundant genetic, physiological, biochemical and structural evidence. The identification of multiple ABA receptors has advanced our understanding of ABA signal perception and transduction while adding an extra layer of complexity. PMID- 21554538 TI - Regulation of meristem size by cytokinin signaling. AB - The plant meristems possess unique features that involve maintaining the stem cell populations while providing cells for continued development. Although both the primary shoot apical meristem (SAM) and the root apical meristem (RAM) are specified during embryogenesis, post-embryonic tissue proliferation is required for their full establishment and maintenance throughout a plants' life. The phytohormone cytokinin (CK) interacts with other systemic signals and is a key regulator of meristem size and functions. The SAM and the RAM respond to CK stimulations in different manners: CK promotes tissue proliferation in the SAM through pathways dominated by homeobox transcription factors, including the class I KNOX genes, STIP, and WUS; and curiously, it favors proliferation at low levels and differentiation at a slightly higher concentration in the RAM instead. Here we review the current understanding of the molecular mechanisms underlying CK actions in regulating meristematic tissue proliferation. PMID- 21554539 TI - Recent advances in the regulation of brassinosteroid signaling and biosynthesis pathways. AB - Brassinosteroids (BRs) play important roles in plant growth, development and responses to environmental cues. BRs signal through plasma membrane receptor BRI1 and co-receptor BAK1, and several positive (BSK1, BSU1, PP2A) and negative (BKI1, BIN2 and 14-3-3) regulators to control the activities of BES1 and BZR1 family transcription factors, which regulate the expression of hundreds to thousands of genes for various BR responses. Recent studies identified novel signaling components in the BR pathways and started to establish the detailed mechanisms on the regulation of BR signaling. In addition, the molecular mechanism and transcriptional network through which BES1 and BZR1 control gene expression and various BR responses are beginning to be revealed. BES1 recruits histone demethylases ELF6 and REF6 as well as a transcription elongation factor IWS1 to regulate target gene expression. Identification of BES1 and BZR1 target genes established a transcriptional network for BR response and crosstalk with other signaling pathways. Recent studies also revealed regulatory mechanisms of BRs in many developmental processes and regulation of BR biosynthesis. Here we provide an overview and discuss some of the most recent progress in the regulation of BR signaling and biosynthesis pathways. PMID- 21554540 TI - Heterologous synthesis of cytochrome c' by Escherichia coli is not dependent on the System I cytochrome c biogenesis machinery. AB - Hydrogenophilus thermoluteolus cytochrome c' (PHCP) has typical spectral properties previously observed for other cytochromes c', which comprise Ambler's class II cytochromes c. The PHCP protein sequence (135 amino acids) deduced from the cloned gene is the most homologous (55% identity) to that of cytochrome c' from Allochromatium vinosum (AVCP). These findings indicate that PHCP forms a four-helix bundle structure, similar to AVCP. Strikingly, PHCP with a covalently bound heme was heterologously synthesized in the periplasm of Escherichia coli strains deficient in the DsbD protein, a component of the System I cytochrome c biogenesis machinery. The heterologous synthesis of PHCP by aerobically growing E. coli also occurred without a plasmid carrying the genes for Ccm proteins, other components of the System I machinery. Unlike Ambler's class I general cytochromes c, the synthesis of PHCP is not dependent on the System I machinery and exhibits similarity to that of E. coli periplasmic cytochrome b(562), a 106 residue four-helix bundle. PMID- 21554541 TI - Unique ganglioside binding by botulinum neurotoxins C and D-SA. AB - The botulinum neurotoxins (BoNTs) are the most potent protein toxins for humans. There are seven serotypes of BoNTs (A-G), based on a lack of cross-antiserum neutralization. The BoNT/C and BoNT/D serotypes include mosaic toxins that are organized as D-C and C-D toxins. One BoNT D-C mosaic toxin, BoNT/D-South Africa (BoNT/D-SA), was not fully neutralized by immunization with a vaccine composed of either prototype BoNT/C-Stockholm or BoNT/D-1873. Whereas several BoNT serotypes utilize dual receptors (gangliosides and proteins) to bind to and enter neurons, the basis for BoNT/C and BoNT/D entry into neurons is less well understood. Recent studies solved the crystal structures of the receptor-binding domains of BoNT/C, BoNT/D, and BoNT/D-SA. Comparative structural analysis showed that BoNT/C, BoNT/D and BoNT/D-SA lacked components of the ganglioside-binding pocket that exists within other BoNT serotypes. With the use of structure-based alignments, biochemical analyses, and cell-binding approaches, BoNT/C and BoNT/D SA have been shown to possess a unique ganglioside-binding domain, the ganglioside-binding loop. Defining how BoNTs enter host cells provides insights towards understanding the evolution and extending the potential therapeutic and immunological values of the BoNT serotypes. PMID- 21554542 TI - Roles of conserved arginines in ATP-binding domains of AAA+ chaperone ClpB from Thermus thermophilus. AB - ClpB, a member of the expanded superfamily of ATPases associated with diverse cellular activities (AAA+), forms a ring-shaped hexamer and cooperates with the DnaK chaperone system to reactivate aggregated proteins in an ATP-dependent manner. The ClpB protomer consists of an N-terminal domain, an AAA+ module (AAA 1), a middle domain, and a second AAA+ module (AAA-2). Each AAA+ module contains highly conserved WalkerA and WalkerB motifs, and two arginines (AAA-1) or one arginine (AAA-2). Here, we investigated the roles of these arginines (Arg322, Arg323, and Arg747) of ClpB from Thermus thermophilus in the ATPase cycle and chaperone function by alanine substitution. These mutations did not affect nucleotide binding, but did inhibit the hydrolysis of the bound ATP and slow the threading of the denatured protein through the central pore of the T. thermophilus ClpB ring, which severely impaired the chaperone functions. Previously, it was demonstrated that ATP binding to the AAA-1 module induced motion of the middle domain and stabilized the ClpB hexamer. However, the arginine mutations of the AAA-1 module destabilized the ClpB hexamer, even though ATP-induced motion of the middle domain was not affected. These results indicated that the three arginines are crucial for ATP hydrolysis and chaperone activity, but not for ATP binding. In addition, the two arginines in AAA-1 and the ATP induced motion of the middle domain independently contribute to the stabilization of the hexamer. PMID- 21554543 TI - Vesicular traffic in cell navigation. AB - Cell navigation is the process whereby cells or cytoplasmic extensions are guided from one point to another in multicellular organisms or, in the case of unicellular eukaryotic organisms, in the environment. Recent work has demonstrated that membrane trafficking plays an important role in this process. Here, we review the role of soluble N-ethylmaleimide-sensitive fusion attachment protein (SNAP) receptors (SNAREs), which constitute the core machinery for membrane fusion and are essential for intracellular vesicular trafficking. We discuss the important functions of several vesicular- and target-SNAREs, in particular vesicular-associated membrane proteins 1, 2, 3, 4 and 7; vti1a/b; SNAP23 and SNAP25; and syntaxins 1, 3, 6 and 13. We conclude that endosomal SNAREs are important for cell navigation, a concept that opens avenues for fundamental research. There are also possible therapeutic applications because some of these SNAREs are the targets of clostridial neurotoxins. PMID- 21554544 TI - The lipid translocase, ABCA4: seeing is believing. AB - Mutations to members of the A subfamily of ATP binding cassette (ABC) proteins are responsible for a number of diseases; typically they are associated with aberrant cellular lipid transport processes. Mutations to the ABCA4 protein are linked to a number of visual disorders including Stargardt's disease and retinitis pigmentosa. Over 500 disease-associated mutations in ABCA4 have been demonstrated; however, the genotype-phenotype link has not been firmly established. This shortfall is primarily because the function of ABCA4 in the visual cycle is not yet fully understood. One hypothesis suggests that ABCA4 mediates the trans-bilayer translocation of retinal-phosphatidylethanolamine conjugates to facilitate the retinal regeneration process in the visual cycle. This review examines the evidence to support, or refute, this working hypothesis on the function of this clinically important protein. PMID- 21554545 TI - Function and regulation of ABCA1--membrane meso-domain organization and reorganization. AB - The ATP-binding cassette protein A1 (ABCA1) mediates the secretion of cellular free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein A I, to form high-density lipoprotein. Because ABCA1 is a key factor in cholesterol homeostasis, elaborate transcriptional and post-transcriptional regulations of ABCA1 have evolved to maintain cholesterol homeostasis. Recent studies suggest that ABCA1 moves lipids not only between membranes but also within membranes to organize and reorganize membrane meso-domains to modulate cell proliferation and immunity. PMID- 21554547 TI - Guanylate cyclase activator YC-1 enhances TRAIL-induced apoptosis in human epithelial ovarian carcinoma cells via activation of apoptosis-related proteins. AB - To assess the ability of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) to promote apoptosis, we investigated the effect of YC-1 on tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in the human epithelial ovarian carcinoma cell lines. In OVCAR-3 and SK-OV-3 cell lines, we examined the stimulatory effect of YC-1 on TRAIL-induced apoptosis by monitoring cell death, nuclear damage, changes in apoptosis-related protein levels, activation of caspases and changes in the mitochondrial transmembrane potential. TRAIL induced a decrease in Bid, Bcl-2 and Bcl-xL protein levels, increase in cleaved Bid and Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3) and an increase in the tumour suppressor p53 levels. YC-1 enhanced TRAIL-induced apoptosis-related protein activation, nuclear damage and cell death. Results from this study suggest that YC-1 may enhance the apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. YC-1 may confer a benefit in TRAIL treatment of epithelial ovarian adenocarcinoma. PMID- 21554546 TI - ABCG transporters and disease. AB - ATP-binding cassette (ABC) transporters form a large family of transmembrane proteins that facilitate the transport of specific substrates across membranes in an ATP-dependent manner. Transported substrates include lipids, lipopolysaccharides, amino acids, peptides, proteins, inorganic ions, sugars and xenobiotics. Despite this broad array of substrates, the physiological substrate of many ABC transporters has remained elusive. ABC transporters are divided into seven subfamilies, A-G, based on sequence similarity and domain organization. Here we review the role of members of the ABCG subfamily in human disease and how the identification of disease genes helped to determine physiological substrates for specific ABC transporters. We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2. PMID- 21554548 TI - Sodium arsenite-induced alteration in hepatocyte function of rat with special emphasis on superoxide dismutase expression pathway and its prevention by mushroom lectin. AB - This study was accomplished to exemplify the possible protective role of ascorbic acid and mushroom lectin against arsenic-induced cytotoxicity and impairment of superoxide dismutase (SOD) production pathway in hepatocytes of rat. Hepatocytes were isolated from rat and treated with sodium arsenite (AS), arsenic plus ascorbic acid (AS + AA) and arsenic plus mushroom lectin (AS + ML). A placebo control was also included. Arsenic treatment resulted in the depletion of cell proliferation, phagocytic activity (nitro blue tetrazolium index) and superoxide dismutase (SOD) activity, relative mRNA expression of superoxide dismutase 2 (SOD(2)) and enhanced production of nitric oxide (NO). Ascorbic acid, a standard antioxidant, could normalize cellular perturbation and SOD production pathway relating to gene expression, whereas partially purified Pleurotus florida lectin (PFL), an edible mushroom containing protein complex, maintained cellular activity and prevented stress by normalizing phagocytic (NBT index) and SOD activities vis-a-vis relative gene expression. It could further defend NO production of hepatocytes. Mushroom lectin strongly prevented sodium arsenite induced damage of SOD production pathway in hepatocytes, and its effect was also comparable to a standard antioxidant, i.e. ascorbic acid. PMID- 21554549 TI - A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus. AB - INTRODUCTION: Patients with diabetes mellitus (DM) are reported to experience more severe erectile dysfunction (ED) symptoms and respond less to ED treatments compared with patients with ED of other etiologies. AIM: This study was undertaken to evaluate the safety and efficacy of udenafil for the treatment of ED in a larger number of patients with DM. METHODS: A placebo-controlled, randomized, double-blind, double-dummy, parallel-group design multicenter study, fixed-dose trial was conducted. The trial involved seven study sites in Korea, with 174 ED patients with DM. The subjects, treated with placebo, 100 mg, or 200 mg of udenafil for 12 weeks, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Question (GAQ) during the study period. MAIN OUTCOME MEASURES: The primary efficacy parameter was the change in the erectile function domain (EFD) score of IIEF from baseline. Secondary parameters were IIEF questions 3 (Q3) and Q4, SEP Q2 and Q3, rate of achieving normal erectile function (EFD >= 26), and the response to GAQ. RESULTS: Compared with the placebo, patients receiving both doses of udenafil showed statistically significant improvements in the IIEF-EFD score, respectively. However, statistically significant difference was not observed between the udenafil 100 mg and the udenafil 200 mg groups. Similar results were observed in the comparison of Q3 and Q4 of IIEF, SEP diary, and GAQ. The percentages of subjects experiencing at least one adverse event related to the study drugs were 3.6%, 15.8%, and 22.4% for the placebo, udenafil 100 mg, and udenafil 200 mg groups, respectively. However, these events were all mild in severity. Major adverse events were flushing, headache, nausea, and conjunctival hyperemia. CONCLUSION: Udenafil was significantly effective for the treatment of ED, demonstrating statistically significant improvement in erectile function in patients with DM. The incidence of adverse events was relatively low and well tolerated in patients with DM. PMID- 21554550 TI - Imbalanced low-grade inflammation and endothelial activation in patients with type 2 diabetes mellitus and erectile dysfunction. AB - INTRODUCTION: Erectile dysfunction (ED) is highly prevalent among type 2 diabetes mellitus patients (T2DM). Although a link among systemic inflammation, endothelial dysfunction, and ED is described in clinical situations mainly related with coronary heart disease (CHD) risk, evidences of this link in T2DM patients are rather limited. AIMS: To evaluate the association between endothelial dysfunction and balance of pro-/anti-inflammatory mediators with ED presence and severity in T2DM. METHODS: We conducted a cross-sectional study of 190 T2DM patients without symptomatic CHD, 150 out of them with ED and 40 without ED. Serum levels of E-selectin, intercellular adhesion molecule-1, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-10 were measured using specific enzyme-linked immunosorbent assays (ELISAs). ED presence and severity were tested by the five-item version of the International Index of Erectile Function questionnaire. MAIN OUTCOME MEASURES: Differences in circulating levels of endothelial dysfunction (ICAM-1, E-selectin) and inflammatory/anti-inflammatory (TNF-alpha, IL-10, TNF-alpha : IL-10 ratio) markers between T2DM patients with and without ED, and assessment of biomarkers ED predictive value while adjusting for other known ED risk factors. RESULTS: Patients with ED were older and had longer duration of diabetes than patients without ED. E-selectin serum levels were significantly increased, while IL-10 were lower in patients with ED; because TNF-alpha levels tend to be higher, TNF-alpha : IL-10 ratio was more elevated in ED patients. No significant differences of ICAM-1 levels were observed between study groups. Endothelial activation markers and TNF-alpha, as well as diabetes duration, were negatively correlated with erectile function. On multivariate analysis including age, duration of diabetes, insulin treatment, hypertension, insulin resistance, fair-to-poor glycemic control, and metabolic syndrome, increments in E-selectin levels and TNF-alpha : IL-10 ratio predicted independently ED presence, while IL-10 increases were associated with lower risk of ED in T2DM patients. CONCLUSIONS: ED in T2DM patients without symptomatic CHD is associated with systemic endothelial dysfunction and a predominant, imbalanced low-grade inflammatory response. PMID- 21554551 TI - Sickle-cell priapism--a series of informational articles and a call to action by the medical community. PMID- 21554553 TI - New insights into the pathophysiology of sickle cell disease-associated priapism. AB - INTRODUCTION: Priapism is defined as an erectile disorder, in which erection persists uncontrollably without sexual purpose. The precise mechanisms involved in the development of sickle cell disease-associated priapism are ill defined. AIM: To summarize the recent developments that increase our understanding of the molecular mechanisms of priapism. METHODS: This article reviews the literature (Medline search 2000-2010) that relates the key molecular signaling pathways that contribute to the development of priapism associated with sickle-cell disease. It focuses on basic science investigations using multiple animal models. MAIN OUTCOME MEASURES: The reader will be informed of the most current research regarding the role of endothelial nitric oxide synthase, phosphodiesterase type 5 (PDE5), adenosine, RhoA/Rho-kinase (ROCK), and opiorphins in the pathophysiology of priapism. RESULTS: New concepts in the field of priapism research suggest that priapism often results from altered vascular homeostatic actions in the penis and is associated with deficient erection control mechanisms on a molecular level. A leading proposal in this regard is the notion of aberrant signaling of the endothelium-derived nitric oxide and PDE5 signal transduction pathway in the penis. Additionally, dysfunctional regulatory control of signal transduction systems which interact with this pathway such as adenosine and RhoA/Rho-kinase may contribute to the development of priapism. Recent investigations of opiorphins also demonstrate a role in regulating corporal smooth muscle tone and thereby dysregulation of erection physiology in priapism. These advances have paved the way for understanding this disorder as having a molecular pathogenesis. CONCLUSIONS: As the science underlying priapism further emerges, increasingly effective therapeutics for sickle cell disease-associated priapism is certain to follow. PMID- 21554552 TI - Priapism in sickle-cell disease: a hematologist's perspective. AB - INTRODUCTION: Priapism is a familiar problem to hematologists, well known for its association with sickle-cell disease (SCD). It also occurs in a variety of other hematological illnesses, nearly all forms of congenital hemolytic anemia, including other hemoglobinopathies and red blood cell membranopathies and enzymopathies. AIM: Provide urologists with a comprehensive review of priapism in SCD, with an emphasis on the perspective of a practicing hematologist. METHODS: Medline searches through July 2010 were conducted using the terms priapism, erectile dysfunction, and sickle cell. MAIN OUTCOME MEASURES: Expert opinion was based on review of the medical literature related to this subject matter. RESULTS: In men with SCD, large epidemiological studies have linked the risk of priapism to clinical markers of the severity of intravascular hemolysis. Extracellular hemoglobin and arginase released during hemolysis has been implicated in reducing nitric oxide bioavailability, although the relevance of hemolysis to vascular dysfunction has been challenged by some scientists. Consistent with the role of impairment of the nitric oxide axis, mice genetically deficient in nitric oxide production have also been shown to develop priapic activity. Provocative new data indicate that hemolysis-linked dysregulation of adenosine signaling in the penis contributes to priapism in sickle cell mice. Serious questions have arisen regarding the efficacy of mainstays of textbook dogma for treatment of acute severe priapism, including intravenous fluids, alkalinization, and exchange transfusion, and there is increasing acceptance for early aspiration and irrigation of the corpus cavernosum. CONCLUSION: For patients with sickle cell with recurrent priapism, there is very limited evidence for a medical prophylaxis role for hydroxyurea, etilefrine, pseudoephedrine, leuprolide, sildenafil, and other agents. Recent publications have highlighted nitric oxide and adenosine signal transduction pathways as worthy of additional research. Research and clinical management of sickle-cell priapism is strengthened by multidisciplinary collaboration between hematologists and urologists. PMID- 21554554 TI - Evaluation of premature ejaculation. AB - INTRODUCTION: Premature ejaculation (PE) is a prevalent, yet often underdiagnosed, sexual disorder that affects men of all ages. Identification of PE is hampered by stigma and embarrassment associated with the condition, and limited awareness that it is treatable. Because diagnosis informs treatment decisions that have an impact on clinical outcomes, the ability to diagnose PE accurately is vital to the successful management of this condition. AIM: Provide an overview of how to evaluate and diagnose PE. METHODS: Review of the literature. MAIN OUTCOME MEASURES: The taxonomy of PE based on onset, time, type, and comorbidities. RESULTS: Diagnosis of PE encompasses seven key steps: (i) Obtaining the patient's general medical and sexual history; (ii) Classifying the symptom on the basis of onset (e.g., lifelong or acquired PE), timing (e.g., prior to or during intercourse), and type (e.g., absolute/generalized or relative/situational); (iii) Involving the partner to determine their view of the situation and the impact of PE on the couple as a whole; (iv) Identifying sexual comorbidities (e.g., erectile dysfunction) to define whether PE is simple (occurring in the absence of other sexual dysfunctions) or complicated (occurring in the presence of other sexual dysfunctions); (v) Performing physical examination to check the man's sexual organs and reflexes; (vi) Identifying underlying etiologies and risk factors (e.g., endocrine-, urological-, or psychorelational-/psychosexual-related) to determine the primary cause of PE and any associated comorbidities; (vii) Discussing treatment options to find the most suitable intervention, according to the needs of the man and his partner. CONCLUSION: A greater understanding of how to diagnose PE correctly, and a more widespread use of a structured diagnostic approach, could lead to better treatment outcomes in the future. PMID- 21554555 TI - Infantile masturbation in monozygotic twins. PMID- 21554556 TI - Novel chiral skeletons for drug discovery: antibacterial tetramic acids. AB - Modification of the ring nucleus of tetramic acids derived from serine gives chiral heterocyclic libraries that exhibit antibacterial activity, and correlation with various physicochemical parameters indicates that chiral tetramic acids may provide a potentially valuable non-aromatic skeleton for fragment-based drug discovery. PMID- 21554557 TI - Early knowledge of the two reactions constituting ventilation-perfusion coupling. PMID- 21554558 TI - There is no slowing of motility speed with increased body size in rat, human, horse and rhinoceros independent on temperature and skeletal muscle myosin isoform. AB - AIM: The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures. METHODS: A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 degrees C. RESULTS: The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature. CONCLUSION: The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors. PMID- 21554559 TI - Dual roles for Wnt signalling during the formation of the vertebrate neuromuscular junction. AB - Wnt proteins play prominent roles in different aspects of neuronal development culminating with the formation of complex neuronal circuits. Here, we discuss new studies addressing the function of Wnt signalling at the peripheral neuromuscular junction (NMJ). In both, invertebrate and vertebrate organisms, Wnt signalling promotes and also inhibits the assembly of the neuromuscular synapse. Here, we focus our attention on recent studies at the vertebrate NMJ that demonstrate that some Wnt proteins collaborate with the Agrin-MuSK signalling to induce post synaptic differentiation. In contrast, Wnts that activate the Wnt/beta-catenin signalling inhibit post-synaptic differentiation. The dual function of different Wnts might finely modulate the proper apposition of the pre- and post-synaptic terminals during NMJ formation and growth. PMID- 21554560 TI - Clinical assessment of a new computerised objective method of measuring facial palsy. AB - OBJECTIVE: To compare the results using a new computerised objective method of assessing the degree of facial palsy with the results obtained using traditional clinical methods. DESIGN: Prospective computerised pixel change analysis and clinical evaluation of videos. SETTING: Tertiary referral centre. PARTICIPANTS: Subjects with varying degrees of unilateral facial palsy. METHODS: Comparison of the results obtained from an objective computerised method, the Glasgow Facial Palsy Scale, with the standard subjective clinical methods of the House-Brackmann Scale, Yanagihara, Sunnybrook Grading Scales and the objective clinical Stennert Limberg-Frentrup Scale. RESULTS: Statistical analysis of the results from the objective computerised system indicated that there is an averagely strong correlation with the results from the House-Brackmann (Spearman's coefficient of 0.64), Sunnybrook (Pearson coefficient of 0.7) and Stennert-Limberg-Frentrup Scale (Pearson coefficient of 0.65), and it therefore has the ability to produce consistent results that agree with traditional clinical methods. It has a strong correlation with the Yanagihara Grading Scale (Pearson coefficient of 0.72) indicating that it may also have the ability to detect and record variations in the different regions of the face. CONCLUSION: This new computerised objective method of assessing the degree of facial palsy shows promise as a standardised objective method of assessing the degree of facial palsy. PMID- 21554561 TI - Bio-palladium: from metal recovery to catalytic applications. AB - While precious metals are available to a very limited extent, there is an increasing demand to use them as catalyst. This is also true for palladium (Pd) catalysts and their sustainable recycling and production are required. Since Pd catalysts exist nowadays mostly under the form of nanoparticles, these particles need to be produced in an environment-friendly way. Biological synthesis of Pd nanoparticles ('bio-Pd') is an innovative method for both metal recovery and nanocatalyst synthesis. This review will discuss the different bio-Pd precipitating microorganisms, the applications of the catalyst (both for environmental purposes and in organic chemistry) and the state of the art of the reactors based on the bio-Pd concept. In addition, some main challenges are discussed, which need to be overcome in order to create a sustainable nanocatalyst. Finally, some outlooks for bio-Pd in environmental technology are presented. PMID- 21554562 TI - MDR-TB in Finland--still rare despite the situation in our neighbouring countries. AB - INTRODUCTION: The multidrug-resistant tuberculosis (MDR-TB) epidemic in Eastern Europe bordering Finland has raised worries concerning the risk of disease in near-frontier contacts. OBJECTIVES: Our aim was to find out the amount of multidrug resistance, characterise the resistance profiles and evaluate the outcome of treatment. In addition, we analysed the isolates by molecular genotyping methods in order to evaluate the origins of the resistant isolates. METHODS: All culture-verified new MDR-TB cases diagnosed during the years 1994 2005 were included. Treatment outcome categories of the World Health Organization collected 36 months from the beginning of the treatment were used for outcome monitoring. The IS6110 restriction fragment length polymorphism (RFLP) test and spoligotyping were carried out according to standard recommendations. RESULTS: There were 19 culture-confirmed MDR-TB cases during the study period. The mean age was 39.9 years. The proportion of foreign-born patients was 73.7%. The outcome of the treatment was favourable in 14 cases (73.7%). When the spoligotypes were compared with the international spoligotype database, a corresponding spoligotype was found in 17 cases. Seven (36.8%) patients were infected by an isolate belonging to the Beijing genotype (SIT1). CONCLUSION: It is very probable that cases of MDR-TB in Finland are mostly caught abroad. Risk of gaining disease in near-frontier contacts seems to be very low. PMID- 21554563 TI - Homemade talc spray atomizer dedicated to flexible-rigid pleuroscope. AB - BACKGROUND: Thoracoscopic talc poudrage is the preferred technique for medical pleurodesis. However, commercial talc spray atomizers are not applicable with the flexible-rigid pleuroscope. Therefore, we developed a simple and cheap homemade talc spray atomizer dedicated to flexible-rigid pleuroscope. OBJECTIVE: To describe the experience in performing talc poudrage using our homemade talc spray atomizer. METHODS: A retrospective review was performed in 22 consecutive patients with symptomatic malignant pleural effusion undergoing thoracoscopic talc poudrage by our talc spray atomizer with the aim of performing a palliative pleurodesis. RESULTS: Under direct flexible-rigid pleuroscopic guidance, we could instill talc throughout the pleural cavity with our talc spray atomizer in all cases. The median procedure time to instill the whole talc was 4 min 15 s. The successful pleurodesis was achieved in 77.3%. CONCLUSIONS: We have introduced a homemade talc spray atomizer dedicated to the flexible-rigid pleuroscope. Uniform distribution of talc could be achieved without additional port placement. PMID- 21554564 TI - A double-blind randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD. AB - OBJECTIVE: To evaluate the efficacy and tolerability of topiramate in patients with posttraumatic stress disorder (PTSD). METHOD: We conducted a 12-week double blind, randomized, placebo-controlled study comparing topiramate to placebo. Men and women aged 18-62 years with diagnosis of PTSD according to DSM-IV were recruited from the outpatient clinic of the violence program of Federal University of Sao Paulo Hospital (Prove-UNIFESP), Sao Paulo City, between April 2006 and December 2009. Subjects were assessed for the Clinician-Administered Posttraumatic Stress Scale (CAPS), Clinical Global Impression, and Beck Depression Inventory (BDI). After 1-week period of washout, 35 patients were randomized to either group. The primary outcome measure was the CAPS total score changes from baseline to the endpoint. RESULTS: 82.35% of patients in the topiramate group exhibited improvements in PTSD symptoms. The efficacy analysis demonstrated that patients in the topiramate group exhibited significant improvements in reexperiencing symptoms: flashbacks, intrusive memories, and nightmares of the trauma (CAPS-B; P= 0.04) and in avoidance/numbing symptoms associated with the trauma, social isolation, and emotional numbing (CAPS-C; P= 0.0001). Furthermore, the experimental group demonstrated a significant difference in decrease in CAPS total score (topiramate -57.78; placebo -32.41; P= 0.0076). Mean topiramate dose was 102.94 mg/d. Topiramate was generally well tolerated. CONCLUSION: Topiramate was effective in improving reexperiencing and avoidance/numbing symptom clusters in patients with PTSD. This study supports the use of anticonvulsants for the improvement of symptoms of PTSD. PMID- 21554565 TI - Naltrexone depot formulations for opioid and alcohol dependence: a systematic review. AB - Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid-dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option. PMID- 21554566 TI - Melatonin receptor agonists: new options for insomnia and depression treatment. AB - The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT1 or MT2 subtype-selective compounds are available up to now. Administration of the MT2-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT2 receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT1 or MT2 receptors are expected in coming years. PMID- 21554567 TI - Numerical simulation of the flow field within the aortic arch during cardiac assist. AB - In recent years, artificial heart devices have been implanted in a considerable number of patients with terminal cardiac failure for bridge to transplantation and even destination therapy. These devices provide either pulsatile or continuous blood flow. To determine eventual physiological effects of these different types of flow on the aorta,a computational fluid dynamics model of the aorta and its thoracic branches was implemented. Pulsatile and continuous flow fields were calculated by implementing a comprehensive computational framework with a stabilized finite element method. The computed results revealed that the pulsatile pump support results in a lower mean shear stress and higher oscillatory shear stress index than the continuous pump support. The flow patterns for the pulsatile pump support above the closed aortic valves show a similar washout as for the continuous pump support. In summary, from the flow pattern simulation there was no particular preference for either pulsatile or continuous devices PMID- 21554568 TI - In vitro and in vivo antimicrobial activity of Xenorhabdus bovienii YL002 against Phytophthora capsici and Botrytis cinerea. AB - AIMS: Developing new bio-agents to control plant disease is desirable. Entomopathogenic bacteria Xenorhabdus spp. have potential antimicrobial activity in agriculture. This work was conducted to evaluate the antimicrobial activity of Xenorhabdus bovienii YL002 on plant pathogenic fungi and oomycete in vitro and the efficiency of this strain to reduce the in vivo incidence of grey mould rot on tomato plants caused by Botrytis cinerea and leaf scorch on pepper plants caused by Phytophthora capsici. METHODS AND RESULTS: The antimicrobial activity of X. bovienii YL002 was firstly determined on in vitro plant pathogenic fungi and oomycete and then on tomato fruits and plants infected with B. cinerea and pepper plants infected with P. capsici. The cell-free filtrate of X. bovienii YL002 exhibited highest inhibition effects (>98%) on mycelia growth of P. capsici and B. cinerea. The 50% inhibition concentration (EC50) of the methanol-extracted bioactive compounds (methanol extract) of the cell-free filtrate against P. capsici and B. cinerea were 164.83 and 42.16 MUg ml-1. The methanol extract also had a strong effect on the spore germination of P. capsici and B. cinerea, with a EC50 of 70.38 and 69.33 MUg ml-1, respectively. At 1000 MUg ml-1, the methanol extract showed a therapeutic effect of 70.82% and a protective effect of 77.4% against B. cinerea on tomato plants compared with the control. The methanol extract also showed potent effect against P. capsici, with a therapeutic effect of 68.14% and a protective effect of 65.46% on pepper plants compared with the control. CONCLUSIONS: Xenorhabdus bovienii YL002 produces antimicrobial compounds with strong activity on plant pathogenic fungi and oomycete and has the potential for controlling grey mould rot of tomato plants and leaf scorch of pepper and could be useful in integrated control against diverse plant pathogenic fungi and oomycete. SIGNIFICANCE AND IMPACT OF THE STUDY: This study showed the potential that X. bovienii YL002 can be used to control the grey mould rot caused by B. cinerea on tomato plants and leaf scorch caused by P. capsici on pepper plants with the objective to reduce treatments with chemical fungicides. PMID- 21554569 TI - Inhibition of sexual maturation in male rats by melatonin: evidence linking the mechanism of action to changes in the regulation of hypothalamic neuropeptide y. AB - Activation of gonadotrophin-releasing hormone (GnRHJ pathways is a pivotal event in the process of sexual maturation, however the regulatory influences that precipitate this change and lead to the onset of puberty remain poorly understood. Recent studies indicate that neuropeptide Y (NPY) may participate in the regulation of luteinizing hormone secretion by modulating the pattern of GnRH secretion and by directly altering the pituitary responsiveness to GnRH stimulation. To determine whether NPY plays a role in puberty-associated changes in hypothalamic function, levels of NPY-like immunoreactivity (NPY-IR) were measured in a fragment of the hypothalamus encompassing the median eminence and medial portion of the arcuate nucleus (ME-AN), and also in the remainder of the hypothalamus from male rats of different ages. To identify changes in hypothaiamic NPY linked to the process of sexual development, the effect of delaying sexual maturation by daily afternoon administration of 100 MUg melatonin (MT) from 20 to 40 days was investigated. In the hypothalamus and ME-AN, total NPY content increased progressively with age. Expressed as a concentration (fmol/MUg extracted protein), peak values for the ME-AN (55.4 +/- 7.0) were observed at 30 days of age followed by a decline to lower levels (30.2 +/- 1.9) at 40 days. Daily afternoon administration of MT from 20 days of age resulted in significant increases (P<0.01) in the levels of NPY-IR in the ME-AN compared to control values at 30 and 40 days of age. MT was without effect on NPY-IR levels in the remainder of the hypothalamus. When MT was administered in the early morning, a procedure which does not delay sexual maturation, NPY-IR values for the ME-AN region were not different from control rats indicating that the MT induced changes in NPY were related to the effects on sexual maturation. Using pituitary luteinizing hormone content and seminal vesicle weight as indices of sexual development, significant inverse correlation coefficients (P<0.001) between these parameters and the NPY concentration in the ME-AN were observed (r =-0.79 and -0.70, respectively). From published data it is not possible to conclude whether the main effects of NPY are exerted at the hypothalamic or pituitary level. However, the changes in the NPY content of the ME-AN observed during the onset of puberty, and the influence of MT on these changes, support assertions that NPY is involved in the regulation of sexual maturation. PMID- 21554570 TI - 6-hydroxydopamine lesions of the locus coeruleus induce a paradoxical increase in growth hormone secretion in male rats. AB - While the pharmacology of noradrenaline effects on growth hormone (GH) secretion has been extensively studied, the precise localization of noradrenergic neurons involved remains unclear. In the present work, we investigated whether A6 noradrenergic neurons located in the locus coeruleus can play a role in the rhythmic pattern of GH secretion or in the sensitivity of the hormone response to different external challenges. Three weeks after bilateral 6-hydroxydopamine injections (8MUg/3MUl) into the locus coeruleus, hypothalamic noradrenaline concentrations were reduced by 60%. Pulsatile GH secretory patterns were observed in unanaesthetized, freely moving control, sham-operated or locus coeruleus lesioned male rats. The amplitude of the pulses and the area under the curves during the 6- or 12-h sampling period were twice as high in locus coeruleus lesioned than in control and sham-operated rats. In contrast, trough levels of GH and intervals between GH peaks were similar in all groups. Prolactin, adrenocorticotrophin, thyroid-stimulating hormone and luteinizing hormone plasma levels were not affected by the lesion. GH responses to two centrally acting drugs i.e. clonidine (2.5, 5 and 10MUg/100g body wt) and morphine (200MUg/100g body wt) were also highly amplified in locus coeruleus-lesioned rats. In contrast, GH responses to two peptides directly acting on somatotrophs i.e. GH releasing factor (0.05 and 1.25MUg/100g body wt) and vasoactive intestinal peptide (1.5MUg/100g body wt) were the same in sham-operated and lesioned animals. These data suggest that noradrenergic inputs from the locus coeruleus exert a selective inhibitory influence on GH secretion through centrally mediated mechanisms. PMID- 21554571 TI - Stress affects the activated form of the corticosteroid-receptor complex in the rat brain. AB - Glucocorticoid actions in the brain, particularly in the hippocampus and the hypothalamus, are critically involved in the response of the organism to stress. The key molecules in this process are the corticosteroid receptors, which upon activation, migrate and act in the nucleus. We have investigated the effect of stress on the activated form of the cytosolic glucocorticoid receptor from the above brain areas, using anion exchange chromatography. Exposure of rats to chronic stress resulted in the disappearance of the chromatographic peak, which corresponds to the activated form (DE II) of the hormone-receptor complex. For this phenomenon to occur, 1) the animal must be exposed to chronic, and not to acute stress, and 2) the adrenals of the animal must be intact. The disappearance of the activated form of the hormone-receptor complex (DE II) following chronic stress is most probably due to proteolysis of the receptor molecule, since it is specifically inhibited by the protease inhibitor leupeptin. This phenomenon may represent an adaptive mechanism which helps the organism cope with a repeated stressor. PMID- 21554572 TI - Changes in proopiomelanocortin primary transcript levels in the anterior pituitary accompany increased adrenocorticotropin secretion during the diurnal surge. AB - Proopiomelanocortin (POMC) gene transcription in the anterior pituitary varies during stress and glucocorticoid feedback. These changes appear to parallel alterations in peptide release. The diurnal rhythm of the hypothalamo-pituitary adrenal axis also involves the periodic excursion of adrenocorticotropin (ACTH) levels in plasma, but it is not clear whether the diurnal release is accompanied by changes at the transcriptional level. In the present study, we have initially characterized the heteronuclear species of POMC (hnPOMC) RNA found in the anterior pituitary by a Northern blot analysis and subsequently used this method to quantitate relative changes in the levels of heteronuclear transcript during diurnal stimulation. Two species of RNA migrating at 6.0 kb and 4.1 kb were found in the nuclear fraction of the anterior pituitary. Successive probing by various POMC cRNAs indicated that the 6.0 kb fragment was the primary transcript and the 4.1 kb fragment corresponded to the intron A-containing processing intermediate of POMC. The nuclear species were quantitated after acute swim stress and during the diurnal ACTH secretion. Acute swim increased plasma ACTH levels by 243% after 30 min. This was paralleled by a 214% increase in the primary transcript RNA levels. Endogenous circadian stimulation in the evening produced a smaller rise of plasma ACTH (79%), and was accompanied by a 34% increase in POMC hnRNA levels. Nuclear processing intermediate (4.1 kb) and the mRNA levels did not vary during the evening. These results suggest that the diurnal mechanism transiently increases ACTH release as well as POMC gene transcription in the anterior pituitary. Release and transcription appear to be tightly coupled during circadian activation as well as during stress. PMID- 21554573 TI - Effects of Cyclic AMP and Andre-gens on in vitro Brain Aromatase Enzyme Activity During Prenatal Development in the Rat. AB - In the rat, there is a marked but transient increase in hypothalamic aromatase activity during the last week of fetal life. The present study was undertaken to gain insight into the regulation of this developmental pattern. Hypothalamic fragments comprising the medial basal hypothalamus and the suprachiasmatic region (henceforth referred to as preoptic area) were explanted and cultured in serum free medium for 2 to 5 days. Aromatase activity was measured by the formation of (3) H(2) O, utilizing either [1beta-(3) H]androstene-dione or [1beta-(3) H]testosterone as substrate. Maximal rates of activity were obtained at a saturating concentration of 0.3 MUM [1beta-(3) H]testosterone. Confirmation of the identity of the [(3) H]estradiol formed was demonstrated by recrystallization of the derivatized estradiol to constant specific activity following incubation with [1,2,6,7-(3) H]testosterone. In agreement with previous reports, in vivo hypothalamic aromatase activity was negligible before gestational day (GD) 16, increased strikingly by GD19 (>5.0 pmol/h/mg protein) and decreased, thereafter, to low levels at GD22 (~1.0 pmol/h/mg protein). Medial basal hypothalamus preoptic area fragments explanted before GD17 failed to develop aromatase activity in vitro. If the tissue was explanted on GD17 or 18 (i.e. when the in vivo rate of activity was increasing), the enzyme activity did not continue to increase, but it was rather maintained for 2 days before decreasing in a manner that closely mimicked the decline observed in vivo. A similar, butimmediate decline was observed when the tissue was explanted on GD19 (i.e. at the time when theactivity peaks in vivo). Exposure of explants to either growth factors (insulin-like growth factor II, epidermal growth factor, and basic or acidic fibroblast growth factor), or steroids (estradiol-17beta, progesterone, testosterone, dihydrotestosterone and corticosterone) failed to either increase aromatase activity before the peak at GD19 or ameliorate its perinatal decline. Increase of Ca(2+) fluxes with the ionophore A23187 or activation of the cyclic AMP, cyclic GMP, or protein kinase C pathways were similarly ineffective, as was angiotensin II, a recently proposed stimulator of neural aromatase. In contrast, aromatase activity was suppressed 2- to 4-fold by activation of the cyclic AMP pathway (with either forskolin or 8-bromo-cyclic AMP) or by the androgens, testosterone and dihydrotestosterone. These results suggest that: 1) the appearance of aromatase activity in the rat hypothalamus before GD17 requires the unfolding of extrahypothalamic events, 2) the increase in aromatase activity that occurs before GD19 also requires extrahypothalamic inputs and does not involve any of the known intracellular signal transduction pathways, and 3) the decline in activity observed after GD19 is regulated within the hypothalamus, and appears to be determined, at least in part, by the activation of cyclic AMP formation. A potential role for androgens is discussed. PMID- 21554574 TI - The effect of signal frequency on the gonadal response of male Syrian hamsters to programmed melatonin infusions. AB - The aim of this study was to investigate which characteristics of the nocturnal melatonin signal, in addition to its duration, convey photoperiodic information to the reproductive axis. To achieve control over the pattern of circulating melatonin, male Syrian hamsters held under stimulatory long daylengths (16h light:8h dark) were pinealectomized to remove the principal source of circulating endogenous hormone and then fitted with chronic subcutaneous cannulae through which programmed infusions of melatonin solution or vehicle could be delivered. Experiment 1 tested whether long intervals between successive melatonin signals impaired the photoperiodic response. Animals which received a short day-like melatonin infusion of 10 h duration once every 24 h (T = 24) for 6 weeks underwent gonadal atrophy. When the same number of signals (42) was delivered at a frequency of once every 32 h (T = 32), they were ineffective and animals remained gonadally active. Two infusion patterns were used to determine if the loss of response to 10 h signals given at T = 32 h was a consequence of the frequency per se or the long interval between signals (22 h). In the first, a 'chimaeric' signal which combined a long duration i.e. short day-like 18 h melatonin signal with a short day-like melatonin-free interval of 14 h (combined signal T = 32 h) was able to induce significant, but only partial, gonadal atrophy. Second, when the 22-h interval between 10-h melatonin signals was interrupted by a short (2 h) melatonin pulse, significant but partial gonadal regression again occurred. Moreover, the response depended upon the timing of the 2 h pulse. When this fell early in the melatonin-free interval, leaving a large portion of it intact, it had no effect on gonadal condition. In contrast, a pulse delivered in the middle of the interval, which divided it up into two short day like segments of 10 h each, was partially effective in restoring a short day response. The second experiment tested whether melatonin signals delivered at a high frequency would induce a photoperiodic response. A 10 h infusion delivered once every 24 h caused gonadal atrophy. The same melatonin infusion delivered at a periodicity of 20 h (T = 20) was also very potent as a short day stimulus. However, when 10-h signals were delivered at the higher frequencies of once every 18 or 16 h, they were less effective. Only a minority of animals exhibited gonadal atrophy and overall the group means were not significantly different from those of saline-infused controls, but were significantly greater than those of the 24 and 20 h groups. These data demonstrate that the photoperiodic response to the melatonin signal is sensitive to the frequency at which the signal is received. However, there is no evidence for a circadian basis to this sensitivity, nor a dependence upon the relationship between the endocrine stimulus and the light-dark cycle, insofar as signals encountered at a non circadian period of 20 h are very effective. Moreover, the effectiveness of signals encountered at longer periodicities can be modified by manipulation of the uninterrupted duration of the interval free of melatonin, demonstrating a role in photoperiodic time measurement for the duration of the interval between signals. PMID- 21554575 TI - The distribution and development of delta sleep-inducing Peptide-like immunoreactivity in postnatal and prepubertal Guinea-pig brain. AB - The distribution and development of delta sleep-inducing peptide (DSIP) in the guinea-pig brain were studied in 2- to 60-day-old animals by using the indirect immunofluorescence method. DSIP-immunoreactive perikarya were observed in the olfactory bulb and tubercle, diagonal band of Broca, septum, preoptic area, anterior and lateral hypothalamus, arcuate nucleus and hippocampus. In addition to the densest innervation of the median eminence, DSIP-immunoreactive fibres were widely localized from forebrain to mesencephalon. The field of immunoreactive fibre endings appeared to be in close association with either the blood vessels of brain, ventricles, subarachnoid space or immunolabelled perikarya. Furthermore, throughout development the topographic distribution pattern of immunolabelled neuronal elements seemed to be similar. However, a generalized increase in number, immunofluorescence intensity and varicosities of DSIP fibres was displayed with the growth. The present results provide an anatomical basis for understanding multiple actions of DSIP in the central nervous system and future research for DSIP on development. PMID- 21554576 TI - Vasoactive intestinal polypeptide/peptide histidine isoleucine-immunoreactive neuron systems in the Basal hypothalamus of a rat strain with deficient prolactin release in response to stress. AB - There is evidence for involvement of vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) in control of prolactin secretion. In fact VIP and PHI-like immunoreactivities have been demonstrated in the hypotha/amic paraventricular nucleus and at the median eminence level. Using immunohistochemistry we have compared the distribution of immunoreactive VIP and PHI in the hypothalamus of male Sprague-Dawley rats and BS rats, a rat strain which has a deficient release of prolactin after stressful stimuli. Quantitative information was obtained by radioimmunoassay for VIP. VIP- and PHI-positive cell bodies were found in the parvocellular part of the paraventricular nucleus in colchicine-treated rats and in nerve fibres within the median eminence of untreated rats to the same extent in both strains. Furthermore, intravenous injection of VIP caused a significant increase in serum prolactin tevets in both strains. However, at the median eminence level in BS rats, the blood vessels located in the lateral aspects of the median eminence did not show the dense VIP/PHI innervation seen in Sprague-Dawley rats. Also, a thick VIP/PHI-positive nerve bundle present on the surface of the median eminence of Sprague-Dawley rats could not be seen in BS rats. Radioimmunoassay analysis revealed that VIP levels in the median eminence were twice as high in Sprague-Dawley as compared to BS rats. Taken together, these results suggest that the defect in the prolactin release mechanism present in BS rats is not confined to the paraventricular system or the pituitary, but could be due to a deficit in VIP/PHI in fibres associated with portal vessels at the median eminence level. PMID- 21554577 TI - Inhibition of prolactin release by gonadotropin-releasing hormone-associated Peptide in benign, dopamine-sensitive and in malignant, dopamine-resistant pituitary tumors. AB - Since the gonadotropin-releasing hormone-associated peptide (GAP) has been reported to be capable of inhibiting prolactin release from normal lactotrophs, with the present study we have examined the in vitro effects of GAP on prolactin release in an estrone-induced, dopamine-sensitive rat pituitary adenoma and two malignant, transplantable and dopamine-resistant rat pituitary tumors, 7315a and MtTW15. Enzymatically dispersed cells obtained from the three types of tumor were cultured in multiwell dishes for 4 days. On the fifth day, the cells were exposed for 4 h to human GAP 1-56 or to the analog GAP 42-56 or to rat GAP 1-53, at various concentrations. In some experiments, the effect of a pretreatment of the cells for 16 h with pertussis toxin before exposure to human GAP was also evaluated. In the three tissues, rat GAP was able to inhibit prolactin release in a dose-dependent manner. Human GAP 1-56 and GAP 42-56 were able to inhibit prolactin release in a dose-dependent manner in all cells except those of the MtTW15 tumor. Furthermore, in adenomatous cells, the inhibitory effects of these peptides were suppressed by pretreatment of the cells with pertussis toxin. These findings indicate that GAP is capable of inhibiting prolactin release even in dopamine-resistant pituitary tumors. This inhibition is exerted through a pertussis toxin-sensitive G-protein-dependent signaling mechanism in adenomatous cells. PMID- 21554578 TI - Effect of enhancement of cholinergic tone on the growth hormone response to acute hyperglycaemia or thyrotropin-releasing hormone in dogs. AB - The effect of enhancement of cholinergic tone by pyridostigmine on the growth hormone (GH) response to thyrotropin-releasing hormone (TRH) or glucose-induced acute hyperglycaemia was tested in six adult unanaesthetized beagle dogs. Both TRH (5MUg/ kg iv) and glucose (2 g/kg orally) did not significantly alter baseline GH levels but reduced the GH response to GH-releasing hormone (GHRH) (2 MUg/kg iv), although this effect was more clear-cut with TRH than with glucose. Pretreatment with pyridostigmine (2 mg/kg orally) counteracted the inhibitory effect of hyperglycaemia on the GHRH-induced GH release, but had no effect on the inhibition induced by TRH. In summary, these results indicate that: 1) acute hyperglycaemia and TRH play an inhibitory role on GHRH-stimulated GH secretion in dogs; 2) the inhibitory effect of acute hyperglycaemia is mediated via hypothalamic cholinergic neurotransmission, whereas other neurotransmitter pathways would be. involved in the effect of TRH. PMID- 21554579 TI - Prostaglandins of the E Series Stimulate Cyclic AMP Accumulation and N Acetylation of Serotonin in Chick Pineal Cells. AB - We investigated the effects of prostaglandins on cyclic AMP (cAMP) levels and on the activity of the rate-limiting enzyme of melatonin biosynthesis, arylalkylamine-N-acetyltransferase (NAT). The study was performed on primary cultures of dispersed chick pineal cells. Prostaglandin E, (PGE,) increased cAMP levels 2-fold and this stimulation went up to 4-fold in the presence of a phosphodiesterase inhibitor. The PGE,- evoked increase in cAMP levels did not desensitize over 6 h. The potency order of a series of prostaglandins to increase cAMP levels (PGE(1) PGE(1) >PGA2>PGD(2) ?PGF(2) alpha) agreed with the pharmacological profile of the adenylate cyclase-coupled prostaglandin receptor. Inhibition of endogenous prostaglandin synthesis by two cyclooxygenase inhibitors (indomethacin and aspirin) caused a 30% decrease in cAMP levels. This effect was completely reversed by the addition of exogenous PGE(1) or PGE(2) . Indomethacin and aspirin also caused a 50% decrease in NAT activity. Prostaglandins of the E series increased NAT activity up to 2-fold above basal level and restored NAT activity after inhibition by indomethacin or aspirin. These results are the first illustration of a role for prostaglandins in chick pineal cells. The correlations observed between cAMP levels and NAT activity suggest that the regulation of NAT activity by prostaglandins of the E series might be mediated by changes in cAMP concentration. PMID- 21554580 TI - Ontogeny of expression and glucocorticoid regulation of the arginine vasopressin gene in the rat hypothalamic paraventricular nucleus. AB - Corticotropin-releasing factor and arginine vasopressin (AVP) are the two major hypothalamic factors that regulate anterior pituitary adrenocorticotropin secretion during stress. We have previously reported that the expression of the corticotropin-releasing factor gene in the hypothalamus and its regulation by glucocorticoids were not mature during the first week of life in the rat, i.e. during the stress non-responsive period. In this report, we studied the ontogeny of expression of the AVP gene in the hypothalamic paraventricular nucleus in rats using in situ hybridization. AVP mRNA was detected as early as day 20 of gestation (E20) both in the parvocellular and the magnocellular portion of the paraventricular nucleus. The levels of expression of the AVP gene increased steadily from E20 to the third day after birth (P3) and remained stable from P3 to P14. Bilateral surgical adrenalectomy induced an increase in AVP mRNA levels in the parvocellular portion of the paraventricular nucleus, but not in the magnocellular portion, in both 7-day-old and 14-day-old rats, suggesting that the glucocorticoid regulation of the AVP synthesizing neurons of the paraventricular nucleus is mature in the developing postnatal rat. PMID- 21554581 TI - Multiplex solution hybridization-ribonuclease protection assay for quantitation of different ribonucleic Acid transcripts from snap-frozen neuroendocrine tissues of individual animals. AB - We have compiled a protocol for simultaneous quantitation of a variety of gene transcripts in multiple individual brain and pituitary gland dissections for studying pretranslational regulation of neuroendocrine systems in vivo, using experimental designs compatible with meaningful statistical power. To facilitate collection of many samples at a time, the tissue was snap-frozen in chilled liquid Freon and stored at -80 degrees C until further processing. In this way, as many as five different brain and pituitary gland dissections per rat could be collected from eight rats in about an hour. The snap-frozen tissue was suitable for isolation of separate cytoplasmic and nuclear RNA fractions using homogenization in the presence of detergents. To facilitate homogenization of many samples at a time, we devised a method in which the tissue was repeatedly expelled through a 22 gauge hypodermic needle attached to a 1-ml plastic syringe used as a disposable, ready-to-use homogenizer. In order to promote dissolution of lipid membrane structures which are prevalent in the brain, the lysis buffer has been optimized to include the detergent sodium deoxycholate in addition to Nonidet P-40. Specific RNA transcripts were analyzed using a quantitative solution hybridization-ribonuclease protection assay coupled with polyacrylamide gel electrophoresis. The value of this highly sensitive assay has been expanded by including several molecular probes against a variety of neuroendocrine mRNA sequences simultaneously (e.g. progonadotropin-releasing hormone, proopiomelanocortin, tyrosine hydroxylase, dopamine D2 receptor, prolactin), thus increasing the amount of information obtained from each sample in one assay. Furthermore, each sample was routinely co-assayed for cyclophilin mRNA, an abundant, generally non-regulated mRNA whose levels reflected the individual variability in sample processing, thus serving as an internal reference. Once stored in hybridization solution, as many as 100 samples could be analyzed simultaneously for several different RNA transcripts in one assay. This protocol provides a powerful tool for studying regulation of neuroendocrine systems at the molecular level in vivo, using sample sizes suitable for applying statistical analysis of meaningful statistical power. PMID- 21554582 TI - Morphine but not Naloxone Enhances Luteinizing Hormone-Releasing Hormone Neuronal Responsiveness to Norepinephrine. AB - Some axon terminals of hypothalamic opiate neurons directly synapse on luteinizing hormone-releasing hormone (LHRH) neurons. To determine whether such synaptic connections affect LHRH neuronal activity, we have examined the profiles and concentrations of LH released in response to intracerebroventricular (icv) norepinephrine (NE, 45 MUg) infusions alone or following medial preoptic area (MPOA) electrochemical stimulation (ECS) in estrogen-treated ovariectomized rats. Similar studies were performed in rats treated with naloxone (5 mg/kg ip) or morphine (20 mg/kg sc) given 15 min prior to MPOA-ECS or 30 min prior to icv NE. Naloxone neither augmented nor suppressed the LH response obtained with NE alone. MPOA-ECS evoked a significant increase in plasma LH. When the preoptic area was stimulated (0 min) and NE was infused at 30 min, a significant amplification of LH release occurred. Prior treatment of rats (-15 min) with naloxone had no effect on LH responses elicited by either preoptic stimulation alone or combined with icv NE. In the second study, morphine was given sc and had no effect on basal plasma LH levels. However, when morphine was given (-15 min) and icv NE infusions were made (30 min), the rise in plasma LH induced by NE was significantly enhanced. Preoptic ECS (0 min) evoked a rise in plasma LH and this response was also enhanced by morphine pretreatment. The major effect on LH release occurred when sc morphine injections (-15 min) were combined with MPOA ECS (0 min) followed by icv NE (30 min). In these rats, a remarkable and highly significant release of LH occurred which reached peak levels even greater than those observed during spontaneous LH surges (2,392 versus 16 to 1,800 ng/ml). Since morphine has profound effects on the serotonergic system, in the third series of studies, morphine was infused into the dorsal raphe nucleus (DRN) and LH responses to MPOA-ECS or icv NE alone or following combined ECS + NE were examined. DRN morphine did not affect basal LH release but it produced a rapid and highly significant rise in plasma prolactin. When DRN morphine was given (-15 min) and NE was infused icv (30 min), there was marked amplification in LH release compared to those values observed after only NE. However, there were no appreciable differences in LH values obtained after sc versus DRN morphine injections in response to NE. Similarly, the amplification of LH release which occurred following DRN morphine (-15 min) + MPOA-ECS (0 min) was not different from that obtained after sc morphine. In the final group of rats, DRN morphine was given (-15 min), the preoptic area was stimulated (0 min) and NE was infused (30 min). Following this treatment, plasma LH release was also markedly enhanced and did not differ appreciably (except at 60 and 120 min) from the levels of LH released after sc morphine. Prolactin concentrations rose slowly after icv NE to reach peak levels 75 min after treatment. Combinations of morphine + MPOA-ECS without or with NE neither augmented nor suppressed the high prolactin concentrations achieved after only DRN morphine infusions. We conclude from these data that: 1) those opiate neuronal terminals which synapse directly on LHRH neurons do not affect LHRH neuronal responsiveness to either NE, to MPOA-ECS or to combined preoptic stimulation+ NE, and 2) morphine has profound effects on LHRH neuronal responsiveness to both NE, to MPOA-ECS and, in particular, to combined ECS + NE. Since amplification of LH release occurs after treatment of rats with morphine either by sc injections or DRN infusions, the augmented LH and prolactin responses observed are most likely due to the morphine-induced release of serotonin and not to direct morphine effects on LHRH neurons. PMID- 21554583 TI - Immunocytochemical localization of 11 Beta-hydroxysteroid dehydrogenase in hippocampus and other brain regions of the rat. AB - The dehydrogenase form of 11 beta-hydroxysteroid dehydrogenase (11-DH) which catalyzes the oxidation of the biologically active steroid, corticosterone, to its inactive metabolite, 11-dehydrocorticosterone, is found in rat brain. The distribution and localization of 11-DH-like labeling in the rat brain was examined by immunocytochemistry. 11-DH-like immunostaining was found in all subfields of the hippocampus and in many other parts of the brain, including the preoptic area (POA), central nucleus of the amygdala, bed nucleus of the stria terminalis (NIST) and the cerebral cortex. Percentages of 11-DH-positive cells ranged from 10% in the POA and NIST to 50% to 60% in the hippocampus. When combined with neuronal or glial markers, 11-DH-like immunostaining was found to be predominantly localized within neurons, ranging from 10% or less glial labeling in hippocampus, amgydala and cortex to 22% glial labeling in the POA and NIST. Immunostaining was present in both the cytoplasmic and nuclear components of some cells in addition to their projections. In the kidney, 11-DH has been postulated to be a key component in a mechanism by which aldosterone gains access to renal Type I receptors despite the presence of much higher concentrations of glucocorticoids. The present data is consistent with a similar mechanism occurring in at least some parts of the brain, although the hippocampus appears to be an important exception because it does not appear to be differentially responsive to aldosterone in spite of its high 11-DH activity and immunoreactivity. However, the hippocampus is not implicated in neural control of salt appetite and fluid balance, whereas some of the other brain regions like the POA, NIST and amygdala are believed to be involved. Other aspects of 11-DH localization must therefore be examined in future studies, including the co presence of mineraiocorticoid receptors and 11-DH in the same or adjacent cells and the possible significance of the relatively high glial localization of 11-DH immunoreactivity in the POA and NIST. PMID- 21554584 TI - Corticosterone Reduces Synaptic Inhibition in Rat Hippocampal and Neocortical Neurons in vitro. AB - We examined the effect of corticosterone (10(-7) to 10(-5) M) on membrane properties and postsynaptic potentials, by means of intracellular recordings from neocortical and hippocampal CA1 pyramidal neurons of the intact adult rat in vitro. Corticosterone reduced both the early and the late components of the orthodromically-evoked inhibitory postsynaptic potential in both structures. The glucocorticoid receptor antagonist RU 38486 (10(-6) M) prevented this effect in the hippocampus. In hippocampal, but not in neocortical pyramidal neurons, corticosterone reduced a depolarizing membrane transient evoked by a depolarizing current step and increased the threshold for eliciting action potentials evoked by depolarizing current pulses. Corticosterone did not detectably alter the afterhyperpolarization following repetitive neuronal discharges evoked by current injection, in either the neocortex or in the hippocampus. Excitatory postsynaptic potentials, action potentials, membrane potential and membrane input resistance were also unchanged. The decrease in synaptic inhibition together with the reduction of electrical excitability in the hippocampus, would imply a modulation of response characteristics in pyramidal neurons such that repeated synaptic inputs become more efficient and low frequency input is blunted. PMID- 21554585 TI - Long-Term Treatments with Morphine and Naloxone have Sex-Differentiated Effects on Luteinizing Hormone Secretion in Chronically Catheterized Fetal Pigs. AB - Short- (one bolus injection) and long-term (repeated injections over a period of at least 7 days) effects of drugs on pituitary function in pig fetuses were studied to investigate the influence of morphine and naloxone on luteinizing hormone secretion in the chronically catheterized pig fetus between days 102 and 110 of gestation (term: 113+/-1 SD day). Both substances were intravenously administered in two doses: 0.1 mg and 1 mg/fetus. Repeated injections at 2-day intervals enabled us to study short- as well as long-term effects. Morphine acutely inhibited luteinizing hormone secretion both in male and female fetuses. Long-term treatment with morphine at both doses caused an inhibition of basal luteinizing hormone (levels before treatment on each day) in females (0.1 mg: r= 0.60, P<0.001; 1 mg: r=-0.45, P<0.05) while male fetuses were unaffected. Naloxone did not have any short-term effects, either in females or in males. In the long-term study, however, naloxone at 1 mg dose decreased basal luteinizing hormone levels in male fetuses (r=-0.55, P<0.01), whereas in females no effect was evident. Co-administration of 0.1 mg naloxone +0.1 mg morphine abolished the long-term inhibitory effect observed in females when 0.1 mg morphine alone was given. These results indicate that the link between opioids and the luteinizing hormone system is functional in the pig from at least 2 weeks before birth. Furthermore, there is a sex difference in the long-term effects of both morphine and naloxone. The origin of the apparently paradoxical long-term effect of naloxone in male fetuses remains unclear. PMID- 21554586 TI - Cellular levels of messenger ribonucleic acids encoding vasoactive intestinal Peptide and gastrin-releasing Peptide in neurons of the suprachiasmatic nucleus exhibit distinct 24-hour rhythms. AB - There is strong evidence supporting the view that the Suprachiasmatic nucleus (SCN) functions as a circadian clock; however, the neural and molecular events underlying SCN function remain unclear. A specific subpopulation of neurons within the ventrolateral aspect of the SCN that contains three peptides, vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) and gastrin-releasing peptide (GRP), play an important role in SCN function. VIP containing neurons of the SCN receive synapses from photic projections, and co injection of all three peptides mimics the phase-delaying effects of light on circadian activity rhythms. In principle, the signaling potential of a neuron containing several transmitters may be affected by the concentration ratio of co released factors; hence, one mechanism by which VIP/PHI/GRP-containing neurons could influence SCN function is by changing the concentration ratio of these peptides throughout the light-dark cycle. The present study was performed to examine this possibility. Relative cellular levels of mRNA encoding both VIP/PHI and GRP were determined within the SCN every 4 h in rats housed in a 14 h light: 10 h dark cycle. Quantitative in situ hybridization revealed a statistically significant (P<0.005) 24-h profile of changes in VIP/PHI mRNA that peaked during the dark phase, and a significant (P<0.005) 24-h profile of changes in GRP mRNA that peaked during the light phase. These data support the interpretation that cellular levels of mRNAs encoding VIP/PHI and GRP within the SCN exhibit distinct profiles of changes throughout the light-dark cycle. Further, these findings are consistent with the hypothesis that the concentration ratio of VIP and PHI to GRP changes over the light-dark cycle, and that this may be an important mechanism by which circadian rhythms are generated or entrained. PMID- 21554587 TI - Sex-Related Differences in Chromogranin A, Chromogranin B and Secretogranin II Gene Expression in Rat Pituitary. AB - Chromogranin A, an acidic secretory protein, is widely distributed throughout diverse endocrine cells and the central and peripheral nervous systems. Chromogranin A is co-stored and co-secreted from secretory vesicles together with the endogenous hormones or neurotransmitters. Recently, two peptides derived from the Chromogranin A precursor have been shown to inhibit secretion from endocrine cells. In the present study, we investigated the regulation of the biosynthesis of Chromogranin A by estrogen in various tissues. In the pituitary, steady-state levels of Chromogranin A mRNA were markedly reduced by 64% in estrogen-treated male rats. At the protein level, a comparable decrease was found. Chromogranin B and secretogranin II, two other secretory proteins co-stored with Chromogranin A, were slightly increased by estrogen. In pituitaries of female rats Chromogranin A mRNA and protein levels were significantly lower than in males. For Chromogranin B on the other hand, a 2-fold increase of mRNA levels was found. Our observations demonstrate that physiologic concentrations of estrogen strongly affect Chromogranin A levels in the pituitary resulting in a sex-related difference in Chromogranin A gene expression. Based on these and previous results demonstrating increased biosynthesis of Chromogranin A by glucocorticoids and calciferol, we suggest that a typical and characteristic feature of the Chromogranin A gene is its regulation by at least three different classes of steroid hormones. PMID- 21554588 TI - Effects on plasma luteinizing hormone levels of microinjection of noradrenaline and adrenaline into the septo-preoptic area of the brain of the ovariectomized ewe: changes with season and chronic oestrogen treatment. AB - We have investigated the effects on luteinizing hormone (LH) secretion of noradrenaline (NA) and adrenaline (A) microinjected (1 MUl) into the septo preoptic area of ovariectomized (OVX) ewes with or without oestrogen (E) treatment and across the breeding and non-breeding seasons. Guide tubes (19 gauge) were placed into the septo-preoptic area of OVX ewes using lateral ventriculograms for localization of the target area. The sheep were tamed so that injections could be made into conscious animals during blood sampling procedures. Jugular venous blood was collected at 10-min intervals for 3 h, an injection of NA or A (10 MUg) or saline was given and samples collected for a further 3 h. The plasma samples were assayed for LH. On completion of the experiments the brains were sectioned to locate the site of injection. In the non-breeding season of the first year, 9 ewes were used of which 3 had correct guide tube placement; in these 3 ewes NA and A had no effect in OVX ewes. In OVX ewes treated with 0.5 cm Silastic (r)implants of E for 1 week, plasma LH levels were reduced from 9.1 +/- 1.96 nglrnl before E treatment to 2.8+/-0.95 ng/ml after E treatment. In these E treated ewes NA and A caused a robust increase in plasma LH levels. In the breeding season, 9 ewes were used of which 7 had correct guide tube placement; in these 7 ewes NA and A had no effect in OVX ewes. When OVX ewes were treated with 0.5cm E implants, NA or A injection decreased LH interpulse interval. In OVX ewes which received 1.0 cm E, NA caused a pronounced but transient suppression of plasma LH secretion due to an increase in interpulse interval. When 3.0 cm E implants were given to OVX ewes there was a strong suppression of plasma LH secretion with pulsatility abolished; NA injection had no effect in these sheep. In the second year, in the non breeding-season, 17 ewes were used of which 14 had correct guide tube placement although a number of injections were above the target region. NA injection had no effect on plasma LH levels in OVX ewes but had a variable effect on OVX ewes treated with 0.5 cm E implants, depending upon the degree of suppression of plasma LH secretion by E. When plasma LH was fully suppressed by E, injection of 1Opg NA provoked a profound and sustained increase in plasma LH levels. When plasma LH secretion was pulsatile after E treatment, NA injection decreased LH interpulse interval. Similar responses were obtained with 0.5cm E-treated sheep when injected with 1.Opg NA. When OVX ewes were given 3.0cm E implants a small and non-significant (P = 0.09) rise in plasma LH levels occurred, following 10 pg NA injection. These results provide further evidence of involvement of NA/A systems in the regulation of gonadotrophin-releasing hormone (GnRH) secretion at the level of the GnRH cell bodies in the septo-preoptic area, with clear influences of season and E status on this regulation. In the OVX sheep the GnRH pulse generation system is probably subserved by endogenous permissive NA/A input rendering exogenous input ineffective. In the breeding season NAlA can inhibit GnRH/LH secretion in the presence of physiological doses of E whereas in the non-breeding season, E profoundly suppresses GnRH/LH secretion, possibly by the removal of permissive NA inputs, which can be overcome by the injection of NAlA into the septo-preoptic area. PMID- 21554589 TI - Adrenocorticotropin release induced by N-methyl-d-aspartate or stress: mediation by the area postrema. AB - N-methyl-D-aspartic acid (NMDA) is known to stimulate adrenocorticotropin (ACTH) release after peripheral administration in spite of its inability to readily cross the blood-brain barrier (BBB). The importance of the area postrema, the hindbrain circumventricular organ which lacks a BBB, for NMDA action and ACTH release during stress was evaluated in this study. ACTH response to NMDA injection (4 mg/kg ip) was significantly reduced in rats with ablation of the area postrema compared to sham-operated animals. Integrity of the area postrema was also found to be required for full ACTH release in response to two stress stimuli (immobilization, handling). The data show that the area postrema is a brain region involved in the control of the hypothalamic-pituitary-adrenocortical (HPA) axis mediating, at least partially, the stimulatory action of NMDA and of stress stimuli on ACTH release. PMID- 21554590 TI - Fos-like immunoreactivity in the brainstem of the rat following peripheral administration of cholecystokinin. AB - Ninety min after intraperitoneal (ip) injection of Cholecystokinin (CCK, 50 MUg/kg body wt) Fos-like protein was expressed in cells throughout the nucleus of the tractus solitarii (NTS) and area postrema, and also in scattered cells in the lateral reticular area of the brainstem. Using dual fluorescent immunocytochemistry for Fos-like protein and tyrosine hydroxylase (TH), catecholaminergic cells in the A2 region of the NTS and the A1 region of the lateral reticular area were shown to be activated. PMID- 21554591 TI - Lack of glucocorticoids enhances the early activation of the medullary catecholaminergic cell groups triggered by restraint stress. AB - We have investigated whether the stress-induced activation of the medullary catecholaminergic neurons, that was shown previously to provide the main central activation input to the hypothalamo-pituitary-adrenocortical axis during an immobilization stress, is sensitive to circulating corticosteroids. Experiments were carried out on adrenalectomized rats that were first maintained on corticosterone in the drinking water for 5 days following surgery and then switched to corticosterone-free water 15 h before stress application. Some of the latter animals were injected with dexamethasone. Activation of the brainstem Catecholaminergic neurons was estimated by assaying 3,4-dihydroxyphenylacetic acid (DOPAC), a side metabolite of the noradrenaline and adrenaline biosynthesis pathway that was established previously as a reliable index of the activity of these neurons. In the so-called A(1) C(1) and A(2) C(2) Catecholaminergic groups of the medulla, lack of corticosterone under these experimental conditions did not modify the basal level of DOPAC but led to a further enhancement (+ 35% to 40%) of the approximately 2-fold increase in DOPAC content observed 15 min after the onset of the 5-min immobilization stress. No significant further enhancement of the stress-induced DOPAC increase was observed in the locus coeruleus. In these adrenalectomized rats, dexamethasone pretreatment prevented the enhancement of the stress-induced increase in DOPAC level observed in the medullary cell groups but did not abolish the response to stress. Lack of endogenous corticosteroids led to a 10-fold enhancement of the adrenocorticotropin increase following immobilization stress. Pretreatment with dexamethasone fully abolished the stress-induced increase in adrenocorticotropin plasma level. Our results show that circulating corticosteroids reduce the stress-induced activation of the medullary A(1) and A(2) C(2) groups i.e. those that contribute mainly to the catecholaminergic innervation of the hypothalamo-pituitary-adrenocortical axis within the hypothalamic paraventricular nuclei. However, since the feedback regulation of the central catecholaminergic systems is much less efficient than the feedback actually observed on the adrenocorticotropin secretion, we suggest that it is likely to play a minor physiological role in the overall feedback regulation exerted by circulating corticosteroids on the hypothalamo-pituitary adrenocortical axis. PMID- 21554592 TI - cFos Activity Identifies Recruitment of Luteinizing Hormone-Releasing Hormone Neurons During the Ascending Phase of the Proestrous Luteinizing Hormone Surge. AB - The proto-oncogene product of the c-fos gene, cFos, is a useful marker for luteinizing hormone-releasing hormone (LHRH) neuronal activation. While recent data indicate that in the rat, an LHRH surge plays an active role in stimulating the proestrous luteinizing hormone (LH) surge, the mechanics of the LHRH surge remain unknown. The aim of this study was to determine whether LHRH neuronal activation occurs entirely at the beginning of the LH surge or whether the number of LHRH neurons activated increases during the ascending phase of the surge. To accomplish this aim, we determined the relationship between the number of LHRH neurons expressing cFos and LH concentrations during the ascending limb of the proestrous LH surge. During the estrous cycle in the rat, on the afternoon of proestrus, the number of LHRH neurons expressing cFos increased as plasma LH levels increased to reach peak concentrations. The regression line describing these two variables had a very highly significant correlation coefficient, indicating a linear relationship. Treatment with RU486 to block progesterone's action on the afternoon of proestrus significantly reduced both the number of LHRH neurons expressing cFos and the magnitude of LH secretion during the entire ascending phase of the LH surge. An analysis of covariance with comparison of regression lines from untreated and RU486-treated animals revealed that while both sets of data established significant linear relationships between the degree of activation of LHRH neurons and plasma LH values, the slopes of the two lines were different (P = 0.031) with no statistical difference in the two intercepts. These data, together with the demonstration of an overall reduction of cFos intensity following removal of progesterone's actions, suggest progesterone alters the dynamics of LHRH neuronal activation by significantly reducing the recruitment of LHRH neurons and suppressing the level of activation of individual LHRH neurons. The results of our study support the hypothesis that the ascending phase of the LH surge results from the gradual recruitment of LHRH neurons into the active state. PMID- 21554593 TI - Neurohormonal Factors Involved in the Control of the Nocturnal Prolactin Surge that Precedes Parturition in the Rat. AB - A nocturnal surge of prolactin (PRL) occurs in the dark period preceding parturition in the rat. The roles of oxytocin, vasoactive intestinal peptide (VIP), serotonin and the opioids in controlling the antepartum PRL surge were investigated by examining PRL secretion over the last 2 days of pregnancy in the presence of antagonists to these neurohormonal factors. Serial blood samples were collected from unanesthetized, freely moving rats via indwelling jugular cannulae, and plasma PRL was measured by radioimmunoassay. In control rats PRL levels rose in a nocturnal surge peaking at 223 +/- 34 ng/ml (n = 6) at 0500 h on day 21 of pregnancy, the day of parturition. Intra-arterial infusion of the oxytocin antagonist desGly-NH(2) d(CH(2) )(5) [Tyr(Me)(2) , Thr(4) ]-OVT at a dose sufficient to completely block milk ejection (10 MUg/h) had no effect on this PRL surge. Infusion of the VIP antagonist [4Cl-D-Phe(6) ,Leu(17) ]-VIP at 2 MUg/h from 2200 h on day 20 until 0500 h on day 21 significantly attenuated the antepartum PRL surge, reducing the peak to 76 +/- 28 ng/ml at 0500 h on day 21 (n = 6; P<0.001). Naloxone, the opiate receptor antagonist, inhibited the antepartum PRL surge in a dose-dependent manner. Infused at 2 mg/h naloxone partially reduced the magnitude of the PRL surge, which peaked at 128 +/- 24 ng/ml at 0300 h on day 21 (n = 4; P<0.05), while at 10 mg/h naloxone totally abolished the PRL surge (n = 6; P<0.001). Injection of the serotonin synthesis inhibitor rho chlorophenylalanine (250 mg/kg, sc at 1700 h on days 19 and 20 of pregnancy) increased the magnitude of the antepartum PRL surge to a peak of 327 +/- 48 ng/ml at 0500 h on day 21 (n = 5), compared with 244 +/- 24 ng/ml at the same time in vehicle-injected controls (P<0.05; n = 5). The results demonstrate that the antepartum PRL surge is stimulated by an opioid mechanism, and also by VIP. Oxytocin and serotonin have no role in stimulating PRL secretion during late pregnancy. PMID- 21554594 TI - Acute luteinizing hormone and prolactin responses to paced mating stimulation in the estrous female rat. AB - The present experiments sought to characterize the particular stimuli received during mating in the female rat which induce acute increases in luteinizing hormone (LH) and prolactin (PRL) following copulation. Comparisons were made between cycling females mated on the evening of proestrus in partitioned chambers in which spontaneous patterns of approach/withdrawal toward the male served to pace copulatory stimulation (paced), in non-partitioned chambers in which female regulation of intervals between copulatory mounts was prevented (non-paced), or under conditions in which they received mounts-without-intromission (mounts only). Frequent blood samples were withdrawn via surgically implanted intra atrial catheters. In experiment 1, blood samples for LH determinations were taken at 15-min intervals for 1 h prior to and for 2 h after mating on the evening of proestrus. In experiment 2, samples for PRL determinations were taken at 10-min intervals for 30 min prior to and for 90 min after mating on proestrus and at 0300, 0400 and 0500 h on the day of estrus (reported times corrected for reversed light cycle). LH levels were significantly higher in paced animals 15 min after initiation of mating than in non-paced and mounts-only females; no differences in LH were seen between females who subsequently became or did not become pregnant/pseudopregnant (P/PSP). PRL values were not different between groups receiving the different mating treatments at any time; however, P/PSP animals showed significantly higher levels of PRL between 20 to 60 min after mating than did non-P/PSP females. No differences in PRL were seen between mating treatments or pseudopregnancy condition at 0300 to 0500 h on estrus. Paced females in both experiments received intromissions at a significantly slower rate than did non paced females. There was a significant positive correlation (r = 0.619, P<0.001) between LH concentration at 15 min and the inter-intromission interval (in seconds) in paced and non-paced groups of females. These data suggest that an LH response to mating is dependent upon the particular characteristics of mating stimulation received. In addition, they demonstrate that PRL increases acutely after mating stimulation in animals destined to become P/PSP but does not increase in response to those characteristics of mating stimulation which induced increases in LH. PMID- 21554595 TI - Afferent stimulation regulates oxytocin messenger ribonucleic Acid during early lactation in rats. AB - The physiological factors that regulate the levels of oxytocin (OT) mRNA in the rat hypothalamo-neurohypophyseal system during lactation are unknown. The major objective of the present studies was to test whether afferent stimuli provided by the offspring influence the level of OT mRNA in the magnocellular nuclei of the hypothalamus, i.e. the paraventricular nucleus (PVN), supraoptic nucleus (SON) and anterior commissural nucleus (ACN), during lactation. In addition, these studies provide a detailed description of the changes that occur in OT mRNA levels in these nuclei during pregnancy and lactation. Levels of OT mRNA were determined in the total RNA extracted from pooled PVN/SON/ACN, which were microdissected from pregnant and lactating Holtzman rats, by slot-blot hybridization. RNA blots were hybridized sequentially with a [(32) P]5'end labeled, 25-base oligonucleotide probe complementary to bases 912-936 of the OT gene and with a random primer-labeled cDNA complementary to alpha-tubulin mRNA, which was used for normalization. Autoradiographs were quantitated by scanning laser densitometry. Compared to the levels on day 1 of pregnancy (the day of mated estrus) the relative levels of OT mRNA were decreased on pregnancy days 7 and 14, and then returned to the mated estrus value on days 16 to 20. The level of OT mRNA again declined prior to parturition on day 23, although it was restored to the estrus value the day after parturition and generally remained at this level throughout lactation. To assess the influence of stimuli provided by the offspring for the regulation of OT mRNA levels during lactation, lactating females were separated from their litters immediately after parturition or on lactation day 8. As compared to nonseparated, time-matched controls, removal of the litters immediately after parturition resulted in a statistically significant reduction of approximately 25% in the levels of OT mRNA 24 and 48 h later, which returned to control levels by 72 h. In contrast, removal of the litters on lactation day 8 did not significantly alter the level of OT mRNA in the PVN/SON/ACN over the next 3 days. These findings suggest that the level of OT mRNA in hypothalamic magnocellular nuclei is influenced to some extent by afferent stimuli provided by the offspring during an early period of lactation but, thereafter, becomes unresponsive to removal of this influence. Afferent suckling stimuli may be one component of a multifactorial regulation responsible for the maintenance of OT mRNA expression during lactation. PMID- 21554596 TI - Characterization of melatonin binding sites in the pars tuberalis of the European hamster. AB - Melatonin binding sites in the pars tuberalis of the European hamster (Cricetus cricetus) have been characterized using the radioligand 2-[(125) I]iodomelatonin. Specific 2-[(125) I]iodomelatonin binding was assessed using radioreceptor studies of pars tuberalis membrane preparations. Saturation studies revealed a single, high affinity site (K(d) 39.8 (+/- 7.6 SEM) pM and B(max) 4.1 (+/- 0.5 SEM) fmol/mg protein, n=4). Kinetic experiments showed the 2-[(125) I]iodomelatonin binding to be rapid, saturable and reversible. The K(d) calculated from the dissociation and association rate constants was 19.4 pM. The order of potency of different indoles for inhibition of 2-[(125) I]iodomelatonin binding was 6-chloromelatonin > melatonin > 6-hydroxymelatonin > N acetylserotonin > 5-methoxytryptophol > serotonin > 5-methoxytryptamine. GTP caused a dose-dependent inhibition of the 2-[(125) I]iodomelatonin binding. A saturation study showed that GTP reduced the number of binding sites by a third without altering their affinity. These results imply the presence of a G-protein coupled melatonin receptor in the pars tuberalis of sexually active European hamsters. PMID- 21554597 TI - Functionally and anatomically distinct populations of vasopressinergic magnocellular neurons in the female golden hamster. AB - The present study was done to determine whether the vasopressinergic neurons in the hypothalamus controlling flank marking behavior are distinct from the magnocellular neurons comprising the hypothalamo-neurohypophysial system. Animals were either hypophysectomized or injected with a suicide transport lectin, volkensin, into the neurohypophysis. Both procedures resulted in a pronounced loss of vasopressin-immunoreactive perikarya throughout the hypothalamus concomitant with increases in water intake and urine output and decreases in circulating levels of vasopressin. The loss of the hypothalamo-neurohypophysial system was most pronounced in volkensin-treated animals that presented with frank diabetes insipidus and exceedingly low levels of plasma vasopressin. However, the vasopressinergic fibers and magnocellular neurons in and around the anterior hypothalamus implicated in the control of flank marking survived the volkensin treatment. Volkensin-treated animals exhibited levels of flank marking typical of untreated animals. These data suggest the presence of anatomically and functionally distinct populations of vasopressinergic magnocellular neurons in the hypothalamus of the golden hamster. PMID- 21554598 TI - Sexual behavior triggers the appearance of non-neuronal cells containing gonadotropin-releasing hormone-like immunoreactivity. AB - Gonadotropin-releasing hormone (GnRH) regulates the secretion of pituitary gonadotropins and facilitates the display of sexual behavior. We report that in doves, following a brief period of courtship, non-neuronal cells containing GnRH like immunoreactivity (ir) are seen in the habenula of both male and female doves. These cells appear to be translocated from either the cerebrospinal fluid or from capillaries in the pia or choroid plexus into the parenchyma of the brain. Immunoreactive cells are virtually absent in the habenula in control animals housed alone. The identity of the ir cells that enter the habenula is unknown but they would appear to be of either the macrophage or the mast cell lineage. Both of these blood-derived cells have heterochromatic nuclei and irregular cell surfaces with many filamentous processes, as do the GnRH-ir cells. The vacuolated granules of the ir cells could be indicative of mast cell degranulation or of endocytic vesicles of a phagocytosing cell. These data suggest that there is a population of cells within the habenula that are of similar size and morphology to the GnRH-ir ceils and are metachromatic when stained with toluidine blue. The latter is a property of heparin-containing mast cells. Lineage specific markers that permit a double-label study will be required to determine the exact nature of the GnRH-ir cells. Whatever their lineage, the translocation of non-neuronal cells into the undamaged adult central nervous system has not been described previously, and may provide a means of delivering biologically active substances into specific brain regions. PMID- 21554599 TI - Luteinizing hormone surge in adult female rats after androgen priming. AB - The effects of androgens alone and in combination with oestrogens on luteinizing hormone secretion in adult female rats were studied after 1, 2 and 4 months of priming. Each adult female rat was implanted with a Silastic capsule filled with testosterone or dihydrotestosterone alone or together with another similar capsule of oestradiol. An oestrogen challenge test was carried out in each rat after priming. Blood samples were collected before androgen priming. During the oestrogen challenge test, blood samples were collected before (0 h or day 0) and at 12, 24, 36 and 48 h after the intramuscular injection of 50 MUg oestradiol vaierate for rats primed for 1 month, or daily for 5 days (days 1 to 5) for other rats. An oestrogen challenge test was also performed in two groups of untreated male and female rats which served as controls. The results indicated that long term androgen priming had resulted in the attenuation or total blockade of the luteinizing hormone surge which normally occurs during an oestrogen challenge test in adult female rats. This suggests that androgens may be important modulators of the luteinizing hormone surge mechanism in rats. Furthermore, the fact that the luteinizing hormone surge can be blocked by androgen priming in adult female rats suggests that the sexual dimorphic response to oestrogen feedback is not immutably imprinted in the hypothalamic-pituitary axis as was originally proposed. PMID- 21554600 TI - Cerebral metabolic and vasopressin and oxytocin responses during osmotic stimulation in conscious rats. AB - Intravenous infusion of hypertonic saline increased plasma [Na (+) ] and osmolality and induced a short-latency drinking response. These changes were associated with increased glucose utilization in the supraoptic and paraventricular nuclei and neural lobe, and decreases in the medial septum and nucleus ambiguus. The increases in glucose utilization were more accentuated in the supraoptic nuclei than in paraventricular nuclei, indicating that they are more sensitive to osmotic stimulation than the paraventricular nuclei. In association with enhanced activity in the hypothalamo-neurohypophysial system, plasma vasopressin and oxytocin concentrations increased, with a preferential increase of oxytocin over vasopressin. The hormonal contents in the neural lobe were not depleted by the osmotic stimulus despite the large increases of their concentrations in the plasma. PMID- 21554601 TI - Characterization and ontogenesis of N-methyl-d-aspartate-evoked luteinizing hormone secretion in immature female rats. AB - The excitatory amino-acid L-glutamate appears to be involved in the neural regulation of puberty. We have now characterized the stimulatory effect of the glutamate agonist N-methyl-D-aspartic acid (NMDA) on the secretion of luteinizing hormone (LH) in immature female rats. NMDA injections (subcutaneously) rapidly induce LH secretion (maximum at 8 min) with an ED(50) of 3.25 mg/kg determined at postnatal day 30. The LH response to NMDA develops between 10 and 15 days after birth, reaches a maximum at approximately day 27 and disappears again by day 32, an age at which 80% of the rats are still prepubertal. In confirmation of work by others, we also showed that postpubertal male rats are unresponsive to NMDA. The effect of NMDA on LH release is blocked by prior injection of the glutamate antagonist MK-801 (0.1 mg/kg). MK-801 alone is able to reduce LH secretion in acutely ovariectomized rats but has little effect in intact, prepubertal rats. NMDA may not act exclusively on the gonadotropin-releasing hormone neuron since inhibition of norepinephrine biosynthesis by the drug U-14,624 largely prevents NMDA-induced LH secretion. Interestingly, rats treated neonatally with the neurotoxin monosodium glutamate responded normally to NMDA when tested at postnatal day 25. Finally, removal of the ovaries 48 h previously reduced the LH response to NMDA. Full responsiveness was restored following estrogen priming. In summary, hypothalamic glutamate receptors of the NMDA subtype comprise a significant regulatory component of LH secretion in prepubertal female rats. LH responsiveness appears to be age-, dose-, estrogen- and norepinephrine-dependent. PMID- 21554602 TI - Inhibition of luteinizing hormone secretion in the ewe by progesterone: associated changes in the release of gamma-aminobutyric Acid and noradrenaline in the preoptic area as measured by intracranial microdialysis. AB - Progesterone inhibits the pulsatile release of luteinizing hormone (LH) in sheep by an action in the brain to suppress the release of LH-releasing hormone (LHRH). In addition, progesterone blocks the preovulatory surge of LH in this species. The neural basis of this inhibitory action is unknown, but as LHRH cells do not appear to contain progestin receptors other neural systems must mediate the action of this ovarian steroid on LH release. This study focuses on a possible role for the inhibitory amino-acid GABA and the monoamines (noradrenaline, adrenaline, dopamine and serotonin). The technique of microdialysis was used to monitor changes in these substances in the vicinity of the LHRH cell bodies (in the preoptic area) both before and following the administration of progesterone. Levels of this steroid, similar to those measured during the mid-luteal phase of the oestrous cycle, inhibited LH release and this was associated with significant alterations in the release of GABA and noradrenaline (but not adrenaline, dopamine or serotonin). Specifically, progesterone augmented GABA while noradrenaline release was depressed. Whether steroid actions on these neurotransmitters were mediated by opioids was also investigated. This possibility arises because of the reported involvement of opioids in progesterone negative feedback in the ewe. The long-acting opioid antagonist, naltrexone, was administered and GABA and noradrenaline release monitored for a further period both in the presence and absence of progesterone. Naltrexone significantly depressed GABA release in steroid-treated (but not untreated) ewes suggesting that the actions of progesterone on GABA are mediated by the endogenous opioid peptides. However, noradrenaline release was unaltered. In an earlier study we demonstrated that GABA release fell prior to the LH surge while noradrenaline release increased. These data, in conjunction with those from the present study, suggest that the mechanism by which progesterone is able to inhibit the preovulatory surge of LH in the ewe is by enhancing GABA and depressing noradrenaline release in the vicinity of the LHRH cell bodies. As opioid tone is also reported to fall prior to the surge, the interaction between opiate and GABAergic systems in the regulation of gonadotrophin secretion warrants further investigation. PMID- 21554603 TI - Angiotensin peptides in brain and pituitary of rat and sheep. AB - Several lines of evidence indicate that angiotensin peptides may be formed in the brain, where angiotensin II (Ang II) and angiotensin-(1-7) (Ang-(1-7)) may function as neurotransmitters. However, there is considerable controversy concerning the identity and levels of angiotensin peptides in the brain. We have used a novel high performance liquid chromatography-based radioimmunoassay to measure Ang-(1-7), Ang II, Ang-(1-9) and Ang I in various brain regions and in the pituitary of the rat and sheep. We also studied the effect of different methods of tissue extraction, and the effect of the converting enzyme inhibitor ramipril, on angiotensin peptide levels in the rat hypothalamus. The levels of Ang-(1-7), Ang II, Ang-(1-9) and Ang I were low (<25 fmol/g) in all brain regions examined, except for the sheep median eminence and cerebellar cortex where Ang II levels were 385+/-116 and 193+/-37 fmol/g (mean +/- SEM, n = 6), respectively. Pituitary Ang II levels were 103+/-13 fmol/g in the rat and 63+/-18 fmol/g in the sheep. The levels of Ang-(1-7), Ang-(1-9) and Ang I were much lower than those of Ang II in brain and pituitary. Ang-(1-7) levels in the rat hypothalamus were low (<6 fmol/g) but methods of extraction which involved freezing and thawing of the tissue resulted in substantially higher levels of this peptide. Ang II levels in the rat hypothalamus (18+/-3 fmol/g) were reduced to undetectable levels (<6 fmol/g) by ramipril administration. The low levels of angiotensin peptides in the hypothalamus and brainstem indicate that if these peptides function as neurotransmitters in these regions, then they are of particularly low abundance. Moreover, our results indicate that the high levels of Ang-(1-7) reported previously for rat hypothalamus may be artefactual, due to the method of tissue extraction. PMID- 21554604 TI - A Rat Pituitary Tumour K(+) Channel Expressed in Frog Oocytes Induces a Transient K(+) Current Indistinguishable from that Recorded in Native Cells. AB - A voltage-gated K(+) channel protein has been cloned from a cDNA library derived from poly(A)(+) RNA of the rat pituitary tumour cell line GH(3) /B(6) by the polymerase chain reaction technique. The clone referred to as RGHK9 encodes a protein sequence very similar to a recently cloned K(+) channel protein from rat brain and heart, with deviations in a few amino-acid positions. In situ hybridization experiments show that RGHK9 mRNA is also present in the anterior pituitary as well as in other brain regions and that it is particularly abundant in the hippocampus. After injection of cRNA transcribed from the RGHK9 cDNA clone into Xenopus oocytes, the expressed protein induces a transient K(+) current. Except for the activation kinetics the properties of this current are indistinguishable from that of the native transient K(+) current measured in GH(3) /B(6) cells, e.g. both K(+) currents are blocked by 4-aminopyridine and show the same voltage dependence and slope of steady state activation and inactivation as well as identical time constants of, and slow recovery from, inactivation. Taken together, these data show that the outward-rectifying voltage gated K(+) channel protein encoded by the RGHK9 cDNA correlates well in its functional properties with that of a very similar, if not identical, K(+) channel present in GH(3) /B(6) cells. PMID- 21554605 TI - Estradiol and progesterone modulation of norepinephrine neurotransmission: implications for the regulation of female reproductive behavior. PMID- 21554606 TI - Progesterone Receptor-Containing Neurons in the Guinea-Pig Mediobasal Hypothalamus have Axonal Projections to the Medial Preoptic Area. AB - The location and number of progesterone receptor-containing neurons in the mediobasal hypothalamus that project to the medial preoptic area were determined by combining retrograde fluorescent tract tracing with progesterone receptor immunocytochemistry. Injections of the retrograde tract tracer Fluoro-gold were made in the preoptic area of female guinea-pigs ovariectomized and primed with estradiol. After 5 days survival to allow for retrograde transport, tissue sections were incubated with monoclonal antibodies to the progesterone receptor to detect the presence of progesterone receptor-immunoreactive neurons. Cell bodies were labelled with Fluoro-gold throughout the arcuate nucleus. These neurons were not concentrated in any particular area of the nucleus but were diffusely distributed bilaterally. Retrogradely-labelled neurons were also observed in the ventrolateral and ventromedial nuclei mainly contralateral to the injection site. Progesterone receptor immunofluorescence labelled a subpopulation (7% to 10%) of these retrogradely-labelled cells particularly in the arcuate nucleus, including the median eminence. The double-labelled cells were more numerous in the anterior two-thirds of the arcuate nucleus. Although our estimates of the proportion of hypothalamic progesterone receptor-immunoreactive neurons that sent axons directly to the medial preoptic area were low, (about 0.35%), these neurons may be part of a neural circuit involved in the regulation of reproductive processes. PMID- 21554607 TI - Corticotropin-releasing factor binding sites undergo axonal transport in the rat vagus nerve. AB - Corticotropin-releasing factor (CRF) binding sites were found to be present in the rat vagus nerve and underwent axonal transport. Binding sites accumulated on both sides of ligatures placed on the nerve and at similar rates following ligation of right or left cervical vagal trunks of either male or female rats. CRF binding sites also accumulated proximal and distal to ligatures on subdiaphragmatic vagal trunks. Binding was specific, reversible and inhibited by the CRF receptor antagonist alpha-helical-CRF(9-41). [(125) l]Tyr(0) -ovine-CRF binding to rat vagus nerve was not guanine nucleotide-sensitive. CRF and cholecystokinin binding sites were transported at a similar rate in the cervical vagus, although turnover of CRF binding sites was more rapid. No differences in CRF binding site transport were observed between Zucker rats of lean or obese genotype. PMID- 21554608 TI - Melatonin binding sites in the ovine brain and pituitary: characterization during the oestrous cycle. AB - The distribution of putative melatonin receptors in the sheep has been investigated using in vitro autoradiography and the high affinity, high specific activity ligand 2-[(125) l]iodomelatonin. A wide distribution of specific labelling was found in both the ovine brain and pituitary gland as previously reported. Several novel areas of binding were also identified in the present study, including a fine layer of labelling at the medial edge of the diagonal band of Broca, the trigeminal nucleus, laminae II and III of the substantia gelatinosa, the molecular layer of the cerebellum as well as a scattered labelling in the pars distalis of the pituitary. There was no evidence of specific labelling in any of the peripheral tissues examined. Characterization studies performed on both neuronal and pituitary melatonin binding sites revealed that binding was time- and temperature-dependent and reversible on addition of 1 MUM melatonin. The binding of 2-[(125) l]iodomelatonin was also competitively inhibited by increasing concentrations of 2-iodomelatonin and melatonin. The inhibition constants (K(i) ) estimated for each of these substances were similar for both neuronal and pituitary sites. Saturation studies also revealed similarities between neuronal and pituitary tissues with 2-[(125) l]iodomelatonin binding specifically to a single class of high affinity binding sites. Values for equilibrium constants (K(d) ) were within a range of 28 to 48 pM, and values were found to be not significantly different amongst the four regions of the brain investigated and the pars tuberalis of the pituitary. In contrast, the concentration of 2-[(125) l]iodomelatonin binding sites (B(max) ) ranged from 3 to 218fmol/mg protein and were maximal for the pars tuberalis. Saturation studies on brain and pituitary tissues taken from ewes killed either on the day of oestrus or during the luteal phase of the oestrous cycle, indicated that no differences exist in the affinity or concentration of 2-[(125) l]iodomelatonin binding in any region between the two times of the cycle investigated. PMID- 21554609 TI - Interactions between the hypothalamo-pituitary adrenal axis and the thymus in the rat: a role for corticotrophin in the control of thymulin release. AB - Our recent observations in man suggested that the secretion of the thymic peptide, thymulin, is influenced by hormones of the pituitary-adrenal axis. In the present study, we have used the rat as a model in order to examine 1) the effects of corticotrophin (ACTH) and glucocorticoids on the release of thymulin in vivo and in vitro, and 2) the influence of an acute rise in plasma thymulin on the secretion of corticosterone and luteinizing hormone. Immunoreactive thymulin was readily detectable in plasma from male Sprague-Dawley rats(?200 g). Chronic bilateral adrenalec-tomy, which effectively removed endogenous corticosterone, produced highly significant (P<0.01) increases in the plasma concentrations of both ACTH and thymulin. Treatment of the adrenalectomized rats with dexamethasone, in a dose sufficient to suppress the hypersecretion of ACTH, maintained the plasma thymulin at a low level which did not differ significantly (P > 0.2) from that in sham-operated controls. In vitro, two non-specific depolarizing agents, K(+) (56 mM) and veratridine (10 ?M), caused significant (P<0.01) Ca(2+) -dependent increases in thymulin release from segments of rat thymic tissue. Their effects were mimicked by ACTH(1-39) . The secretory responses to ACTH (0.025 to 1 ng/ml) were concentration-dependent but a very high concentration (2 ng/ml) of the peptide was without effect. Dexamethasone (0.1 MUM) reduced (P<0.05) the spontaneous release of thymulin in vitro but potentiated markedly (P<0.01) the secretory responses to ACTH (0.5 to 1.0 ng/ml). Administration of thymulin (0.1 and 10 MUg/kg ip) produced, within 10 min, striking increases in the plasma thymulin concentration which were still evident at 30 min. The peptide concentration then declined rapidly and, within 24 h, was lower than that in the corresponding vehicle-treated controls. The serum concentrations of corticosterone and luteinizing hormone were unaffected by the thymulin treatment. The saline vehicle (2.0 ml/kg ip) also produced a small increase in plasma thymulin concentration which was maximal at 10 min; a further small rise was evident 6 h after the injection but thereafter the thymulin values were indistinguishable from those in uninjected controls. A similar biphasic profile of serum corticosterone was apparent after the saline injection but the serum luteinizing hormone was unaffected. The results suggest that ACTH is a physiological enhancer of thymulin release and that, in certain circumstances, its effects may be potentiated by glucocorticoids. PMID- 21554610 TI - Ibotenate lesions of the diagonal band of broca attenuate baroreceptor sensitivity of rat supraoptic vasopressin neurons. AB - Previous electrophysiological studies in the rat suggest that neurons in the diagonal band of Broca participate in baroreceptor-induced suppression of the spontaneous activity of vasopressin-secreting neurons in the hypothalamic supraoptic nucleus. In order to test this hypothesis, extracellular recordings were obtained from phasically-active vasopressin neurons in the supraoptic nucleus of anesthetized rats injected at least 3 days previously with ibotenic acid (1.25 MUg/250 nl) in the diagonal band of Broca, the medial and lateral septum, or the median preoptic nucleus. In normal rats, brief increases in blood pressure produced by injections of metaraminol (10 MUg/10 MUl iv) that were sufficient to activate peripheral baroreceptors, suppressed the activity of a majority (21 tested, 19 suppressed) of phasically-active vasopressin-secreting neurons. In rats with ibotenic acid lesions of the diagonal band of Broca, the number of phasically-active neurons that were baroreceptor-sensitive was significantly reduced (21 tested, 8 suppressed) while lesions of the medial and lateral septum (17 tested, 16 suppressed) or the median preoptic nucleus (21 tested, 20 suppressed) had no effect. The results support the hypothesis that diagonal band of Broca neurons participate in a central pathway mediating the inhibitory effects of peripheral baroreceptor stimulation on the activity of vasopressin-secreting neurons in the rat supraoptic nucleus. PMID- 21554611 TI - Further Evidence that Most Luteinizing Hormone-Releasing Hormone Neurons are not Directly Estrogen-Responsive: Simultaneous Localization of Luteinizing Hormone Releasing Hormone and Estrogen Receptor Immunoreactivity in the Guinea-Pig Brain. AB - Gonadotropin secretion from the pituitary is regulated in large part by steroid action on the brain. An important question concerns whether luteinizing hormone releasing hormone (LHRH) neurons themselves transduce steroid signals, or whether, alternatively, steroid-sensitive interneuronal populations regulate their activity. A previous study in the rat employing steroid autoradiography combined with LHRH immunocytochemistry revealed that only an exceedingly small percentage of LHRH-immunoreactive (ir) neurons was estrogen concentrating. This study has examined the relationship of estrogen receptive and LHRH-ir cells in the male and female guinea-pig brain with double label immunocytochemistry. Since estrogen receptor-ir, as demonstrated with antibody H222, is known to be confined predominantly to the cell nucleus, whereas LHRH-ir is localized mainly in the cytoplasm, single cells can be double-labeled. Diaminobenzidine tetrahydrochloride was used for localization of LHRH-ir while nickel-enhanced diaminobenzidine tetrahydrochloride was used for localization of estrogen receptor-ir. The results revealed that there were many brain nuclei that contained both LHRH and estrogen receptor-positive cells, including the preventricular periventricular nucleus, the anterior subcompact nucleus of the medial preoptic nucleus (MPNa), the remainder of the medial preoptic nucleus, the retrochiasmatic area, and the anterior, dorsomedial, ventrolateral and arcuate nuclei. However, of a total of 2,604 LHRH-ir cells that were examined, we observed only 5 double-labeled cells (<0.2%). The double-labeled cells were not restricted to a single nucleus; they were present in the MPNa, the retrochiasmatic area and the arcuate nucleus. Moreover, at the light microscopic level, LHRH cells quite frequently appeared to be apposed to estrogen receptor positive cells (8.8% in the female), especially in the MPNa. These results lend further support to the notion that estrogen-mediated regulation of the LHRH system is achieved primarily through estrogen receptive interneurons. However, due to the existence of LHRH-LHRH synaptic interactions, the possibility also exists that a small population of estrogen-sensitive LHRH neurons could contribute to generalized activation of the LHRH system. PMID- 21554612 TI - Central noradrenergic lesion impairs the adrenocorticotrophin response to release of endogenous catecholamines. AB - Activation of hypothalamic alpha(1) -adrenoceptors stimulates the secretion of corticotrophin-releasing factors which in turn stimulate pituitary adrenocorticotrophin (ACTH). This mechanism is important in the physiological control of ACTH secretion. This study assesses the feasibility of using the ACTH response to release of endogenous catecholamines as a means of detecting a hypothalamic noradrenergic lesion in vivo. Intracerebroventricular infusion of the catecholamine neurotoxin, 6-hydroxydopamine, was used to destroy noradrenergic nerve endings in rats, with the purpose of producing a model that could be used to study alterations in ACTH responses that may result from a lesion involving central noradrenergic neurons. 6-Hydroxydopamine (250 MUg icv) significantly reduced hypothalamic noradrenaline content, indicating damage to noradrenergic nerve endings, without affecting postsynaptic receptor function, as judged by preservation of the effect of a selective alpha(1) -adrenergic agonist. Pharmacological release of endogenous catecholamines, effected by combined administration of a catecholamine precursor and an alpha(2) -adrenergic antagonist, stimulated the secretion of ACTH in control, but not in 6 hydroxydopamine-treated rats. Degeneration of hypothalamic noradrenergic nerve endings is not followed by denervation hypersensitivity, and is therefore accompanied by impairment of the ACTH response to release of endogenous catecholamines. PMID- 21554613 TI - Hypothalamic effects of C-type natriuretic Peptide on luteinizing hormone secretion. AB - Previous studies have demonstrated hypothalamic sites of action of A-type natriuretic peptide (ANP) in the inhibition of luteinizing hormone (LH) secretion, acting at least in part, via an opiatergic mechanism. C-type natriuretic peptide (CNP) was identified recently and is thought to be the predominant brain form of the family of natriuretic peptides. Third cerebroventricular injection of CNP in doses of either 0.1, 1.0 or 2.0 nmole significantly inhibited, in a dose-related fashion, plasma LH levels when compared to levels present in saline-injected controls. When compared to the LH inhibiting action of ANP, CNP appeared more potent (effective at lower doses) and efficacious (longer duration of action for the maximum effective doses). The LH inhibiting effect of CNP was blocked by prior treatment with the delta-opioid receptor antagonist naltrindole (50 MUg), suggesting an enkephalinergic mechanism of action. CNP in log doses ranging from 0.01 to 1,000 nM did not significantly alter LH release from dispersed pituitary cells harvested from random cycle female rats, either under static or dynamic (perifusion) incubation conditions. These results indicate that CNP, like ANP, acts at the hypothalamic level to alter LH secretion and suggest that CNP may be the preferential neuroactive members of this family of peptides. PMID- 21554614 TI - Differential regulation of luteinizing hormone-releasing hormone and galanin messenger ribonucleic Acid levels by alpha(1) adrenergic agents in the ovariectomized rat. AB - alpha(1) -Adrenergic control of luteinizing hormone-releasing hormone (LHRH) and galanin mRNA levels was examined in ovariectomized rats. Each rat was ovariectomized and a permanent bilateral cannula was implanted 1 mm dorsal to the preoptic area. Eleven to 14 days later, each rat received one of three treatments: prazosin (alpha(1) antagonist, n = 8), methoxamine (alpha(1) agonist, n = 5) or control (no drug, n = 7). Each drug was suspended in a polyacrylamide gel matrix and delivered to the preoptic area via the bilateral cannula. After 24 h of continuous exposure to the adrenergic agents (or control), rats were anesthetized, decapitated and brains were stored in liquid nitrogen until sectioned (7 MUm) on a cryostat. In situ hybridization was performed using a [(32) P]-end-labelled 59mer complementary to LHRH mRNA. Reduced silver grains, proportional to LHRH mRNA content, were quantified for number of LHRH cells per section, number of grains per labelled cell and total number of grains in labelled cells. Compared to the controls, prazosin caused a 32% decrease (P<0.05) in the number of cells expressing the LHRH gene. The LHRH cells from untreated animals had a median of 53 grains/cell with a smooth distribution above and below the median. Treatment with prazosin reduced the median number of grains/cell to 36 (P<0.05). When the number of grains in labelled cells were totalled, prazosin decreased (P<0.01) the number of grains by 47%. Surprisingly, methoxamine caused no quantitative changes in any of the parameters examined. This might be explained if LHRH transcription in control animals was proceeding at near-maximal rates supported, in part, by an endogenous alpha(1) ligand. Alternatively, continuous exposure to this agonist may have resulted in desensitization to its stimulatory effects. When anatomically matched brain tissue sections from these animals were examined for galanin mRNA, no differences among experimental groups were detected. In conclusion, administration of an alpha(1) -adrenergic antagonist into the preoptic area suppressed levels of LHRH mRNA but not galanin mRNA. Therefore, the data suggest that an endogenous alpha(1) ligand, such as norepinephrine (or epinephrine), is required to maintain a high level of LHRH gene expression in the ovariectomized rat. PMID- 21554615 TI - Pineal photoreceptor cells: photoperiodic control of melatonin production after cell dissociation and culture. AB - Trout pineal cells were dissociated using a trypsin-DNase digestion technique. An enriched population of photoreceptor cells was selected from a Percoll gradient centrifugation. The ability of cultured photoreceptor cells (selected or not on a Percoll gradient) to produce melatonin rhythmically was investigated during seven 24 h light/dark cycles. During each cycle, trout pineal photoreceptor cells released low amounts of melatonin during daytime and high amounts during night time. Under continuous darkness, melatonin release was continually high. The profile of its rhythm and that of the activity of the hydroxyindole-O methyltransferase-the last enzyme of the melatonin biosynthetic pathway-depended on the substrates and on the culture media used. Some of them appear suitable for short- or long-term culture of photoreceptor cells permitting the study of their neuroendocrine properties. PMID- 21554616 TI - Arginine vasotocin gene expression during osmotic challenge in the chicken. AB - The avian hypothalamic nonapeptide arginine vasotocin (AVT) is released from axon terminals in the neural lobe upon the application of osmotic stimuli. We have investigated whether, and to what extent, hormone secretion from the neurohypophysis is related to gene expression in the hypothalamus. Results from hybridization experiments with an AVT-specific cDNA probe indicate that in adult chickens stimulated by water deprivation or by hypertonic saline (2% w/v) drinking water, an upregulation of the AVT mRNA pool takes place, since consistently higher AVT mRNA levels compared to controls were monitored in osmotically challenged birds. This stimulatory effect was even visible at the transcriptional level after 19 h of water deprivation when osmolality was still near the basal value. In hens osmotically challenged by hypertonic saline drinking water for 5 days, a dissociation between osmolality and AVT plasma concentration was visible: extremely high plasma osmolality was accompanied by only moderately increased plasma AVT concentration. This might be caused either by exhaustion of stored hormone, or by downregulation of the system after chronic challenge. The latter suggestion is supported by the fact that the AVT mRNA concentration after 5 days of hypertonic saline challenge was well below the AVT mRNA levels of the groups with the more short-term stimuli of water deprivation for 19 or 48 h. In 30-day-old chicks the hypothalamic AVT mRNA concentration hardly reached 70% of the adult value, although AVT plasma concentrations were similar to those in the mature bird. We conclude that osmotic challenge of the hypothalamo-neurohypophysial system not only causes secretion of AVT from stores in the neural lobe but is accompanied by upregulation of AVT gene expression. Upregulation already occurs after marginal increase in plasma osmolality, as seen after 19 h of water deprivation in hens. In 30-day-old chicks gene expression is only slightly upregulated after short-term water deprivation while increase in plasma AVT is even greater compared to hens. PMID- 21554617 TI - Developmental aspect of differences in hypothalamic preproneuropeptide y messenger ribonucleic Acid content in lean and genetically obese zucker rats. AB - The genetically obese Zucker rat is a well characterized model of early onset human obesity. Many of the endocrine and metabolic abnormalities of obese animals are common to other strains of genetically obese animals as well as morbidly obese humans. Neuropeptide Y (NPY), a potent orexigenic agent, was recently found to be elevated in adult obese animals compared to their lean littermates. In this study we first examined hypothalamic expression of preproNPY mRNA, using solution hybridization/ nuclease protection analysis, in phenotypically-matched, i.e. lean or obese, immature (5-week-old) and mature (33-week-old) animals. Although changes were not statistically different, a trend toward decreased hypothalamic preproNPY mRNA levels was detected in both lean and obese mature animals. We next compared hypothalamic preproNPY mRNA levels between age-matched lean and obese animals at 5, 14 and 33 weeks of age and found elevated preproNPY mRNA levels in obese rats at all three ages. These data suggest that increased levels of hypothalamic NPY are an early manifestation of the obese phenotype and may, therefore, contribute to hyperphagia and increased weight gain in obese Zucker rats. PMID- 21554618 TI - Regulation of Prolactin Messenger Ribonucleic Acid Levels by Estradiol and Dihydrotestosterone as Evaluated by in situ Hybridization Performed on Implanted Pituitary Glands and Anterior Pituitary Cells in Culture in the Male Rat. AB - We have recently demonstrated that 17beta-estradiol (E(2) ) administration increases protactin (PRL) mRNA levels in the male rat anterior pituitary gland and that this stimulatory effect is partially inhibited by concomitant administration of dihydrotestosterone. In order to gain more information about the site(s) of action of E(2) and dihydrotestosterone on PRL gene expression, we have studied the effects of these two hormones in pituitaries implanted under the kidney capsule as well as in anterior pituitary cells in culture. In implanted pituitaries, PRL mRNA levels were increased by 90% as compared to values obtained in the stalk-connected pituitaries from the same animals. Administration of E(2) induced a further increase of PRL mRNA levels in implanted pituitaries, while dihydrotestosterone did not produce any change in animals which had been treated or not with E(2) . In anterior pituitary cells in culture, addition of E(2) to the culture medium resulted in a 60% increase of PRL mRNA levels over control values. Supplementation with dihydrotestosterone did not induce any variation in the concentration of PRL mRNA in cells which were treated or not with E(2) . These results indicate that E(2) exerts a direct action on PRL cells at the pituitary level and strongly support the key role of the hypothalamus in the inhibitory effect of androgens on estrogen-induced stimulation of PRL mRNA in the male rat pituitary. PMID- 21554619 TI - Evidence that Dopaminergic Neurons are not Involved in the Negative Feedback Effect of Testosterone on Luteinizing Hormone in Rams in the Non-Breeding Season. AB - In this study we tested the hypothesis that the negative feedback effects by testosterone on the secretion of luteinizing hormone (LH) in rams involves dopaminergic afferents to gonadotrophin-releasing hormone neurons operating via D(2) receptors in the non-breeding season. In the first experiment, three groups (n = 5) of rams were treated with an intravenous injection of vehicle or 10 or 20 mg of the dopaminergic D(2) antagonist pimozide and jugular venous samples were collected every 10 min for 3 h before and 3 h following treatment. The plasma was assayed for LH. Three groups of ewes (n = 4 to 5) were similarly treated. There were no significant effects of treatment of the rams with pimozide on the plasma concentrations of LH or LH pulse frequency or pulse amplitude and the response of individual rams in each group was inconsistent. In contrast, treatment of the ewes with 20 mg pimozide significantly (P<0.001) increased the mean (+/- SEM) plasma LH concentrations (pretreatment 0.37 +/- 0.04; post-treatment 2.42+/-0.25 ng/ml) and decreased (P<0.001) the LH inter-pulse interval (pretreatment 180.0; post-treatment 88.0+/-11.1 min); the 10 mg dose of pimozide did not affect these parameters. In the second experiment, two groups of rams (n = 5) and ewes (n = 7) were treated with an intravenous injection of vehicle or 0.33 mg pimozide/kg liveweight and jugular venous samples were collected every 10 min for 2 h before and 6 h following treatment. As in the first experiment, the mean (+/- SEM) concentrations of plasma LH were not affected by treatment with pimozide in the rams (pretreatment 0.18 +/- 0.25; post-treatment 0.43 +/- 0.14 ng/ml) but were significantly (P<0.05) increased in the ewes (pretreatment 1.12+/-0.22; post treatment 1.93 +/- 0.23 ng/ml). In the third experiment, four adult rams were castrated and 3 weeks later each animal had two cannulae inserted to allow injection into the lateral cerebral ventricles. Vehicle or 100 MUg pimozide was injected intracerebroventricularly and blood samples were collected as in the other experiments. A Latin Square design was used so that each animal received each treatment (n = 4). This procedure was repeated after the animals had been injected (intramuscularly) with 16 mg testosterone propionate twice daily for at least 7 days. Treatment with testosterone propionate significantly decreased (P < 0.001) the plasma concentrations of LH (pre-treatment 7.71+/-0.27; post-treatment 0.75 +/- 0.27 ng/ml; mean +/- SEM) and follicle-stimulating hormone (pre treatment 79.61+/-8.47; post-treatment 42.53 +/- 6.08 ng/ml; mean +/- SEM) and increased the mean (+/- SEM) LH inter-pulse interval (53.14 +/- 3.58 min pre treatment and 292.5 +/- 32.94 min post-treatment) but had no effect on the amplitude of LH pulses (pre-treatment 3.61 +/- 0.36; post-treatment 1.86+/-1.76 ng; mean +/- SEM). Pimozide had no effect on the plasma concentrations of gonadotrophins. These results suggest that, in the ram, dopaminergic neurons do not influence the gonadotrophin-releasing hormone neurons via D(2) receptors in the non-breeding season and are not involved in the negative feedback effect of testosterone on the secretion of gonadotrophins. Conversely, our data suggest that such a mechanism is integral to the negative feedback effects of oestradiol on LH in anoestrous ewes. Finally, it also appears that the steroid-independent suppression of the secretion of gonadotrophins during the non-breeding season in rams is not mediated via D(2) receptors. PMID- 21554620 TI - NADPH-Diaphorase (Nitric Oxide Synthase) Staining in the Rat Supraoptic Nucleus is Activity-Dependent: Possible Functional Implications. AB - NADPH-diaphorase has recently been shown to be the enzyme nitric oxide (NO) synthase, and to be present in the rat supraoptic nucleus (SON) and posterior pituitary. Investigations were carried out to assess whether there is any difference in the extent to which this enzyme is present, as assessed by light microscopic histochemistry, in SON of normal and dehydrated male Wistar rats. In normal rats there was clear cellular heterogeneity; cells located in the ventral and caudal areas of the SON stained only weakly or not at all, while cells in the rostro-dorsal areas of the nucleus stained strongly. Dehydration of rats for 12 h caused a large and rapid increase in staining intensity of the nucleus, particularly of cells in its ventral and caudal parts. On the basis of its known biological actions, and the kinetics of its induction, it is suggested that NO would be a strong candidate as a modulator of SON and posterior pituitary morphology and function, with the potential to rapidly modulate blood flow, neuronal activity, and possibly astrocyte morphology, in response to changes in neuronal activity. PMID- 21554621 TI - Simultaneous display of sexual and ingestive behaviour by rats. AB - Intraoral infusion of sucrose activates consummatory ingestive behaviour in rats selectively, i.e. the rat only emits the responses used to ingest food. Activation of consummatory ingestive behaviour in this way had no effect on the subsequent display of sexual behaviour by male or female rats and vice versa. Rats infused intraorally with sucrose and presented with a sexual partner showed ingestive and sexual behaviour simultaneously. Pretreatment with cholecystokinin octapeptide inhibited the ingestion of sucrose in both males and females but had no effect on the simultaneous display of sexual behaviour. Ingestion of sucrose from a drinking spout, a test in which the rat has to emit responses to obtain food, i.e. show appetitive ingestive behaviour, was inhibited by the presentation of a sexual partner in rats of both sexes. These results show that the mechanisms controlling consummatory sexual and ingestive behaviour operate independently and that the presentation of a sexual partner inhibits appetitive ingestive behaviour. Daily intraoral infusion of sucrose reduced pellet intake in ovariectomized rats while the rats maintained their body weight. Implantation of an oestradiol-filled implant reduced body weight and inhibited daily intake of pellets but had no effect on the intake of intraorally administered sucrose. Subsequent removal of the oestradiol implant increased sucrose intake and body weight but did not have a marked effect on pellet intake. Thus, rats respond to a lowering of the set point for body weight by decreasing their intake of the least preferable kind of food and increase their intake of the most preferable kind of food in response to an elevation of the set point for body weight. Ovariectomized rats infused intraorally once daily with a highly nutritive milk diet in the absence of food pellets ingested very large amounts and reduced their intake in response to oestradiol implantation. Thus, although oestradiol can inhibit consummatory ingestive behaviour, its suppressive effect on ingestion cannot be described in terms of selective effects on appetitive and/or consummatory aspects of the behaviour nor in terms of an alteration in the preference for a sweet solution. Inhibition of ingestive behaviour occurred within 24 h after oestrogen treatment as opposed to stimulation of sexual behaviour which had a longer latency, suggesting that oestradiol affects ingestive and sexual behaviour via different mechanisms. While the mechanisms controlling consummatory ingestive and sexual behaviour must be different, there is evidence for a common mechanism mediating the incentive motivation and reward aspects of these behaviours. The mechanisms which enable rats to select between two, possibly equally rewarding courses of action, i.e. display of sexual or ingestive responses, however, are unknown. PMID- 21554622 TI - Steroid regulation and sex differences in [(3) h]muscimol binding in hippocampus, hypothalamus and midbrain in rats. AB - The gonadal steroids estradiol and progesterone have previously been shown to modulate the specific binding of the GABA(A) agonist, [(3) H]muscimol, in the CA1 region of the hippocampus, the ventromedial nucleus of the hypothalamus and the midbrain central gray of ovariectomized female rats. In this report we show a sex difference in the level of binding in the very caudal ventromedial nucleus of the hypothalamus. In contrast to females, there is no steroid modulation of [(3) H]muscimol binding in the ventromedial nucleus of the hypothalamus and midbrain central gray of males. These effects may be functionally related to GABAergic control of female sexual behavior. In contrast, steroid modulation of [(3) H]muscimol binding in the CA1 region of the hippocampus occurred to the same degree in males and females, and there was no difference in the level of binding in any region of the hippocampus between gonadectomized males and females. Incubation of brain slices with progesterone or its metabolite 5alpha-3alpha pregnanolone dissolved in ethanol, produced a significant increase in [(3) H]muscimol binding in most brain regions as compared to control brain slices treated with ethanol alone. Moreover, there was also a marked increase in [(3) H]muscimol binding in all brain areas in the control condition which contained 100 mM ethanol, as compared to brain slices not preincubated with ethanol. The increase in binding after in vitro treatment with either progesterone or 5alpha 3alpha-pregnanolone is notably different from that seen after progesterone given in vivo 4 h prior to assay in that it is not site-specific, does not depend on prior treatment with estradiol and shows no sex difference. These results suggest different mechanisms for progesterone effects on the GABA(A) receptor when administered in vivo as compared to in vitro. PMID- 21554623 TI - Glucocorticoid effects on the molecular forms of adrenocorticotrophic hormone secreted by cultures of rat anterior pituitary cell monolayers. AB - The effects of glucocorticoids and corticotrophin-releasing factor (CRF) on the release of various molecular forms of adrenocorticotrophic hormone (ACTH) have been investigated in primary cultures of rat anterior pituitary. The rat cells responded to a 30 min challenge with CRF by secreting increased amounts of ACTH, as assessed both by bioassay, using rat adrenocortical cells, and by radioimmunoassay. Inclusion of a synthetic glucocorticoid, such as dexamethasone (DEX), in the incubation for 5 min prior to, and during the CRF challenge, had no effect on the response as measured by radioimmunoassay. Bioassay, however, indicated profound suppression of the response to CRF. This discrepancy between ACTH immuno- and bioactivity was investigated by fractionating the immunoreactive ACTH species using high-performance liquid chromatography. The lower molecular weight (<15kd) forms (ACTH(1-39) , phosphorylated ACTH(1-39) and glycosylated ACTH(1+/-39) ) were separated from higher molecular weight (>15kd) forms (i.e. ACTH biosynthetic intermediate and proopiomelanocortin) using C-18 Sep-Pak. The lower molecular weight molecules were further resolved into glycosylated and non glycosylated ACTH, using an acetonitrile gradient high-performance liquid chromatography with trifluoroacetic acid as an ion-pairer. Neither the proportion of low molecular weight forms of ACTH, nor that of glycosylated ACTH(1-39) secreted in response to CRF, were affected by DEX. Further fractionation of non glycosylated ACTH, also using acetonitrile gradient high-performance liquid chromatography but with heptafluorobutyric acid as the ion-pairer, yielded peaks corresponding to phosphorylated and non-phosphorylated ACTH(1-39) . DEX significantly increased the proportion of phosphorylated ACTH secreted in response to CRF by 18%. An additional effect of DEX was revealed when Sep-Pak extracts were treated with alkaline phosphatase, prior to analysis. After dephosphorylation, it became clear that the peptides released by CRF-stimulated cells were different if DEX was present in the medium. The peptide released in the presence of DEX (ACTH-S) had a slightly, but consistently, different retention time on high-performance liquid chromatography and very little biological activity. Antibody cross-reactivity studies suggested that ACTH-S was modified in the 1-24 region of the peptide. It is concluded that challenge of anterior pituitary cells in primary culture with CRF, following 5 min previous exposure to DEX, results in a molecular change. The consequence of this is that ACTH immunoreactivity is released, but the molecule has reduced biological activity. This may be part of the mechanism by which fast feedback inhibition of ACTH secretion is effected. PMID- 21554624 TI - Hemorrhage-Induced Activations of Adrenocorticotropin Release and Catecholamine Metabolism in the Ventrolateral Medulla are Differently Affected by Glucocorticoid Feedback. AB - We have compared the effects of increasing doses of dexamethasone on the hemorrhage-induced stimulation of the corticotropic axis and the metabolism of the catecholamines of the A1 group in the ventrolateral medulla. Adrenocorticotropin was measured in sequential samples of plasma while the metabolism of the catecholamines was recorded by in vivo electrochemistry in urethane-anesthetized rats. Combined intracerebroventricular injection of specific adrenergic blockers (alpha(1) -antagonist, prazosin and beta-antagonist, propranolol) prevented the stimulation of the adrenocorticotropin release by hemorrhage. Pretreatment with dexamethasone (1 mg/kg sc) fully blocked the hemorrhage-induced adrenocorticotropin release but did not affect the concomitant stimulation of the catecholamine metabolism in A1 cells. The latter was partially decreased only with the highest dose (10 mg/kg sc). While a central catecholaminergic input appears to be necessary for the hemorrhage-induced stimulation of the corticotropic axis, it does not seem to play a significant role in the feedback regulation by glucocorticoids. PMID- 21554625 TI - Central Somatostatin Inhibits Cholecystokinin-lnduced Oxytocin Secretion in Conscious Rats. AB - Recent studies have demonstrated the presence of fibres immunoreactive for somatostatin-28 (SS-28), which originate in the brainstem and selectively innervate the magnocellular oxytocin (OT) cells of the supraoptic nucleus. The potential physiological relevance of this pathway was investigated in the present study by measuring plasma OT levels in response to intraperitoneal administration of cholecystokinin in conscious male rats pretreated with intracerebroventricular injections of either SS-28 or artificial cerebrospinal fluid. Cholecystokinin treatment produced the expected marked rise in plasma OT levels in control rats pretreated intracerebroventricularly with artificial cerebrospinal fluid. However, this response was markedly blunted by prior intracerebroventricular administration of SS-28, even though SS-28 itself had no effect on basal plasma OT levels, nor did it impair OT release in response to hypertonic saline injection. These results demonstrate that centrally injected SS-28 can selectively block cholecystokinin-stimulated release of OT in rats, and support an inhibitory role for this peptide in brainstem-mediated neurohypophysial hormone secretion. Central SS-28 administration also elicited up to 3-fold increases in the amount of food ingested in 1 h by previously sated rats. These observations suggest the possibility that endogenous SS-28 may be involved in stimulating food intake in rats, and establish the basis for future studies to clarify the role of this neuropeptide in controlling ingestive behaviours. PMID- 21554626 TI - Reproductive history affects the synaptology of the ageing gonadotropin-releasing hormone system in the male rat. AB - This study is an examination of the density of synaptic input to gonadotropin releasing hormone (GnRH) neurons in young adult and aged retired breeder male rats. In earlier experiments on aged virgin male rats we observed an increase in synaptic input to this specific neuronal population, ascribable in part to synapses containing flattened vesicles, suggesting GABAergic input. The present study utilized retired breeders in order to dissect the effects of ageing from those associated with reproductive behavioral history. Tissue from the preoptic area was treated for the simultaneous electron microscopic immunocytochemical demonstration of GnRH with tetramethylbenzidine and glutamic acid decarboxylase (the essential enzyme in the production of GABA) using 3,3'-diaminobenzidine. Estimates of the density of synaptic input to the soma of GnRH neurons were made by calculating the percentage of perikaryal membrane with postsynaptic modification. Five GnRH neurons per animal were measured using computerized morpho-metrics and differences in the percent of membrane with synaptic modification between experimental groups were tested using the Mann-Whitney U non parametric statistic. There was no difference in the total density of synaptic input to GnRH neurons in the young and old animals, or in the proportion of this input that was immunoreactive for glutamic acid decarboxylase. Similar measurements were made on random, non-identified neurons in the same region and a significant decrease with ageing in total synaptic input was found, though the glutamic acid decarboxylase component was unchanged. The present results are in contrast to our earlier findings on virgin males and suggest that reproductive behavioral experience affects the connectivity of GnRH neurons. PMID- 21554627 TI - Development of oxytocinergic neurons in monolayer cultures derived from embryonic, fetal and postnatal rat hypothalami. AB - Monolayer cultures from hypothalami of embryonic, fetal and postnatal rats were established to study the development of oxytocin-secreting neurons in vitro. Particular culture conditions, known to enhance the survival and growth of different types of neural cells in vitro, were used to investigate the conditions necessary for the appearance and survival of these peptide-producing cells in culture. They included increasing the concentration of potassium in the culture milieu and/or the addition of triiodothyronine (T(3) ). The use of immunocytochemical procedures with a monoclonal antibody that recognizes oxytocin associated neurophysin (NP-OT) and polyclonal antibodies specific for oxytocin permitted us to identify the neurons. In cultures derived from embryonic (E16 E17) hypothalami, no NP-OT- or oxytocin-positive neurons were detected and their appearance could not be provoked by increasing extracellular potassium concentration or by administration of T(3) . On the other hand, in cultures obtained from fetal (E18-E19) rat hypothalami, a few neurons showed immunoreactivity for NP-OT (but not for oxytocin); the immunoreactivity was localized essentially in somata and proximal portions of neurites. When 10(8) M T(3) was included in the culture medium, there were cells showing immunoreactivity not only for NP-OT, but also for oxytocin, visible in somata and in dendritic- and axonal-like processes. In comparison, T(3) did not influence the total number of neurons developing in these cultures. Lastly, in cultures derived from young postnatal (PO-P2) rat hypothalami, NP-OT- and oxytocin immunopositive neurons were found regularly; their appearance did not require any special pretreatment of the cultures. In all cultures, high extracellular potassium concentration (25 mM) resulted in a general improvement in the survival of neurons but did not induce the appearance of more oxytocin-immunoreactive cells. Our observations support in vivo results showing that although presumptive oxytocin-producing cells appear early in the development of the hypothalamus, their maturation, and in particular, their ability to produce oxytocin, occurs late at the time of birth. A factor that selectively enhances their differentiation, is the thyroid hormone, T(3) . PMID- 21554628 TI - Brain Angiotensin II Receptor Subtypes and the Control of Luteinizing Hormone and Prolactin Secretion in Female Rats. AB - The present experiments examined the role of the two recently identified angiotensin II (Ang II) receptor subtypes, AT, and AT(2) , in the central nervous system regulation of luteinizing hormone (LH) and prolactin secretion in estrogen and progesterone-treated ovariectomized rats. In this animal model, intracerebroventricular (icv) injection of Ang II stimulates LH and inhibits prolactin release. The specific Ang II receptor subtype antagonists losartan (AT(1) ) or PD123177 (AT(2) ) were administered (icv) in various doses (10 ng to 1,000 ng) 10 min prior to icv injection of Ang II (100 ng). Control animals were pretreated with artificial cerebrospinal fluid prior to Ang II administration. Blood samples for LH and prolactin determinations were taken from conscious, freely-moving rats prior to and following injection of the antagonists and Ang II. Water intake was measured. Ang ll-induced water intake was attenuated 62% by 1,000 ng losartan; water intake was not affected by lower doses of losartan or by any dose of PD123177. Ang ll-induced stimulation of LH release was abolished by the 1,000 ng doses of losartan and PD123177 and attenuated by the 500 ng doses of both drugs. Lower doses did not affect Ang ll-induced LH secretion. Ang ll induced inhibition of prolactin release was significantly reduced by the 1,000 ng doses of both losartan and PD123177. Lower doses of either drug did not affect the Ang II inhibition of prolactin release. Previous studies had shown that Ang II administration into the anterior hypothalamus-medial preoptic (AHPO) area stimulated LH release. This brain area contains AT(1) receptors. To investigate the potential brain site where the AT(2) receptor may influence LH release, Ang II was injected into the locus ceruleus, a brain nucleus which contains predominately the AT(2) receptor subtype. Ang II administration into the locus ceruleus was paired with an injection of artificial cerebrospinal fluid or Ang II into the AHPO area. Injection of Ang II into the AHPO area stimulated LH release. Injection into the locus ceruleus did not affect LH secretion, nor did it modify the rise in LH elicited by administration of Ang II into the AHPO area. Plasma levels of prolactin were not altered by any of these injections. Taken together, these data demonstrate that, in estrogen- and progesterone-treated female rats, icv Ang ll-induced water intake is mediated by the AT, receptor subtype, while Ang ll-induced changes in LH and prolactin secretion appear to be mediated by both the AT(2) and AT(2) receptor subtypes. The latter observations are one of the first suggesting a potential function for the AT(2) subtype in vivo, although the physiological relevance of this observation, as well as the site of action for the effects on LH and prolactin, remain to be established. PMID- 21554629 TI - Dopaminergic regulation of galanin gene expression in the rat anterior pituitary gland. AB - Estrogen dramatically increases galanin mRNA and peptide levels in the rat anterior pituitary gland. We recently reported that galanin secretion in vitro from estrogen-exposed anterior pituitary cells is regulated by hypothalamic factors; dopamine and somatostatin inhibit galanin secretion, and thyrotrophin releasing hormone stimulates galanin release. To determine whether galanin is regulated by a dopaminergic mechanism in vivo, we used ovariectomized Fischer 344 rats treated with 17beta-estradiol-containing or empty Silastic capsules. Rats were also administered bromocriptine, a dopamine receptor agonist, haloperidol, a dopamine receptor antagonist, or placebo for 2 weeks. Galanin peptide levels were measured in the anterior pituitary, neurointermediate lobe, medial basal hypothalamus, and plasma by radioimmunoassay. Plasma and pituitary prolactin levels were also determined. Bromocriptine decreased gaianin peptide levels in the anterior pituitary gland of ovariectomized rats by 30%, but had no effect on galanin in the neurointermediate lobe or medial basal hypothalamus. In contrast, haloperidol had no effect on galanin in the anterior pituitary or medial basal hypothalamus of ovariectomized rats, but decreased galanin peptide levels in the neurointermediate lobe. In the anterior pituitary gland of estrogen-treated rats, bromocriptine increased and haloperidol decreased both galanin and prolactin levels. Galanin mRNA levels were quantified in the anterior pituitary gland by solution hybridization. Bromocriptine increased galanin mRNA levels 3-fold in the anterior pituitary, whereas haloperidol had no effect. Galanin mRNA levels in the anterior pituitary were elevated 10-fold by estrogen. Bromocriptine reduced galanin mRNA levels in the pituitary by 50% in estrogen-treated rats, where again haloperidol had no effect. Estrogen increased plasma galanin levels 4-fold compared to ovariectomized rats and this effect was reduced 60% by bromocriptine and increased 20% by haloperidol. We conclude 1) galanin synthesis and release from the estrogen-exposed anterior pituitary gland is inhibited by a dopaminergic mechanism in vivo, 2) dopamine regulates galanin gene expression in the ovariectomized rat, 3) the changes in galanin peptide levels in the anterior pituitary of rats treated with estrogen and dopamine receptor ligands are primarily due to alterations in peptide secretion, and 4) galanin release from the neurointermediate lobe may also be regulated by a dopaminergic mechanism in vivo. These data, in conjunction with previous studies, provide evidence for the co-regulation of galanin and prolactin in estrogen-treated rats, and further discriminate between the regulation of galanin in the hypothalamus and pituitary gland. PMID- 21554630 TI - Effect of constant light, pinealectomy and guanosine triphosphate gamma-s on the density of melatonin receptors in the rat suprachiasmatic nucleus: a possible implication of melatonin action. AB - We report here the effects of pinealectomy and exposition to constant light on the density of melatonin receptors in the suprachiasmatic nuclei of the rat using quantitative autoradiography. The B(max) values were significantly increased when the animals were maintained in constant light for 3 days (8.22 +/- 0.95 fmol/mg protein versus 4.55+/-0.14 fmol/mg protein in control group, 12 h light/12 h dark cycle (12L/12D), n = 6). A similar increase was also observed in rats pinealectomized 3 days before sacrifice and then maintained either under 12L/12D (B(max) 7.56+/-0.80 fmol/mg protein) or in constant light (B(max) 7.85+/-1.02 fmol/mg protein), while K(d) values failed to show any variations after constant light and/or pinealectomy. The effect of GTPgammaS on the density of rnelatonin binding sites was also investigated in control animals and after 3 days of constant light. In 12L/12D animals, the B(max) shifted from 5.94 +/- 0.14 fmol/mg protein in the absence of GTPgammaS to 3.97+/-0.22 fmol/ mg protein in the presence of 50MUiM GTPgammaS. In animals maintained for 3 days in constant light, a similar decrease in the B(max) value was observed (8.95 +/- 0.25 fmol/mg protein in absence and 5.95 +/- 0.22 fmol/mg protein in presence of 50 MU GTPgammaS). In both cases, K(d) values were not affected by GTPgammaS. Pinealectomy and constant light exposition are known to induce a suppression of the nocturnal peak of plasma rnelatonin and to keep plasma rnelatonin concentrations at a very low level. These results could suggest a regulatory effect of rnelatonin on the density of its own receptors which are shown here to be also coupled with a G-protein. PMID- 21554631 TI - Characterization of the parabrachial nucleus input to the hypothalamic paraventricular nucleus in the rat. AB - The brainstem parabrachial nucleus (PBN) is viewed as an increasingly important site for the transfer of autonomic-related information to more rostral structures in the forebrain including the hypothalamus. In this study, we examined electrophysiologically in vivo and anatomically the nature of PBN input to the hypothalamic paraventricular nucleus (PVN) and particularly to the vasopressin and oxytocin-secreting magnocellular neurosecretory cells within this nucleus. In urethane-anaesthetized rats, extracellular recordings from 108 antidromically identified neurosecretory PVN cells revealed an excitatory (37/43 cells) and less frequently an inhibitory (6/43 cells) response consequent to electrical stimulation in the PBN. Both vasopressin (12/37 cells)-and oxytocin (9/37 cells) secreting neurons appear to respond to the PBN stimulus. Four cells projecting to the neurohypophysis could also be antidromically activated from PBN, and this observation may be indicative of collateral branching in some PVN neurosecretory neurons. In addition, recordings from 60 non-magnocellular (i.e. non neurohypophysially-projecting) PVN cells revealed a facilitatory response (43/60 cells) following PBN stimulation, Iontophoretic injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA-L) were made within the rat lateral PBN and brains prepared for immunocytochemical examination of projections to the PVN region. PHA-L-labelled fibres and terminals were visualized within both the parvocellular and magnocellular divisions of the PVN. In addition, labelled fibres were also seen in a region immediately dorsal to the PVN. PHA-L labelled fibres with axonal varicosities and boutons were visualized over immunocyto-chemically-identified vasopressin and oxytocin neurons within the magnocellular PVN. These convergent electrophysiological and anatomical data provide evidence for a PBN projection to the PVN that is predominantly excitatory to both magnocellular neurosecretory and non-magnocellular cells. Moreover, with respect to vasopressin-and oxytocin-secreting cells, the PBN input appears to be directed at both populations of peptidergic neurons. PMID- 21554632 TI - Spontaneous Intracellular Calcium Oscillations and G(s) alpha Subunit Expression are Inversely Correlated with Secretory Granule Content in Pituitary Cells. AB - Cells of the pituitary tumour cell line GH(4) C(1) were exposed to epidermal growth factor, estradiol and insulin for 5 days, a treatment which resulted in 1) increased prolactin storage in secretory granules, 2) the loss of spontaneous [Ca(2+) ](1) oscillations, and 3) a selective reduction of the protein G(s) alpha, seen in immunoblots, cholera toxin labelling, and vasoactive intestinal peptide stimulation of adenylyl cyclase. In contrast, the glucocorticoid dexamethasone, which increases the expression of G(s) alpha, partially restored spontaneous [Ca(2+) ](1) oscillations and decreased prolactin storage. It is concluded that G(s) alpha levels in tumoral cells result in spontaneous electrical activity which may empty prolactin stores by the continuous activation of exocytosis. PMID- 21554633 TI - Central amygdaloid involvement in neuroendocrine correlates of conditioned stress responses. AB - The purpose of this study was to examine the effects of bilateral electrolytic lesions of the central nucleus of the amygdala (CEA) in comparison with sham lesions on neuroendocrine responses during conditioned emotional stress in male Wistar rats. Lesions in the CEA, made either before or after the single learning trial of inescapable footshock, failed to affect the conditioned response of plasma epinephrine levels. Plasma levels of norepinephrine showed neither a conditioned stress effect nor were influenced by lesioning. Pre-training CEA lesions, but not post-training intervention, abolished the conditioned elevations of circulating plasma corticosterone and prolactin. These results suggest that the CEA is involved in the conditioning rather than the retention of neuroendocrine stress responses. The effects of pre-training lesioning of the CEA can possibly be explained by a reduced feedback of all these neuroendocrine factors during or shortly after acquisition. In addition, there is a remarkable differentiation between various hormonal correlates of conditioned stress following CEA lesioning. Only corticosterone and prolactin, that appear to be correlates of a passive behavioural stress response, were abolished. The lesions failed to affect the sympatho-active stress parameters (epinephrine and norepinephrine). Relations between coping strategy-active and passive behaviour and physiology in connection with CEA functioning are discussed. PMID- 21554634 TI - Localization of Insulin-Like Growth Factor-II Receptors in Rat Brain by in vitro Autoradiography and Immunohistochemistry. AB - Insulin-like growth factor-ll (IGF-II) and its receptor, which is homologous with the mannose-6-phosphate (M6P) receptor, are found in high levels in adult rat and human brain, though their role remains unclear. In order to point to possible regional functions, we have mapped and quantified IGF-II/M6P receptors in sagittal sections of adult rat brain by in vitro autoradiography/computerized densitometry and immunohistochemistry. While in vitro autoradiography allowed mapping and quantitation, immunohistochemistry both confirmed mapping and allowed more detailed determination of cellular distribution of receptors. The two methods were generally in agreement with few areas of mismatching. By in vitro autoradiography, a discrete and characteristic distribution of IGF-II receptor binding was demonstrated, with specific binding representing 85% of total binding. Displacement and specificity competition curves in arcuate nucleus and choroid plexus were typical for authentic IGF-II receptors with half maximal displacement at 1 nM cold IGF-II. IGF-II receptor density, estimated by in vitro autoradiography, was very high in circumventricular organs, especially the median eminence, which had the highest binding in the brain. In the remainder of the brain there was concordance between the distribution of receptors identified by the two techniques, with greatest densities in the olfactory bulb and olfactory pathways, the hippocampus and discrete regions of the cerebral cortex, cerebellum, hypothalamus, thalamus and brainstem. There were however, some notable mismatches. Autoradiographic binding was high to very high in the median eminence, arcuate nucleus, suprachiasmatic nucleus and anterodorsal thalamic nucleus, whereas these areas were only poorly immunostained. Conversely, the septum showed moderate autoradiographic binding, but very prominent immunostaining of neurons in its dorsolat-eral aspect. Using the immunohistochemical technique IGF-II receptors were localized to specific neuronal groups such as the mitral cells of the olfactory bulb, Purkinje cells of the cerebellum and neurons in the red nucleus. Fibre pathways were not labelled by either technique. We conclude that IGF-II/M6P receptors are widespread throughout rat brain, specifically in neurons and blood vessels, with a similar, but distinct distribution to IGF-I and insulin receptors. Many of these regions have in common high rates of metabolic and synthetic activity, which may be mediated by IGF-II/M6P and their receptors. PMID- 21554635 TI - The chicken vasotocin gene. AB - cDNA clones corresponding to the vasotocin precursor polypeptide were isolated from a chicken hypothalamic library and sequenced. The derived amino-acid sequence indicates a precursor of comparable structural organization to that described for members of the vasotocin/vasopressin gene family from other species. Unlike in mammals the C-terminal glycopeptide moiety appears not be cleaved off from the neurophysin. Subsequent screening of a chicken genomic library permitted an analysis also of the vasotocin gene structure and exonic composition. The 5'region upstream of the first exon was sequenced and revealed an unusual pattern of 49 repetitive -YYCYCYAAAYY- motifs, together with a polyadenyl region supporting a bend in the DNA, and a long pyrimidine-rich sequence. Three AP2-like elements, identified in the mammalian vasopressin gene, were also observed in the immediate upstream region. There was no obvious homology to the promoter regions of the known oxytocin genes, nor to any other sequence deposited in available databases, nor to other known cis-elements. PMID- 21554636 TI - Stress, feedback and facilitation in the hypothalamo-pituitary-adrenal axis. PMID- 21554637 TI - Expression of the oxytocin and vasopressin genes. PMID- 21554638 TI - Norepinephrine inhibits vasopressin-stimulated flank marking in the Syrian hamster by acting within the medial preoptic-anterior hypothalamus. AB - Syrian hamsters exhibit a form of scent marking behavior called flank marking. Flank marking, which is elicited during social contact with other hamsters and by the odors of other hamsters, communicates socially important information such as mate choice and dominance status. Vasopressinergic activity within the medial preoptic-anterior hypothalamic continuum (MPOA-AH) is essential for the expression of flank marking. In female hamsters, an inverse relationship exists between the expression of flank marking and sexual receptivity during the 4-day estrous cycle. Since norepinephrine (NE) appears to facilitate sexual receptivity, the present study investigated whether NE might have an inhibitory effect on flank marking by acting on Vasopressinergic activity within the MPOA AH. Microinjection of 9.0 MUM arginine vasopressin (AVP) into the MPOA-AH stimulated high levels of flank marking. Microinjection of 9.0 MUM AVP combined with NE in concentrations of 4.0, 0.4 or 0.2 nM, drastically reduced or eliminated flank marking. In contrast, AVP in combination with 0.09, 0.04 or 0.004 nM NE produced no significant reductions in flank marking. In addition, microinjection of 9.0 MUM AVP, in combination with epinephrine (4.0 nM), but not dopamine (4.0 nM), serotonin (4.0 nM) or neuropeptide Y (900 MUM), significantly reduced AVP-induced flank marking. In male hamsters, microinjection of NE (4.0 nM) combined with AVP (9.0 MUM) into the MPOA-AH was not found to inhibit AVP stimulated flank marking. These results suggest that NE is involved in regulating the expression of flank marking during the estrous cycle by acting on Vasopressinergic activity within the MPOA-AH. PMID- 21554639 TI - Colocalization of fos- and glucocorticoid receptor-like immunoreactivities in the rat amygdaloid complex after immobilization stress. AB - In the present paper we demonstrate the effect of immobilization stress on c-fos like immunoreactivity (Fos-LI) in the rat amygdaloid complex. Furthermore, since the subnuclei of the amygdaloid complex contain numerous glucocorticoid receptor immunoreactive (GR-IR) neurons, we also studied the possible colocalization of GR and Fos-LI ie. Fos-Lls and the action of a synthetic glucocorticoid, dexamethasone, and an anti-glucocorticoid, RU 38486, on Fos-LI. Immobilization stress caused a remarkable increase in the number of the Fos-IR neurons in all the subnuclei of the amygdaloid complex except in the lateral nucleus. The majority of Fos-IR neurons also contained GR-LI, with the highest colocalization in the central amygdaloid nucleus. A similar induction of Fos-LI after immobilization was seen in the hypothalamic paraventricular nucleus and almost all the Fos-IR neurons in this nucleus also exhibited GR-LI. Treatments with dexamethasone or RU 38486 prior to stress did not have any marked effect on Fos LI when compared to stress alone. The present findings suggest that Fos may function as a transcriptional regulator in the amygdaloid complex after stress and affect the synthesis of neurotransmitters and receptors in the amygdaloid neurons. Since we did not observe any effect of dexamethasone or RU 38486 on Fos LI, it is likely that glucocorticoids do not directly regulate the expression of the c-fos gene or the formation of Fos protein. In view of the fact that Fos is capable of forming a stabile complex with GR and repress the transactivational capacity of GR, Fos may inhibit the negative feedback effect of circulating glucocorticoids and thus maintain elevated plasma glucocorticoid levels in stress. PMID- 21554640 TI - Melatonin regulates the synthesis and secretion of several proteins by pars tuberalis cells of the ovine pituitary. AB - The pars tuberalis (PT) of the pituitary may be an important target for melatonin action, but the secretory output of the melatonin-responsive cells is unknown. Using [(35) S]methionine, protein synthesis and secretion have been studied in primary cultures of ovine PT cells, and analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis. Only 4% of the labelled proteins appeared in the medium with the majority retained in the cells. Stimulation of the cells with 10MUM forskolin increased the accumulation of several labelled proteins in the medium without corresponding changes in the cell (72, 62, 44, 39, 29, 24, 23, 18 and 14 kd). Two-dimensional gel electrophoresis showed the proteins to have mildly acidic isoelectric points. Melatonin (1 MUM) counteracted the stimulatory effect of forskolin on all but one (23 kd) of these secreted proteins. Immunoprecipitation showed this to be prolactin. Furthermore, melatonin alone appeared to have an inhibitory effect on the synthesis and release of proteins into the medium. The synthesis and secretion of the melatonin-responsive proteins was not inhibited by actinomycin D (1 MUg/ml), indicating control at the translational level. This contrasts with the regulation of prolactin which is actinomycin D-sensitive. Pulse-chase experiments demonstrated that it requires 30 min for the secretory proteins to appear in the medium, consistent with intracellular processing and packaging prior to secretion. The secretory proteins labelled in the ovine PT, and responsive to melatonin, did not appear to be specific to the PT, as a similar profile of labelled secretory proteins was produced in primary cultures of pars distalis cells. However, melatonin had no effect on the synthesis and secretion of proteins by the pars distalis. These results demonstrate that in the ovine PT melatonin regulates the synthesis and export of several secretory proteins. These are possibly packaging proteins of secretory granules, similar to the granin family of proteins. Thus, the results confirm that melatonin-responsive cells are secretory cells and further imply that the PT-specific product is not a protein. PMID- 21554641 TI - Desensitization of pituitary cells by gonadotrophin-releasing hormone or its analogues in the superfusion system: different pattern for males and females. AB - The effect of a 6-h infusion of gonadotrophin-releasing hormone (GnRH) or its analogues on dispersed anterior pituitary cells from male or female rats was investigated. The cells were stimulated with 3-min pulses of K(+) and GnRH. Thereafter GnRH (1 nM) or GnRH analogues ([D-Trp(6) ]GnRH-ethylamide ([D-Trp(6) ]GnRH, 50 pM), [D-Phe(6) , Gln(8) ]GnRH-ethylamide (Folligen, 100 pM) and [Asu(6) ]GnRH-ethylamide ([Asu(6) ]GnRH, 33 pM)) were applied for 6 h. In cells from female rats this treatment resulted in a 20-fold increase in luteinizing hormone (LH) secretion during the first 90-min period of the 6-h incubation. Following this a gradual decrease in LH release occurred, and during the fourth 90-min period the amount of LH secreted was only one-third or less of the initial value. The pituitary cells of male rats responded to the same treatment with only a 7 fold rise of LH secretion during the first period. In the second 90-min of the 6 h incubation a 20% to 30% increase was observed. Even in the fourth 90-min period the amount of LH secreted was two-thirds or more greater than that of the first 90-min period. When using 10-fold greater concentrations of the same peptides in males, the increase in hormone secretion in the second 90-min was not seen and the hormone release decreased to around 50%. We found definite differences in the responses of male and female rat pituitary cells to the 6-h infusion of GnRH or its analogues: the initial amplitude of the response in females was higher but desensitization was stronger. In males, the initial response was weaker; however, even using doses one magnitude greater, the level of desensitization did not reach the values obtained in females. The results were similar both with GnRH and the analogues. The responses to 3-min K(+) and GnRH stimuli given after the 6-h incubation were strongly reduced in cells from female rats compared to the initial responses; however, in cells from male rats the reaction was higher or unchanged. The ratio of LH released by the final K(+) stimulus relative to the actual LH content of the cells decreased in females but increased in males. Our data show that the differences between the pattern of desensitization in cells from male and female rats may be caused by the differences in the amount and ratio of immediately releasable hormone and the hormone replenishment into these pools. PMID- 21554642 TI - Electrical activity of dorsal horn neurons during the suckling-induced milk ejection reflex in the lactating rat. AB - In lactating rats, suckling elicits the milk ejection reflex which consists of an intermittent synchronous activation of hypothalamic oxytocin neurons which releases oxytocin into the bloodstream. We here investigated the electrophysiological behaviour of spinal cord neurons linked to mammary innervation in relation to suckling and the suckling-induced milk ejection reflex. Experiments were carried out on 58 urethane-anaesthetized rats, paralysed with gallamine triethiodide and artificially ventilated. Fixation of the spinal cord and laminectomy significantly slowed down the reflex, which occurred in only 27% of the animals. In these rats, 31 dorsal horn neurons at the thoraco-lumbar level were found to be excited by nipple stimulation. During suckling by a litter of at least nine pups, they displayed an irregular pattern of brief bursts of activity (peak firing rate 22.0 +/- 3.2 Hz, mean +/- SD) correlated to the bouts of suckling of the pups. Seventeen out of 19 cells tested by stimulation of at least 2 adjacent nipples received convergent input from different ipsilateral nipples. Out of 11 cells tested, 8 were also activated by stimulation of a contralateral nipple. Fourteen out of 30 units were recorded through at least one reflex milk ejection. Their firing rate was significantly higher than the firing rate of cells recorded in animals which failed to milk eject (4.4 Hz +/- 2.8 versus 1.5 Hz +/- 0.7). At the moment of the high frequency discharge of action potentials, occurring in oxytocinergic cells 10 to 15 s before each milk ejection, spinal neurons showed no systematic change in electrical activity. In contrast, the stretch reaction of the pups, which corresponds to an intense period of suckling when milk ejection has started, induced, in 12 cells, a considerable increase in electrical activity. One unit was found to be inhibited by suckling and during the stretch reaction. Ten more units, which were not activated by stimulation of the nipples but responded to stimulation of excitatory receptive fields near the last three pairs of nipples, were recorded through reflex milk ejections: 8 remained silent during reflex milk ejections but 2 were activated when the pups stimulated their excitatory receptive field. We conclude that some dorsal horn neurons, able to respond readily to the suckling movements of pups, appear to receive an ungated input from the nipples. At the time of the activation of oxytocin neurons, they present no particular pattern of activation or inhibition which could account in a simple manner for the intermittence of the high frequency discharge in oxytocinergic cells. However, in so far as these dorsal horn neurons may be part of the milk ejection reflex pathway, their activity, showing convergence and summation of input, and being facilitated in milk ejecting animals, indicates that the reflex does undergo a certain degree of processing at the spinal cord level. PMID- 21554643 TI - Glucocorticoids are Required for Food Deprivation-Induced Increases in Hypothalamic Neuropeptide Y Expression. AB - Neuropeptide Y (NPY), a 36 amino-acid peptide found within the hypothalamus, is thought to be an important regulator of food intake. Hypothalamic NPY gene expression, synthesis and secretion are all known to be increased in models of increased metabolic demand in which serum glucocorticoids are also elevated. The present studies were designed to test the hypothesis that glucocorticoids are required for increased hypothalamic preproNPY mRNA levels induced by food deprivation (FD). First, animals underwent bilateral sham-adrenalectomy (sham) or not (control), and were subjected to 72 h FD, or not. Total RNA was isolated from hypothalamic tissue blocks and the content of preproNPY mRNA was measured by solution hybridization/RNase protection analysis. This study revealed that there was no significant difference in hypothalamic preproNPY mRNA content between shamfed and control-fed groups, or between sham-FD and control-FD groups. In the second experiment, animals underwent bilateral adrenalectomy (ADX), were allowed to feed ad libitum and were sacrificed 1 day, 4 days and 7 days after ADX. Nuclease protection analysis revealed no significant effect of ADX on hypothalamic preproNPY mRNA levels over this time-course. Finally, we examined the role of glucocorticoids in regulating NPY gene expression following FD. Animals underwent bilateral ADX, or not. At the time of surgery, ADX animals received placebo, or corticosterone (B) replacement in the form of constant release pellets, at one of two doses. Food was removed from half of the animals in each group 24 h after surgery; all animals were sacrificed 72 h thereafter. There was no difference in preproNPY mRNA content between the ADX-FD and ADX-fed groups, relative to the fed controls. Replacement with corticosterone [ADX(B)] did not alter preproNPY mRNA content in fed animals, however preproNPY mRNA content in FD animals was increased 2.5-fold. These studies demonstrate that glucocorticoids are necessary and serve a stimulatory role in the increase in hypothalamic preproNPY mRNA levels observed under conditions of FD, and suggest that hypothalamic NPY gene expression may be directly responsive to peripheral metabolic and hormonal signals. PMID- 21554644 TI - C-type natriuretic Peptide stimulates prolactin secretion by a hypothalamic site of action. AB - The most recently discovered member of the family of natriuretic peptides, C-type natriuretic peptide (CNP), exerts many pharmacologic actions similar to its structural homolog A-type natriuretic peptide (ANP). Like ANP it failed to significantly alter prolactin release from dispersed, rat anterior pituitary cells incubated under static or dynamic conditions. Unlike ANP, however, which inhibits prolactin secretion in vivo by a hypothalamic action, CNP injection into the third cerebroventricle significantly stimulated prolactin secretion in ovariectomized, conscious rats. The effect was highly significant 15 min after injection and transient, lasting 30 min in animals injected with 2 nmole CNP. In a companion group of rats, significant inhibition of plasma prolactin levels was observed after central administration of similar doses of ANP. These results suggest differing hypothalamic actions of the CNP and ANP perhaps mediated by multiple natriuretic peptide receptors present in the tissue. Further, they provide additional support for unique roles exerted within the central nervous system by these structural homologs. PMID- 21554645 TI - Tyrosine Hydroxylase Messenger Ribonucleic Acid Levels Increase in A1 but not Locus Ceruleus Noradrenergic Neurons in Proestrous Rats but not in Diestrous or Androgen-Sterilized Animals. AB - Norepinephrine (NE) turnovers (an index of secretion) increase in the hypothalamus of proestrous rats concomitant with luteinizing hormone surges, whereas, neither of these events are observed in diestrous nor in androgen sterilized rats. Increased hypothalamic NE release may occur as a consequence of the withdrawal of local inhibitory gamma-aminobutyric acid and opiate controls on specific presynaptic NE terminals and/or as a result of an increase in activity within noradrenergic neurons. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of NE and our earlier studies revealed that increases in TH mRNA in A1 and locus ceruleus (LC) neurons can serve as an index of increased activity within these cells. In the present study, we evaluated whether TH message levels change in A1 and LC neurons prior to and during the hours when luteinizing hormone surges and increased NE turnovers are observed. As controls, TH mRNA levels in A1 and LC neurons were evaluated at the same hours of day in diestrous day 2 and in androgen-sterilized rats. In situ hybridization histochemistry and quantitative image analysis methods were used to measure changes in TH mRNA levels. Luteinizing hormone surges in proestrous rats began at 1500 h, peaked between 1600 and 1700 h and declined, thereafter, to 2000 h. In contrast, plasma luteinizing hormone remained basal throughout the day in diestrous and androgen-sterilized rats. While A1 neuronal TH mRNA levels did not differ in the three groups of rats during the morning (0930 to 1030 h), these message levels were significantly elevated in proestrous rats during the afternoon (1645 to 1715 h) and remained high at 2000 to 2030 h. In contrast, no changes in TH mRNA levels were observed in A1 neurons throughout the afternoon in diestrous animals or androgen-sterilized rats. TH mRNA levels in the LC did not differ in the three groups of rats and they remained unchanged throughout the afternoon hours we examined. From these observations we conclude that concomitant with afternoon proestrous luteinizing hormone surges and the accompanying increase in hypothalamic NE secretion, there is an increase in activity within A1 but not LC neurons. These data suggest that the proestrous increase in hypothalamic NE turnover we previously observed is not due solely to withdrawal of local inhibitory controls of presynaptic NE release but it also involves an increase in activity within A1 but not LC neurons. PMID- 21554646 TI - Galanin message-associated Peptide-like immunoreactivity in the nervous system of the blowfly: distribution and chromatographic characterization. AB - Galanin message-associated peptide (GMAP) is a flanking peptide in mammalian preprogalanin located C-terminally of galanin (GAL). GMAP-like immunoreactive (LI) material in the brain of the blowfly Phormia terraenovae was analysed by radioimmunoassay combined with reversed-phase high-performance liquid chromatography and immunocytochemistry and compared to GAL-LI material. A sensitive radioimmunoassay, developed against a species-conserved portion of mammalian GMAP (synthetic porcine GMAP(19-41)amide), was applied to serially diluted blowfly head extracts. High-performance liquid chromatography combined with radioimmunoassay showed that the GMAP-LI material eluted as several different components with one major component coeluting with the synthetic GMAP fragment. One GMAP-LI peak co-eluted with a GAL-LI component of the extract. By immunocytochemistry it was shown that a distinct set of GMAP-LI neurons and neurosecretory cells is present in the blowfly brain and thoracico-abdominal ganglion. About 150 GMAP-LI cell bodies were found in the brain, distributed in the protocerebrum, tritocerebrum and suboesophageal ganglion. Several hundred GMAP-LI cell bodies were detected in the medulla of the optic lobe. In the fused thoracico-abdominal ganglion there are about 70 GMAP-LI cell bodies distributed in a segmental fashion. Several of the GMAP-LI neurons also contain GAL-LI material whereas some do not. In addition, there are GAL-LI neurons that do not react with the GMAP antiserum. Some of the GMAP-LI interneurons and neurosecretory cells could be traced in detail enabling a resolution of putative sites of action of the peptide. PMID- 21554647 TI - Regulation of corticotropin-releasing hormone receptors and hypothalamic pituitary adrenal axis responsiveness during cold stress. AB - The relationship between pituitary corticotropin-releasing hormone (CRH) receptor changes and corticotrope responsiveness was studied during chronic cold stress. Exposure of rats to 4 degrees C caused a gradual increase in plasma adrenocorticotropic hormone (ACTH), reaching 3-fold over the basal levels by 6 h (P< 0.005), followed by a reduction to levels only 1.3-fold over basal by 60 h. Plasma corticosterone was significantly increased after 1 h (P<0.005) and remained elevated for up to the 60 h cold exposure (P < 0.005). No significant changes in plasma thyroid-stimulating hormone, prolactin, growth hormone or vasopressin were observed at 60 h of cold exposure. CRH receptor concentration in the anterior pituitary was unchanged after 18 or 60 h cold stress, whereas in neurointermediate lobe membranes was markedly elevated. Autoradiographic analysis of pituitary CRH receptors confirmed that the increase in CRH binding was confined to the intermediate pituitary. CRH receptor levels in membranes from two brain areas, frontal cortex and amygdala, were unchanged following 60 h cold stress. The areas under the curve for the plasma ACTH and corticosterone levels following an injection of 10MUg/kg ovine CRH in conscious rats, were of similar magnitude in control and 60 h cold exposed rats. Plasma ACTH responses to ether stress were significantly higher in rats exposed to cold for 60 h than in controls. In the intermediate pituitary, basal beta-endorphin/lipotropin release from isolated intermediate pituitary cells was significantly lower in cold stressed rats, and despite the increase in CRH receptors CRH-stimulated values were not higher than in controls. Following 60 h cold exposure, immunoreactive CRH content was decreased in neurointermediate pituitary extracts, while it was slightly increased in the median eminence. Exposure to ether for 5 min resulted in a significant decrease in immunoreactive CRH in the median eminence of cold stressed rats, but not in the controls. The data show a lack of correlation between changes in CRH receptor levels and responsiveness of the corticotrope in the anterior and intermediate pituitary lobes. This suggests that postreceptor events and interaction of CRH with other regulators of ACTH secretion are more likely to account for the changes in pituitary responsiveness during chronic stress. PMID- 21554648 TI - Oestrogen positive feedback reduces arcuate proopiomelanocortin messenger ribonucleic Acid. AB - Oestradiol-17beta, in its positive feedback mode, as well as stimulating the release of luteinizing hormone-releasing hormone. (LHRH), also stimulates LHRH mRNA synthesis in medial preoptic neurons. Our aim was to determine whether the action of oestradiol might be mediated in part by inhibiting arcuate proopiomelanocortin (POMC) neurons which terminate on LHRH neurons. Female rats were ovariectomized at about 1000 h of dioestrus, given a subcutaneous injection of oil or oestradiol benzoate and killed at 1600 h the same day (presumptive dioestrus), presumptive pro-oestrus and oestrus and at 1000 h of presumptive pro oestrus. In situ hybridization of brain sections was carried out with a [(35) S]UTP-labelled riboprobe containing 538 bases of a cDNA identical to exon 3 of the POMC gene, which includes the beta-endorphin coding domain. The amount of POMC mRNA in cells of the anterior arcuate nucleus, as assessed by grain counts, was significantly decreased in oestradiol benzoate- compared with oil-treated animals at 1600 h of pro-oestrus, but at none of the other times studied. This finding, together with other data, suggests that the positive feedback stimulation of LHRH mRNA synthesis by oestradiol-17beta may be due, in part, to the disinhibition of LHRH neurons consequent on inhibition of POMC mRNA biosynthesis in arcuate neurons. PMID- 21554649 TI - Central administration of serotonin decreases tyrosine hydroxylase catalytic activity and messenger ribonucleic Acid signal levels in the hypothalamus of female rats. AB - We investigated the effect of central serotonin (5-hydroxytryptamine, 5-HT) administration on hypothalamic tuberoinfundibular dopamine neurons and related changes in neuronal activity to circulating prolactin (PRL) levels. Ovariectomized rats were treated with either vehicle or 5-HT through a lateral ventricular cannula in one of two dose paradigms: 1) a bolus of 20 MUg, with tissues taken at 30 min, or 2) the same bolus immediately followed by 20 MUg/30 min via a syringe pump for 120 min, and tissues taken at 120 min. Blood samples were taken throughout experiments and plasma PRL determined by radioimmunoassay. Under both paradigms, NSD 1015, a dihydroxyphenylalanine (DOPA) decarboxylase inhibitor (25 mg/kg intraarterially) was injected 10 min before decapitation and brain excision followed by stalk-median eminence dissection. The rate of DOPA accumulation, determined by measuring DOPA levels in the stalk-median eminence by high-performance liquid chromatography with electrochemical detection was used as a measure of tyrosine hydroxylase (TH) catalytic activity. Stalk-median eminence DOPA accumulation in control rats was 29.9 +/- 4.2 and 28.8 +/- 4,4 ng/mg protein (30 and 120 min experiments, respectively). DOPA accumulation in 5-HT-treated rats was significantly reduced (P<0.05) after 30 min to 17.8 +/- 1.2 ng/mg protein, but it was similar (21.7 +/- 3.9) to controls after 120 min of 5-HT infusion. 5-HT levels in the stalk-median eminence of rats treated with 5-HT were 13- to 17-fold greater than controls (16.9 to 18.5 ng/mg protein). Plasma PRL levels in both groups increased 10-fold after 5-HT treatment with a peak at 5 min, returning to baseline by 120 min. TH mRNA levels were determined by in situ hybridization in a second group of rats which were treated with the 20MUg bolus and subsequent 120 min infusion of 5-HT. TH mRNA signal levels in the arcuate nucleus of control rats averaged 144 +/- 21 grains/cell. After treatment with 5 HT, TH mRNA levels in the arcuate nucleus were significantly lower (P<0.0001) with 69+/-14 grains/cell. In a third group of rats, the effects of the 30 min 5 HT treatment on TH catalytic activity and circulating PRL levels was challenged with two 5-HT(2) receptor antagonists, LY53857 (5 mg/kg intraperitoneally) or ketanserin (10 mg/kg intraperitoneally). Neither the 5-HT-induced decrease in TH catalytic activity nor the increase in PRL was altered by pretreatment (120 min) with 5-HT(2) antagonists. These data suggest that central 5-HT is capable of decreasing TH activity and TH mRNA levels in the tuberoinfundibular dopamine neurons and that the decrease in dopaminergic neuronal activity may contribute to the 5-HT-induced PRL rise. The changes in TH catalytic activity and PRL after intracerebroventricular administration of 5-HT do not appear to be mediated by 5 HT(2) receptors. PMID- 21554650 TI - Pineal photoreceptor cells in culture: fine structure, and light/ dark control of cyclic nucleotide levels and melatonin secretion. AB - Trout pineal photoreceptor cells were dissociated by trypsin-DNase digestion and further purified by a Percoll gradient centrifugation. Total cells or purified photoreceptor cells were then embedded in a collagen gel, or layered on culture treated polycarbonate membranes, or maintained in suspension, with RPMI 1640 medium or BGjb medium. It has been shown that cells maintain a rhythmic production of melatonin for at least seven 24 h light/dark cycles under these conditions. In this complementary study, the morphofunctional state of the photoreceptor cells was examined 1) by electron (transmission, scanning) microscopy, and 2) by pharmacological tests under different lighting conditions. Using polycarbonate membranes together with RPMI 1640 medium appeared the most suitable. The segmented organization of photoreceptor cells was well preserved when using the culture-treated membranes. It tended to disappear in cells embedded in the collagen gel and was lost after passage through the Percoll gradient. However, this one allowed obtention of an homogeneous population of photoreceptors, as recognized by their intracellular components. Intracellular organelles were rather well preserved in the embedded photoreceptors. The study also provides novel information on the nature of second messengers involved in the photoperiodic control of melatonin production in photoreceptor cells. From the effects of an adenylyl cyclase activator and a phosphodiesterase inhibitor it appeared that 1) total cells and Percoll-selected cells behaved similarly, 2) the nocturnal rise in melatonin secretion was associated with an increase in cAMP content, and 3) a fall in cAMP may be a mechanism through which light reduces melatonin secretion by photoreceptor cells. Cyclic GMP, the metabolism of which also appeared to be controlled by light, did not seem involved in the photoperiodic control of melatonin production. The method proposed herein offers interesting perspectives for the study of the photoneuroendocrine properties of isolated photoreceptor cells. PMID- 21554651 TI - Removal of 3'untranslated sequences dramatically enhances transient expression of ovine follicle-stimulating hormone Beta gene messenger ribonucleic Acid. AB - The influence of the 3'untranslated (3'-UT) region of the ovine follicle stimulating hormone (FSH) beta mRNA on the level of transcript expression was studied. Only very low levels of FSH beta mRNA were detected following transient transfection of COS cells with a eukaryotic expression vector containing a full length ovine FSH beta cDNA that includes 1.1 kilobases (kb) of 3'-UT. In contrast, deletion of all but 135 basepairs (bp) of the 3'-UT resulted in a striking increase in FSH beta mRNA expression following transfection of the truncated cDNA construct. These observations suggest that sequences within the 3' UT of the ovine FSH beta mRNA may play a significant role in the post transcriptional regulation of FSH beta expression. PMID- 21554652 TI - Immunocytochemical identification of oestrogen receptors in the ovine pars tuberalis: localization within gonadotrophs. AB - The pars tuberalis (PT) of the pituitary gland shows dense binding of melatonin and consequently this region may be involved in modulating seasonal reproduction. Oestrogen is well established as a critical gonadal steroid in controlling seasonally via its ability to alter luteinizing hormone (LH) release. Using immunocytochemistry techniques with antibodies specific for the oestrogen receptor (ER) and the ovine betaLH (obetaLH) subunit, we have identified large populations of ER-immunoreactive (-IR) and LH-IR cells in the anteroventral region of the ovine PT. In contrast, few ER- or LH-IR cells were identified in the anterodorsal or posterior regions of the PT. Double-labelling experiments revealed that all ER-IR cells in the PT are also immunoreactive for LH. These results show that cells immunoreactive for the ER are concentrated in the anteroventral aspect of the PT and that these receptors are located in the nuclei of the PT gonadotrophs. These results suggest that the anteroventral PT, a region which also expresses high melatonin binding, may be a site of integrated oestrogen and melatonin action on LH secretion from the PT. PMID- 21554653 TI - Thyrotropin-releasing hormone mediates growth hormone release induced by milk and nursing in neonatal rats. AB - Previous evidence from this laboratory suggested that growth hormone (GH) release induced by milk in vitro and by nursing in vivo from neonatal rat pituitary glands is mediated by an alternative GH-releasing factor(s) (GRF) distinct from GH-releasing hormone (GHRH(1-43) ). In the present experiments we tested whether thyrotropin-releasing hormone (TRH) could fulfil the criteria of this alternative GRF in neonatal rats. The water-soluble fraction of rat milk (infranatant, prepared by ultracentrifugation) and its methanol/acetic acid extract (milk-borne peptides) stimulated GH release from perifused pituitary glands obtained from 2 day-old rats. Dialysis of the infranatant (mol wt cut-off: 2,000) against 500 volumes of culture medium at 4 degrees C eliminated its GH-releasing activity in the perifusion system, while the infranatant retained its full GRF-like activity when incubated at 4 degrees C without dialysis. The milk-borne GRF eluted as a single peak and coeluted with TRH in a combined gel permeation chromatography (Sephadex G-10) and perifusion set-up. Prolactin secretion was also stimulated simultaneously with the release of GH induced either by milk or by TRH. In a stepwise C(18) reversed-phase chromatography, milk-borne GRF was highly hydrophilic and coeluted with synthetic TRH. The in vitro GH-releasing bioactivities of synthetic TRH and a milk extract purified in C(18) reversed phase chromatography were abolished by proline-specific endopeptidase. Thus, TRH and milk-borne GRF displayed similar molecular weights, hydropathic characteristics and proteolytic enzyme resistance. In vivo, nursing (which has been reported as a potent stimulus of GH secretion even in the absence of milk intake) increased serum GH levels in 2-day-old pups. A supramaximal dose of TRH (10 ng/g intraperitoneally) stimulated GH release in 2-day-old pups separated from their mothers for 6 h to a similar extent as nursing. Nursing-induced levels of serum GH were not further elevated by TRH. This failure of TRH to further increase serum GH levels was not due to a maximal GH output by the neonatal pituitary gland, since the GH release induced by the serotonin precursor 5 hydroxy-L-tryptophan was augmented either by TRH or by nursing. These data provide evidence that the milk-borne GRF-like activity in vitro is indistinguishable from TRH, and suggest that TRH (probably of hypothalamic origin) might be the mediator of the nursing-induced release of GH in vivo as a physiological GRF in neonatal rats. PMID- 21554654 TI - The Biosynthesis of Melanin-Concentrating Hormone in Trout Kept Under Different Conditions of Background Colour and Stress, as Determined by an in vitro Method. AB - The aim of this study was to develop a method to monitor the synthetic activity of neurons which secrete the neurohypophysial melanin-concentrating hormone (MCH), a hormone implicated in two separate physiological roles in fish pigmentary regulation and the response to stress. Trout hypothalamic fragments, containing the MCH neuronal cell bodies, were incubated in vitro in a medium including [(35) S]methionine. Labelled MCH-related products were separated by immunoprecipitation. Gel electrophoresis showed that radioactive methionine was incorporated into MCH precursors and into mature MCH, much as in vivo. Thus, de novo hormone synthesis continues in vitro. Trout reared at a fish-farm and adapted to black or white tanks for 39 days displayed nearly a 2-fold difference in their rate of methionine incorporation. Transferring fish from a black to a white background also doubled the rate of incorporation within 7 days and this rate increased only very slightly during the following 3 weeks. The rate of methionine incorporation by tissue from trout reared in black tanks was very depressed, and 4-fold lower than that of fish reared in white tanks, suggesting that very long-term adaptation to one or other background has increasingly marked effects on the activity and perhaps the number of synthetically active neurons. Stress also influenced the rate of methionine incorporation: a mild daily stress was stimulatory but more frequent stress had an inhibitory effect in many cases. The effects of daily dexamethasone administration were inconclusive. It is suggested that these differences in methionine incorporation reflect the relative rates of MCH synthesis in vivo, and that the method is useful to investigate conditions which modulate the biosynthesis of MCH in the trout. PMID- 21554655 TI - Neuropeptide Y-lmmunoreactive Nerve Fibres in the Pineal Gland of the Macaque (Macaca fascicularis). AB - The distribution of neuropeptide Y (NPY)- and the C-fianking peptide of NPY (CPON)-immunoreactive elements in the pineal gland of the macaque was investigated by means of immunohistochemistry. NPY- and CPON-immunoreactive nerve fibres were located in the precommissural nucleus, around the stria medullaris, and in the posterior commissure. NPY- and CPON-immunoreactive nerve fibres endowed with bulbous varicosities, were traced from the brain via the pineal stalk into the rostral part of the pineal gland. Furthermore, CPON immunoreactive, and to a lesser extent NPY-immunoreactive nerve fibres, were distributed in the meninges, the choroid plexus and the vasculature related to the pineal organ. Nerve fibres located in the pineal capsule penetrated into the pineal parenchyma, where groups of individual fibres were found most often in an interlobular position. Occasionally, individual nerve fibres dispersed between the pinealocytes were observed. In contrast to the nerve fibres originating from the brain, those originating from the periphery were endowed with smaller immunoreactive nerve terminals. Another apparent difference was that the peripheral nerve fibres innervated only the caudal two-thirds of the gland, whereas the central fibres were found exclusively in the rostral part of the pineal organ. Rarely, positive neuronal-like cells were found in the pineal parenchyma. These results show the presence of a moderate number of NPY- and CPON immunoreactive nerve fibres within the primate pineal organ and strongly indicate that the primate pineal gland is innervated by NPYergic nerve fibres originating from both a peripheral and a central source. PMID- 21554656 TI - Repeated immobilization stress alters tyrosine hydroxylase, corticotropin releasing hormone and corticosteroid receptor messenger ribonucleic Acid levels in rat brain. AB - In situ hybridization histochemistry was used to localize and quantify the effects of acute and repeated immobilization stress on mRNA levels of tyrosine hydroxylase (TH) in catecholaminergic neurons in the locus ceruleus and substantia nigra and on mRNA levels of relevant markers of the hypothalamic pituitary-adrenal axis, namely corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN), proopiomelanocortin in the pituitary, and mineralocorticoid receptors (MR, type I) and glucocorticoid receptors (GR, type II) in the hippocampus, PVN and pituitary. Control, acutely stressed (1 * lMO, sacrificed immediately after 2 h of immobilization), and repeatedly stressed (6 * IMO plus delay, sacrificed 24 h after 6 daily 2-h immobilizations and 6 * lMO plus challenge, sacrificed immediately after the seventh daily 2-h immobilization) male Sprague-Dawley rats were examined. TH mRNA expression was increased in the locus ceruleus in the acutely stressed and repeatedly stressed animals. The increase in TH mRNA levels was greatest in the repeatedly stressed (6 * IMO plus challenge) group. TH mRNA levels were not altered in the substantia nigra. CRH mRNA levels in the PVN were significantly increased in the three stressed groups and the increase was greatest in the 6 * IMO plus challenge group. CRH mRNA levels were increased in the central nucleus of the amygdala only after acute stress. Proopiomelanocortin mRNA levels were elevated in the anterior pituitary during acute and repeated stress, but the magnitude of the effect was largest after acute stress. The changes in the hypothalamic-pituitary-adrenal axis were accompanied by an acute stress-induced increase in MR mRNA levels in the hippocampus, MR and GR mRNA levels in the PVN and GR mRNA levels in the pituitary. MR mRNA levels continued to be elevated in the PVN in the 6 * IMO plus challenge animals. Plasma corticosterone levels were elevated in the acute and repeated stress conditions. The results show that repeated immobilization stress produces a rapid and persistent increase in mRNA expression of TH in the locus ceruleus, CRH in the PVN, and proopiomelanocortin in the anterior pituitary. The TH-containing neurons in the locus ceruleus and the CRH-containing neurons in the PVN appear to preserve the capability to respond to repeated stimulation (6 * IMO plus challenge) indicating altered feedback mechanisms under repeated stress conditions. GR and MR mRNA levels are differentially regulated in the hippocampus, PVN and pituitary by acute and repeated stress. It is of interest that the central nervous system systems which are activated during repeated stress, namely the locus ceruleus-norepinephrine system and hypothalamic pituitary-adrenal axis, are dysregulated in melancholic depression. Further studies of the central nervous system effects of prolonged exposure to stress may help elucidate the mechanisms underlying dysregulation of the locus ceruleus norepinephrine system and hypothalamic-pituitary-adrenal axis in depression and other stress-related psychiatric diseases. PMID- 21554657 TI - The role of the mu(1) opioid receptor subtype in the regulation of prolactin and growth hormone secretion by Beta-endorphin in female rats: studies with naloxonazine. AB - The MU opioid receptor subtype has been reported to mediate the prolactin secretory response to opioids. This receptor subtype has been implicated in the morphine-induced prolactin increase, as well as the prolactin response to MU specific opioid peptides. Subtypes of the MU receptor have been proposed and the MU(1) , site has been postulated as the receptor subtype involved in the morphine induced prolactin secretory response. However, the role of this receptor subtype in mediating the endocrine effects of the endogenous opioid peptides has not been characterized. In order to determine the physiological significance of this receptor subtype, animals were pretreated with saline, WIN 44,441-3 (a MU, delta and kappa antagonist) or naloxonazine (a MU(1) antagonist) followed by a stimulatory dose of morphine or beta-endorphin. A dose response study for beta endorphin was conducted to determine the minimal stimulatory dose of beta endorphin on the prolactin and growth hormone (GH) secretory response. The dose response study indicated that beta-endorphin is a more potent stimulus for prolactin release than for GH. A dose as low as 25 ng increased prolactin levels as much as 100-fold in both lactating and diestrous female rats. In contrast, 2.5 MUg beta-endorphin was required in order to consistently and significantly increase circulating levels of GH by 2- to 3-fold. WIN 44,441-3 antagonized the stimulatory effects of beta-endorphin on both prolactin and GH secretion. Naloxonazine pretreatment abolished the morphine-induced prolactin secretory response, without affecting the GH increase in diestrous females. Naloxonazine also antagonized the prolactin response to beta-endorphin in both lactating and diestrous females. In addition, it attenuated the GH secretory response but did not totally abolish it. These data indicate that beta-endorphin elicits an increase in prolactin release through an opioid specific receptor which appears to be the MU(1) opioid receptor subtype. They further suggest that beta-endorphin may increase GH levels, at least partially, via its action at this MU(1) site. PMID- 21554658 TI - Novel hypothalamic and preoptic sites of prepro-melanin-concentrating hormone messenger ribonucleic Acid and Peptide expression in lactating rats. AB - The deduced structure of the rat melanin-concentrating hormone (MCH) precursor predicted the existence of at least two peptides that may be processed from it, one similar to teleost MCH and a second novel neuropeptide, NEI. Cellular localization studies confirmed that prepro-MCH (ppMCH) mRNA and the MCH and NEI peptides are expressed predominantly in cells in the zona incerta and caudal lateral hypothalamic area with minor contingents seen in the olfactory tubercle and pons. A moderate MCH-and NEI-immunoreactive axonal projection to the median eminence and, particularly, to oxytocin-rich regions of the posterior pituitary suggested some anatomical heterogeneity of ppMCH-expressing neurons in the hypothalamus, and an involvement in neuroendocrine function. In the present study, immunohistochemical and hybridization histochemical methods were used to follow MCH gene and peptide expression as a function of reproductive status in female rats. Nursing dams sacrificed after 8 to 21 days of lactation consistently displayed ppMCH mRNA and MCH and NEI immunoreactivity in a discrete and contiguous band, encompassing the ventral aspect of the medial part of the medial preoptic nucleus, the periventricular preoptic nucleus, and the most rostral aspects of the paraventricular nucleus of the hypothalamus (PVH). Combined immunohistochemical (for oxytocin) and hybridization histochemical (for ppMCH mRNA) staining failed to reveal a significant degree of congruence in the two chemically-specified cell populations in the PVH of lactating dams. The apparent induction of ppMCH-derived peptides and mRNA in the preoptic area and PVH was not apparent in animals sacrificed 4 to 8 days after weaning, during late pregnancy, or at any point in the estrous cycle. Moreover, no frank alterations in ppMCH mRNA were evident in the principal sites at which ppMCH is expressed at constitutively high levels, i.e. in the lateral hypothalamic area and zona incerta, as a function of reproductive status. The loci and apparent state dependency of the induction of ppMCH mRNA and peptide expression suggests a role for these gene products in the control of lactation. PMID- 21554659 TI - Effects of Ibotenic Acid-Induced Neuronal Degeneration in the Hypothalamus upon Proceptivity and Sexual Receptivity in the Female Marmoset (Callithrix jacchus). AB - The sexual behaviour of 16, oestradiol-treated, ovariectomized common marmosets was recorded before and after bilateral microinfusions of ibotenic acid (n = 8) or isotonic saline (n = 8) into the hypothalamus. Ibotenic acid-induced neuronal degeneration occurred in 5 females, mainly affecting the anterior and dorsomedial hypothalamus. Marked decreases in proceptivity (tongue-flicking, staring and immobile displays) occurred after ibotenic acid lesions, whereas sexual receptivity (refusals and terminations of male partners' mounts) was unchanged. In 3 females where microinfusions of ibotenic acid were attempted but failed to produce lesions, sexual behaviour was unaffected and resembled that measured in saline-treated controls. These results provide the first evidence that selective lesions of neuronal cell bodies in the anteromedial hypothalamus disrupt proceptivity whilst sparing sexual receptivity in a primate species. PMID- 21554660 TI - A comparison between the effect of cholecystokinin octapeptide and apomorphine on ingestion of intraorally administered sucrose in male rats. AB - The involvement of dopamine receptors in the inhibitory effect of Cholecystokinin octapeptide on ingestive behaviour was investigated. Male rats were infused intraorally with a 1 M solution of sucrose and the amount ingested after treatment with the dopamine receptor agonist apomorphine was compared with that after treatment with Cholecystokinin octapeptide. The test allows a distinction between the consummatory aspects of ingestive behaviour, i.e. responses used to ingest food, from the appetitive aspects, i.e. responses used to obtain food, because it ignores the latter aspects. Comparisons were also made between the effects of apomorphine and Cholecystokinin octapeptide on pellet intake, a test in which the rat has to display appetitive ingestive behaviour. Injection of apomorphine (400 MUg) increased the concentration of plasma apomorphine within 0.3 min and the concentration of dopamine in the cerebrospinal fluid within 1 min of injection and induced behavioural stereotypes within 10 min in food-deprived male rats. Plasma apomorphine and cerebrospinal fluid dopamine levels had decreased by 30 min and the behavioural stereotypies had decreased by 40 min after the injection. Injection of apomorphine also inhibited the consumption of food pellets and the ingestion of sucrose. Inhibition of pellet and sucrose ingestion paralleled the effect of apomorphine on Stereotypie behaviour. Thus, injection of a dopamine receptor agonist is followed by alterations in plasma levels of the agonist, cerebrospinal fluid dopamine levels and in Stereotypie and ingestive behaviour which occur in parallel, in an inverted U-shaped manner and with a temporal delay between each event. These results show a close correlation between dopamine receptor stimulation and inhibition of ingestive behaviour. However, reversal of the inhibitory effect of apomorphine on ingestive behaviour required pretreatment with a lower dose of a dopamine receptor antagonist (cis flupentixol) (0.1 mg) than reversal of Stereotypie behaviour (0.8 mg). The effect of dopamine receptor stimulation on consummatory ingestive behaviour is thus relatively weak and not secondary to the induction of Stereotypic behaviour. Treatment with a high dose of cis-flupentixol (0.8 mg) caused a prolonged period of immobility but had no effect on the ingestion of sucrose. Dopamine receptor blockade, therefore, interferes with appetitive, but not consummatory ingestive behaviour. Injection of Cholecystokinin octapeptide (5 MUg) suppressed pellet and sucrose intake in a manner comparable to that of apomorphine, but induced no behavioural stereotypes and caused a gradual, rather than inverted U-shaped, increase in the concentration of dopamine in the cerebrospinal fluid that did not correlate with the effect on ingestive behaviour. Furthermore, while the inhibitory effect of apomorphine on the ingestion of sucrose was reversed by pretreatment with a low dose of cis-flupentixol (0.1 mg), the inhibitory effect of Cholecystokinin octapeptide was only partially reversed by cis-flupentixol and a higher dose (0.8 mg) was required. Blockade of cholecystokinin-A receptors, by treatment with L-364,718, but not cholecystokinin-B receptors, by treatment with L-365,260, blocked the inhibitory effect of Cholecystokinin octapeptide and, by itself, L-364,718 increased the amount of ingested sucrose. The inhibitory effect of Cholecystokinin octapeptide on consummatory ingestive behaviour, which is mediated by cholecystokinin-A receptors, is likely to involve mechanisms in addition to dopaminergic ones. PMID- 21554661 TI - Evidence that Release of Dopamine in the Brain is Involved in the Inhibitory Effect of Cholecystokinin Octapeptide on Ingestion of Intraorally Administered Sucrose in Male Rats. AB - To study the possibility that release of dopamine in the brain mediates the inhibitory effect of Cholecystokinin octapeptide on ingestive behaviour, the effect of amphetamine on intake of pellets or an intraorally administered sucrose solution was compared with that of Cholecystokinin octapeptide. Additionally, comparisons were made between the effect of Cholecystokinin octapeptide and pargyline, a monoamine oxidase inhibitor, and alpha-methyl-rho-tyrosine, a tyrosine hydroxylase inhibitor. While amphetamine dose-dependently inhibited pellet intake it failed to inhibit sucrose intake in doses which caused behavioural stereotypies (<800 MUg). Cholecystokinin octapeptide (5 MUg) inhibited ingestive behaviour in both tests. A very high dose of amphetamine (2 mg) was required to inhibit sucrose intake to a level comparable to that of Cholecystokinin octapeptide. Pargyline (5 to 25 mg) or alpha-methyl-p-tyrosine (25 to 100 mg) dose-dependently inhibited pellet intake but had only weak effects on the intake of sucrose. Pargyline increased the concentration of dopamine and 3 methoxytyramine in the dorsal striatum and decreased the concentration of 3,4 dihydroxyphenylacetic acid. alpha-Methyl-rho-tyrosine decreased the concentration of dopamine and 3,4-dihydroxyphenylacetic acid, but not that of 3 methoxytyramine. Injection of amphetamine (2 mg), but not Cholecystokinin octapeptide, in rats pretreated with pargyline increased the concentration of 3 methoxytyramine in the dorsal striatum and this effect was blocked by pretreatment with alpha-methyl-rho-tyrosine. Pretreatment with alpha-methyl-rho tyrosine partially reversed the inhibitory effect of Cholecystokinin octapeptide on sucrose ingestion, enhanced the effect of amphetamine but did not affect that of apomorphine, a dopamine agonist. The results support the possibility that the inhibitory effect of Cholecystokinin octapeptide on consummatory ingestive behaviour, in part, is mediated via release of dopamine in the brain. PMID- 21554662 TI - Luteinizing Hormone-Releasing Hormone Neurons which are R-etrogradely Labeled After Peripheral Fluoro-Gold Administration in the Male Ferret. AB - This study identified luteinizing hormone-releasing hormone (LHRH)-producing neurons which have access to fenestrated capillaries in prepubertal male European ferrets. Fluoro-Gold was injected intraperitoneally to retrogradely label neurons with terminals outside the blood-brain barrier. LHRH neurons were identified by immunofluorescence using a secondary antibody tagged with tetramethylrhodamine isothiocyanate. Cell bodies which demonstrated both tetramethylrhodamine isothiocyanate and Fluoro-Gold fluorescence were defined as LHRH-producing neurons with axon terminals in regions containing fenestrated capillaries. The total number and neuroanatomical distribution of immunopositive (LHRH +) cells concurred with previous studies in the ferret in which cell bodies were diffusely distributed from rostral forebrain through caudal diencephalon, with approximately 70% of the LHRH + cell bodies located in retrochiasmatic hypothalamus. In the present study, an average of 59.8% of all LHRH+ neuronal perikarya also contained Fluoro-Gold. The majority of Fluoro-Gold filled LHRH+ neurons demonstrated only faint to moderate amounts of Fluoro-Gold when compared to other Fluoro-Gold filled neurosecretory neurons. This limited uptake of Fluoro Gold may be due to a relative inactivity of LHRH neurons projecting outside the blood-brain barrier. Double-labeled LHRH + neurons were dispersed throughout the entire population of LHRH+ cell bodies and no apparent nuclear groups of double labeled neurons were found. This observation suggests that the LHRH+ neurons responsible for neurosecretion into the median eminence coexist with the LHRH+ neurons responsible for intracerebral neurotransmission or neuromodulation. One distinguishable population of LHRH + neurons was consistently observed in all the brains. Only 26% of total LHRH+ perikarya within the caudal arcuate nucleus contained Fluoro-Gold, while at least 50% of LHRH+ neurons in other structures, including the rostral arcuate nucleus, contained Fluoro-Gold. Thus, in the prepubertal male ferret, the majority of LHRH cell bodies located in the caudal arcuate nucleus may be differentially regulated and/or involved in non neuroendocrine functions. PMID- 21554663 TI - Adenosine inhibits alpha-melanocyte-stimulating hormone release from frog pituitary melanotrophs. Evidence for the involvement of a(1) adenosine receptors negatively coupled to adenylate cyclase. AB - Adenosine is recognized as an important modulator of cell activity. In particular, adenosine regulates the secretion of adrenocorticotropin from anterior pituitary cells. However, the possible role of adenosine on the pars intermedia has never been investigated. In the present study, we have examined the effect of adenosine on alpha-melanotropin (alpha-MSH) secretion from the intermediate lobe of the pituitary of the frog (Rana ridibunda), using the perifusion technique. When whole neurointermediate lobes were exposed to graded doses of adenosine (10(-9) to 10(-4) M), a dose-dependent inhibition of a-MSH release was observed. Repeated pulses of adenosine (5 +/- 10(-5) M) induced a reproducible inhibition of alpha-MSH secretion without any desensitization phenomenon. The effect of adenosine was mimicked by the non-selective agonist 5' N-ethylcarboxamide-adenosine and the highly specific adenosine A, receptor agonist N(6) -[R-phenylisopropyl]-adenosine (R-PIA). In contrast the selective adenosine A(2) receptor agonist, CGS 21680, induced a slight stimulation of alpha MSH release. Adenosine-induced inhibition of alpha-MSH secretion was blocked by the non-selective adenosine antagonist, 8-(p-sulfophenyl)-theophyline. Adenosine and R-PIA also inhibited alpha-MSH secretion from acutely dispersed pars intermedia cells. Adenosine did not block thyrotropin-releasing hormone-induced alpha-MSH release from perifused neurointermediate lobes. In contrast, adenosine inhibited both acetylcholine-evoked and muscarine-evoked alpha-MSH secretion. Finally, R-PIA induced a significant inhibition of basal and forskolin-stimulated cyclic AMP levels in whole neurointermediate lobes. The present results demonstrate that adenosine exerts a direct inhibitory effect on alpha-MSH release from melanotrope cells through activation of the A(1) receptor subtype, negatively coupled to adenylate cyclase. These data suggest that adenosine may play a physiological role in the regulation of hormone release from the intermediate lobe of the pituitary. PMID- 21554664 TI - Changes in vasoactive intestinal Peptide binding site densities in the female rat central nervous system and pituitary during lactation. AB - Using quantitative autoradiography, vasoactive intestinal peptide (VIP) binding site densities were investigated in the female rat during lactation. Plasma prolactin levels were significantly (P<0.01) elevated on days 3 and 10 of lactation. In the brain, there was a significant (P<0.05) increase in VIP binding sites during lactation in the striatum, thalamus, anterior portion of the paraventricular nucleus of the hypothalamus, and several cortical areas compared to virgin female diestrous rats. VIP binding density in the anterior pituitary was significantly higher (P<0.01) when measured on day 3 of lactation, and decreased to diestrous levels by day 10. Pup removal resulted in a significant reversal of the lactation-induced increase in VIP binding density in the thalamus, parietal and insular cortices, and the anterior portion of the paraventricular nucleus. Taken together, modifications in VIP binding site density in the pituitary and in several central areas are associated with changes in the level of prolactin secretion. Moreover, the pattern of VIP receptor induction during lactation suggests a role for VIP in the brain that extends beyond the regulation of prolactin secretion. PMID- 21554665 TI - Dysregulation of the Hypothalamus-Pituitary-Adrenal Axis in Male and Female, Genetically Obese (ob/ob) Mice. AB - The autosomal, recessive obesity of ob/ob mice is associated with hypercorticosteronemia and amelioration of most symptoms of obesity following adrenalectomy. Increased adrenocorticotropic hormone (ACTH) secretion has been hypothesized on the basis of several reports of higher pituitary ACTH content in ob/ob mice compared to lean littermates. However, the only measurement of ACTH blood concentration found lower levels in ob/ob mice than in leans suggesting that hypercorticosteronemia might result solely from an enhanced adrenal response to ACTH and also suggesting that the ob/ob's elevated pituitary ACTH content might be due to decreased ACTH secretion rather than increased ACTH synthesis. In our study, basal serum ACTH levels were higher in ob/ob males and females compared to sex-matched lean littermates. Anterior pituitary ACTH synthesis was also elevated as indicated by increased content of ACTH and proopiomelanocortin mRNA in obese mice of both sexes; however hypothalamic corticotropin-releasing factor content was not different in lean and obese mice. Basal serum ACTH and corticosterone (CS) levels showed normal circadian rhythm in both phenotypes and sexes, but the circadian increase in CS level was much greater in obese mice than in leans despite equal serum ACTH increases in the two phenotypes. Ether stress at both peak and trough of the circadian rhythm also stimulated much larger serum CS increases in obese mice even though ACTH increases were again equal in the two phenotypes. Taken together, these results strongly indicate that ob/ob mice have increased synthesis and secretion of pituitary ACTH despite the presence of chronically elevated serum CS. This hyperactivity of the hypothalamo-pituitary adrenal axis appears to be most pronounced in ob/ob females since pituitary ACTH content was equal in obese males and females despite much higher circulating CS levels in the females. Furthermore, the results also indicate an enhanced response to ACTH by the adrenal cortex of the obese mouse. Thus, ob/ob mice exhibit abnormal hypothalamo-pituitary-adrenal axis function with hyperactivity occurring at the level of pituitary ACTH synthesis/secretion as well as at the level of adrenocortical response to ACTH. PMID- 21554666 TI - Diencephalic Noradrenaline Depletion Impairs the Corticosterone Response to Footshock but does not Affect Conditioned Fear. AB - This study tested the hypothesis that hypothalamic noradrenaline (NA) depletion induced by 6-hydroxydopamine alters neuroendocrine, but not behavioural, responses to aversive stimuli. Sham-operated and NA depleted rats were exposed to pairings of an auditory (clicker) CS and (footshock) US in a distinctive environment. Subjects were tested for preference of a 'safe' environment over the one in which they were shocked, as a measure of effective conditioning to the contextual stimuli present in the distinctive environment. Subjects were also tested, in a separate operant chamber, for the suppression of drinking in the presence of the auditory stimulus, as a measure of effective conditioning to the explicit auditory CS. Blood samples were collected immediately following each phase of the behavioural experiment and were later analysed for plasma Corticosterone concentration. Behavioural and Corticosterone responses of individual control animals to the CS were positively correlated, consistent with previous results. This correlation was not present in the NA depleted group. The lesioned rats also showed a severely attenuated Corticosterone response to the footshock US. By contrast, NA depletion had no effect on any behavioural measure of CS or contextual conditioning. Together with previous experiments, these results suggest that diencephalic NA projections are more likely to mediate neuroendocrine, and coeruleo-cortical NA projections are more likely to mediate behavioural responses to conditioned and unconditioned aversive stimuli. PMID- 21554667 TI - Proliferation/quiescence: the controversial "aller-retour". AB - The vast majority of cells, from prokaryotes up to vertebrate organisms, spend most of their time in quiescence, a state defined as a temporary and reversible absence of proliferation. Establishing the quiescent state while maintaining the capacity to re-enter the proliferation cycle are critical for cell survival and must be tightly orchestrated to avoid pathological proliferation. Hence, studying the biology of quiescent cells is an exciting research field. Taking advantage of technical progress in genomic, transcriptomic and metabolomic, the nature of transitions between proliferation and quiescence have been recently re-visited in budding yeast. Together with new findings in cell biology, these studies resuscitate an old demon in the field: the controversial existence of a "quiescence program". PMID- 21554668 TI - PHENOPSIS DB: an information system for Arabidopsis thaliana phenotypic data in an environmental context. AB - BACKGROUND: Renewed interest in plant*environment interactions has risen in the post-genomic era. In this context, high-throughput phenotyping platforms have been developed to create reproducible environmental scenarios in which the phenotypic responses of multiple genotypes can be analysed in a reproducible way. These platforms benefit hugely from the development of suitable databases for storage, sharing and analysis of the large amount of data collected. In the model plant Arabidopsis thaliana, most databases available to the scientific community contain data related to genetic and molecular biology and are characterised by an inadequacy in the description of plant developmental stages and experimental metadata such as environmental conditions. Our goal was to develop a comprehensive information system for sharing of the data collected in PHENOPSIS, an automated platform for Arabidopsis thaliana phenotyping, with the scientific community. DESCRIPTION: PHENOPSIS DB is a publicly available (URL: http://bioweb.supagro.inra.fr/phenopsis/) information system developed for storage, browsing and sharing of online data generated by the PHENOPSIS platform and offline data collected by experimenters and experimental metadata. It provides modules coupled to a Web interface for (i) the visualisation of environmental data of an experiment, (ii) the visualisation and statistical analysis of phenotypic data, and (iii) the analysis of Arabidopsis thaliana plant images. CONCLUSIONS: Firstly, data stored in the PHENOPSIS DB are of interest to the Arabidopsis thaliana community, particularly in allowing phenotypic meta analyses directly linked to environmental conditions on which publications are still scarce. Secondly, data or image analysis modules can be downloaded from the Web interface for direct usage or as the basis for modifications according to new requirements. Finally, the structure of PHENOPSIS DB provides a useful template for the development of other similar databases related to genotype*environment interactions. PMID- 21554669 TI - Automated experimentation in ecological networks. AB - BACKGROUND: In ecological networks, natural communities are studied from a complex systems perspective by representing interactions among species within them in the form of a graph, which is in turn analysed using mathematical tools. Topological features encountered in complex networks have been proved to provide the systems they represent with interesting attributes such as robustness and stability, which in ecological systems translates into the ability of communities to resist perturbations of different kinds. A focus of research in community ecology is on understanding the mechanisms by which these complex networks of interactions among species in a community arise. We employ an agent-based approach to model ecological processes operating at the species' interaction level for the study of the emergence of organisation in ecological networks. RESULTS: We have designed protocols of interaction among agents in a multi-agent system based on ecological processes occurring at the interaction level between species in plant-animal mutualistic communities. Interaction models for agents coordination thus engineered facilitate the emergence of network features such as those found in ecological networks of interacting species, in our artificial societies of agents. CONCLUSIONS: Agent based models developed in this way facilitate the automation of the design an execution of simulation experiments that allow for the exploration of diverse behavioural mechanisms believed to be responsible for community organisation in ecological communities. This automated way of conducting experiments empowers the study of ecological networks by exploiting the expressive power of interaction models specification in agent systems. PMID- 21554670 TI - Behavioral mechanisms and morphological symptoms of zombie ants dying from fungal infection. AB - BACKGROUND: Parasites that manipulate host behavior can provide prominent examples of extended phenotypes: parasite genomes controlling host behavior. Here we focus on one of the most dramatic examples of behavioral manipulation, the death grip of ants infected by Ophiocordyceps fungi. We studied the interaction between O. unilateralis s.l. and its host ant Camponotus leonardi in a Thai rainforest, where infected ants descend from their canopy nests down to understory vegetation to bite into abaxial leaf veins before dying. Host mortality is concentrated in patches (graveyards) where ants die on sapling leaves ca. 25 cm above the soil surface where conditions for parasite development are optimal. Here we address whether the sequence of ant behaviors leading to the final death grip can also be interpreted as parasite adaptations and describe some of the morphological changes inside the heads of infected workers that mediate the expression of the death grip phenotype. RESULTS: We found that infected ants behave as zombies and display predictable stereotypical behaviors of random rather than directional walking, and of repeated convulsions that make them fall down and thus precludes returning to the canopy. Transitions from erratic wandering to death grips on a leaf vein were abrupt and synchronized around solar noon. We show that the mandibles of ants penetrate deeply into vein tissue and that this is accompanied by extensive atrophy of the mandibular muscles. This lock-jaw means the ant will remain attached to the leaf after death. We further present histological data to show that a high density of single celled stages of the parasite within the head capsule of dying ants are likely to be responsible for this muscular atrophy. CONCLUSIONS: Extended phenotypes in ants induced by fungal infections are a complex example of behavioral manipulation requiring coordinated changes of host behavior and morphology. Future work should address the genetic basis of such extended phenotypes. PMID- 21554671 TI - Comparison of commercial kits to measure cytokine responses to Plasmodium falciparum by multiplex microsphere suspension array technology. AB - BACKGROUND: Multiplex cytokine profiling systems are useful tools for investigating correlates of protective immunity. Several Luminex and flow cytometry methods are commercially available but there is limited information on the relative performance of different kits. A series of comparison experiments were carried out to determine the most appropriate method for our subsequent studies. METHODS: Two Luminex methods were compared, the Bio-Rad human 17-plex panel and the Invitrogen (formerly BioSource) human cytokine 10-plex kit, and two flow cytometry methods, the Becton Dickinson Human Th1/Th2 Cytokine Kit (CBA) and the Bender MedSystems Human Th1/Th2 11plex FlowCytomix Multiplex Kit. All kits were tested for the measurement of cytokines in supernatants collected from human leukocytes stimulated with viable Plasmodium falciparum infected red blood cells (iRBC) or P. falciparum schizont lysates. RESULTS: Data indicated that the kits differed in sensitivity and reproducibility depending on the cytokine, and detected different quantities of some cytokines. The Bio-Rad 17-plex kit was able to detect more positive responses than the Invitrogen 10-plex kit. However, only when detecting IL-1, IL-6 or TNF did the two Luminex based methods correlate with one another. In this study, the flow cytometry based techniques were less variable and correlated better with one another. The two flow cytometry based kits showed significant correlation when detecting IFN-gamma, IL-2, TNF, IL-10 and IL-6, but overall the BD kit detected more positive responses than the Bender MedSystems kit. CONCLUSIONS: The microsphere suspension array technologies tested differed in reproducibility and the absolute quantity of cytokine detected. Sample volume, the number of cytokines measured, and the time and cost of the assays also differed. These data provide an accurate assessment of the four techniques, which will allow individual researchers to select the tool most suited for their study population. PMID- 21554672 TI - Human-derived IgG level as an indicator for EBV-associated lymphoma model in Hu PBL/SCID chimeras. AB - BACKGROUND: Epstein-Barr virus (EBV) has a close association with various types of human lymphomas. Animal models are essential to elucidate the pathogenesis of human EBV-associated lymphomas. The aim of the present study is to evaluate the association between human IgG concentration and EBV-associated lymphoma development in huPBL/SCID mice. METHODS: Human peripheral blood lymphocytes (hu PBL) from EBV-seropositive donors were inoculated intraperitoneally into SCID mouse. Immunohistochemical staining was used to examine differentiated antigens of tumor cells. EBV infection of the induced tumors was detected by in situ hybridization. IgG concentrations in the serums of 12 SCID mice were measured by unidirectional immunodiffusion assay. RESULTS: 21 out of 29 mice developed tumors in their body. Immunohistochemical staining showed that all induced tumors were LCA (leukocyte common antigen) positive, B-cell markers (CD20, CD79a) positive, and T-cell markers (both CD3 and CD45RO) negative. The tumors can be diagnosed as human B-cell lymphomas by these morphological and immunohistochemical features. In situ hybridization exhibited resultant tumor cells had EBV encoded small RNA-1 (EBER-1). Human-derived IgG could be found in the serum from SCID mice on the 15th day following hu-PBL transplantation, and IgG levels increased with the tumor development in 6 hu-PBL/SCID chimeras. CONCLUSIONS: Intraperitoneal transfer of hu-PBLs from EBV+ donors to SCID mice leads to high human IgG levels in mouse serum and B cell lymphomas. Our findings suggest that increasing levels of human-derived IgG in peripheral blood from hu-PBL/SCID mice could be used to monitor EBV-related human B-cell lymphoma development in experimental animals. PMID- 21554673 TI - A Disease Register for ME/CFS: Report of a Pilot Study. AB - BACKGROUND: The ME/CFS Disease Register is one of six subprojects within the National ME/CFS Observatory, a research programme funded by the Big Lottery Fund and sponsored by Action for ME. A pilot study in East Anglia, East Yorkshire, and London aimed to address the problem of identifying representative groups of subjects for research, in order to be able to draw conclusions applicable to the whole ME/CFS population.While not aiming for comprehensive population coverage, this pilot register sought to recruit participants with ME/CFS in an unbiased way from a large population base. Those recruited are constituting a cohort for long term follow-up to shed light on prognosis, and a sampling frame for other studies. FINDINGS: Patients with unidentified chronic fatigue were identified in GP databases using a READ-code based algorithm, and conformity to certain case definitions for ME/CFS determined. 29 practices, covering a population aged 18 to 64 of 143,153, participated.510 patients with unexplained chronic fatigue were identified. 265 of these conformed to one or more case definitions. 216 were invited to join the register; 160 agreed. 96.9% of participants conformed to the CDC 1994 (Fukuda) definition; the Canadian definition defined more precisely a subset of these. The addition of an epidemiological case definition increased case ascertainment by approximately 4%. A small-scale study in a specialist referral service in East Anglia was also undertaken.There was little difference in pattern of conformity to case definitions, age or sex among disease register participants compared with subjects in a parallel epidemiological study who declined to participate.One-year follow-up of 50 subjects showed little change in pain or fatigue scores. There were some changes in conformity to case definitions. CONCLUSIONS: Objective evaluation indicated that the aim of recruiting participants with ME/CFS to a Disease Register had been fulfilled, and confirmed the feasibility of our approach to case identification, data processing, transmission, storage, and analysis. Future developments should include expansion of the ME/CFS Register and its linkage to a tissue sample bank and post mortem tissue archive, to facilitate support for further research studies. PMID- 21554674 TI - Influence of family size and birth order on risk of cancer: a population-based study. AB - BACKGROUND: Family size and birth order are known to influence the risk of some cancers. However, it is still unknown whether these effects change from early to later adulthood. We used the data of the Swedish Family-Cancer Database to further analyze these effects. METHODS: We selected over 5.7 million offspring with identified parents but no parental cancer. We estimated the effect of birth order and family size by Poisson regression adjusted for age, sex, period, region and socioeconomic status. We divided the age at diagnosis in two groups, below and over 50 years, to identify the effect of family size and birth order for different age periods. RESULTS: Negative associations for increasing birth order were found for endometrial, testicular, skin, thyroid and connective tissue cancers and melanoma. In contrast, we observed positive association between birth order and lung, male and female genital cancers. Family size was associated with decreasing risk for endometrial and testicular cancers, melanoma and squamous cell carcinoma; risk was increased for leukemia and nervous system cancer. The effect of birth order decreased for lung and endometrial cancer from age at diagnosis below to over 50 years. Combined effects for birth order and family size were marginally significant for thyroid gland tumors. Especially, the relative risk for follicular thyroid gland tumors was significantly decreased for increasing birth order. CONCLUSION: Our findings suggest that the effect of birth order decreases from early to late adulthood for lung and endometrial cancer. PMID- 21554675 TI - IsoBED: a tool for automatic calculation of biologically equivalent fractionation schedules in radiotherapy using IMRT with a simultaneous integrated boost (SIB) technique. AB - BACKGROUND: An advantage of the Intensity Modulated Radiotherapy (IMRT) technique is the feasibility to deliver different therapeutic dose levels to PTVs in a single treatment session using the Simultaneous Integrated Boost (SIB) technique. The paper aims to describe an automated tool to calculate the dose to be delivered with the SIB-IMRT technique in different anatomical regions that have the same Biological Equivalent Dose (BED), i.e. IsoBED, compared to the standard fractionation. METHODS: Based on the Linear Quadratic Model (LQM), we developed software that allows treatment schedules, biologically equivalent to standard fractionations, to be calculated. The main radiobiological parameters from literature are included in a database inside the software, which can be updated according to the clinical experience of each Institute. In particular, the BED to each target volume will be computed based on the alpha/beta ratio, total dose and the dose per fraction (generally 2 Gy for a standard fractionation). Then, after selecting the reference target, i.e. the PTV that controls the fractionation, a new total dose and dose per fraction providing the same isoBED will be calculated for each target volume. RESULTS: The IsoBED Software developed allows: 1) the calculation of new IsoBED treatment schedules derived from standard prescriptions and based on LQM, 2) the conversion of the dose-volume histograms (DVHs) for each Target and OAR to a nominal standard dose at 2Gy per fraction in order to be shown together with the DV-constraints from literature, based on the LQM and radiobiological parameters, and 3) the calculation of Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP) curve versus the prescribed dose to the reference target. PMID- 21554676 TI - Analysis of anther transcriptomes to identify genes contributing to meiosis and male gametophyte development in rice. AB - BACKGROUND: In flowering plants, the anther is the site of male gametophyte development. Two major events in the development of the male germline are meiosis and the asymmetric division in the male gametophyte that gives rise to the vegetative and generative cells, and the following mitotic division in the generative cell that produces two sperm cells. Anther transcriptomes have been analyzed in many plant species at progressive stages of development by using microarray and sequence-by synthesis-technologies to identify genes that regulate anther development. Here we report a comprehensive analysis of rice anther transcriptomes at four distinct stages, focusing on identifying regulatory components that contribute to male meiosis and germline development. Further, these transcriptomes have been compared with the transcriptomes of 10 stages of rice vegetative and seed development to identify genes that express specifically during anther development. RESULTS: Transcriptome profiling of four stages of anther development in rice including pre-meiotic (PMA), meiotic (MA), anthers at single-celled (SCP) and tri-nucleate pollen (TPA) revealed about 22,000 genes expressing in at least one of the anther developmental stages, with the highest number in MA (18,090) and the lowest (15,465) in TPA. Comparison of these transcriptome profiles to an in-house generated microarray-based transcriptomics database comprising of 10 stages/tissues of vegetative as well as reproductive development in rice resulted in the identification of 1,000 genes specifically expressed in anther stages. From this sub-set, 453 genes were specific to TPA, while 78 and 184 genes were expressed specifically in MA and SCP, respectively. The expression pattern of selected genes has been validated using real time PCR and in situ hybridizations. Gene ontology and pathway analysis of stage-specific genes revealed that those encoding transcription factors and components of protein folding, sorting and degradation pathway genes dominated in MA, whereas in TPA, those coding for cell structure and signal transduction components were in abundance. Interestingly, about 50% of the genes with anther-specific expression have not been annotated so far. CONCLUSIONS: Not only have we provided the transcriptome constituents of four landmark stages of anther development in rice but we have also identified genes that express exclusively in these stages. It is likely that many of these candidates may therefore contribute to specific aspects of anther and/or male gametophyte development in rice. In addition, the gene sets that have been produced will assist the plant reproductive community in building a deeper understanding of underlying regulatory networks and in selecting gene candidates for functional validation. PMID- 21554677 TI - The prevalence of canine Leishmania infantum infection in western China detected by PCR and serological tests. AB - BACKGROUND: Canine leishmaniasis (CanL) is endemic in western China, resulting in important public health problem. It is essential to evaluate the prevalence of canine Leishmania infantum infection for designing control policy. In the present study we report for the first time prevalence of Leishmania infection in dogs living in Jiuzhaigou County (Sichuan Provence, China), which is not only an important endemic area of CanL but also a tourism scenic spot, detected by PCR, ELISA and dipstick test. The results could provide key information for designing control programs against canine and human leishmaniasis. In addition, the complete sequence of the Leishmania isolate from Sichuan Province has not been reported to date and we present the sequences of 116 base-pair (bp) fragment of the conserved region in the minicircle kinetoplast DNA (kDNA) and the results of phylogenetic analyses based on the sequence of the amplified fragment. RESULTS: The proportion of dogs infected with Leishmania in Jiuzhaigou County was 36.79%, 9.43%, and 51.88% detected by ELISA, dipstick test, and PCR, respectively. The ELISA and PCR tests were more sensitive than dipstick test. The PCR method is the most sensitive way to detect dogs infected with Leishmania parasites. The total positive rate for infected dogs in the area was 59.43% by the three methods. The PCR products of 116-bp fragment amplified from the kDNA conserved region of dog blood samples and laboratory maintained L. infantum were DNA sequenced and the variation of the sequences was observed. The phylogenetic tree based on the sequences of 116-bp fragment reveals that L. infantum is more genetically related to visceralizing species L. donovani than to the Leishmania species associated with cutaneous disease. CONCLUSIONS: More than half of dogs living in the endemic Jiuzhaigou County were infected by L. infantum. Control measures, such as treatment or eradication of infected dogs, or prohibition of maintaining dogs, must be taken against these infected dogs due to their role in the transmission of the infection to vectors. The phylogenetic tree based on the sequences of conserved region in kDNA of Leishmania can effectively distinguish species of Leishmania. PMID- 21554678 TI - Alpha-fetoprotein-producing primary lung carcinoma: a case report. AB - Alpha-fetoprotein (AFP)-producing lung adenocarcinoma is a rare type of lung cancer, with its characteristics not yet fully clarified. We recently encountered a case of this type of lung cancer. The patient was a 69-year-old man who consulted an internist with the chief complaint of epigastric pain. Chest X-ray and CT revealed a lobulated mass measuring 70 mm in diameter in the right lower lung field and a metastasis in the right hilar lymph nodes. Of the tumor markers, the serum AFP was elevated (4620 ng/ml), and the serum carcinoembryonic antigen and carbohydrate antigen 19-9 were also slightly elevated. Transbronchial lung biopsy revealed the diagnosis of lung cancer. Under thoracoscopic assistance, right lower lobectomy + mediastinal lymph node dissection was carried out. Immunostaining showed the tumor cells to be AFP-positive. The tumor was thus diagnosed as an AFP-producing lung adenocarcinoma. The patient followed an uneventful clinical course after the surgery, with serum AFP decreasing to the normal range by about 2 weeks after the surgery. As of this writing, no sign of tumor recurrence has been noted. This case is presented here with a review of the literature. PMID- 21554679 TI - Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: a randomised, double blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients. Experimental studies suggest that treatment with beta agonists may be helpful in ARDS. The Beta Agonist Lung Injury TrIal (BALTI-2) is a multicentre, pragmatic, randomised, double-blind, placebo controlled clinical trial which aims to determine if sustained treatment with intravenous (IV) salbutamol will improve survival in ARDS. METHODS/DESIGN: Patients fulfilling the American-European Consensus Conference Definition of ARDS will be randomised in a 1:1 ratio to receive an IV infusion either of salbutamol (15 MUg kg ideal body weight-1 hr-1) or placebo (0.9% sodium chloride solution), for a maximum of seven days. Allocation to randomised groups will use minimisation to ensure balance with respect to hospital of recruitment, age group (<64, 65-84, >85 years) and PaO2/FiO2 ratio (<=6.7, 6.8- 13.2, >=13.3 kPa). Data will be recorded by participating ICUs until hospital discharge, and all surviving patients will be followed up by post at six and twelve months post randomisation. The primary outcome is mortality at 28 days after randomisation; secondary outcomes are mortality in ICU, mortality in hospital, number of ventilator-free days, number of organ failure-free days, mortality at twelve months post-randomisation, quality of life at six and twelve months, length of stay in ICU, length of stay in hospital, adverse effects (tachycardia, arrhythmia or other side effects sufficient to stop treatment drug). 1,334 patients will be recruited from about fifty ICUs in the UK. An economic evaluation will be conducted alongside the trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38366450. PMID- 21554681 TI - Reproductive factors and oesophageal cancer in Chinese women: a case-control study. AB - BACKGROUND: Previous studies showed that sex hormone might play a role in the development of oesophageal cancer in Western countries. However, evidence from Chinese populations is still lacking. METHODS: We performed a hospital-based case control study in Guangzhou, China. From June 2006 to May 2009, face-to-face interviews were conducted on 73 cases and 157 controls. Cases were Chinese females with newly diagnosed primary oesophageal cancer. Controls were hospitalized individuals without cancer and frequency matched by age groups. The interviews included questions about childbearing and menarche history, together with potential confounders. Unconditional logistic regression was used to estimate the risk of factors. RESULTS: Women who had given birth before were not at increased risk compared to childless women (adjusted OR = 1.17, 95% CI: 0.48 ~ 2.85). The risk of oesophageal cancer increased with age at first birth: the adjusted OR for women first giving birth at age 25 or later was 2.02 (95% CI: 1.01 ~ 4.04) compared with those reporting their first birth before age 22. History of spontaneous abortion was not significantly associated with increased risk (adjusted OR = 1.37, 95% CI: 0.49 ~ 3.83). No significant association was observed between menstrual variables (age at menarche, age at menopause, and years of menstruation) and risk of oesophageal cancer. CONCLUSIONS: Giving birth at later age may increase the risk of oesophageal cancer in women. Further studies in Chinese populations with larger sample sizes are still needed. PMID- 21554680 TI - Reconstructing the 2003/2004 H3N2 influenza epidemic in Switzerland with a spatially explicit, individual-based model. AB - world has not faced a severe pandemic for decades, except the rather mild H1N1 one in 2009, pandemic influenza models are inherently hypothetical and validation is, thus, difficult. We aim at reconstructing a recent seasonal influenza epidemic that occurred in Switzerland and deem this to be a promising validation strategy for models of influenza spread. METHODS: We present a spatially explicit, individual-based simulation model of influenza spread. The simulation model bases upon (i) simulated human travel data, (ii) data on human contact patterns and (iii) empirical knowledge on the epidemiology of influenza. For model validation we compare the simulation outcomes with empirical knowledge regarding (i) the shape of the epidemic curve, overall infection rate and reproduction number, (ii) age-dependent infection rates and time of infection, (iii) spatial patterns. RESULTS: The simulation model is capable of reproducing the shape of the 2003/2004 H3N2 epidemic curve of Switzerland and generates an overall infection rate (14.9 percent) and reproduction numbers (between 1.2 and 1.3), which are realistic for seasonal influenza epidemics. Age and spatial patterns observed in empirical data are also reflected by the model: Highest infection rates are in children between 5 and 14 and the disease spreads along the main transport axes from west to east. CONCLUSIONS: We show that finding evidence for the validity of simulation models of influenza spread by challenging them with seasonal influenza outbreak data is possible and promising. Simulation models for pandemic spread gain more credibility if they are able to reproduce seasonal influenza outbreaks. For more robust modelling of seasonal influenza, serological data complementing sentinel information would be beneficial. PMID- 21554682 TI - Hypercholesterolemia and a candidate gene within the 12q24 locus. AB - BACKGROUND: The 12q24 locus entails at least one gene responsible for hypercholesterolemia. Within the 12q24 locus lies the gene of proteasome modulator 9 (PSMD9). PSMD9 is in linkage with type 2 diabetes (T2D), T2D nephropathy and macrovascular pathology in Italian families and PSMD9 rare mutations contribute to T2D. AIMS: In the present study, we aimed at determining whether the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3 + nt460 A > G, IVS3 + nt437 T > C and E197G A > G are linked to hypercholesterolemia in 200 T2D Italian families. METHODS: We characterized 200 Italian families for presence and/or absence of hypercholesterolemia characterized by LDL levels >= 100 mg/dl in drug-naive patients and/or presence of a diagnosis of hypercholesterolemia in a patient treated with statin medication. The phenotypes were described as unknown in all cases in which the diagnosis was either unclear or the data were missing. We tested in the 200 Italians families for evidence of linkage of the PSMD9 SNPs with hypercholesterolemia. The non-parametric linkage analysis was performed for the qualitative phenotype by using the Merlin software; the Lod score and correspondent P-value were calculated. For the significant linkage score, 1000 replicates were performed to calculate the empirical P-value. RESULTS: The PSMD9 gene SNPs studied show linkage to hypercholesterolemia. The results are not due to random chance. CONCLUSIONS: PSMD9 should be tested in all populations reporting linkage to hypercholesterolemia within the chromosome 12q24 locus. The impact of this gene on hypercholesterolemia and contribution to cardio and cerebrovascular events may be high. PMID- 21554683 TI - Comparative genomic hybridization on microarray (a-CGH) in constitutional and acquired mosaicism may detect as low as 8% abnormal cells. AB - BACKGROUND: The results of cytogenetic investigations on unbalanced chromosome anomalies, both constitutional and acquired, were largely improved by comparative genomic hybridization on microarray (a-CGH), but in mosaicism the ability of a CGH to reliably detect imbalances is not yet well established. This problem of sensitivity is even more relevant in acquired mosaicism in neoplastic diseases, where cells carrying acquired imbalances coexist with normal cells, in particular when the proportion of abnormal cells may be low.We constructed a synthetic mosaicism by mixing the DNA of three patients carrying altogether seven chromosome imbalances with normal sex-matched DNA. Dilutions were prepared mimicking 5%, 6%, 7%, 8%, 10% and 15% levels of mosaicism. Oligomer-based a-CGH (244 K whole-genome system) was applied on the patients' DNA and customized slides designed around the regions of imbalance were used for the synthetic mosaics. RESULTS AND CONCLUSIONS: The a-CGH on the synthetic mosaics proved to be able to detect as low as 8% abnormal cells in the tissue examined. Although in our experiment some regions of imbalances escaped to be revealed at this level, and were detected only at 10-15% level, it should be remarked that these ones were the smallest analyzed, and that the imbalances recurrent as clonal anomalies in cancer and leukaemia are similar in size to those revealed at 8% level. PMID- 21554684 TI - Modeling left ventricular diastolic dysfunction: classification and key indicators. AB - BACKGROUND: Mathematical modeling can be employed to overcome the practical difficulty of isolating the mechanisms responsible for clinical heart failure in the setting of normal left ventricular ejection fraction (HFNEF). In a human cardiovascular respiratory system (H-CRS) model we introduce three cases of left ventricular diastolic dysfunction (LVDD): (1) impaired left ventricular active relaxation (IR-type); (2) increased passive stiffness (restrictive or R-type); and (3) the combination of both (pseudo-normal or PN-type), to produce HFNEF. The effects of increasing systolic contractility are also considered. Model results showing ensuing heart failure and mechanisms involved are reported. METHODS: We employ our previously described H-CRS model with modified pulmonary compliances to better mimic normal pulmonary blood distribution. IR-type is modeled by changing the activation function of the left ventricle (LV), and R-type by increasing diastolic stiffness of the LV wall and septum. A 5th-order Cash-Karp Runge-Kutta numerical integration method solves the model differential equations. RESULTS: IR-type and R-type decrease LV stroke volume, cardiac output, ejection fraction (EF), and mean systemic arterial pressure. Heart rate, pulmonary pressures, pulmonary volumes, and pulmonary and systemic arterial-venous O2 and CO2 differences increase. IR-type decreases, but R-type increases the mitral E/A ratio. PN-type produces the well-described, pseudo-normal mitral inflow pattern. All three types of LVDD reduce right ventricular (RV) and LV EF, but the latter remains normal or near normal. Simulations show reduced EF is partly restored by an accompanying increase in systolic stiffness, a compensatory mechanism that may lead clinicians to miss the presence of HF if they only consider LVEF and other indices of LV function. Simulations using the H-CRS model indicate that changes in RV function might well be diagnostic. This study also highlights the importance of septal mechanics in LVDD. CONCLUSION: The model demonstrates that abnormal LV diastolic performance alone can result in decreased LV and RV systolic performance, not previously appreciated, and contribute to the clinical syndrome of HF. Furthermore, alterations of RV diastolic performance are present and may be a hallmark of LV diastolic parameter changes that can be used for better clinical recognition of LV diastolic heart disease. PMID- 21554685 TI - Walk-ins seeking treatment at an emergency department or general practitioner out of-hours service: a cross-sectional comparison. AB - BACKGROUND: Emergency Departments (ED) in Switzerland are faced with increasing numbers of patients seeking non-urgent treatment. The high rate of walks-ins with conditions that may be treated in primary care has led to suggestions that those patients would best cared for in a community setting rather than in a hospital. Efficient reorganisation of emergency care tailored to patients needs requires information on the patient populations using the various emergency services currently available. The aim of this study is to evaluate the differences between the characteristics of walk-in patients seeking treatment at an ED and those of patients who use traditional out-of-hours GP (General Practitioner) services provided by a GP-Cooperative (GP-C). METHODS: In 2007 and 2009 data was collected covering all consecutive patient-doctor encounters at the ED of a hospital and all those occurring as a result of contacting a GP-C over two evaluation periods of one month each. Comparison was made between a GP-C and the ED of the Waid City Hospital in Zurich. Patient characteristics, time and source of referral, diagnostic interventions and mode of discharge were evaluated. Medical problems were classified according to the International Classification of Primary Care (ICPC-2). Patient characteristics were compared using non-parametric tests and multiple logistic regression analysis was applied to investigate independent determinants for contacting a GP-C or an ED. RESULTS: Overall a total of 2974 patient encounters were recorded. 1901 encounters were walk-ins and underwent further analysis (ED 1133, GP-C 768). Patients consulting the GP-C were significantly older (58.9 vs. 43.8 years), more often female (63.5 vs. 46.9%) and presented with non-injury related medical problems (93 vs. 55.6%) in comparison with patients at the ED. Independent determining factors for ED consultation were injury, male gender and younger age. Walk-in distribution in both settings was equal over a period of 24 hours and most common during daytime hours (65%).Outpatient care was predominant in both settings but significantly more so at the GP-C (79.9 vs. 85.7%). CONCLUSIONS: We observed substantial differences between the two emergency settings in a non gate-keeping health care system. Knowledge of the distribution of diagnoses, their therapy, of diagnostic measures and of the factors which determine the patients' choice of the ED or the GP-C is essential for the efficient allocation of resources and the reduction of costs. PMID- 21554686 TI - Synthesis and crystal structure of 1,4,10,13-tetraoxa-7,16-diazoniumcyclo octadecane bis(4-chloro-2-methyl-phenoxyacetate). AB - The title compound was prepared by the reaction of 1,4,10,13-tetraoxa-7,16 diazacyclo-octadecane with 4-chloro-2-methyl-phenoxyacetic acid in a ratio of 1:2. The structure has been proved by the data of elemental analysis, IR spectroscopy, NMR (1H, 13C) technique and by X-ray diffraction analysis. Intermolecular hydrogen bonds between the azonium protons and oxygen atoms of the carboxylate groups were found. Immunoactive properties of the title compound have been screened. The compound has the ability to suppress spontaneous and Con A stimulated cell proliferation in vitro and therefore can be considered as immunodepressant. PMID- 21554687 TI - Phylogeography of a successful aerial disperser: the golden orb spider Nephila on Indian Ocean islands. AB - BACKGROUND: The origin and diversification patterns of lineages across the Indian Ocean islands are varied due to the interplay of the complex geographic and geologic island histories, the varying dispersal abilities of biotas, and the proximity to major continental landmasses. Our aim was to reconstruct phylogeographic history of the giant orbweaving spider (Nephila) on western Indian Ocean islands (Madagascar, Mayotte, Reunion, Mauritius, Rodrigues), to test its origin and route of dispersal, and to examine the consequences of good dispersal abilities for colonization and diversification, in comparison with related spiders (Nephilengys) inhabiting the same islands, and with other organisms known for over water dispersal. We used mitochondrial (COI) and nuclear (ITS2) markers to examine phylogenetic and population genetic patterns in Nephila populations and species. We employed Bayesian and parsimony methods to reconstruct phylogenies and haplotype networks, respectively, and calculated genetic distances, fixation indices, and estimated clade ages under a relaxed clock model. RESULTS: Our results suggest an African origin of Madagascar Nephila inaurata populations via Cenozoic dispersal, and the colonization of the Mascarene islands from Madagascar. We find evidence of gene flow across Madagascar and Comoros. The Mascarene islands share a common 'ancestral' COI haplotype closely related to those found on Madagascar, but itself absent, or as yet unsampled, from Madagascar. Each island has one or more unique haplotypes related to the ancestral Mascarene haplotype. The Indian Ocean N. inaurata are genetically distinct from the African populations. CONCLUSIONS: Nephila spiders colonized Madagascar from Africa about 2.5 (0.6-5.3) Ma. Our results are consistent with subsequent, recent and rapid, colonization of all three Mascarene islands. On each island, however, we detected unique haplotypes, consistent with a limited gene flow among the islands subsequent to colonization, a scenario that might be referred to as speciation in progress. However, due to relatively small sample sizes, we cannot rule out that we simply failed to collect Mascarene haplotypes on Madagascar, a scenario that might imply human mediated dispersal. Nonetheless, the former interpretation better fits the available data and results in a pattern similar to the related Nephilengys. Nephilengys, however, shows higher genetic divergences with diversification on more remote islands. That the better disperser of the two lineages, Nephila, has colonized more islands but failed to diversify, demonstrates how dispersal ability can shape both the patterns of colonization and formation of species across archipelagos. PMID- 21554688 TI - ChIP-seq Analysis in R (CSAR): An R package for the statistical detection of protein-bound genomic regions. AB - BACKGROUND: In vivo detection of protein-bound genomic regions can be achieved by combining chromatin-immunoprecipitation with next-generation sequencing technology (ChIP-seq). The large amount of sequence data produced by this method needs to be analyzed in a statistically proper and computationally efficient manner. The generation of high copy numbers of DNA fragments as an artifact of the PCR step in ChIP-seq is an important source of bias of this methodology. RESULTS: We present here an R package for the statistical analysis of ChIP-seq experiments. Taking the average size of DNA fragments subjected to sequencing into account, the software calculates single-nucleotide read-enrichment values. After normalization, sample and control are compared using a test based on the ratio test or the Poisson distribution. Test statistic thresholds to control the false discovery rate are obtained through random permutations. Computational efficiency is achieved by implementing the most time-consuming functions in C++ and integrating these in the R package. An analysis of simulated and experimental ChIP-seq data is presented to demonstrate the robustness of our method against PCR-artefacts and its adequate control of the error rate. CONCLUSIONS: The software ChIP-seq Analysis in R (CSAR) enables fast and accurate detection of protein-bound genomic regions through the analysis of ChIP-seq experiments. Compared to existing methods, we found that our package shows greater robustness against PCR-artefacts and better control of the error rate. PMID- 21554689 TI - Elastic SCAD as a novel penalization method for SVM classification tasks in high dimensional data. AB - BACKGROUND: Classification and variable selection play an important role in knowledge discovery in high-dimensional data. Although Support Vector Machine (SVM) algorithms are among the most powerful classification and prediction methods with a wide range of scientific applications, the SVM does not include automatic feature selection and therefore a number of feature selection procedures have been developed. Regularisation approaches extend SVM to a feature selection method in a flexible way using penalty functions like LASSO, SCAD and Elastic Net.We propose a novel penalty function for SVM classification tasks, Elastic SCAD, a combination of SCAD and ridge penalties which overcomes the limitations of each penalty alone.Since SVM models are extremely sensitive to the choice of tuning parameters, we adopted an interval search algorithm, which in comparison to a fixed grid search finds rapidly and more precisely a global optimal solution. RESULTS: Feature selection methods with combined penalties (Elastic Net and Elastic SCAD SVMs) are more robust to a change of the model complexity than methods using single penalties. Our simulation study showed that Elastic SCAD SVM outperformed LASSO (L1) and SCAD SVMs. Moreover, Elastic SCAD SVM provided sparser classifiers in terms of median number of features selected than Elastic Net SVM and often better predicted than Elastic Net in terms of misclassification error.Finally, we applied the penalization methods described above on four publicly available breast cancer data sets. Elastic SCAD SVM was the only method providing robust classifiers in sparse and non-sparse situations. CONCLUSIONS: The proposed Elastic SCAD SVM algorithm provides the advantages of the SCAD penalty and at the same time avoids sparsity limitations for non-sparse data. We were first to demonstrate that the integration of the interval search algorithm and penalized SVM classification techniques provides fast solutions on the optimization of tuning parameters.The penalized SVM classification algorithms as well as fixed grid and interval search for finding appropriate tuning parameters were implemented in our freely available R package 'penalizedSVM'.We conclude that the Elastic SCAD SVM is a flexible and robust tool for classification and feature selection tasks for high-dimensional data such as microarray data sets. PMID- 21554690 TI - Modeling spatial accessibility to parks: a national study. AB - BACKGROUND: Parks provide ideal open spaces for leisure-time physical activity and important venues to promote physical activity. The spatial configuration of parks, the number of parks and their spatial distribution across neighborhood areas or local regions, represents the basic park access potential for their residential populations. A new measure of spatial access to parks, population weighted distance (PWD) to parks, combines the advantages of current park access approaches and incorporates the information processing theory and probability access surface model to more accurately quantify residential population's potential spatial access to parks. RESULTS: The PWD was constructed at the basic level of US census geography - blocks - using US park and population data. This new measure of population park accessibility was aggregated to census tract, county, state and national levels. On average, US residential populations are expected to travel 6.7 miles to access their local neighborhood parks. There are significant differences in the PWD to local parks among states. The District of Columbia and Connecticut have the best access to local neighborhood parks with PWD of 0.6 miles and 1.8 miles, respectively. Alaska, Montana, and Wyoming have the largest PWDs of 62.0, 37.4, and 32.8 miles, respectively. Rural states in the western and Midwestern US have lower neighborhood park access, while urban states have relatively higher park access. CONCLUSIONS: The PWD to parks provides a consistent platform for evaluating spatial equity of park access and linking with population health outcomes. It could be an informative evaluation tool for health professionals and policy makers. This new method could be applied to quantify geographic accessibility of other types of services or destinations, such as food, alcohol, and tobacco outlets. PMID- 21554691 TI - Target for improvement: a cluster randomised trial of public involvement in quality-indicator prioritisation (intervention development and study protocol). AB - BACKGROUND: Public priorities for improvement often differ from those of clinicians and managers. Public involvement has been proposed as a way to bridge the gap between professional and public clinical care priorities but has not been studied in the context of quality-indicator choice. Our objective is to assess the feasibility and impact of public involvement on quality-indicator choice and agreement with public priorities. METHODS: We will conduct a cluster randomised controlled trial comparing quality-indicator prioritisation with and without public involvement. In preparation for the trial, we developed a 'menu' of quality indicators, based on a systematic review of existing validated indicator sets. Participants (public representatives, clinicians, and managers) will be recruited from six participating sites. In intervention sites, public representatives will be involved through direct participation (public representatives, clinicians, and managers will deliberate together to agree on quality-indicator choice and use) and consultation (individual public recommendations for improvement will be collected and presented to decision makers). In control sites, only clinicians and managers will take part in the prioritisation process. Data on quality-indicator choice and intended use will be collected. Our primary outcome will compare quality-indicator choice and agreement with public priorities between intervention and control groups. A process evaluation based on direct observation, videorecording, and participants' assessment will be conducted to help explain the study's results. The marginal cost of public involvement will also be assessed. DISCUSSION: We identified 801 quality indicators that met our inclusion criteria. An expert panel agreed on a final set of 37 items containing validated quality indicators relevant for chronic disease prevention and management in primary care. We pilot tested our public-involvement intervention with 27 participants (11 public representatives and 16 clinicians and managers) and our study instruments with an additional 21 participants, which demonstrated the feasibility of the intervention and generated important insights and adaptations to engage public representatives more effectively. To our knowledge, this study is the first trial of public involvement in quality-indicator prioritisation, and its results could foster more effective upstream engagement of patients and the public in clinical practice improvement. TRIAL REGISTRATION: NTR2496 (Netherlands National Trial Register, http://www.trialregister.nl). PMID- 21554693 TI - MR spectroscopy-based brain metabolite profiling in propionic acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation. AB - BACKGROUND: Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes. METHODS: Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging. RESULTS: MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group. CONCLUSIONS: The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction. PMID- 21554692 TI - Patterns of chloroquine use and resistance in sub-Saharan Africa: a systematic review of household survey and molecular data. AB - BACKGROUND: As a result of widespread chloroquine and sulphadoxine-pyrimethamine (SP) resistance, 90% of sub-Saharan African countries had adopted policies of artemisinin-based combination therapy (ACT) for treatment of uncomplicated malaria by 2007. In Malawi, cessation of chloroquine use was followed by the re emergence of chloroquine-susceptible malaria. It was expected that introduction of ACT would lead to a return in chloroquine susceptibility throughout Africa, but this has not yet widely occurred. This observation suggests that there is continuing use of ineffective anti-malarials in Africa and that persistent chloroquine-resistant malaria is due to ongoing drug pressure despite national policy changes. METHODS: To estimate drug use on a national level, 2006-2007 Demographic Health Survey and Multiple Indicator Cluster Survey data from 21 African countries were analysed. Resistance data were compiled by systematic review of the published literature on the prevalence of the Plasmodium falciparum chloroquine resistance transporter polymorphism at codon 76, which causes chloroquine resistance. RESULTS: Chloroquine was the most common anti-malarial used according to surveys from 14 of 21 countries analysed, predominantly in West Africa. SP was most commonly reported in two of 21 countries. Among eight countries with longitudinal molecular resistance data, the four countries where the highest proportion of children treated for fever received chloroquine (Uganda, Burkina Faso, Guinea Bissau, and Mali) also showed no significant declines in the prevalence of chloroquine-resistant infections. The three countries with low or decreasing chloroquine use among children who reported fever treatment (Malawi, Kenya, and Tanzania) had statistically significant declines in the prevalence of chloroquine resistance. CONCLUSIONS: This study demonstrates that in 2006-2007, chloroquine and SP continued to be used at high rates in many African countries. In countries reporting sustained chloroquine use, chloroquine-resistant malaria persists. In contrast, a low level of estimated chloroquine use is associated with a declining prevalence of chloroquine resistance. PMID- 21554694 TI - The effects of high dose interferon-beta1a on plasma microparticles: correlation with MRI parameters. AB - OBJECTIVES: We previously reported a correlation between levels of micro particles carrying CD31 (PMP(CD31+)) and disease activity in MS. However, the effects of long term (12 month) treatment with high dose, high frequency interferon-beta1a (RebifTM) on plasma levels of PMP(CD31+), PMP(CD146+), and PMP(CD54+) and MRI measures of disease activity have not yet been assessed. METHODS: During this prospective 1-year study, we used flow cytometry to measure changes in plasma micro particles (PMP) bearing CD31 (PMP(CD31+)), CD146 (PMP(CD146+)), and CD54/ICAM-1 (PMP(CD54+)) in 16 consecutive patients with relapsing-remitting MS (RRMS) before and after 3, 6, and 12 months of subcutaneous therapy with interferon-beta1a (44 micrograms, 3X weekly). At each visit, clinical exams and expanded disability status scale (EDSS) scores were recorded. RESULTS: Plasma levels of PMP(CD31+), and PMP(CD54+) were significantly reduced by treatment with IFN-beta1a. PMP(CD146+) appeared to decrease only at 3 months and did not persist at 6 and 12 months (p = 0.0511). In addition, the decrease in plasma levels of PMP(CD31+) and PMP(CD54+) levels at 12 months were associated with a significant decrease in the number and volume of contrast enhancing T1-weigthed lesions. CONCLUSION: Our data suggest that serial measurement of plasma micro particles (PMP), particularly in the initial stages of MS (when neuro-inflammatory cascades are more intense), may serve as reliable and reproducible surrogate markers of response to IFN-beta1a therapy for MS. In addition, the progressive decline in plasma levels of PMP(CD31+) and PMP(CD54+) further supports the concept that IFN-beta1a exerts stabilizing effect on the cerebral endothelial cells during pathogenesis of MS. PMID- 21554695 TI - The characterization of a new set of EST-derived simple sequence repeat (SSR) markers as a resource for the genetic analysis of Phaseolus vulgaris. AB - BACKGROUND: Over recent years, a growing effort has been made to develop microsatellite markers for the genomic analysis of the common bean (Phaseolus vulgaris) to broaden the knowledge of the molecular genetic basis of this species. The availability of large sets of expressed sequence tags (ESTs) in public databases has given rise to an expedient approach for the identification of SSRs (Simple Sequence Repeats), specifically EST-derived SSRs. In the present work, a battery of new microsatellite markers was obtained from a search of the Phaseolus vulgaris EST database. The diversity, degree of transferability and polymorphism of these markers were tested. RESULTS: From 9,583 valid ESTs, 4,764 had microsatellite motifs, from which 377 were used to design primers, and 302 (80.11%) showed good amplification quality. To analyze transferability, a group of 167 SSRs were tested, and the results showed that they were 82% transferable across at least one species. The highest amplification rates were observed between the species from the Phaseolus (63.7%), Vigna (25.9%), Glycine (19.8%), Medicago (10.2%), Dipterix (6%) and Arachis (1.8%) genera. The average PIC (Polymorphism Information Content) varied from 0.53 for genomic SSRs to 0.47 for EST-SSRs, and the average number of alleles per locus was 4 and 3, respectively. Among the 315 newly tested SSRs in the BJ (BAT93 X Jalo EEP558) population, 24% (76) were polymorphic. The integration of these segregant loci into a framework map composed of 123 previously obtained SSR markers yielded a total of 199 segregant loci, of which 182 (91.5%) were mapped to 14 linkage groups, resulting in a map length of 1,157 cM. CONCLUSIONS: A total of 302 newly developed EST-SSR markers, showing good amplification quality, are available for the genetic analysis of Phaseolus vulgaris. These markers showed satisfactory rates of transferability, especially between species that have great economic and genomic values. Their diversity was comparable to genomic SSRs, and they were incorporated in the common bean reference genetic map, which constitutes an important contribution to and advance in Phaseolus vulgaris genomic research. PMID- 21554696 TI - Perceptions of general practitioners towards the use of a new system for treating back pain: a qualitative interview study. AB - BACKGROUND: Changing clinicians' behaviour is recognised as a major challenge. It is clear that behaviour change not only depends on demonstrating the proven effectiveness of clinical interventions; contextual and occupational factors, such as 'change readiness', may be central to their implementation. This paper highlights the context of behaviour change in relation to a healthcare innovation introduced within primary care, highlighting the importance of organisational and interpersonal factors that may help explain the dynamics of implementation. METHODS: Qualitative interviews were conducted with general practitioners (GPs) before (n = 32) and after (n = 9) the introduction of a subgrouping for targeted treatment system. GPs were offered an electronic six-item subgrouping tool, to identify patients according to their risk of poor outcome ('high', 'low') in order to help inform their decision making about treatment approaches. Recruitment was based on a 'maximum diversification sample', to obtain a wide representation of views across all five practices. A coding scheme was developed based on the emergent findings, and the data were analysed using 'constant comparison', drawing upon insights and developing connections between themes. We adopted the normalisation process theory (NPT) to explain the uptake of the new system and to examine the relevance of coherence for the implementation of innovations in organisations. RESULTS: GPs perceived back pain as a low clinical priority, and highlighted the importance of 'practical' and 'relational' coherence in decisions to adopt and engage with the new subgrouping for targeted treatment system. Health professionals often engage in 'sense making' about new innovations to 'road test' their applicability or relevance to daily clinical routines. Low back pain was generally perceived as an 'uninteresting' and clinically unchallenging health problem by GPs, which may partly explain their lack of engagement with the new subgrouping for targeted treatment system. The adoption of this new way of working by GPs was determined by the meaning that they ascribed to it in the context of their daily clinical routines. CONCLUSIONS: We conclude that the key obstacle to implementation of the new subgrouping for targeted treatment system for low back pain in primary care was an initial failure to achieve 'coherence' of the desired practice change with GPs. Despite this, GPs used the tool to different degrees, though this signified a general commitment to participating in the study rather than a deeper attitude change towards the new system. PMID- 21554697 TI - Image guidance using 3D-ultrasound (3D-US) for daily positioning of lumpectomy cavity for boost irradiation. AB - PURPOSE: The goal of this study was to evaluate the use of 3D ultrasound (3DUS) breast IGRT for electron and photon lumpectomy site boost treatments. MATERIALS AND METHODS: 20 patients with a prescribed photon or electron boost were enrolled in this study. 3DUS images were acquired both at time of simulation, to form a coregistered CT/3DUS dataset, and at the time of daily treatment delivery. Intrafractional motion between treatment and simulation 3DUS datasets were calculated to determine IGRT shifts. Photon shifts were evaluated isocentrically, while electron shifts were evaluated in the beam's-eye-view. Volume differences between simulation and first boost fraction were calculated. Further, to control for the effect of change in seroma/cavity volume due to time lapse between the 2 sets of images, interfraction IGRT shifts using the first boost fraction as reference for all subsequent treatment fractions were also calculated. RESULTS: For photon boosts, IGRT shifts were 1.1 +/- 0.5 cm and 50% of fractions required a shift >1.0 cm. Volume change between simulation and boost was 49 +/- 31%. Shifts when using the first boost fraction as reference were 0.8 +/- 0.4 cm and 24% required a shift >1.0 cm. For electron boosts, shifts were 1.0 +/- 0.5 cm and 52% fell outside the dosimetric penumbra. Interfraction analysis relative to the first fraction noted the shifts to be 0.8 +/- 0.4 cm and 36% fell outside the penumbra. CONCLUSION: The lumpectomy cavity can shift significantly during fractionated radiation therapy. 3DUS can be used to image the cavity and correct for interfractional motion. Further studies to better define the protocol for clinical application of IGRT in breast cancer is needed. PMID- 21554698 TI - Metabolic syndrome and dietary components are associated with coronary artery disease risk score in free-living adults: a cross-sectional study. AB - BACKGROUND: Coronary artery disease (CAD) is among the main causes of death in developed countries, and diet and lifestyle can influence CAD incidence. OBJECTIVE: To evaluate the association of coronary artery disease risk score with dietary, anthropometric and biochemical components in adults clinically selected for a lifestyle modification program. METHODS: 362 adults (96 men, 266 women, 53.9 +/- 9.4 years) fulfilled the inclusion criteria by presenting all the required data. The Framingham score was calculated and the IV Brazilian Guideline on Dyslipidemia and Prevention of Atherosclerosis was adopted for classification of the CAD risks. Anthropometric assessments included waist circumference (WC), body fat and calculated BMI (kg/m2) and muscle-mass index (MMI kg/m2). Dietary intake was estimated through 24 h dietary recall. Fasting blood was used for biochemical analysis. Metabolic Syndrome (MS) was diagnosed using NCEP-ATPIII (2001) criteria. Logistic regression was used to determine the odds of CAD risks according to the altered components of MS, dietary, anthropometric, and biochemical components. RESULTS: For a sample with a BMI 28.5 +/- 5.0 kg/m2 the association with lower risk (<10% CAD) were lower age (<60 years old), and plasma values of uric acid. The presence of MS within low, intermediary, and high CAD risk categories was 30.8%, 55.5%, and 69.8%, respectively. The independent risk factors associated with CAD risk score was MS and uric acid, and the protective factors were recommended intake of saturated fat and fiber and muscle mass index. CONCLUSION: Recommended intake of saturated fat and dietary fiber, together with proper muscle mass, are inversely associated with CAD risk score. On the other hand, the presence of MS and high plasma uric acid are associated with CAD risk score. PMID- 21554699 TI - S1P, dihydro-S1P and C24:1-ceramide levels in the HDL-containing fraction of serum inversely correlate with occurrence of ischemic heart disease. AB - BACKGROUND: The lysosphingolipid sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence suggests that many of the effects of HDL on cardiovascular function may be attributable to its S1P cargo. METHODS: Here we have evaluated how levels of S1P and related sphingolipids in an HDL-containing fraction of human serum correlate with occurrence of ischemic heart disease (IHD). To accomplish this we used liquid chromatography-mass spectrometry to measure S1P levels in the HDL-containing fraction of serum (depleted of LDL and VLDL) from 204 subjects in the Copenhagen City Heart Study (CCHS). The study group consisted of individuals having high serum HDL cholesterol (HDL-C) (females:>= 73.5 mg/dL; males:>= 61.9 mg/dL) and verified IHD; subjects with high HDL-C and no IHD; individuals with low HDL-C (females:<= 38.7 mg/dL; males:<= 34.1 mg/dL) and IHD, and subjects with low HDL-C and no IHD. RESULTS: The results show a highly significant inverse relationship between the level of S1P in the HDL-containing fraction of serum and the occurrence of IHD. Furthermore, an inverse relationship with IHD was also observed for two other sphingolipids, dihydro-S1P and C24:1-ceramide, in the HDL-containing fraction of serum. Additionally, we demonstrated that the amount of S1P on HDL correlates with the magnitude of HDL-induced endothelial cell barrier signaling. CONCLUSIONS: These findings indicate that compositional differences of sphingolipids in the HDL containing fraction of human serum are related to the occurrence of IHD, and may contribute to the putative protective role of HDL in IHD. PMID- 21554700 TI - Influence of the training set on the accuracy of surface EMG classification in dynamic contractions for the control of multifunction prostheses. AB - BACKGROUND: For high usability, myo-controlled devices require robust classification schemes during dynamic contractions. Therefore, this study investigates the impact of the training data set in the performance of several pattern recognition algorithms during dynamic contractions. METHODS: A 9 class experiment was designed involving both static and dynamic situations. The performance of various feature extraction methods and classifiers was evaluated in terms of classification accuracy. RESULTS: It is shown that, combined with a threshold to detect the onset of the contraction, current pattern recognition algorithms used on static conditions provide relatively high classification accuracy also on dynamic situations. Moreover, the performance of the pattern recognition algorithms tested significantly improved by optimizing the choice of the training set. Finally, the results also showed that rather simple approaches for classification of time domain features provide results comparable to more complex classification methods of wavelet features. CONCLUSIONS: Non-stationary surface EMG signals recorded during dynamic contractions can be accurately classified for the control of multi-function prostheses. PMID- 21554701 TI - Life-threatening aortic thrombosis in a trauma patient homozygous for factor V Leiden mutation: Case report. AB - We report a case of near fatal aortic thrombosis in a trauma patient homozygous for mutation of Factor V Leiden. He responded well to vascular surgery and intensive care unit management and was discharged successfully from the hospital one month later. PMID- 21554702 TI - New clues to understand how CENP-A maintains centromere identity. AB - The centromere is a specialized chromosomal region that directs the formation of the kinetochore, a huge protein assembly that acts as the attachment site for spindle microtubules and carries out chromosome movement during cell division. Centromere loss or the presence of extra centromeres adversely affect chromosome segregation and may result in aneuploidy, a condition found in many human tumors and a major cause of miscarriages and birth defects. Consequently, understanding the basis of centromere determination and propagation is of great relevance to both fundamental and clinical research. In recent years, it has become clear that centromeres are defined by the presence of a histone H3 variant known as Centromere Protein A, CENP-A, or CenH3. Much effort has been devoted to understanding the mechanisms that drive the assembly of CENP-A containing nucleosomes exclusively onto centromeric DNA, as well as the peculiar structure of these nucleosomes. We have recently developed an immunofluorescence-based assay that measures CENP-A incorporation in the centromeres of chromosomes assembled in Xenopus egg extracts. The spatial and temporal specificity of CENP-A deposition observed in human cells can be recapitulated in this in vitro system, making it suitable to dissect the precise role of the different factors that contribute to this pathway. Here, we discuss our results together with other recent advances in our understanding of the mechanisms that mediate centromere inheritance. PMID- 21554703 TI - N-acetylcysteine lacks universal inhibitory activity against influenza A viruses. AB - N-acetylcysteine (NAC) has been recently proposed as an adjuvant therapeutic drug for influenza pneumonia in humans. This proposal is based on its ability to restrict influenza virus replication in vitro and to attenuate the severity of the disease in mouse models. Although available studies were made with different viruses (human and avian), published information related to the anti-influenza spectrum of NAC is scarce. In this study, we show that NAC is unable to alter the course of a fatal influenza pneumonia caused by inoculation of a murinized swine H1N1 influenza virus. NAC was indeed able to inhibit the swine virus in vitro but far less than reported for other strains. Therefore, susceptibility of influenza viruses to NAC appears to be strain-dependent, suggesting that it cannot be considered as a universal treatment for influenza pneumonia. PMID- 21554704 TI - Evaluation of three high abundance protein depletion kits for umbilical cord serum proteomics. AB - BACKGROUND: High abundance protein depletion is a major challenge in the study of serum/plasma proteomics. Prior to this study, most commercially available kits for depletion of highly abundant proteins had only been tested and evaluated in adult serum/plasma, while the depletion efficiency on umbilical cord serum/plasma had not been clarified. Structural differences between some adult and fetal proteins (such as albumin) make it likely that depletion approaches for adult and umbilical cord serum/plasma will be variable. Therefore, the primary purposes of the present study are to investigate the efficiencies of several commonly-used commercial kits during high abundance protein depletion from umbilical cord serum and to determine which kit yields the most effective and reproducible results for further proteomics research on umbilical cord serum. RESULTS: The immunoaffinity based kits (PROTIA-Sigma and 5185-Agilent) displayed higher depletion efficiency than the immobilized dye based kit (PROTBA-Sigma) in umbilical cord serum samples. Both the PROTIA-Sigma and 5185-Agilent kit maintained high depletion efficiency when used three consecutive times. Depletion by the PROTIA-Sigma Kit improved 2DE gel quality by reducing smeared bands produced by the presence of high abundance proteins and increasing the intensity of other protein spots. During image analysis using the identical detection parameters, 411 +/- 18 spots were detected in crude serum gels, while 757 +/- 43 spots were detected in depleted serum gels. Eight spots unique to depleted serum gels were identified by MALDI- TOF/TOF MS, seven of which were low abundance proteins. CONCLUSIONS: The immunoaffinity based kits exceeded the immobilized dye based kit in high abundance protein depletion of umbilical cord serum samples and dramatically improved 2DE gel quality for detection of trace biomarkers. PMID- 21554705 TI - Alertness and visuospatial attention in clinical depression. AB - BACKGROUND: Cognitive deficits are a substantial burden in clinical depression. The present study considered dysfunction in the right-hemispheric attention network in depression, examining alertness and visuospatial attention. METHODS: Three computerized visuospatial attention tests and an alertness test were administered to 16 depressive patients and 16 matched healthy controls. RESULTS: Although no significant group effect was observed, alertness predicted reduced visuospatial performance in the left hemifield. Furthermore, sad mood showed a trend towards predicting left visual field omissions. CONCLUSIONS: Decreased alertness may lead to lower left hemifield visuospatial attention; this mechanism may be responsible for a spatial bias to the right side in depression, even though treatment of depression and anxiety may reduce this cognitive deficit. PMID- 21554706 TI - AKAP5 and AKAP12 Form Homo-oligomers. AB - BACKGROUND: A-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, G-protein coupled receptors and ion channels. We studied AKAP5 (AKAP79; MW ~47 kDa) and AKAP12 (gravin, SSECKS; MW ~191 kDa) to probe if these AKAP scaffolds oligomerize. RESULTS: In gel analysis and sodium-dodecyl sulfate denaturation, AKAP12 behaved with a MW of a homo-dimer. Only in the presence of the chaotropic agent 8 M urea did gel analysis reveal a monomeric form of AKAP12. By separation by steric-exclusion chromatography, AKAP12 migrates with MW of ~840 kDa, suggestive of higher-order complexes such as a tetramer. Interestingly, the N-(1 840) and C-(840-1782) terminal regions of AKAP12 themselves retained the ability to form dimers, suggesting that the structural basis for the dimerization is not restricted to a single "domain" found within the molecule. In either sodium dodecyl sulfate or urea, AKAP5 displayed a relative mobility of a monomer, but by co-immunoprecipitation in native state was shown to oligomerize. When subjected to steric-exclusion chromatography, AKAP5 forms higher-order complexes with MW ~220 kDa, suggestive of tetrameric assemblies. CONCLUSION: Both AKAP5 and AKAP12 display the capacity to form supermolecular homo-oligomeric structures that likely influence the localization and function of these molecular scaffolds. PMID- 21554707 TI - Crystal structures of Burkholderia cenocepacia dihydropteroate synthase in the apo-form and complexed with the product 7,8-dihydropteroate. AB - BACKGROUND: The enzyme dihydropteroate synthase (DHPS) participates in the de novo synthesis of folate cofactors by catalyzing the formation of 7,8 dihydropteroate from condensation of p-aminobenzoic acid with 6-hydroxymethyl-7,8 dihydropteroate pyrophosphate. DHPS is absent from humans, who acquire folates from diet, and has been validated as an antimicrobial therapeutic target by chemical and genetic means. The bacterium Burkholderia cenocepacia is an opportunistic pathogen and an infective agent of cystic fibrosis patients. The organism is highly resistant to antibiotics and there is a recognized need for the identification of new drugs against Burkholderia and related Gram-negative pathogens. Our characterization of the DHPS active site and interactions with the enzyme product are designed to underpin early stage drug discovery. RESULTS: An efficient recombinant protein expression system for DHPS from B. cenocepacia (BcDHPS) was prepared, the dimeric enzyme purified in high yield and crystallized. The structure of the apo-enzyme and the complex with the product 7,8-dihydropteroate have been determined to 2.35 A and 1.95 A resolution respectively in distinct orthorhombic crystal forms. The latter represents the first crystal structure of the DHPS-pterin product complex, reveals key interactions involved in ligand binding, and reinforces data generated by other structural studies. Comparisons with orthologues identify plasticity near the substrate-binding pocket and in particular a range of loop conformations that contribute to the architecture of the DHPS active site. These structural data provide a foundation for hit discovery. An intriguing observation, an artifact of the analysis, that of a potential sulfenamide bond within the ligand complex structure is mentioned. CONCLUSION: Structural similarities between BcDHPS and orthologues from other Gram-negative species are evident as expected on the basis of a high level of sequence identity. The presence of 7,8-dihydropteroate in the binding site provides details about ligand recognition by the enzyme and the different states of the enzyme allow us to visualize distinct conformational states of loops adjacent to the active site. Improved drugs to combat infections by Burkholderia sp. and related Gram-negative bacteria are sought and our study now provides templates to assist that process and allow us to discuss new ways of inhibiting DHPS. PMID- 21554708 TI - Common and unique elements of the ABA-regulated transcriptome of Arabidopsis guard cells. AB - BACKGROUND: In the presence of drought and other desiccating stresses, plants synthesize and redistribute the phytohormone abscisic acid (ABA). ABA promotes plant water conservation by acting on specialized cells in the leaf epidermis, guard cells, which border and regulate the apertures of stomatal pores through which transpirational water loss occurs. Following ABA exposure, solute uptake into guard cells is rapidly inhibited and solute loss is promoted, resulting in inhibition of stomatal opening and promotion of stomatal closure, with consequent plant water conservation. There is a wealth of information on the guard cell signaling mechanisms underlying these rapid ABA responses. To investigate ABA regulation of gene expression in guard cells in a systematic genome-wide manner, we analyzed data from global transcriptomes of guard cells generated with Affymetrix ATH1 microarrays, and compared these results to ABA regulation of gene expression in leaves and other tissues. RESULTS: The 1173 ABA-regulated genes of guard cells identified by our study share significant overlap with ABA-regulated genes of other tissues, and are associated with well-defined ABA-related promoter motifs such as ABREs and DREs. However, we also computationally identified a unique cis-acting motif, GTCGG, associated with ABA-induction of gene expression specifically in guard cells. In addition, approximately 300 genes showing ABA regulation unique to this cell type were newly uncovered by our study. Within the ABA-regulated gene set of guard cells, we found that many of the genes known to encode ion transporters associated with stomatal opening are down-regulated by ABA, providing one mechanism for long-term maintenance of stomatal closure during drought. We also found examples of both negative and positive feedback in the transcriptional regulation by ABA of known ABA-signaling genes, particularly with regard to the PYR/PYL/RCAR class of soluble ABA receptors and their downstream targets, the type 2C protein phosphatases. Our data also provide evidence for cross-talk at the transcriptional level between ABA and another hormonal inhibitor of stomatal opening, methyl jasmonate. CONCLUSIONS: Our results engender new insights into the basic cell biology of guard cells, reveal common and unique elements of ABA-regulation of gene expression in guard cells, and set the stage for targeted biotechnological manipulations to improve plant water use efficiency. PMID- 21554709 TI - PeakRanger: a cloud-enabled peak caller for ChIP-seq data. AB - BACKGROUND: Chromatin immunoprecipitation (ChIP), coupled with massively parallel short-read sequencing (seq) is used to probe chromatin dynamics. Although there are many algorithms to call peaks from ChIP-seq datasets, most are tuned either to handle punctate sites, such as transcriptional factor binding sites, or broad regions, such as histone modification marks; few can do both. Other algorithms are limited in their configurability, performance on large data sets, and ability to distinguish closely-spaced peaks. RESULTS: In this paper, we introduce PeakRanger, a peak caller software package that works equally well on punctate and broad sites, can resolve closely-spaced peaks, has excellent performance, and is easily customized. In addition, PeakRanger can be run in a parallel cloud computing environment to obtain extremely high performance on very large data sets. We present a series of benchmarks to evaluate PeakRanger against 10 other peak callers, and demonstrate the performance of PeakRanger on both real and synthetic data sets. We also present real world usages of PeakRanger, including peak-calling in the modENCODE project. CONCLUSIONS: Compared to other peak callers tested, PeakRanger offers improved resolution in distinguishing extremely closely-spaced peaks. PeakRanger has above-average spatial accuracy in terms of identifying the precise location of binding events. PeakRanger also has excellent sensitivity and specificity in all benchmarks evaluated. In addition, PeakRanger offers significant improvements in run time when running on a single processor system, and very marked improvements when allowed to take advantage of the MapReduce parallel environment offered by a cloud computing resource. PeakRanger can be downloaded at the official site of modENCODE project: http://www.modencode.org/software/ranger/ PMID- 21554710 TI - Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design. AB - BACKGROUND: Obesity leads to an increase in inflammation and insulin resistance. This study determined antioxidant activity of flaxseed and its role in inflammation and insulin resistance in obese glucose intolerant people. METHODS: Using a randomized crossover design, nine obese glucose intolerant people consumed 40 g ground flaxseed or 40 g wheat bran daily for 12 weeks with a 4-week washout period. Plasma inflammation biomarkers (CRP, TNF-alpha, and IL-6), glucose, insulin, and thiobaribituric acid reactive substance (TBARS) were measured before and after of each supplementation. RESULTS: Flaxseed supplementation decreased TBARS (p = 0.0215) and HOMA-IR (p = 0.0382). Flaxseed or wheat bran supplementation did not change plasma inflammatory biomarkers. A positive relationship was found between TBARS and HOMA-IR (r = 0.62, p = 0.0003). CONCLUSIONS: The results of the study weakly support that decreased insulin resistance might have been secondary to antioxidant activity of flaxseed. However, the mechanism(s) of decreased insulin resistance by flaxseed should be further determined using flaxseed lignan. PMID- 21554711 TI - Respondent-driven sampling on the Thailand-Cambodia border. II. Knowledge, perception, practice and treatment-seeking behaviour of migrants in malaria endemic zones. AB - BACKGROUND: Population movements along the Thailand-Cambodia border, particularly among highly mobile and hard-to-access migrant groups from Cambodia and Myanmar, are assumed to play a key role in the spread of artemisinin resistance. Data on treatment-seeking behaviours, knowledge and perceptions about malaria, and use of preventive measures is lacking as characteristics of this population prevent them from being represented in routine surveillance and the lack of a sampling frame makes reliable surveys challenging. METHODS: A survey of migrant populations from Cambodia and Myanmar was implemented in five selected rural locations in Thailand along the Thai-Cambodian border using respondent driven sampling (RDS) to determine demographic characteristics of the population, migratory patterns, knowledge about malaria, and health-care -seeking behaviours. RESULTS: The majority of migrants from Myanmar are long-term residents (98%) with no plans to move back to Myanmar, understand spoken Thai (77%) and can therefore benefit from health messages in Thai, have Thai health insurance (99%) and accessed public health services in Thailand (63%) for their last illness. In comparison, the majority of Cambodian migrants are short-term (72%). Of the short-term Cambodian migrants, 92% work in agriculture, 18% speak Thai, 3.4% have Thai health insurance, and the majority returned to Cambodia for treatment (45%), self treated (11%), or did not seek treatment for their last illness (27%). CONCLUSION: Most highly mobile migrants along the Thai-Cambodia border are not accessing health messages or health treatment in Thailand, increasing their risk of malaria and facilitating the spread of potentially resistant Plasmodium falciparum as they return to Cambodia to seek treatment. Reaching out to highly mobile migrants with health messaging they can understand and malaria diagnosis and treatment services they can access is imperative in the effort to contain the spread of artemisinin-resistant P. falciparum. PMID- 21554712 TI - Quantum dots: a new tool for anti-malarial drug assays. AB - BACKGROUND: Malaria infects over 300 million people every year and one of the major obstacles for the eradication of the disease is parasite's resistance to current chemotherapy, thus new drugs are urgently needed. Quantum dot (QD) is a fluorescent nanocrystal that has been in the spotlight as a robust tool for visualization of live cell processes in real time. Here, a simple and efficient method using QD to directly label Plasmodium falciparum-infected erythrocytes (iRBCs) was searched in order to use the QD as a probe in an anti-malarial drug screening assay. METHODS: A range of QDs with different chemical coatings were tested for their ability to specifically bind iRBCs by immunofluorescence assay (IFA). One QD was selected and used to detect parasite growth and drug sensitivity by flow cytometry. RESULTS: PEGylated-cationic QD (PCQD) was found to specifically label infected erythrocytes preferentially with late stage parasites. The detection of QD-labelled infected erythrocytes by flow cytometry was sensitive enough to monitor chloroquine anti-malarial toxicity with a drug incubation period as short as 24 h (EC50 = 113nM). A comparison of our assay with another widely used anti-malarial drug screening assay, the pLDH assay, showed that PCQD-based assay had 50% improved sensitivity in detecting drug efficacy within a parasite life cycle. An excellent Z-factor of 0.8 shows that the QD assay is suitable for high-throughput screening. CONCLUSIONS: This new assay can offer a rapid and robust platform to screen novel classes of anti-malarial drugs. PMID- 21554713 TI - Biomarker discovery and redundancy reduction towards classification using a multi factorial MALDI-TOF MS T2DM mouse model dataset. AB - BACKGROUND: Diabetes like many diseases and biological processes is not mono causal. On the one hand multi-factorial studies with complex experimental design are required for its comprehensive analysis. On the other hand, the data from these studies often include a substantial amount of redundancy such as proteins that are typically represented by a multitude of peptides. Coping simultaneously with both complexities (experimental and technological) makes data analysis a challenge for Bioinformatics. RESULTS: We present a comprehensive work-flow tailored for analyzing complex data including data from multi-factorial studies. The developed approach aims at revealing effects caused by a distinct combination of experimental factors, in our case genotype and diet. Applying the developed work-flow to the analysis of an established polygenic mouse model for diet induced type 2 diabetes, we found peptides with significant fold changes exclusively for the combination of a particular strain and diet. Exploitation of redundancy enables the visualization of peptide correlation and provides a natural way of feature selection for classification and prediction. Classification based on the features selected using our approach performs similar to classifications based on more complex feature selection methods. CONCLUSIONS: The combination of ANOVA and redundancy exploitation allows for identification of biomarker candidates in multi-dimensional MALDI-TOF MS profiling studies with complex experimental design. With respect to feature selection our method provides a fast and intuitive alternative to global optimization strategies with comparable performance. The method is implemented in R and the scripts are available by contacting the corresponding author. PMID- 21554714 TI - Physical mapping and BAC-end sequence analysis provide initial insights into the flax (Linum usitatissimum L.) genome. AB - BACKGROUND: Flax (Linum usitatissimum L.) is an important source of oil rich in omega-3 fatty acids, which have proven health benefits and utility as an industrial raw material. Flax seeds also contain lignans which are associated with reducing the risk of certain types of cancer. Its bast fibres have broad industrial applications. However, genomic tools needed for molecular breeding were non existent. Hence a project, Total Utilization Flax GENomics (TUFGEN) was initiated. We report here the first genome-wide physical map of flax and the generation and analysis of BAC-end sequences (BES) from 43,776 clones, providing initial insights into the genome. RESULTS: The physical map consists of 416 contigs spanning ~368 Mb, assembled from 32,025 fingerprints, representing roughly 54.5% to 99.4% of the estimated haploid genome (370-675 Mb). The N50 size of the contigs was estimated to be ~1,494 kb. The longest contig was ~5,562 kb comprising 437 clones. There were 96 contigs containing more than 100 clones. Approximately 54.6 Mb representing 8-14.8% of the genome was obtained from 80,337 BES. Annotation revealed that a large part of the genome consists of ribosomal DNA (~13.8%), followed by known transposable elements at 6.1%. Furthermore, ~7.4% of sequence was identified to harbour novel repeat elements. Homology searches against flax-ESTs and NCBI-ESTs suggested that ~5.6% of the transcriptome is unique to flax. A total of 4064 putative genomic SSRs were identified and are being developed as novel markers for their use in molecular breeding. CONCLUSION: The first genome-wide physical map of flax constructed with BAC clones provides a framework for accessing target loci with economic importance for marker development and positional cloning. Analysis of the BES has provided insights into the uniqueness of the flax genome. Compared to other plant genomes, the proportion of rDNA was found to be very high whereas the proportion of known transposable elements was low. The SSRs identified from BES will be valuable in saturating existing linkage maps and for anchoring physical and genetic maps. The physical map and paired-end reads from BAC clones will also serve as scaffolds to build and validate the whole genome shotgun assembly. PMID- 21554715 TI - Similarities and differences in structure, expression, and functions of VLDLR and ApoER2. AB - Very Low Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2) are important receptors in the brain for mediating the signaling effects of the extracellular matrix protein Reelin, affecting neuronal function in development and in the adult brain. VLDLR and ApoER2 are members of the low density lipoprotein family, which also mediates the effects of numerous other extracellular ligands, including apolipoprotein E. Although VLDLR and ApoER2 are highly homologous, they differ in a number of ways, including structural differences, expression patterns, alternative splicing, and binding of extracellular and intracellular proteins. This review aims to summarize important aspects of VLDLR and ApoER2 that may account for interesting recent findings that highlight the unique functions of each receptor. PMID- 21554716 TI - Identification of the protease cleavage sites in a reconstituted Gag polyprotein of an HERV-K(HML-2) element. AB - BACKGROUND: The human genome harbors several largely preserved HERV-K(HML-2) elements. Although this retroviral family comes closest of all known HERVs to producing replication competent virions, mutations acquired during their chromosomal residence have rendered them incapable of expressing infectious particles. This also holds true for the HERV-K113 element that has conserved open reading frames (ORFs) for all its proteins in addition to a functional LTR promoter. Uncertainty concerning the localization and impact of post-insertional mutations has greatly hampered the functional characterization of these ancient retroviruses and their proteins. However, analogous to other betaretroviruses, it is known that HERV-K(HML-2) virions undergo a maturation process during or shortly after release from the host cell. During this process, the subdomains of the Gag polyproteins are released by proteolytic cleavage, although the nature of the mature HERV-K(HML-2) Gag proteins and the exact position of the cleavage sites have until now remained unknown. RESULTS: By aligning the amino acid sequences encoded by the gag-pro-pol ORFs of HERV-K113 with the corresponding segments from 10 other well-preserved human specific elements we identified non synonymous post-insertional mutations that have occurred in this region of the provirus. Reversion of these mutations and a partial codon optimization facilitated the large-scale production of maturation-competent HERV-K113 virus like particles (VLPs). The Gag subdomains of purified mature VLPs were separated by reversed-phase high-pressure liquid chromatography and initially characterized using specific antibodies. Cleavage sites were identified by mass spectrometry and N-terminal sequencing and confirmed by mutagenesis. Our results indicate that the gag gene product Pr74Gag of HERV-K(HML-2) is processed to yield p15-MA (matrix), SP1 (spacer peptide of 14 amino acids), p15, p27-CA (capsid), p10-NC (nucleocapsid) and two C-terminally encoded glutamine- and proline-rich peptides, QP1 and QP2, spanning 23 and 19 amino acids, respectively. CONCLUSIONS: Expression of reconstituted sequences of original HERV elements is an important tool for studying fundamental aspects of the biology of these ancient viruses. The analysis of HERV-K(HML-2) Gag processing and the nature of the mature Gag proteins presented here will facilitate further studies of the discrete functions of these proteins and of their potential impact on the human host. PMID- 21554717 TI - Properties of a short questionnaire for assessing primary care experiences for children in a population survey. AB - BACKGROUND: The Primary Care Assessment Tool (PCAT) is an interesting set of tools for primary care research. A very short version could inform policy makers about consumer experiences with primary care (PC) through health surveys. This work aimed to investigate the validity and reliability of a selection of items from the child short edition (CS) of the PCAT. METHODS: A 24 item questionnaire permitted the identification of a regular source of care and the assessment of the key attributes of first contact, ongoing care over time, coordination, services available and services received (comprehensiveness), and cultural competence. Structural validity, reliability, and construct validity were assessed using responses from 2,200 parents of a representative sample of the population aged 0 to 14 years in Catalonia (Spain) who participated in the 2006 Health Survey. Structural validity was analyzed using exploratory and confirmatory factor analyses and reliability was assessed using Cronbach's alpha. Construct validity was assessed using linear regression analysis between PC experience scores and a measure of overall user satisfaction with healthcare services. RESULTS: A total of 2,095 (95.2%) parents provided useable responses on PC. After Confirmatory Factor Analysis (CFA), the best fitting model was a 5 factor model in which the original dimensions of first contact and ongoing care were collapsed into one. The CFA also showed a second order factor onto which all domains except services available loaded (root mean square error of approximation = 0.000; comparative fit index = 1.00). Cronbach's alpha values for one of the original scales (first-contact) was poor (alpha < 0.50), but improved using the modified factor structure (alpha > 0.70). Scores on the scales were correlated with satisfaction with healthcare services (p < 0.01), thereby providing some preliminary evidence of construct validity. CONCLUSIONS: This very short questionnaire obtained from the PCAT-CE yields information about five attributes of PC and a summary score. It has shown evidence of validity and reliability for judgments about experiences with primary care overall. If space on surveys is at a premium, the instrument could be useful as a measure of PC experiences. PMID- 21554718 TI - Local activation of cannabinoid CB1 receptors in the urinary bladder reduces the inflammation-induced sensitization of bladder afferents. AB - BACKGROUND: Systemic administration of cannabinoid agonists is known to reduce pain induced by bladder inflammation and to modulate cystometric parameters in vivo. We have previously reported that intravesical administration of a cannabinoid agonist reduces the electrical activity of bladder afferents under normal conditions. However, the effects of local activation of bladder cannabinoid receptors on afferent activity during inflammation are unknown. This study was aimed to assess the effects of intravesical administration of a cannabinoid agonist on the discharges of afferent fibers in inflamed bladders ex vivo. We also characterized the expression of CB1 receptors in the bladder and their localization and co-expression with TRPV1, a marker of nociceptive afferents. RESULTS: Compared to untreated animals, afferent fiber activity in inflamed bladders was increased for intravesical pressures between 10 and 40 mmHg. Local treatment with a non selective cannabinoid agonist (AZ12646915) significantly reduced the afferent activity at intravesical pressures above 20 mmHg. This effect was blocked by AM251 but not by AM630 (selective for CB1 and CB2 respectively). Finally, CB1 was co-expressed with TRPV1 in control and inflamed bladders. CONCLUSION: These results demonstrate that sensitization of bladder afferents induced by inflammation is partly suppressed by intravesical activation of cannabinoid receptors, an effect that appears to be mediated by CB1 receptors. Also, TRPV1 positive fibers were found to co-express CB1, supporting the hypothesis of a direct action of the cannabinoid agonist on nociceptive afferents. Taken together, these results indicate a peripheral modulation by the cannabinoid system of bladder hypersensitivity during inflammation. PMID- 21554719 TI - Brace technology thematic series - The Sforzesco and Sibilla braces, and the SPoRT (Symmetric, Patient oriented, Rigid, Three-dimensional, active) concept. AB - BACKGROUND: Bracing is an effective strategy for scoliosis treatment, but there is no consensus on the best type of brace, nor on the way in which it should act on the spine to achieve good correction. The aim of this paper is to present the family of SPoRT (Symmetric, Patient-oriented, Rigid, Three-dimensional, active) braces: Sforzesco (the first introduced), Sibilla and Lapadula. METHODS: The Sforzesco brace was developed following specific principles of correction. Due to its overall symmetry, the brace provides space over pathological depressions and pushes over elevations. Correction is reached through construction of the envelope, pushes, escapes, stops, and drivers. The real novelty is the drivers, introduced for the first time with the Sforzesco brace; they allow to achieve the main action of the brace: a three-dimensional elongation pushing the spine in a down-up direction.Brace prescription is made plane by plane: frontal (on the "slopes", another novelty of this concept, i.e. the laterally flexed sections of the spine), horizontal, and sagittal. The brace is built modelling the trunk shape obtained either by a plaster cast mould or by CAD-CAM construction. Brace checking is essential, since SPoRT braces are adjustable and customisable according to each individual curve pattern.Treatment time and duration is individually tailored (18-23 hours per day until Risser 3, then gradual reduction). SEAS (Scientific Exercises Approach to Scoliosis) exercises are a key factor to achieve success. RESULTS: The Sforzesco brace has shown to be more effective than the Lyon brace (matched case/control), equally effective as the Risser plaster cast (prospective cohort with retrospective controls), more effective than the Risser cast + Lyon brace in treating curves over 45 degrees Cobb (prospective cohort), and is able to improve aesthetic appearance (prospective cohort). CONCLUSIONS: The SPoRT concept of bracing (three dimensional elongation pushing in a down-up direction) is different from the other corrective systems: 3-point, traction, postural, and movement-based. The Sforzesco brace, being comparable to casting, may be the best brace for the worst cases. PMID- 21554720 TI - Inferring functional modules of protein families with probabilistic topic models. AB - BACKGROUND: Genome and metagenome studies have identified thousands of protein families whose functions are poorly understood and for which techniques for functional characterization provide only partial information. For such proteins, the genome context can give further information about their functional context. RESULTS: We describe a Bayesian method, based on a probabilistic topic model, which directly identifies functional modules of protein families. The method explores the co-occurrence patterns of protein families across a collection of sequence samples to infer a probabilistic model of arbitrarily-sized functional modules. CONCLUSIONS: We show that our method identifies protein modules - some of which correspond to well-known biological processes - that are tightly interconnected with known functional interactions and are different from the interactions identified by pairwise co-occurrence. The modules are not specific to any given organism and may combine different realizations of a protein complex or pathway within different taxa. PMID- 21554721 TI - PubChem3D: Similar conformers. AB - BACKGROUND: PubChem is a free and open public resource for the biological activities of small molecules. With many tens of millions of both chemical structures and biological test results, PubChem is a sizeable system with an uneven degree of available information. Some chemical structures in PubChem include a great deal of biological annotation, while others have little to none. To help users, PubChem pre-computes "neighboring" relationships to relate similar chemical structures, which may have similar biological function. In this work, we introduce a "Similar Conformers" neighboring relationship to identify compounds with similar 3-D shape and similar 3-D orientation of functional groups typically used to define pharmacophore features. RESULTS: The first two diverse 3-D conformers of 26.1 million PubChem Compound records were compared to each other, using a shape Tanimoto (ST) of 0.8 or greater and a color Tanimoto (CT) of 0.5 or greater, yielding 8.16 billion conformer neighbor pairs and 6.62 billion compound neighbor pairs, with an average of 253 "Similar Conformers" compound neighbors per compound. Comparing the 3-D neighboring relationship to the corresponding 2-D neighboring relationship ("Similar Compounds") for molecules such as caffeine, aspirin, and morphine, one finds unique sets of related chemical structures, providing additional significant biological annotation. The PubChem 3-D neighboring relationship is also shown to be able to group a set of non-steroidal anti-inflammatory drugs (NSAIDs), despite limited PubChem 2-D similarity.In a study of 4,218 chemical structures of biomedical interest, consisting of many known drugs, using more diverse conformers per compound results in more 3-D compound neighbors per compound; however, the overlap of the compound neighbor lists per conformer also increasingly resemble each other, being 38% identical at three conformers and 68% at ten conformers. Perhaps surprising is that the average count of conformer neighbors per conformer increases rather slowly as a function of diverse conformers considered, with only a 70% increase for a ten times growth in conformers per compound (a 68-fold increase in the conformer pairs considered).Neighboring 3-D conformers on the scale performed, if implemented naively, is an intractable problem using a modest sized compute cluster. Methodology developed in this work relies on a series of filters to prevent performing 3-D superposition optimization, when it can be determined that two conformers cannot possibly be a neighbor. Most filters are based on Tanimoto equation volume constraints, avoiding incompatible conformers; however, others consider preliminary superposition between conformers using reference shapes. CONCLUSION: The "Similar Conformers" 3-D neighboring relationship locates similar small molecules of biological interest that may go unnoticed when using traditional 2-D chemical structure graph-based methods, making it complementary to such methodologies. The computational cost of 3-D similarity methodology on a wide scale, such as PubChem contents, is a considerable issue to overcome. Using a series of efficient filters, an effective throughput rate of more than 150,000 conformers per second per processor core was achieved, more than two orders of magnitude faster than without filtering. PMID- 21554722 TI - The prognostic effect of ethnicity for gastric and esophageal cancer: the population-based experience in British Columbia, Canada. AB - BACKGROUND: Gastric and esophageal cancers are among the most lethal human malignancies. Their epidemiology is geographically diverse. This study compares the survival of gastric and esophageal cancer patients among several ethnic groups including Chinese, South Asians, Iranians and Others in British Columbia (BC), Canada. METHODS: Data were obtained from the population-based BC Cancer Registry for patients diagnosed with invasive esophageal and gastric cancer between 1984 and 2006. The ethnicity of patients was estimated according to their names and categorized as Chinese, South Asian, Iranian or Other. Cox proportional hazards regression analysis was used to estimate the effect of ethnicity adjusted for patient sex and age, disease histology, tumor location, disease stage and treatment. RESULTS: The survival of gastric cancer patients was significantly different among ethnic groups. Chinese patients showed better survival compared to others in univariate and multivariate analysis. The survival of esophageal cancer patients was significantly different among ethnic groups when the data was analyzed by a univariate test (p = 0.029), but not in the Cox multivariate model adjusted for other patient and prognostic factors. CONCLUSIONS: Ethnicity may represent underlying genetic factors. Such factors could influence host-tumor interactions by altering the tumor's etiology and therefore its chance of spreading. Alternatively, genetic factors may determine response to treatments. Finally, ethnicity may represent non-genetic factors that affect survival. Differences in survival by ethnicity support the importance of ethnicity as a prognostic factor, and may provide clues for the future identification of genetic or lifestyle factors that underlie these observations. PMID- 21554723 TI - The caregiving relationship and quality of life among partners of stroke survivors: a cross-sectional study. AB - BACKGROUND: Since the majority of stroke survivors return home following their stroke, families play a pivotal role in their care. Few studies have addressed both positive and negative aspects of this role or the broader construct of health-related quality of life (HRQL). Furthermore, little consideration has been given to the context of care in terms of relationship quality, and reciprocity. The present study examined the relationships between caregiver quality of life (HRQL), caregiver role, relationship satisfaction, balance and reciprocity in caregivers of partners who had experienced a stroke. Specific hypotheses were made based on equity theory in social relations. METHODS: Fifty-six partner caregivers completed a postal survey that included measures of HRQL (SF-36), caregiver role (negative and positive aspects), relationship satisfaction, reciprocity and balance. Data were also collected on the care recipients' quality of life (Stroke Specific Quality of Life scale). RESULTS: Compared to a normative sample, caregivers' HRQL was lower for all SF-36 domains. Care recipient and caregiver age, care recipient quality of life and caregiver role (negative) significantly predicted physical component summary scores on the SF-36, while care recipient quality of life and caregiver role (negative) significantly correlated with mental component summary scores. Relationship satisfaction and intrinsic rewards of caregiving were found to be important predictors of positive aspects of the caregiver role. Caregivers who viewed their relationship as less balanced in terms of give and take had significantly greater caregiver burden than those who viewed their relationship as more equitable. CONCLUSIONS: The study highlights the importance of taking a broader approach to examining partner caregiving in the context of stroke, in terms of the caregiving relationship and their influence on the health and well-being of caregivers. PMID- 21554724 TI - YqiC of Salmonella enterica serovar Typhimurium is a membrane fusogenic protein required for mice colonization. AB - BACKGROUND: Salmonella enterica serovar Typhimurium is an intracellular bacterial pathogen which can colonize a variety of hosts, including human, causing syndromes that vary from gastroenteritis and diarrhea to systemic disease. RESULTS: In this work we present structural information as well as insights into the in vivo function of YqiC, a 99-residue protein of S. Typhimurium, which belongs to the cluster of the orthologous group 2960 (COG2960). We found that YqiC shares biophysical and biochemical properties with Brucella abortus BMFP, the only previously characterized member of this group, such as a high alpha helix content, a coiled-coil domain involved in trimerization and a membrane fusogenic activity in vitro. In addition, we demonstrated that YqiC localizes at cytoplasmic and membrane subcellular fractions, that a S. Typhimurium yqiC deficient strain had a severe attenuation in virulence in the murine model when inoculated both orally and intraperitoneally, and was impaired to replicate at physiological and high temperatures in vitro, although it was still able to invade and replicate inside epithelial and macrophages cell lines. CONCLUSION: This work firstly demonstrates the importance of a COG2960 member for pathogen host interaction, and suggests a common function conserved among members of this group. PMID- 21554725 TI - The distribution of potential West Nile virus vectors, Culex pipiens pipiens and Culex pipiens quinquefasciatus (Diptera: Culicidae), in Mexico City. AB - BACKGROUND: Culex spp. mosquitoes are considered to be the most important vectors of West Nile virus (WNV) detected in at least 34 species of mosquitoes in the United States. In North America, Culex pipiens pipiens, Culex pipiens quinquefasciatus, and Culex tarsalis are all competent vectors of WNV, which is considered to be enzootic in the United States and has also been detected in equines and birds in many states of Mexico and in humans in Nuevo Leon. There is potential for WNV to be introduced into Mexico City by various means including infected mosquitoes on airplanes, migrating birds, ground transportation and infected humans. Little is known of the geographic distribution of Culex pipiens complex mosquitoes and hybrids in Mexico City. Culex pipiens pipiens preferentially feed on avian hosts; Culex pipiens quinquefasciatus have historically been considered to prefer mammalian hosts; and hybrids of these two species could theoretically serve as bridge vectors to transmit WNV from avian hosts to humans and other mammalian hosts. In order to address the potential of WNV being introduced into Mexico City, we have determined the identity and spatial distribution of Culex pipiens complex mosquitoes and their hybrids. RESULTS: Mosquito larvae collected from 103 sites throughout Mexico City during 2004-2005 were identified as Culex, Culiseta or Ochlerotatus by morphological analysis. Within the genus Culex, specimens were further identified as Culex tarsalis or as belonging to the Culex pipiens complex. Members of the Culex pipiens complex were separated by measuring the ratio of the dorsal and ventral arms (DV/D ratio) of the male genitalia and also by using diagnostic primers designed for the Ace.2 gene. Culex pipiens quinquefasciatus was the most abundant form collected. CONCLUSIONS: Important WNV vectors species, Cx. p. pipiens, Cx. p. quinquefasciatus and Cx. tarsalis, are all present in Mexico City. Hybrids of Cx. p. pipiens and Cx. p. quinquefasciatus were also collected and identified. The presence and abundance of these WNV competent vectors is a cause for concern. Understanding the distribution of these vectors can help improve viral surveillance activities and mosquito control efforts in Mexico City. PMID- 21554726 TI - Expression of matrix metalloproteinase-1 (MMP-1) in Wistar rat's intervertebral disc after experimentally induced scoliotic deformity. AB - INTRODUCTION: A scoliotic deformity on intervertebral discs may accelerate degeneration at a molecular level with the production of metalloproteinases (MMPs). In the present experimental study we evaluated the presence of MMP-1 immunohistochemically after application of asymmetric forces in a rat intervertebral disc and the impact of the degree of the deformity on MMP-1 expression. MATERIAL-METHOD: Thirty female Wistar rats (aged 2 months old, weighted 200 +/- 10 grams) were used. All animals were age, weight and height matched. A mini Ilizarov external fixator was applied at the base of a rat tail under anaesthesia in order to create a scoliotic deformity of the intervertebral disc between the 9th and 10th vertebrae. Rats were divided into three groups according to the degree of the deformity. In group I, the deformity was 10 degrees , in group II 30 degrees and in group III 50 degrees . The rats were killed 35 days after surgery. The discs were removed along with the neighbouring vertebral bodies, prepared histologically and stained immunohistochemically. Immunopositivity of disc's cells for MMP-1 was determined using a semi quantitative scored system. RESULTS: MMP-1 immunopositivity was detected in disc cells of annulus fibrosus of all intervertebral disc specimens examined. The percentage of MMP-1 positive disc cells in annulus fibrosus in group I, II and III were 20%, 43% and 75%, respectively. MMP-1 positivity was significantly correlated with the degree of the deformity (p < 0,001). An increase of chondrocyte-like disc cells was observed in the outer annulus fibrosus and at the margin of the intervertebral disc adjacent to the vertebral end plates. The difference in the proportion of MMP-1 positive disc cells between the convex and the concave side was statistically not significant in group I (p = 0,6), in group II this difference was statistically significant (p < 0,01). In group III the concave side showed a remarkable reduction in the number of disc's cells and a severe degeneration of matrix microstructure. CONCLUSION: The present study showed that an experimentally induced scoliotic deformity on a rat tail intervertebral disc results in over-expression of MMP-1, which is dependent on the degree of the deformity and follows a dissimilar distribution between the convex and the concave side. PMID- 21554727 TI - An effective assay for high cellular resolution time-lapse imaging of sensory placode formation and morphogenesis. AB - BACKGROUND: The vertebrate peripheral nervous system contains sensory neurons that arise from ectodermal placodes. Placodal cells ingress to move inside the head to form sensory neurons of the cranial ganglia. To date, however, the process of placodal cell ingression and underlying cellular behavior are poorly understood as studies have relied upon static analyses on fixed tissues. Visualizing placodal cell behavior requires an ability to distinguish the surface ectoderm from the underlying mesenchyme. This necessitates high resolution imaging along the z-plane which is difficult to accomplish in whole embryos. To address this issue, we have developed an imaging system using cranial slices that allows direct visualization of placode formation. RESULTS: We demonstrate an effective imaging assay for capturing placode development at single cell resolution using chick embryonic tissue ex vivo. This provides the first time lapse imaging of mitoses in the trigeminal placodal ectoderm, ingression, and intercellular contacts of placodal cells. Cell divisions with varied orientations were found in the placodal ectoderm all along the apical-basal axis. Placodal cells initially have short cytoplasmic processes during ingression as young neurons and mature over time to elaborate long axonal processes in the mesenchyme. Interestingly, the time-lapse imaging data reveal that these delaminating placodal neurons begin ingression early on from within the ectoderm, where they start to move and continue on to exit as individual or strings of neurons through common openings on the basal side of the epithelium. Furthermore, dynamic intercellular contacts are abundant among the delaminating placodal neurons, between these and the already delaminated cells, as well as among cells in the forming ganglion. CONCLUSIONS: This new imaging assay provides a powerful method to analyze directly development of placode-derived sensory neurons and subsequent ganglia formation for the first time in amniotes. Viewing placode development in a head cross-section provides a vantage point from which it is possible to study comprehensive events in placode formation, from differentiation, cell ingression to ganglion assembly. Understanding how placodal neurons form may reveal a new mechanism of neurogenesis distinct from that in the central nervous system and provide new insight into how cells acquire motility from a stationary epithelial cell type. PMID- 21554728 TI - Phenotypic characteristics of isolates of Aspergillus section Fumigati from different geographic origins and their relationships with genotypic characteristics. AB - BACKGROUND: Epidemiological studies worldwide have shown that A. fumigatus exhibits important phenotypic and genotypic diversity, and these findings have been of great importance in improving the diagnosis and treatment of diseases caused by this fungus. However, few studies have been carried out related to the epidemiology of this fungus in Latin America. This study's aim is to report on the epidemiology of the fungus by analyzing the phenotypic variability of Aspergillus section Fumigati isolates from different Latin American countries and the relationship between this variability, the geographical origin and genotypic characteristics. METHODS: We analyzed the phenotypic characteristics (macro- and micromorphology, conidial size, vesicles size, antifungal susceptibility and thermotolerance at 28, 37 and 48 degrees C) of A. section Fumigati isolates from Mexico (MX), Argentina (AR), Peru (PE) and France (FR). The results were analyzed using analysis of variance (ANOVA) and Tukey's multiple comparison test to detect significant differences. Two dendrograms among isolates were obtained with UPGMA using the Euclidean distance index. One was drawn for phenotypic data, and the other for phenotypic and genotypic data. A PCoA was done for shown isolates in a space of reduced dimensionality. In order to determine the degree of association between the phenotypic and genotypic characteristics AFLP, we calculated the correlation between parwise Euclidean distance matrices of both data sets with the nonparametric Mantel test. RESULTS: No variability was found in the macromorphology of the studied isolates; however, the micromorphology and growth rate showed that the PE isolates grew at a faster rate and exhibited the widest vesicles in comparison to the isolates from MX, AR and FR. The dendrogram constructed with phenotypic data showed three distinct groups. The group I and II were formed with isolates from PE and FR, respectively, while group III was formed with isolates from MX and AR. The dendrogram with phenotypic and genotypic data showed the same cluster, except for an isolate from FR that formed a separate cluster. This cluster was confirmed using PCoA. The correlation between the phenotypic and genotypic data of the isolates revealed a statistically significant association between these characteristics. CONCLUSIONS: The PE isolates showed specific phenotypic characteristics that clearly differentiate them from the rest of the isolates, which matches the genotypic data. The correlation between the phenotypic and genotypic characteristics showed a statistically significant association. In conclusion, phenotypic and genotypic methods together increase the power of correlation between isolates. PMID- 21554729 TI - Decision to take osteoporosis medication in patients who have had a fracture and are 'high' risk for future fracture: a qualitative study. AB - BACKGROUND: Patients' values and preferences are fundamental tenets of evidence based practice, yet current osteoporosis (OP) clinical guidelines pay little attention to these issues in therapeutic decision making. This may be in part due to the fact that few studies have examined the factors that influence the initial decision to take OP medication. The purpose of our study was to examine patients' experiences with the decision to take OP medication after they sustained a fracture. METHODS: A phenomenological qualitative study was conducted with outpatients identified in a university teaching hospital fracture clinic OP program. Individuals aged 65+ who had sustained a fragility fracture within 5 years, were 'high risk' for future fracture, and were prescribed OP medication were eligible. Analysis of interview data was guided by Giorgi's methodology. RESULTS: 21 patients (6 males, 15 females) aged 65-88 years participated. All participants had low bone mass; 9 had OP. Fourteen patients were taking a bisphosphonate while 7 patients were taking no OP medications. For 12 participants, the decision to take OP medication occurred at the time of prescription and involved minimal contemplation (10/12 were on medication). These patients made their decision because they liked/trusted their health care provider. However, 4/10 participants in this group indicated their OP medication taking status might change. For the remaining 9 patients, the decision was more difficult (4/9 were on medication). These patients were unconvinced by their health care provider, engaged in risk-benefit analyses using other information sources, and were concerned about side effects; 7/9 patients indicated that their OP medication-taking status might change at a later date. CONCLUSIONS: Almost half of our older patients who had sustained a fracture found the decision to take OP medication a difficult one. In general, the decision was not considered permanent. Health care providers should be aware of their potential role in patients' decisions and monitor patients' decisions over time. PMID- 21554730 TI - Divergence in cis-regulatory sequences surrounding the opsin gene arrays of African cichlid fishes. AB - BACKGROUND: Divergence within cis-regulatory sequences may contribute to the adaptive evolution of gene expression, but functional alleles in these regions are difficult to identify without abundant genomic resources. Among African cichlid fishes, the differential expression of seven opsin genes has produced adaptive differences in visual sensitivity. Quantitative genetic analysis suggests that cis-regulatory alleles near the SWS2-LWS opsins may contribute to this variation. Here, we sequence BACs containing the opsin genes of two cichlids, Oreochromis niloticus and Metriaclima zebra. We use phylogenetic footprinting and shadowing to examine divergence in conserved non-coding elements, promoter sequences, and 3'-UTRs surrounding each opsin in search of candidate cis-regulatory sequences that influence cichlid opsin expression. RESULTS: We identified 20 conserved non-coding elements surrounding the opsins of cichlids and other teleosts, including one known enhancer and a retinal microRNA. Most conserved elements contained computationally-predicted binding sites that correspond to transcription factors that function in vertebrate opsin expression; O. niloticus and M. zebra were significantly divergent in two of these. Similarly, we found a large number of relevant transcription factor binding sites within each opsin's proximal promoter, and identified five opsins that were considerably divergent in both expression and the number of transcription factor binding sites shared between O. niloticus and M. zebra. We also found several microRNA target sites within the 3'-UTR of each opsin, including two 3'-UTRs that differ significantly between O. niloticus and M. zebra. Finally, we examined interspecific divergence among 18 phenotypically diverse cichlids from Lake Malawi for one conserved non-coding element, two 3'-UTRs, and five opsin proximal promoters. We found that all regions were highly conserved with some evidence of CRX transcription factor binding site turnover. We also found three SNPs within two opsin promoters and one non-coding element that had weak association with cichlid opsin expression. CONCLUSIONS: This study is the first to systematically search the opsins of cichlids for putative cis-regulatory sequences. Although many putative regulatory regions are highly conserved across a large number of phenotypically diverse cichlids, we found at least nine divergent sequences that could contribute to opsin expression differences in cis and stand out as candidates for future functional analyses. PMID- 21554731 TI - Validated stability indicating liquid chromatographic determination of ebastine in pharmaceuticals after pre column derivatization: Application to tablets and content uniformity testing. AB - An accurate, simple, sensitive and selective reversed phase liquid chromatographic method has been developed for the determination of ebastine in its pharmaceutical preparations. The proposed method depends on the complexation ability of the studied drug with Zn2+ ions. Reversed phase chromatography was conducted using an ODS C18 (150 * 4.6 mm id) stainless steel column at ambient temperature with UV-detection at 260 nm. A mobile phase containing 0.025%w/v Zn2+ in a mixture of (acetonitril/methanol; 1/4) and Britton Robinson buffer (65:35, v/v) adjusted to pH 4.2, has been used for the determination of ebastine at a flow rate of 1 ml/min. The calibration curve was rectilinear over the concentration range of 0.3 - 6.0 MUg/ml with a detection limit (LOD) of 0.13 MUg/ml, and quantification limit (LOQ) of 0.26 MUg/ml. The proposed method was successfully applied for the analysis of ebastine in its dosage forms, the obtained results were favorably compared with those obtained by a comparison method. Furthermore, content uniformity testing of the studied pharmaceutical formulations was also conducted. The composition of the complex as well as its stability constant was also investigated. Moreover, the proposed method was found to be a stability indicating one and was utilized to investigate the kinetics of alkaline and ultraviolet induced degradation of the drug. The first-order rate constant and half life of the degradation products were calculated. PMID- 21554732 TI - Expression of mutant alpha-synuclein modulates microglial phenotype in vitro. AB - BACKGROUND: Increased reactive microglia are a histological characteristic of Parkinson's disease (PD) brains, positively correlating with levels of deposited alpha-synuclein protein. This suggests that microglial-mediated inflammatory events may contribute to disease pathophysiology. Mutations in the gene coding for alpha-synuclein lead to a familial form of PD. Based upon our prior findings that alpha-synuclein expression regulates microglial phenotype we hypothesized that expression of mutant forms of the protein may contribute to the reactive microgliosis characteristic of PD brains. METHODS: To quantify the effects of wild type and mutant alpha-synuclein over-expression on microglial phenotype a murine microglial cell line, BV2, was transiently transfected to express human wild type (WT), and mutant alpha-synuclein (A30P and A53T) proteins. Transfected cells were used to assess changes in microglia phenotype via Western blot analysis, ELISA, phagocytosis, and neurotoxicity assays. RESULTS: As expected, over-expression of alpha-synuclein induced a reactive phenotype in the transfected cells. Expression of alpha-synuclein increased protein levels of cycloxygenase-2 (Cox-2). Transfected cells demonstrated increased secretion of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), as well as increased nitric oxide production. Transfected cells also had impaired phagocytic ability correlating with decreased protein levels of lysosomal-associated membrane protein 1 (LAMP-1). In spite of the increased cytokine secretion profile, the transfected cells did not exhibit increased neurotoxic ability above control non-transfected BV2 cells in neuron microglia co-cultures. CONCLUSIONS: These data demonstrated that over-expression of alpha-synuclein drives microglial cells into a form of reactive phenotype characterized by elevated levels of arachidonic acid metabolizing enzymes, cytokine secretion, and reactive nitrogen species secretion all superimposed upon impaired phagocytic potential. PMID- 21554733 TI - A modulated empirical Bayes model for identifying topological and temporal estrogen receptor alpha regulatory networks in breast cancer. AB - BACKGROUND: Estrogens regulate diverse physiological processes in various tissues through genomic and non-genomic mechanisms that result in activation or repression of gene expression. Transcription regulation upon estrogen stimulation is a critical biological process underlying the onset and progress of the majority of breast cancer. Dynamic gene expression changes have been shown to characterize the breast cancer cell response to estrogens, the every molecular mechanism of which is still not well understood. RESULTS: We developed a modulated empirical Bayes model, and constructed a novel topological and temporal transcription factor (TF) regulatory network in MCF7 breast cancer cell line upon stimulation by 17beta-estradiol stimulation. In the network, significant TF genomic hubs were identified including ER-alpha and AP-1; significant non-genomic hubs include ZFP161, TFDP1, NRF1, TFAP2A, EGR1, E2F1, and PITX2. Although the early and late networks were distinct (<5% overlap of ERalpha target genes between the 4 and 24 h time points), all nine hubs were significantly represented in both networks. In MCF7 cells with acquired resistance to tamoxifen, the ERalpha regulatory network was unresponsive to 17beta-estradiol stimulation. The significant loss of hormone responsiveness was associated with marked epigenomic changes, including hyper- or hypo-methylation of promoter CpG islands and repressive histone methylations. CONCLUSIONS: We identified a number of estrogen regulated target genes and established estrogen-regulated network that distinguishes the genomic and non-genomic actions of estrogen receptor. Many gene targets of this network were not active anymore in anti-estrogen resistant cell lines, possibly because their DNA methylation and histone acetylation patterns have changed. PMID- 21554734 TI - The STRATOB study: design of a randomized controlled clinical trial of Cognitive Behavioral Therapy and Brief Strategic Therapy with telecare in patients with obesity and binge-eating disorder referred to residential nutritional rehabilitation. AB - BACKGROUND: Overweight and obesity are linked with binge eating disorder (BED). Effective interventions to significantly reduce weight, maintain weight loss and manage associated pathologies like BED are typically combined treatment options (dietetic, nutritional, physical, behavioral, cognitive-behavioral, pharmacological, surgical). Significant difficulties with regard to availability, costs, treatment adherence and long-term efficacy are present. Particularly Cognitive Behavioral Therapy (CBT) is the therapeutic approach indicated both in in-patient and in out-patient settings for BED. In recent years systemic and systemic-strategic psychotherapies have been implemented to treat patients with obesity and BED involved in familiar problems. Particularly a brief protocol for the systemic-strategic treatment of BED, using overall the strategic dialogue, has been recently developed. Moreover telemedicine, a new promising low cost method, has been used for obesity with BED in out-patient settings in order to avoid relapse after the in-patient step of treatment and to keep on a continuity of care with the involvement of the same clinical in-patient team. METHODS: The comparison between CBT and Brief Strategic Therapy (BST) will be assessed in a two-arm randomized controlled clinical trial. Due to the novelty of the application of BST in BED treatment (no other RCTs including BST have been carried out), a pilot study will be carried out before conducting a large scale randomized controlled clinical trial (RCT). Both CBT and BST group will follow an in-hospital treatment (diet, physical activity, dietitian counseling, 8 psychological sessions) plus 8 out-patient telephone-based sessions of psychological support and monitoring with the same in-patient psychotherapists. Primary outcome measure of the randomized trial will be the change in the Global Index of the Outcome Questionnaire (OQ-45.2). Secondary outcome measures will be the percentage of BED patients remitted considering the number of weekly binge episodes and the weight loss. Data will be collected at baseline, at discharge from the hospital (c.a. 1 month after) and after 6-12-24 months from the end of the in-hospital treatment. Data at follow-up time points will be collected through tele-sessions. DISCUSSION: The STRATOB (Systemic and STRATegic psychotherapy for OBesity), a comprehensive two-phase stepped down program enhanced by telepsychology for the medium-term treatment of obese people with BED seeking intervention for weight loss, will shed light about the comparison of the effectiveness of the BST with the gold standard CBT and about the continuity of care at home using a low-level of telecare (mobile phones). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01096251 PMID- 21554735 TI - The impact of oxygen on the transcriptome of recombinant S. cerevisiae and P. pastoris - a comparative analysis. AB - BACKGROUND: Saccharomyces cerevisiae and Pichia pastoris are two of the most relevant microbial eukaryotic platforms for the production of recombinant proteins. Their known genome sequences enabled several transcriptomic profiling studies under many different environmental conditions, thus mimicking not only perturbations and adaptations which occur in their natural surroundings, but also in industrial processes. Notably, the majority of such transcriptome analyses were performed using non-engineered strains.In this comparative study, the gene expression profiles of S. cerevisiae and P. pastoris, a Crabtree positive and Crabtree negative yeast, respectively, were analyzed for three different oxygenation conditions (normoxic, oxygen-limited and hypoxic) under recombinant protein producing conditions in chemostat cultivations. RESULTS: The major differences in the transcriptomes of S. cerevisiae and P. pastoris were observed between hypoxic and normoxic conditions, where the availability of oxygen strongly affected ergosterol biosynthesis, central carbon metabolism and stress responses, particularly the unfolded protein response. Steady state conditions under low oxygen set-points seemed to perturb the transcriptome of S. cerevisiae to a much lesser extent than the one of P. pastoris, reflecting the major tolerance of the baker's yeast towards oxygen limitation, and a higher fermentative capacity. Further important differences were related to Fab production, which was not significantly affected by oxygen availability in S. cerevisiae, while a clear productivity increase had been previously reported for hypoxically grown P. pastoris. CONCLUSIONS: The effect of three different levels of oxygen availability on the physiology of P. pastoris and S. cerevisiae revealed a very distinct remodelling of the transcriptional program, leading to novel insights into the different adaptive responses of Crabtree negative and positive yeasts to oxygen availability. Moreover, the application of such comparative genomic studies to recombinant hosts grown in different environments might lead to the identification of key factors for efficient protein production. PMID- 21554736 TI - Coendangered hard-ticks: threatened or threatening? AB - The overwhelming majority of animal conservation projects are focused on vertebrates, despite most of the species on Earth being invertebrates. Estimates state that about half of all named species of invertebrates are parasitic in at least one stage of their development. The dilemma of viewing parasites as biodiversity or pest has been discussed by several authors. However, ticks were omitted. The latest taxonomic synopses of non-fossil Ixodidae consider valid 700 species. Though, how many of them are still extant is almost impossible to tell, as many of them are known only from type specimens in museums and were never collected since their original description. Moreover, many hosts are endangered and as part of conservation efforts of threatened vertebrates, a common practice is the removal of, and treatment for external parasites, with devastating impact on tick populations. There are several known cases when the host became extinct with subsequent coextinction of their ectoparasites. For our synoptic approach we have used the IUCN status of the host in order to evaluate the status of specifically associated hard-ticks. As a result, we propose a number of 63 coendangered and one extinct hard-tick species. On the other side of the coin, the most important issue regarding tick-host associations is vectorial transmission of microbial pathogens (i.e. viruses, bacteria, protozoans). Tick borne diseases of threatened vertebrates are sometimes fatal to their hosts. Mortality associated with pathogens acquired from ticks has been documented in several cases, mostly after translocations. Are ticks a real threat to their coendangered host and should they be eliminated? Up to date, there are no reliable proofs that ticks listed by us as coendangered are competent vectors for pathogens of endangered animals. PMID- 21554737 TI - Interviewer versus self-administered health-related quality of life questionnaires - does it matter? AB - BACKGROUND: Patient-reported outcomes are measured in many epidemiologic studies using self- or interviewer-administered questionnaires. While in some studies differences between these administration formats were observed, other studies did not show statistically significant differences important to patients. Since the evidence about the effect of administration format is inconsistent and mainly available from cross-sectional studies our aim was to assess the effects of different administration formats on repeated measurements of patient-reported outcomes in participants with AIDS enrolled in the Longitudinal Study of Ocular Complications of AIDS. METHODS: We included participants enrolled in the Longitudinal Study of Ocular Complications in AIDS (LSOCA) who completed the Medical Outcome Study [MOS] -HIV questionnaire, the EuroQol, the Feeling Thermometer and the Visual Function Questionnaire (VFQ) 25 every six months thereafter using self- or interviewer-administration. A large print questionnaire was available for participants with visual impairment. Considering all measurements over time and adjusting for patient and study site characteristics we used linear models to compare HRQL scores (all scores from 0-100) between administration formats. We defined adjusted differences of >=0.2 standard deviations [SD]) to be quantitatively meaningful. RESULTS: We included 2,261 participants (80.6% males) with a median of 43.1 years of age at enrollment who provided data on 23,420 study visits. The self-administered MOS-HIV, Feeling Thermometer and EuroQol were used in 70% of all visits and the VFQ-25 in 80%. For eight domains of the MOS-HIV differences between the interviewer- and self- administered format were < 0.1 SD. Differences in scores were highest for the social and role function domains but the adjusted differences were still < 0.2 SD. There was no quantitatively meaningful difference between administration formats for EuroQol, Feeling Thermometer and VFQ-25 domain scores. For ocular pain (VFQ-25), we found a statistically significant difference of 3.5 (95% CI 0.2, 6.8), which did, however, not exceed 0.2 SD. For all instruments scores were similar for the large and standard print formats with all adjusted differences < 0.2 SD. CONCLUSIONS: Our large study provides evidence that administration formats do not have a meaningful effect on repeated measurements of patient reported outcomes. As a consequence, longitudinal studies may not need to consider the effect of different administration formats in their analyses. PMID- 21554738 TI - Aboriginal premature mortality within South Australia 1999-2006: a cross sectional analysis of small area results. AB - BACKGROUND: This paper initially describes premature mortality by Aboriginality in South Australia during 1999 to 2006. It then examines how these outcomes vary across area level socio-economic disadvantage and geographic remoteness. METHODS: The retrospective, cross-sectional analysis uses estimated resident population by sex, age and small areas based on the 2006 Census, and Unit Record mortality data. Premature mortality outcomes are measured using years of life lost (YLL). Subsequent intrastate comparisons are based on indirect sex and age adjusted YLL results. A multivariate model uses area level socio-economic disadvantage rank, geographic remoteness, and an interaction between the two variables to predict premature mortality outcomes. RESULTS: Aboriginal people experienced 1.1% of total deaths but 2.2% of YLL and Aboriginal premature mortality rates were 2.65 times greater than the South Australian average. Premature mortality for Aboriginal and non-Aboriginal people increased significantly as area disadvantage increased. Among Aboriginal people though, a significant main effect for area remoteness was also observed, together with an interaction between disadvantage and remoteness. The synergistic effect shows the social gradient between area disadvantage and premature mortality increased as remoteness increased. CONCLUSIONS: While confirming the gap in premature mortality rates between Aboriginal South Australians and the rest of the community, the study also found a heterogeneity of outcomes within the Aboriginal community underlie this difference. The results support the existence of relationship between area level socio-economic deprivation, remoteness and premature mortality in the midst of an affluent society. The study concludes that vertically equitable resourcing according to population need is an important response to the stark mortality gap and its exacerbation by area socio-economic position and remoteness. PMID- 21554739 TI - Analysis of the anti-tumor effect of cetuximab using protein kinetics and mouse xenograft models. AB - BACKGROUND: The binding of EGFR and its ligands leads to autophosphorylation of receptor tyrosine kinase as well as subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. An EGFR inhibitor, cetuximab binds to EGFR and consequently blocks a variety of cellular processes. KRAS/BRAF mutations are known to be associated with a low response rate to cetuximab. In the present study, to clarify the anti tumor mechanisms of cetuximab, we evaluated the KRAS/BRAF status, phosphorylation level of the EGFR pathway, and the tumor suppression effect in vivo, using a human colon cancer cell line HT29, which exhibited the highest EGFR expression in response to the cetuximab therapy among the 6 colorectal cancer cell lines tested. FINDINGS: The conventional growth suppression assay did not work efficiently with cetuximab. EGF, TGF-alpha, and IGF activated the EGFR/MAPK cell signaling pathway by initiating the phosphorylation of EGFR. Cetuximab partially inhibited the EGFR/MAPK pathway induced by EGF, TGF-alpha, and IGF. However, cetuximab exposure induced the EGFR, MEK, and ERK1/2 phosphorylation by itself. Mouse xenograft tumor growth was significantly inhibited by cetuximab and both cetuximab-treated and -untreated xenograft specimens exhibited phosphorylations of the EGFR pathway proteins. CONCLUSIONS: We have confirmed that cetuximab inhibited the EGFR/MAPK pathway and reduced tumor growth in the xenografts while the remaining tumor showed EGFR pathway activation. These results suggest that: ( i ) The effect of cetuximab in growth signaling is not sufficient to induce complete growth suppression in vitro; ( ii ) time-course monitoring may be necessary to evaluate the effect of cetuximab because EGFR signaling is transmitted in a minute order; and ( iii ) cetuximab treatment may have cells acquired resistant selectively survived in the heterogeneous cancer population. PMID- 21554740 TI - Iron specificity of a biosensor based on fluorescent pyoverdin immobilized in sol gel glass. AB - Two current technologies used in biosensor development are very promising: 1. The sol-gel process of making microporous glass at room temperature, and 2. Using a fluorescent compound that undergoes fluorescence quenching in response to a specific analyte. These technologies have been combined to produce an iron biosensor. To optimize the iron (II or III) specificity of an iron biosensor, pyoverdin (a fluorescent siderophore produced by Pseudomonas spp.) was immobilized in 3 formulations of porous sol-gel glass. The formulations, A, B, and C, varied in the amount of water added, resulting in respective R values (molar ratio of water:silicon) of 5.6, 8.2, and 10.8. Pyoverdin-doped sol-gel pellets were placed in a flow cell in a fluorometer and the fluorescence quenching was measured as pellets were exposed to 0.28 - 0.56 mM iron (II or III). After 10 minutes of exposure to iron, ferrous ion caused a small fluorescence quenching (89 - 97% of the initial fluorescence, over the range of iron tested) while ferric ion caused much greater quenching (65 - 88%). The most specific and linear response was observed for pyoverdin immobilized in sol-gel C. In contrast, a solution of pyoverdin (3.0 MUM) exposed to iron (II or III) for 10 minutes showed an increase in fluorescence (101 - 114%) at low ferrous concentrations (0.45 - 2.18 MUM) while exposure to all ferric ion concentrations (0.45 - 3.03 MUM) caused quenching. In summary, the iron specificity of pyoverdin was improved by immobilizing it in sol-gel glass C. PMID- 21554741 TI - Probing genomic diversity and evolution of Streptococcus suis serotype 2 by NimbleGen tiling arrays. AB - BACKGROUND: Our previous studies revealed that a new disease form of streptococcal toxic shock syndrome (STSS) is associated with specific Streptococcus suis serotype 2 (SS2) strains. To achieve a better understanding of the pathogenicity and evolution of SS2 at the whole-genome level, comparative genomic analysis of 18 SS2 strains, selected on the basis of virulence and geographic origin, was performed using NimbleGen tiling arrays. RESULTS: Our results demonstrate that SS2 isolates have highly divergent genomes. The 89K pathogenicity island (PAI), which has been previously recognized as unique to the Chinese epidemic strains causing STSS, was partially included in some other virulent and avirulent strains. The ABC-type transport systems, encoded by 89K, were hypothesized to greatly contribute to the catastrophic features of STSS. Moreover, we identified many polymorphisms in genes encoding candidate or known virulence factors, such as PlcR, lipase, sortases, the pilus-associated proteins, and the response regulator RevS and CtsR. On the basis of analysis of regions of differences (RDs) across the entire genome for the 18 selected SS2 strains, a model of microevolution for these strains is proposed, which provides clues into Streptococcus pathogenicity and evolution. CONCLUSIONS: Our deep comparative genomic analysis of the 89K PAI present in the genome of SS2 strains revealed details into how some virulent strains acquired genes that may contribute to STSS, which may lead to better environmental monitoring of epidemic SS2 strains. PMID- 21554742 TI - A cross-sectional study of HIV and syphilis infections among male students who have sex with men (MSM) in northeast China: implications for implementing HIV screening and intervention programs. AB - BACKGROUND: China has 76.2 million high school and college students, in which the number of reported HIV/AIDS cases is increasing rapidly. Most of these cases are attributed to male-to-male sexual contact. Few studies have explored HIV prevalence and behavioural characteristics of Chinese male students who have sex with men (MSM). METHODS: A cross-sectional study of MSM high school and college students in Liaoning Province was conducted. Data were collected through face-to face interviews and blood specimens were obtained and tested for HIV and syphilis. RESULTS: There were 436 eligible participants. HIV and syphilis prevalence was 3.0% and 5.0%, respectively. In multivariate analysis, sexual orientation known by family members (OR: 7.3; 95% CI: 1.5-34.6), HIV/AIDS information obtained from clinical doctors (OR: 6.7; 95% CI: 1.7-25.9), HIV/AIDS information obtained through free educational services and materials such as voluntary counseling and testing (VCT) and condom distribution services (OR: 0.2; 95% CI: 0.4-1.0), inconsistent condom use (OR: 5.7; 95%: 1.3-25.3), sexual partner experienced anal bleeding after insertive anal intercourse (OR: 6.8; 95% CI: 1.6-28.4), and history of illegal drug use (OR: 18.9; 95% CI: 2.2-165.3) were found to be significantly associated with HIV infection. CONCLUSIONS: Greater effort should be made towards stemming the HIV and syphilis epidemics among Chinese student MSM. Immediate screening and comprehensive interventions towards student MSM should be implemented in order to curb the spread of HIV. Family and school-based interventions should be considered to target this educated, yet vulnerable, population. PMID- 21554743 TI - Selection of drug resistant mutants from random library of Plasmodium falciparum dihydrofolate reductase in Plasmodium berghei model. AB - BACKGROUND: The prevalence of drug resistance amongst the human malaria Plasmodium species has most commonly been associated with genomic mutation within the parasites. This phenomenon necessitates evolutionary predictive studies of possible resistance mutations, which may occur when a new drug is introduced. Therefore, identification of possible new Plasmodium falciparum dihydrofolate reductase (PfDHFR) mutants that confer resistance to antifolate drugs is essential in the process of antifolate anti-malarial drug development. METHODS: A system to identify mutations in Pfdhfr gene that confer antifolate drug resistance using an animal Plasmodium parasite model was developed. By using error-prone PCR and Plasmodium transfection technologies, libraries of Pfdhfr mutant were generated and then episomally transfected to Plasmodium berghei parasites, from which pyrimethamine-resistant PfDHFR mutants were selected. RESULTS: The principal mutation found from this experiment was S108N, coincident with the first pyrimethamine-resistance mutation isolated from the field. A transgenic P. berghei, in which endogenous Pbdhfr allele was replaced with the mutant PfdhfrS108N, was generated and confirmed to have normal growth rate comparing to parental non-transgenic parasite and also confer resistance to pyrimethamine. CONCLUSION: This study demonstrated the power of the transgenic P. berghei system to predict drug-resistant Pfdhfr mutations in an in vivo parasite/host setting. The system could be utilized for identification of possible novel drug-resistant mutants that could arise against new antifolate compounds and for prediction the evolution of resistance mutations. PMID- 21554744 TI - Respondent-driven sampling on the Thailand-Cambodia border. I. Can malaria cases be contained in mobile migrant workers? AB - BACKGROUND: Reliable information on mobility patterns of migrants is a crucial part of the strategy to contain the spread of artemisinin-resistant malaria parasites in South-East Asia, and may also be helpful to efforts to address other public health problems for migrants and members of host communities. In order to limit the spread of malarial drug resistance, the malaria prevention and control programme will need to devise strategies to reach cross-border and mobile migrant populations. METHODOLOGY: The Respondent-driven sampling (RDS) method was used to survey migrant workers from Cambodia and Myanmar, both registered and undocumented, in three Thai provinces on the Thailand-Cambodia border in close proximity to areas with documented artemisinin-resistant malaria parasites. 1,719 participants (828 Cambodian and 891 Myanmar migrants) were recruited. Subpopulations of migrant workers were analysed using the Thailand Ministry of Health classification based on length of residence in Thailand of greater than six months (long-term, or M1) or less than six months (short-term, or M2). Key information collected on the structured questionnaire included patterns of mobility and migration, demographic characteristics, treatment-seeking behaviours, and knowledge, perceptions, and practices about malaria. RESULTS: Workers from Cambodia came from provinces across Cambodia, and 22% of Cambodian M1 and 72% of Cambodian M2 migrants had been in Cambodia in the last three months. Less than 6% returned with a frequency of greater than once per month. Of migrants from Cambodia, 32% of M1 and 68% of M2 were planning to return, and named provinces across Cambodia as their likely next destinations. Most workers from Myanmar came from Mon state (86%), had never returned to Myanmar (85%), and only 4% stated plans to return. CONCLUSION: Information on migratory patterns of migrants from Myanmar and Cambodia along the malaria endemic Thailand-Cambodian border within the artemisinin resistance containment zone will help target health interventions, including treatment follow-up and surveillance. PMID- 21554745 TI - Prognostic factors in patients with node-negative gastric cancer: an Indian experience. AB - BACKGROUND: The status of the regional nodes is the most important prognostic factor in gastric cancer. There are subgroups of patients with different prognosis even in node-negative patients of gastric cancer. The aim of this study is to analyze the factors influencing the prognosis in Indian patients with node negative gastric cancer. METHODS: This was a retrospective analysis of patients who underwent radical gastrectomy in a tertiary cancer centre in India between 1991 and 2007. The study group included only patients with histologically node negative disease. Various clinical, pathological and treatment related factors in this group of patients were analyzed to determine their prognostic ability by univariate and multivariate analyses. RESULTS: Among the 417 patients who underwent gastrectomy during this period, 122 patients had node-negative disease. A major proportion of the patients had advanced gastric cancer. The 5-year overall survival and disease-free survival in all node-negative gastric cancer patients was 68.2% and 67.5% respectively. The overall recurrence rate in this group was 27.3%. On univariate analysis, the factors found to significantly influence the disease-free survival were the size, location and presence or absence of serosal invasion of the primary tumor. However, on multivariate analysis, only tumor size more than 3 cm and serosal invasion were found to be independently associated with an inferior survival. CONCLUSION: Serosal invasion and primary tumor size more than 3 cm independently predict a poor outcome in patients with node-negative gastric cancer. PMID- 21554746 TI - Reducing conditions are the key for efficient production of active ribonuclease inhibitor in Escherichia coli. AB - BACKGROUND: The eukaryotic RNase ribonuclease/angiogenin inhibitors (RI) are a protein group distinguished by a unique structure - they are composed of hydrophobic leucine-rich repeat motifs (LRR) and contain a high amount of reduced cysteine residues. The members of this group are difficult to produce in E. coli and other recombinant hosts due to their high aggregation tendency. RESULTS: In this work dithiothreitol (DTT) was successfully applied for improving the yield of correctly folded ribonuclease/angiogenin inhibitor in E. coli K12 periplasmic and cytoplasmic compartments. The feasibility of the in vivo folding concepts for cytoplasmic and periplasmic production were demonstrated at batch and fed-batch cultivation modes in shake flasks and at the bioreactor scale.Firstly, the best secretion conditions of RI in the periplasmic space were evaluated by using a high throughput multifactorial screening approach of a vector library, directly with the Enbase fed-batch production mode in 96-well plates. Secondly, the effect of the redox environment was evaluated in isogenic dsbA+ and dsbA- strains at the various cultivation conditions with reducing agents in the cultivation medium. Despite the fusion to the signal peptide, highest activities were found in the cytoplasmic fraction. Thus by removing the signal peptide the positive effect of the reducing agent DTT was clearly proven also for the cytoplasmic compartment. Finally, optimal periplasmic and cytoplasmic RI fed-batch production processes involving externally added DTT were developed in shake flasks and scaled up to the bioreactor scale. CONCLUSIONS: DTT highly improved both, periplasmic and cytoplasmic accumulation and activity of RI at low synthesis rate, i.e. in constructs harbouring weak recombinant synthesis rate stipulating genetic elements together with cultivation at low temperature. In a stirred bioreactor environment RI folding was strongly improved by repeated pulse addition of DTT at low aeration conditions. PMID- 21554747 TI - Breast cancer screening in the Czech Republic: time trends in performance indicators during the first seven years of the organised programme. AB - BACKGROUND: The Czech Breast Cancer Screening Programme (CBCSP) was initiated in September 2002 by establishing a network of accredited centres. The aim of this article is to describe progress in the programme quality over time after the inception of the organised programme. METHODS: The CBCSP is monitored using an information system consisting of three principal components: 1) the national cancer registry, 2) a screening registry collecting data on all screening examinations, further assessments and final diagnoses at accredited programme centres, and 3) administrative databases of healthcare payers. Key performance indicators from the European Guidelines have been adopted for continuous monitoring. RESULTS: Breast cancer incidence in the Czech Republic has steadily been increasing, however with a growing proportion of less advanced stages. The mortality rate has recently stabilised. The screening registry includes 2,083,285 records on screening episodes between 2002 and 2008. In 2007-2008, 51% of eligible women aged 45-69 were screened. In 2008, the detection rates were 6.1 and 3.7 per 1,000 women in initial and subsequent screening respectively. Corresponding recall rates are 3.9% and 2.2%, however, it is necessary to pay attention to further assessment performed during the screening visits. Benign to malignant open biopsy ratio was 0.1. Of invasive cases detected in screening, 35.6% was less than 10 mm in diameter. Values of early performance indicators, as measured by both crude and standardized estimates, are generally improving and fulfil desirable targets set by European Guidelines. CONCLUSIONS: Mammography screening in the Czech Republic underwent successful transformation from opportunistic prevention to an organised programme. Values of early indicators confirm continuous improvement in different aspects of process quality. Further stimulation of participation through invitation system is necessary to exploit the full potential of screening mammography at the population level. PMID- 21554749 TI - Observations on shifted cumulative regulation. AB - A response to Dynamic cumulative activity of transcription factors as a mechanism of quantitative gene regulation by F He, J Buer, AP Zeng and R Balling. Genome Biol 2007, 8:R181. PMID- 21554750 TI - A top-down view on DNA replication and recombination from 9,000 feet above sea level. AB - A report of the Keystone Symposium 'DNA Replication and Recombination' held in Keystone, USA, 27 February to 4 March 2011. PMID- 21554751 TI - The blue marble. PMID- 21554752 TI - How deficient are vitamin D deficient critically ill patients? AB - Vitamin D deficiency is highly prevalent among critically ill patients and may be associated with adverse outcomes. Failure of conventional vitamin D supplementation in correcting deficiency has called for studies to evaluate the efficacy and safety of a high-dose regime in critically ill patients. High-dose vitamin D supplementation that corrects a deficient state effectively and safely allows for intervention studies to be undertaken to determine the impact of vitamin D on morbidity and mortality in critically ill patients. PMID- 21554753 TI - Right sizing funding for Alzheimer's disease. PMID- 21554754 TI - Antinuclear antibodies in healthy people: the tip of autoimmunity's iceberg? AB - Antinuclear antibodies (ANAs) are venerable biomarkers for assessing the diagnosis and prognosis of patients with autoimmunity. While closely associated with diseases such as systemic lupus erythematosus, ANA expression occurs commonly in healthy people. The basis for this expression is unknown, although it may reflect features of the assays for antibody detection or intrinsic immunological disturbances in otherwise normal individuals. Like autoimmunity itself, ANA expression is more common among women than men, pointing to an important determinant of these responses. Future research will clarify the mechanisms of ANA expression and the utility of current assays as antecedent and screening biomarkers. PMID- 21554755 TI - The cullin protein family. AB - Cullin proteins are molecular scaffolds that have crucial roles in the post translational modification of cellular proteins involving ubiquitin. The mammalian cullin protein family comprises eight members (CUL1 to CUL7 and PARC), which are characterized by a cullin homology domain. CUL1 to CUL7 assemble multi subunit Cullin-RING E3 ubiquitin ligase (CRL) complexes, the largest family of E3 ligases with more than 200 members. Although CUL7 and PARC are present only in chordates, other members of the cullin protein family are found in Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana and yeast. A cullin protein tethers both a substrate-targeting unit, often through an adaptor protein, and the RING finger component in a CRL. The cullin-organized CRL thus positions a substrate close to the RING-bound E2 ubiquitin-conjugating enzyme, which catalyzes the transfer of ubiquitin to the substrate. In addition, conjugation of cullins with the ubiquitin-like molecule Nedd8 modulates activation of the corresponding CRL complex, probably through conformational regulation of the interactions between cullin's carboxy-terminal tail and CRL's RING subunit. Genetic studies in several model organisms have helped to unravel a multitude of physiological functions associated with cullin proteins and their respective CRLs. CRLs target numerous substrates and thus have an impact on a range of biological processes, including cell growth, development, signal transduction, transcriptional control, genomic integrity and tumor suppression. Moreover, mutations in CUL7 and CUL4B genes have been linked to hereditary human diseases. PMID- 21554756 TI - Vive la difference: biogenesis and evolution of microRNAs in plants and animals. AB - MicroRNAs are pervasive in both plants and animals, but many aspects of their biogenesis, function and evolution differ. We reveal how these differences contribute to characteristic features of microRNA evolution in the two kingdoms. PMID- 21554757 TI - IP6K gene identification in plant genomes by tag searching. AB - BACKGROUND: Plants have played a special role in inositol polyphosphate (IP) research since in plant seeds was discovered the first IP, the fully phosphorylated inositol ring of phytic acid (IP6). It is now known that phytic acid is further metabolized by the IP6 Kinases (IP6Ks) to generate IP containing pyro-phosphate moiety. The IP6K are evolutionary conserved enzymes identified in several mammalian, fungi and amoebae species. Although IP6K has not yet been identified in plant chromosomes, there are many clues suggesting its presences in vegetal cells. RESULTS: In this paper we propose a new approach to search for the plant IP6K gene, that lead to the identification in plant genome of a nucleotide sequence corresponding to a specific tag of the IP6K family. Such a tag has been found in all IP6K genes identified up to now, as well as in all genes belonging to the Inositol Polyphosphate Kinases superfamily (IPK). The tag sequence corresponds to the inositol-binding site of the enzyme, and it can be considered as characterizing all IPK genes. To this aim we applied a technique based on motif discovery. We exploited DLSME, a software recently proposed, which allows for the motif structure to be only partially specified by the user. First we applied the new method on mitochondrial DNA (mtDNA) of plants, where such a gene could have been nested, possibly encrypted and hidden by virtue of the editing and/or trans-splicing processes. Then we looked for the gene in nuclear genome of two model plants, Arabidopsis thaliana and Oryza sativa. CONCLUSIONS: The analysis we conducted in plant mitochondria provided the negative, though we argue relevant, result that IP6K does not actually occur in vegetable mtDNA. Very interestingly, the tag search in nuclear genomes lead us to identify a promising sequence in chromosome 5 of Oryza sativa. Further analyses are in course to confirm that this sequence actually corresponds to IP6K mammalian gene. PMID- 21554758 TI - Managing and querying gene expression data using Curray. AB - BACKGROUND: In principle, gene expression data can be viewed as providing just the three-valued expression profiles of target biological elements relative to an experiment at hand. Although complicated, gathering expression profiles does not pose much of a challenge from a query language standpoint. What is interesting is how these expression profiles are used to tease out information from the vast array of information repositories that ascribe meaning to the expression profiles. Since such annotations are inherently experiment specific functions, much the same way as queries in databases, developing a querying system for gene expression data appears to be pointless. Instead, developing tools and techniques to support individual assignment has been considered prudent in contemporary research. RESULTS: We propose a gene expression data management and querying system that is able to support pre-expression, expression and post-expression level analysis and reduce impedance mismatch between analysis systems. To this end, we propose a new, platform-independent and general purpose query language called Curray, for Custom Microarray query language, to support online expression data analysis using distributed resources. It includes features to design expression analysis pipelines using language constructs at the conceptual level. The ability to include user defined functions as a first-class language feature facilitates unlimited analysis support and removes language limitations. We show that Curray's declarative and extensible features nimbly allow flexible modeling and room for customization. CONCLUSIONS: The developments proposed in this article allow users to view their expression data from a conceptual standpoint - experiments, probes, expressions, mapping, etc. at multiple levels of representation and independent of the underlying chip technologies. It also allows transparent roll-up and drill-down along representation hierarchies from raw data to standards such as MIAME and MAGE-ML using linguistic constructs. Curray also allows seamless integration with distributed web resources through its LifeDB system of which it is a part. PMID- 21554759 TI - Inferring ethnicity from mitochondrial DNA sequence. AB - BACKGROUND: The assignment of DNA samples to coarse population groups can be a useful but difficult task. One such example is the inference of coarse ethnic groupings for forensic applications. Ethnicity plays an important role in forensic investigation and can be inferred with the help of genetic markers. Being maternally inherited, of high copy number, and robust persistence in degraded samples, mitochondrial DNA may be useful for inferring coarse ethnicity. In this study, we compare the performance of methods for inferring ethnicity from the sequence of the hypervariable region of the mitochondrial genome. RESULTS: We present the results of comprehensive experiments conducted on datasets extracted from the mtDNA population database, showing that ethnicity inference based on support vector machines (SVM) achieves an overall accuracy of 80-90%, consistently outperforming nearest neighbor and discriminant analysis methods previously proposed in the literature. We also evaluate methods of handling missing data and characterize the most informative segments of the hypervariable region of the mitochondrial genome. CONCLUSIONS: Support vector machines can be used to infer coarse ethnicity from a small region of mitochondrial DNA sequence with surprisingly high accuracy. In the presence of missing data, utilizing only the regions common to the training sequences and a test sequence proves to be the best strategy. Given these results, SVM algorithms are likely to also be useful in other DNA sequence classification applications. PMID- 21554760 TI - Local structural alignment of RNA with affine gap model. AB - BACKGROUND: Predicting new non-coding RNAs (ncRNAs) of a family can be done by aligning the potential candidate with a member of the family with known sequence and secondary structure. Existing tools either only consider the sequence similarity or cannot handle local alignment with gaps. RESULTS: In this paper, we consider the problem of finding the optimal local structural alignment between a query RNA sequence (with known secondary structure) and a target sequence (with unknown secondary structure) with the affine gap penalty model. We provide the algorithm to solve the problem. CONCLUSIONS: Based on an experiment, we show that there are ncRNA families in which considering local structural alignment with gap penalty model can identify real hits more effectively than using global alignment or local alignment without gap penalty model. PMID- 21554761 TI - Nonlinear gene cluster analysis with labeling for microarray gene expression data in organ development. AB - BACKGROUND: The gene networks underlying closure of the optic fissure during vertebrate eye development are not well-understood. We use a novel clustering method based on nonlinear dimension reduction with data labeling to analyze microarray data from laser capture microdissected (LCM) cells at the site and developmental stages (days 10.5 to 12.5) of optic fissure closure. RESULTS: Our nonlinear methods created clusters of genes that mapped onto more specific biological processes and functions related to eye development as defined by Gene Ontology at lower false discovery rates than conventional linear cluster algorithms. Our new methods build on the advantages of LCM to isolate pure phenotypic populations within complex tissues in order to identify systems biology relationships among critical gene products expressed at lower copy number. CONCLUSIONS: The combination of LCM of embryonic organs, gene expression microarrays, and nonlinear dimension reduction with labeling is a potentially useful approach to extract subtle spatial and temporal co-variations within the gene regulatory networks that specify mammalian organogenesis and organ function. Our results motivate further analysis of nonlinear dimension reduction with labeling within other microarray data sets from LCM dissected tissues or other cell specific samples to determine the more general utility of our method for uncovering more specific biological functional relationships. PMID- 21554762 TI - Mining the TRAF6/p62 interactome for a selective ubiquitination motif. AB - A new approach is described here to predict ubiquitinated substrates of the E3 ubiquitin ligase, TRAF6, which takes into account its interaction with the scaffold protein SQSTM1/p62. A novel TRAF6 ubiquitination motif defined as [ (hydrophobic)-k-(hydrophobic)-x-x-(hydrophobic)- (polar)-(hydrophobic)-(polar) (hydrophobic)] was identified and used to screen the TRAF6/p62 interactome composed of 155 proteins, that were either TRAF6 or p62 interactors, or a negative dataset, composed of 54 proteins with no known association to either TRAF6 or p62. NRIF (K19), TrkA (K485), TrkB (K811), TrkC (K602 and K815), NTRK2 (K828), NTRK3 (K829) and MBP (K169) were found to possess a perfect match for the amino acid consensus motif for TRAF6/p62 ubiquitination. Subsequent analyses revealed that this motif was biased to the C-terminal regions of the protein (nearly 50% the sites), and had preference for loops (~50%) and helices (~37%) over beta-strands (15% or less). In addition, the motif was observed to be in regions that were highly solvent accessible (nearly 90%). Our findings suggest that specific Lysines may be selected for ubiquitination based upon an embedded code defined by a specific amino acid motif with structural determinants. Collectively, our results reveal an unappreciated role for the scaffold protein in targeting ubiquitination. The findings described herein could be used to aid in identification of other E3/scaffold ubiquitination sites. PMID- 21554763 TI - Constraint-based analysis of gene interactions using restricted boolean networks and time-series data. AB - BACKGROUND: A popular model for gene regulatory networks is the Boolean network model. In this paper, we propose an algorithm to perform an analysis of gene regulatory interactions using the Boolean network model and time-series data. Actually, the Boolean network is restricted in the sense that only a subset of all possible Boolean functions are considered. We explore some mathematical properties of the restricted Boolean networks in order to avoid the full search approach. The problem is modeled as a Constraint Satisfaction Problem (CSP) and CSP techniques are used to solve it. RESULTS: We applied the proposed algorithm in two data sets. First, we used an artificial dataset obtained from a model for the budding yeast cell cycle. The second data set is derived from experiments performed using HeLa cells. The results show that some interactions can be fully or, at least, partially determined under the Boolean model considered. CONCLUSIONS: The algorithm proposed can be used as a first step for detection of gene/protein interactions. It is able to infer gene relationships from time series data of gene expression, and this inference process can be aided by a priori knowledge available. PMID- 21554764 TI - Haplotype inference in general pedigrees with two sites. AB - BACKGROUND: Genetic disease studies investigate relationships between changes in chromosomes and genetic diseases. Single haplotypes provide useful information for these studies but extracting single haplotypes directly by biochemical methods is expensive. A computational method to infer haplotypes from genotype data is therefore important. We investigate the problem of computing the minimum number of recombination events for general pedigrees with two sites for all members. RESULTS: We show that this NP-hard problem can be parametrically reduced to the Bipartization by Edge Removal problem and therefore can be solved by an O(2k . n2) exact algorithm, where n is the number of members and k is the number of recombination events. CONCLUSIONS: Our work can therefore be useful for genetic disease studies to track down how changes in haplotypes such as recombinations relate to genetic disease. PMID- 21554765 TI - Enhancing genome assemblies by integrating non-sequence based data. AB - INTRODUCTION: Many genome projects were underway before the advent of high throughput sequencing and have thus been supported by a wealth of genome information from other technologies. Such information frequently takes the form of linkage and physical maps, both of which can provide a substantial amount of data useful in de novo sequencing projects. Furthermore, the recent abundance of genome resources enables the use of conserved synteny maps identified in related species to further enhance genome assemblies. METHODS: The tammar wallaby (Macropus eugenii) is a model marsupial mammal with a low coverage genome. However, we have access to extensive comparative maps containing over 14,000 markers constructed through the physical mapping of conserved loci, chromosome painting and comprehensive linkage maps. Using a custom Bioperl pipeline, information from the maps was aligned to assembled tammar wallaby contigs using BLAT. This data was used to construct pseudo paired-end libraries with intervals ranging from 5-10 MB. We then used Bambus (a program designed to scaffold eukaryotic genomes by ordering and orienting contigs through the use of paired end data) to scaffold our libraries. To determine how map data compares to sequence based approaches to enhance assemblies, we repeated the experiment using a 0.5* coverage of unique reads from 4 KB and 8 KB Illumina paired-end libraries. Finally, we combined both the sequence and non-sequence-based data to determine how a combined approach could further enhance the quality of the low coverage de novo reconstruction of the tammar wallaby genome. RESULTS: Using the map data alone, we were able order 2.2% of the initial contigs into scaffolds, and increase the N50 scaffold size to 39 KB (36 KB in the original assembly). Using only the 0.5* paired-end sequence based data, 53% of the initial contigs were assigned to scaffolds. Combining both data sets resulted in a further 2% increase in the number of initial contigs integrated into a scaffold (55% total) but a 35% increase in N50 scaffold size over the use of sequence-based data alone. CONCLUSIONS: We provide a relatively simple pipeline utilizing existing bioinformatics tools to integrate map data into a genome assembly which is available at http://www.mcb.uconn.edu/fac.php?name=paska. While the map data only contributed minimally to assigning the initial contigs to scaffolds in the new assembly, it greatly increased the N50 size. This process added structure to our low coverage assembly, greatly increasing its utility in further analyses. PMID- 21554766 TI - Deciphering transcription factor binding patterns from genome-wide high density ChIP-chip tiling array data. AB - BACKGROUND: The binding events of DNA-interacting proteins and their patterns can be extensively characterized by high density ChIP-chip tiling array data. The characteristics of the binding events could be different for different transcription factors. They may even vary for a given transcription factor among different interaction loci. The knowledge of binding sites and binding occupancy patterns are all very useful to understand the DNA-protein interaction and its role in the transcriptional regulation of genes. RESULTS: In the view of the complexity of the DNA-protein interaction and the opportunity offered by high density tiled ChIP-chip data, we present a statistical procedure which focuses on identifying the interaction signal regions instead of signal peaks using moving window binomial testing method and deconvolving the patterns of interaction using peakedness and skewness scores. We analyzed ChIP-chip data of 4 different DNA interacting proteins including transcription factors and RNA polymerase in fission yeast using our procedure. Our analysis revealed the variation of binding patterns within and across different DNA interacting proteins. We present their utility in understanding transcriptional regulation from ChIP-chip data. CONCLUSIONS: Our method can successfully detect the signal regions and characterize the binding patterns in ChIP-chip data which help appropriate analysis of the ChIP-chip data. PMID- 21554767 TI - MetaPath: identifying differentially abundant metabolic pathways in metagenomic datasets. AB - BACKGROUND: Enabled by rapid advances in sequencing technology, metagenomic studies aim to characterize entire communities of microbes bypassing the need for culturing individual bacterial members. One major goal of metagenomic studies is to identify specific functional adaptations of microbial communities to their habitats. The functional profile and the abundances for a sample can be estimated by mapping metagenomic sequences to the global metabolic network consisting of thousands of molecular reactions. Here we describe a powerful analytical method (MetaPath) that can identify differentially abundant pathways in metagenomic datasets, relying on a combination of metagenomic sequence data and prior metabolic pathway knowledge. METHODS: First, we introduce a scoring function for an arbitrary subnetwork and find the max-weight subnetwork in the global network by a greedy search algorithm. Then we compute two p values (pabund and pstruct) using nonparametric approaches to answer two different statistical questions: (1) is this subnetwork differentically abundant? (2) What is the probability of finding such good subnetworks by chance given the data and network structure? Finally, significant metabolic subnetworks are discovered based on these two p values. RESULTS: In order to validate our methods, we have designed a simulated metabolic pathways dataset and show that MetaPath outperforms other commonly used approaches. We also demonstrate the power of our methods in analyzing two publicly available metagenomic datasets, and show that the subnetworks identified by MetaPath provide valuable insights into the biological activities of the microbiome. CONCLUSIONS: We have introduced a statistical method for finding significant metabolic subnetworks from metagenomic datasets. Compared with previous methods, results from MetaPath are more robust against noise in the data, and have significantly higher sensitivity and specificity (when tested on simulated datasets). When applied to two publicly available metagenomic datasets, the output of MetaPath is consistent with previous observations and also provides several new insights into the metabolic activity of the gut microbiome. The software is freely available at http://metapath.cbcb.umd.edu. PMID- 21554768 TI - AOM in children. AB - INTRODUCTION: In the UK, about 30% of children under 3 years of age visit their GP each year with acute otitis media (AOM), and 97% of these receive antibiotics. In the US, AOM is the most common reason for outpatient antibiotic treatment. Without antibiotics, AOM resolves within 24 hours in about 60% of children, and within 3 days in about 80% of children. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for AOM in children; and what are the effects of interventions to prevent recurrence? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 29 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics, antibiotics, delayed antibiotics, immediate antibiotics, long-term antibiotic prophylaxis, longer courses of antibiotics, myringotomy, pneumococcal vaccination, tympanostomy with ventilation tubes, xylitol syrup or gum, and influenza vaccination. PMID- 21554769 TI - Regulation of fusion of the nucleolar precursor bodies following activation of mouse oocytes: roles of the maturation-promoting factors and mitogen-activated protein kinases. AB - Fusion of nucleoli or nucleolus precursor bodies (NPBs) has been observed during somatic cell interphase and pronuclear development of human zygotes; however, the underlying mechanism is unknown. NPB fusion and its regulation by mitogen activated protein kinase (MAPK) and maturation-promoting factor (MPF) were studied in activated mouse oocytes. Small NPBs appeared about 4 h after ethanol activation, and took about 1.5 h to fuse into a large NPB, which persisted for about 10 h before disappearance. Analysis of the temporal windows for kinase action indicated that a high MAPK activity during the first 2 h and a low MPF activity during the first 3-4 h after activation were essential for subsequent NPB fusion. A preactivation decline in MAPK activity was associated with decreased NPB fusion following activation of aged oocytes. While MAPK inactivation by regulator U0126 prevented NPB fusion in oocytes activated by ethanol or 5 min Sr2+ treatments, it had no effect on oocytes fertilized or activated by 6 h Sr2+ treatment. In most cases, while rates of pronuclear formation did not differ, rates of NPB fusion differed significantly between different treatments. Our results suggest that: (i) the MAPK and MPF activities at the initial stage of activation regulate NPB fusion after pronuclear formation; (ii) pronuclear assembly and NPB fusion are two separable events that might be controlled by different mechanisms; and (iii) high MAPK activity and low MPF activity at the initial stage of activation is essential for NPB fusion when only one calcium rise is induced by ethanol, while inhibition of MAPK activity does not affect NPB fusion when the repetitive intracellular Ca2+ rises are induced after fertilization. PMID- 21554770 TI - Blastocysts derived from adult fibroblasts of a rhesus monkey ( Macaca mulatta) using interspecies somatic cell nuclear transfer. AB - In non-human primates, it is difficult to collect sufficient numbers of oocytes for producing identical embryos by somatic cell nuclear transfer (SCNT). Because of this factor, inter-species SCNT (iSCNT) using heterospecific oocytes is an attractive alternative approach. The objective of this study was to produce iSCNT derived blastocysts using enucleated cow (Bos taurus) metaphase II oocytes and adult rhesus monkey (Macaca mulatta) fibroblasts. Ear skin tissue from a 6-year old male rhesus monkey was collected by biopsy and fibroblasts were isolated. Immature cumulus-oocyte complexes from cow ovaries were collected and matured in vitro in Medium 199. The enucleated oocytes were reconstructed with rhesus monkey fibroblasts and iSCNT embryos were cultured in modified synthetic oviduct fluid in an atmosphere of 5-5.5% CO2 under various conditions (37-39 degrees C and 5 20% O2) to examine the effects of in vitro culture conditions. Most embryos were arrested at the 8- or 16-cell stage and only three blastocysts were derived in this way using iSCNT from a total of 1153 cultured activated embryos (0.26% production rate). Two of the three blastocysts were used for counting nuclear numbers using bisbenzimide staining, which were 51 and 24. The other iSCNT derived blastocyst was used to analyse mitochondrial DNA (mtDNA) by PCR, and both rhesus monkey and cow mtDNA were detected. Although the development rate was extremely low, this study established that iSCNT using two phylogenetically distant species, including a primate, could produce blastocysts. With improvements in the development rate, it may be possible to produce rhesus monkey iSCNT-derived embryonic stem cell lines for studies on primate nucleus and cow mitochondria interaction mechanisms. PMID- 21554771 TI - Involvement of cAMP and calmodulin in endocytic yolk uptake during Xenopus laevis oogenesis. AB - The aim of the present study was to show the participation and physiological role of calmodulin (CaM) and cAMP during vitellogenin endocytic uptake in the amphibian Xenopus laevis. The results showed a differential distribution of CaM in the ovary follicles during oogenesis. The CaM intracellular localization was not affected by gap junction's downregulation and CaM inhibition did not completely abolished the endocytic activity of oocytes. We showed that cAMP was able to completely rescue the endocytic competence in follicles in which gap junctional communication had been disrupted by octanol. Moreover cAMP was capable of restoring oocyte endocytic capability in the presence of octanol and stelazine, a CaM inhibitor. We propose that, in Vtg uptake regulation, cAMP is upstream of CaM during the endocytic signalling pathway. PMID- 21554772 TI - Administration of cyclosporin A to recipients improves the potential of mouse somatic cell nuclear-transferred oocytes to develop to fetuses. AB - Somatic cell nuclear-transferred (SCNT) oocytes have a high potential for development in vitro, but a large proportion of embryos that are transferred to recipients is aborted before parturition. The precise mechanism for the high abortion rate is unknown, but abnormal placenta formation is frequently observed in SCNT-cloned pregnancies. The present study examined the effects of treating the recipients with cyclosporin A (CsA), an immunoprotectant, on the proportion of fetuses resulting from SCNT-cloned pregnancies. Cloned embryos developed from enucleated oocytes and receiving cumulus cells from F1 (C57BL/6 * DBA, H-2b/d) females were transferred to outbred ICR (in which the H-2 complex was not fixed) recipient females. Each recipient received an intraperitoneal injection of CsA or vehicle. Compared with vehicle, administration of CsA to recipients on day 4.5 of pregnancy significantly increased the proportion of fetuses observed on day 10.5. The proportion of fetuses at day 18.5 of pregnancy in recipients receiving CsA treatment was slightly higher than that in controls. This study is the first to report that CsA administration increases the proportion of fetuses resulting from SCNT-cloned pregnancies. PMID- 21554773 TI - Germ cell differentiation and proliferation in the developing testis of the South American plains viscacha, Lagostomus maximus (Mammalia, Rodentia). AB - Cell proliferation and cell death are essential processes in the physiology of the developing testis that strongly influence the normal adult spermatogenesis. We analysed in this study the morphometry, the expression of the proliferation cell nuclear antigen (PCNA), cell pluripotency marker OCT-4, germ cell marker VASA and apoptosis in the developing testes of Lagostomus maximus, a rodent in which female germ line develops through abolished apoptosis and unrestricted proliferation. Morphometry revealed an increment in the size of the seminiferous cords with increasing developmental age, arising from a significant increase of PCNA-positive germ cells and a stable proportion of PCNA-positive Sertoli cells. VASA showed a widespread cytoplasmic distribution in a great proportion of proliferating gonocytes that increased significantly at late development. In the somatic compartment, Leydig cells increased at mid-development, whereas peritubular cells showed a stable rate of proliferation. In contrast to other mammals, OCT-4 positive gonocytes increased throughout development reaching 90% of germ cells in late-developing testis, associated with a conspicuous increase in circulating FSH from mid- to late-gestation. TUNEL analysis was remarkable negative, and only a few positive cells were detected in the somatic compartment. These results show that the South American plains viscacha displays a distinctive pattern of testis development characterized by a sustained proliferation of germ cells throughout development, with no signs of apoptosis cell demise, in a peculiar endocrine in utero ambiance that seems to promote the increase of spermatogonial number as a primary direct effect of FSH. PMID- 21554774 TI - Regional distribution of nitrergic neurons in the inner retina of the chicken. AB - Using both NADPH diaphorase and anti-nNOS antibodies, we have identified-from retinal flatmounts-neuronal types in the inner retina of the chicken that are likely to be nitrergic. The two methods gave similar results and yielded a total of 15 types of neurons, comprising 9 amacrine cells, 5 ganglion cells, and 1 centrifugal midbrain neuron. Six of these 15 cell types are ubiquitously distributed, comprising 3 amacrine cells, 2 displaced ganglion cells, and a presumed orthotopic ganglion cell. The remaining nine cell types are regionally restricted within the retina. As previously reported, efferent fibers of midbrain neurons and their postsynaptic partners, the unusual axon-bearing target amacrine cells, are entirely confined to the ventral retina. Also confined to the ventral retina, though with somewhat different distributions, are the "bullwhip" amacrine cells thought to be involved in eye growth, an orthotopic ganglion cell, and two types of large axon-bearing amacrine cells whose dendrites and axons lie in stratum 1 of the inner plexiform layer (IPL). Intracellular fills of these two cell types showed that only a minority of otherwise morphologically indistinguishable neurons are nitrergic. Two amacrine cells that branch throughout the IPL are confined to an equatorial band, and one small-field orthotopic ganglion cell that branches in the proximal IPL is entirely dorsal. These findings suggest that the retina uses different processing on different regions of the visual image, though the benefit of this is presently obscure. PMID- 21554775 TI - Segregation of frontoparietal and cerebellar components within saccade and vergence networks using hierarchical independent component analysis of fMRI. AB - PURPOSE: Cortical and subcortical functional activity stimulated via saccade and vergence eye movements were investigated to examine the similarities and differences between networks and regions of interest (ROIs). METHODS: Blood oxygenation level-dependent (BOLD) signals from stimulus-induced functional Magnetic Resonance Imaging (MRI) experiments were analyzed studying 16 healthy subjects. Six types of oculomotor experiments were conducted using a block design to study both saccade and vergence circuits. The experiments included a simple eye movement task and a more cognitively demanding prediction task. A hierarchical independent component analysis (ICA) process began by analyzing individual subject data sets with spatial ICA to extract spatial independent components (sIC), which resulted in three ROIs. Using the time series from each of the three ROIs per subject, per oculomotor experiment, a temporal ICA was used to compute individual temporal independent components (tICs). For each of the three ROIs, the individual tICs from multiple subjects were entered into a second temporal ICA to compute group-level tICs for comparison. RESULTS: Two independent spatial maps were observed for each subject (one sIC showing activity in the frontoparietal regions and another sIC in the cerebellum) during the six oculomotor tasks. Analysis of group-level tICs revealed an increased latency in the cerebellar region when compared to the frontoparietal region. CONCLUSION: Shared neuronal behavior has been reported in the frontal and parietal lobes, which may in part explain the segregation of frontoparietal functional activity into one sIC. The cerebellum uses multiple time scales for motor learning. This may result in an increased latency observed in the BOLD signal of the cerebellar group-level tIC when compared to the frontal and parietal group-level tICs. The increased latency offers a possible explanation to why ICA dissects the cerebellar activity into an sIC. The hierarchical ICA process used to calculate group-level tICs can yield insight into functional connectivity within complex neural networks. PMID- 21554776 TI - Long-term evolution of the roo transposable element copy number in mutation accumulation lines of Drosophila melanogaster. AB - The rate of insertion of transposable elements (TEs) is a fundamental parameter to understand both their dynamics and role in the evolution of the eukaryotic genome. Nonetheless, direct estimates of insertion rates are scarce because transposition is in general a rare phenomenon. A great deal of our previous work on transposition was based on a set of long-term mutation accumulation (MA) lines of Drosophila melanogaster started in 1987 (Oviedo lines), where roo was found highly active, with a rate of insertion of 7*10-4 insertions per element and generation, as compared with other 15 TE families that presented transposition rates around 10-5. Here, we study the evolution of the roo transposition rate, by in situ hybridization, after 60-75 additional generations of MA in two subsets of the Oviedo lines, O and O', which had achieved average numbers of roo insertions of 77 and 84, respectively. In the O lines, insertions accumulated at a rate that remained constant (7*10-4 insertions per element and generation); however, the subset of lines O' showed a lower accumulation rate of 4*10-4 insertions per element per generation, suggesting a regulation of transposition that depends on the number of elements. However, one of the O' lines reached a number of 103 insertions, departing from the group mean by 4.6 sd, and showing that it escapes regulation. Hence, 'de novo' mutations affecting the regulation of transposition are relatively common. These results are discussed in relation to the possible mechanisms of containment of TEs. PMID- 21554777 TI - Mating system and the critical migration rate for swamping selection. AB - Crow et al. (1990) and Barton (1992) have examined the critical migration rate for swamping selection in the nuclear system. Here, I use the same methodology to examine the critical migration rate in the cytonuclear system for hermaphrodite plants with a mixed mating system. Two selection schemes for a nuclear gene (heterozygote disadvantage and directional selection) and the directional selection scheme for organelle genes are considered. Results show that under random mating, the previous results are applicable to plant species by appropriate re-parameterization of the migration rate for nuclear and paternal organelle genes. A simple complementary relationship exists between seed and pollen flow in contributing to the critical migration rate. Under the mixed mating system, the critical migration rate of seeds and pollen for nuclear and paternal organelle genes can be changed due to the effects of selection and the cytonuclear linkage disequilibrium generated by migration and inbreeding. A negative but not complementary relationship exists between seed and pollen flow in contributing to the critical migration rate, varying with the mating system. Partial selfing can also adjust the critical seed flow for the maternal organelle gene, with a small critical migration rate for species of a high selfing rate. Both concordance and discordance among cytonuclear genes can occur under certain conditions during the process of swamping selection. This theory predicts the presence of various contributions of seed versus pollen flow to genetic swamping for plants with diverse mating systems. PMID- 21554778 TI - Informal payments for health care--the phenomenon and its context. AB - This paper reviews current research and literature on the issue of informal payments for health care and its context and suggests a new perspective for a better understanding of this phenomenon. This perspective, based on political culture and behavior and on wider social processes, is already used to explain various phenomena from different fields of public policy. The paper explains the impact of a specific type of political culture, called 'alternative politics' (AP) in the Israeli literature, on healthcare policy and institutional healthcare settings. AP is based on a 'do-it-yourself' approach adopted by citizens to address their dissatisfaction with governmental services. When such a mode of political culture is diffused to all sectors and levels of society, all players, including bureaucrats and politicians, are guided by short-term considerations and apply unilateral strategies that bypass formal rules either through illegal activity or by marginalizing formal rules. Explaining informal payments by analyzing social processes and political culture and behavior has some disadvantages, but it provides us with a better understanding of the phenomenon while covering most of its characteristics and configurations. PMID- 21554779 TI - Public health approach to detection of non-O157 Shiga toxin-producing Escherichia coli: summary of two outbreaks and laboratory procedures. AB - Routine laboratory testing may not detect non-O157 Shiga toxin-producing Escherichia coli (STEC) reliably. Active clinical, epidemiological, environmental health, and laboratory collaboration probably influence successful detection and study of non-O157 STEC infection. We summarized two outbreak investigations in which such coordinated efforts identified non-O157 STEC disease and led to effective control measures. Outbreak 1 involved illness associated with consuming unpasteurized apple cider from a local orchard. Public health personnel were notified by a local hospital; stool specimens from ill persons contained O111 STEC. Outbreak 2 involved bloody diarrhoea at a correctional facility. Public health personnel were notified by the facility infection control officer; O45 STEC was the implicated agent. These reports highlight the ability of non-O157 STEC to cause outbreaks and demonstrate that a coordinated effort by clinicians, infection-control practitioners, clinical diagnostic laboratorians, and public health personnel can lead to effective identification, investigation, and prevention of non-O157 STEC disease. PMID- 21554780 TI - Mumps outbreak in Israel's highly vaccinated society: are two doses enough? AB - Mumps outbreaks in recent years have given rise to questions about the effectiveness of the mumps vaccine. This study examined the epidemiological data from a recent mumps outbreak in Israel and from outbreaks in other countries with high vaccination coverage, and considered whether long-established vaccination policies designed to protect against mumps are in need of revision. Of over 5000 case patients in the Israeli outbreak, half of whom were in the Jerusalem health district, nearly 40% were aged >=15 years and, of those whose vaccination status was known, 78% had been fully vaccinated for their age - features similar to those in recent mumps outbreaks in Europe and North America. The epidemiological and laboratory evidence suggests that many previously vaccinated adolescents and young adults are now susceptible to mumps because their vaccine-based immunity has waned. Booster vaccination programmes for those at high risk of infection during mumps outbreaks - particularly those in congregate living environments - merit priority consideration. PMID- 21554781 TI - Costs of illness due to endemic cholera. AB - Economic analyses of cholera immunization programmes require estimates of the costs of cholera. The Diseases of the Most Impoverished programme measured the public, provider, and patient costs of culture-confirmed cholera in four study sites with endemic cholera using a combination of hospital- and community-based studies. Families with culture-proven cases were surveyed at home 7 and 14 days after confirmation of illness. Public costs were measured at local health facilities using a micro-costing methodology. Hospital-based studies found that the costs of severe cholera were US$32 and US$47 in Matlab and Beira. Community based studies in North Jakarta and Kolkata found that cholera cases cost between US$28 and US$206, depending on hospitalization. Patients' cost of illness as a percentage of average monthly income were 21% and 65% for hospitalized cases in Kolkata and North Jakarta, respectively. This burden on families is not captured by studies that adopt a provider perspective. PMID- 21554782 TI - A systematic review/meta-analysis of primary research investigating swine, pork or pork products as a source of zoonotic hepatitis E virus. AB - The objectives of our study were to identify and categorize primary research investigating swine/pork as a source of zoonotic hepatitis E virus (HEV) using the relatively new technique of scoping study, and to investigate the potential association between human exposure to swine/pork and HEV infection quantitatively using systematic review/meta-analysis methodology. From 1890 initially identified abstracts, 327 were considered for the review. Five study design types (cross sectional, prevalence, genotyping, case-report and experimental transmission studies) were identified. A significant association between occupational exposure to swine and human HEV IgG seropositivity was reported in 10/13 cross-sectional studies. The association reported between pork consumption and HEV IgG seropositivity was inconsistent. The quantification of viral load in swine and retail pork, viral load required for infection in primates, cohort and case control studies in humans, and formal risk assessment are recommended before specific public-health policy actions are taken. PMID- 21554783 TI - Carbapenem-resistant Acinetobacter baumannii: diversity of resistant mechanisms and risk factors for infection. AB - Carbapenem-resistant Acinetobacter baumannii (CRAB) are an increasing infectious threat in hospitals. We investigated the clinical epidemiology of CRAB infections vs. colonization in patients, and examined the mechanisms of resistance associated with elevated minimum inhibitory concentrations (MICs) for carbapenems. From January to June 2009, 75 CRAB strains were collected. CRAB infection was significantly associated with malignancy and a high APACHE II score. The most dominant resistance mechanism was ISAba1 preceding OXA-51, producing strains with overexpression of efflux pump. Strains carrying blaOXA-23 like enzymes had higher carbapenem MICs than those carrying blaOXA-51-like enzymes; however, the presence of multiple mechanisms did not result in increased resistance to carbapenems. There was no difference in the resistance mechanisms in strains from infected and colonized patients. The majority of strains were genetically diverse by DNA macrorestriction although there was evidence of clonal spread of four clusters of strains in patients. PMID- 21554784 TI - Elaborating a hypothetical concept: comments on the special series on cognitive reserve. PMID- 21554785 TI - The culture of time in neuropsychological assessment: exploring the effects of culture-specific time attitudes on timed test performance in Russian and American samples. AB - Cultural differences in time attitudes and their effect on timed neuropsychological test performance were examined in matched non-clinical samples of 100 Russian and American adult volunteers using 8 tests that were previously reported to be relatively free of cultural bias: Color Trails Test (CTT); Ruff Figural Fluency Test (RFFT); Symbol Digit Modalities Test (SDMT); and Tower of London-Drexel Edition (ToL(Dx)). A measure of time attitudes, the Culture of Time Inventory (COTI-33) was used to assess time attitudes potentially affecting time limited testing. Americans significantly outscored Russians on CTT, SDMT, and ToL(Dx) (p,.05) while differences in RFFT scores only approached statistical significance. Group differences also emerged in COTI-33 factor scores, which partially mediated differences in performance on CTT-1, SDMT, and ToL(Dx) initiation time, but did not account for the effect of culture on CTT-2. Significant effect of culture was revealed in ratings of familiarity with testing procedures that was negatively related to CTT, ToL(Dx), and SDMT scores. Current findings indicated that attitudes toward time may influence results of time limited testing and suggested that individuals who lack familiarity with timed testing procedures tend to obtain lower scores on timed tests. PMID- 21554786 TI - Neuropsychological effects of sleep loss: implication for neuropsychologists. AB - There is rapidly accumulating evidence of a close relationship between sleep loss and cognition. Neuropsychologists need to become aware of this body of knowledge as the effects of sleep loss on brain functions are significant. The current study (a) outlines the extent to which insufficient sleep affects performance on cognitive tasks in otherwise healthy people, (b) discusses the relationship between sleep and neurocognitive disorders, and (c) highlights key issues that merit consideration for neuropsychologists. This review shows that sleep loss has a measurable impact on performance through decreases in cognitive functions and effects on biological pathways that support cognitive performance. Sleep loss reliably produces reductions in speed of processing and attention. Higher order cognitive functions are affected to a lesser extent, and there is sparing on tasks of crystallized abilities. Deficits worsen with increasing time awake, but may be overturned after normal sleep is resumed. The review also shows that sleep disorders are a major feature of neuropsychological conditions contributing to the pattern of cognitive impairment. Overall, neuropsychologists must be alert to sleep problems in their clients, so that sleep interventions, or referrals, are put in place in the rehabilitation plan of individuals with cognitive dysfunctions. Recommendations also include routine screening of sleep as part of cognitive assessment. PMID- 21554787 TI - Metacognitive monitoring in moderate and severe traumatic brain injury. AB - The ability to engage in self-reflective processes is a capacity that may be disrupted after neurological compromise; research to date has demonstrated that patients with traumatic brain injury (TBI) show reduced awareness of their deficits and functional ability compared to caretaker or clinician reports. Assessment of awareness of deficit, however, has been limited by the use of subjective measures (without comparison to actual performance) that are susceptible to report bias. This study used concurrent measurements from cognitive testing and confidence judgments about performance to investigate in the-moment metacognitive experiences after moderate and severe traumatic brain injury. Deficits in metacognitive accuracy were found in adults with TBI for some but not all indices, suggesting that metacognition may not be a unitary construct. Findings also revealed that not all indices of executive functioning reliably predict metacognitive ability. PMID- 21554788 TI - Verbal learning strategy following mild traumatic brain injury. AB - That learning and memory deficits persist many years following mild traumatic brain injury (mTBI) is controversial due to inconsistent objective evidence supporting subjective complaints. Our prior work demonstrated significant reductions in performance on the initial trial of a verbal learning task and overall slower rate of learning in well-motivated mTBI participants relative to demographically matched controls. In our previous work, we speculated that differences in strategy use could explain the differences in rate of learning. The current study serves to test this hypothesis by examining strategy use on the California Verbal Learning Test-Second Edition. Our present findings support the primary hypothesis that mTBI participants under-utilize semantic clustering strategies during list-learning relative to control participants. Despite achieving comparable total learning scores, we posit that the persisting learning and memory difficulties reported by some mTBI patients may be related to reduced usage of efficient internally driven strategies that facilitate learning. Given that strategy training has demonstrated improvements in learning and memory in educational and occupational settings, we offer that these findings have translational value in offering an additional approach in remediation of learning and memory complaints reported by some following mTBI. PMID- 21554789 TI - Enhanced manual and oral motor reaction time in young adult female fragile X premutation carriers. AB - A previous study reported preliminary results of enhanced processing of simple visual information in the form of faster reaction times, in female fragile X premutation carriers (fXPCs). In this study, we assessed manual and oral motor reaction times in 30 female fXPCs and 20 neurotypical (NT) controls. Participants completed two versions of the reaction time task; one version required a manual motor response and the other version required an oral motor response. Results revealed that the female fXPCs displayed faster reaction times for both manual and oral motor responses relative to NT controls. Molecular measures including CGG repeat length, FMR1 mRNA levels, and age were not associated with performance in either group. Given previously reported age and CGG repeat modulated performance on a magnitude comparison task in this same group of premutation carriers, results from the current study seem to suggest that female fXPCs may have spared basic psychomotor functionality. PMID- 21554790 TI - "Do your eyes play tricks on you?" Asking older people about visual hallucinations in a general eye clinic. PMID- 21554791 TI - Plasma homocysteine and cognitive decline in older hypertensive subjects. AB - BACKGROUND: Elevated plasma homocysteine concentrations have been associated with both cognitive impairment and dementia. However, it is unclear whether some cognitive domains are more affected than others, or if this relationship is independent of B12 and folate levels, which can also affect cognition. We examined the relationship between plasma homocysteine and cognitive decline in an older hypertensive population. METHODS: 182 older people (mean age 80 years) with hypertension and without dementia, were studied at one center participating in the Study on COgnition and Prognosis in the Elderly (SCOPE). Annual cognitive assessments were performed using a computerized assessment battery and executive function tests, over a 3-5 year period (mean 44 months). Individual rates of decline on five cognitive domains were calculated for each patient. End of study plasma homocysteine, folate and B12 concentrations were measured. The relationship between homocysteine levels and cognitive decline was studied using multivariate regression models, and by comparing high versus low homocysteine quartile groups. RESULTS: Higher homocysteine showed an independent association with greater cognitive decline in three domains: speed of cognition (beta = 27.33, p = 0.001), episodic memory (beta = -1.25, p = 0.02) and executive function (beta = -0.05, p = 0.04). The association with executive function was no longer significant after inclusion of folate in the regression model (beta = 0.032, p = 0.22). Change in working memory and attention were not associated with plasma homocysteine, folate or B12. High homocysteine was associated with greater decline with a Cohen's d effect size of approximately 0.7 compared to low homocysteine. CONCLUSIONS: In a population of older hypertensive patients, higher plasma homocysteine was associated with cognitive decline. PMID- 21554792 TI - Attitudes towards Alzheimer's disease as a risk factor for caregiver burden. AB - BACKGROUND: There is abundant literature on the determinants of caregiver burden in Alzheimer's disease (AD), but little is known about the possible implication of specific patterns of a caregiver's attitudes towards the disease that could increase their risk of--or protect them from--emotional distress and burden. The aim of this study was to test the hypothesis that negative attitudes towards AD are associated with an increased level of burden experienced by caregivers of AD patients. METHODS: Family caregivers of 51 patients with AD were asked to complete a questionnaire regarding their attitudes towards AD. In addition, we assessed the level of their quality of life, anxiety and depression as well as their perceived level of burden. In parallel, we documented the patients' characteristics: global cognitive efficiency (Mini-Mental State Examination), behavioral and affective symptoms (Neuropsychiatric Inventory) and functional level (Instrumental Activities of Daily Living). RESULTS: The score of caregiver burden was positively correlated with negative attitudes such as authoritarianism (r = 0.41, p < 0.01) and social restrictiveness (r = 0.49, p < 0.001) as well as emotional reactions of anxiety (r = 0.44, p < 0.01) and aggressiveness (r = 0.47, p < 0.001). In addition, scores of social restrictiveness, rejection and anxiety were significantly higher in women than in men. CONCLUSION: These results may have implications in terms of the prevention of caregiver burden. In particular, educational and support programs for caregivers should not be limited to developing their knowledge and skills but should also target attitudes towards the disease. PMID- 21554793 TI - Prevalence and influence of psychiatric comorbidity on rehabilitation outcome for older hospital inpatients. AB - BACKGROUND: The objectives of this study were to characterize the psychiatric comorbidity of a group of older subacute inpatients and then determine whether their psychiatric comorbidity affected measures of rehabilitation outcomes. METHODS: Eighty-eight older subacute inpatients were recruited for this prospective study. Psychiatric comorbidity was defined according to a participants' performance on four inventory scales: the Geriatric Depression Scale (GDS), Geriatric Anxiety Inventory (GAI), Brief Psychiatric Rating Scale and Health of the Nation Outcome Scale 65+. Rehabilitation outcome referred to the participants' length of stay and their performance at discharge on the EuroQol-5D health-related quality of life questionnaire and Barthel index. RESULTS: 68% of the participants scored in the clinical range on at least one of the four scales assessing psychiatric comorbidity at admission, with 51% in the clinical range for GDS and 32% for the GAI. The decrease in scores by the time of discharge was significant for all four scales. Linear regression analyses pointed to a trend for depressive symptoms at admission to be an influential but nonsignificant predictor of rehabilitation outcome. An interesting association was found between the length of the previous acute admission and the GDS score on admission to the subacute unit. CONCLUSION: A high prevalence of psychological symptoms was identified upon admission, with a significant decrease by the time of discharge. These factors did not significantly predict the selected measures of rehabilitation outcome. Opportunities for future longitudinal research on the prevalence and impact of psychiatric comorbidities on patient outcomes are considered. PMID- 21554794 TI - Luria's three-step test: what is it and what does it tell us? AB - BACKGROUND: The purpose of this study is to determine if the three-step Luria test is useful for differentiating between cognitive disorders. METHODS: A retrospective record review of performance on the three-step Luria test was conducted on 383 participants from a university-based dementia clinic. The participants ranged in their diagnosis from frontotemporal dementia (FTD; n = 43), Alzheimer disease (AD; n = 153), mild cognitive impairment (MCI; n = 56), and normal controls (NC; n = 131). Performance of the Luria test was graded as normal or abnormal. RESULTS: An abnormal test occurred in 2.3% of NC, 21.4% of MCI, 69.8% of FTD, and 54.9% of AD subjects. The frequency of abnormal tests in all diagnostic groups increased with functional impairment as assessed by the Clinical Dementia Rating scale (CDR). When CDR = 3 (severe), 100% of the FTD and 72.2% of the AD subjects had abnormal Luria tests. CONCLUSIONS: The three-step Luria test distinguished NC and persons with MCI from FTD and AD, but did not distinguish FTD from AD subjects. PMID- 21554795 TI - Cross-country variation in sleep disturbance among working and older age groups: an analysis based on the European Social Survey. AB - BACKGROUND: Sleep disturbance is a common complaint in the general population. There is, however, little cross-national comparative evidence on the prevalence of sleep disturbance and its association with age. METHODS: Cross-sectional data from the third wave of the European Social Survey were used to compare both the prevalence of sleep disturbances and its relationship to age among 27,103 respondents over the age of 40 years from 23 European countries. The outcome measures for the study were based on the proportion of respondents reporting restless sleep over the past week and percentage change in the reporting of restless sleep between the 41-65 age group and the 66 and over age group. RESULT: The prevalence rate of sleep disturbance varied between and within age groups, as well as between the 23 European countries. Depressive symptoms (OR = 4.14), anxiety (OR = 2.80), and general health (OR = 1.52) were the strongest correlates of sleep disturbance among both the 41-65 age group and the over 66 age group. The highest positive correlation with change in restless sleep reports occurred with respect to health deterioration. Satisfaction with living standards showed the strongest negative association with change in restless sleep reports. CONCLUSION: There is considerable variation in reports of sleep disturbance across different European countries. Being in an older age group appears to be associated with worsening sleep, though not always. Different patterns of sleep disturbance seem to indicate the considerable variability of the aging experience across Europe. PMID- 21554796 TI - Inappropriate sexual behavior in a geriatric population. AB - BACKGROUND: Inappropriate sexual behavior (ISB) is an important topic in geriatrics; etiologies remain unclear and evidence for the efficacy of treatment strategies is limited. The aims of this study were to provide a description of the phenomenology of ISB in the geriatric population, to identify potential contributing factors, and to review the efficacy of interventions aimed at reducing ISB. METHODS: A retrospective chart review was conducted of ten patients admitted to an academic inpatient geriatric psychiatry ward because of their ISB (study group) and ten patients matched in age and gender (control group). A comprehensive chart review inventory was done to determine variables that may contribute to ISB. For the study group, effectiveness, adverse effects, and discontinuation due to adverse effects of interventions aimed at reducing ISB were reviewed. RESULTS: A significant finding was the association of a history of right frontal lobe stroke with ISB (Fisher's Exact Probability Test p < 0.05). Also significant was performance on cognitive testing and the presence of dementia (Fisher's Exact Probability Test p < 0.05) in the study group. Citalopram was well tolerated but with minimal reduction of ISB. Atypical antipsychotics olanzapine and risperidone were effective in some cases but also had adverse effects. Medroxyprogesterone acetate was well tolerated and effective in all cases in which it was utilized (n = 5). CONCLUSIONS: This study suggests that ISB in the geriatric population is associated with a history of right frontal lobe stroke and with severity of dementia. Case examples of pharmacologic interventions are reviewed. PMID- 21554797 TI - Change in psychotropic drug use among community-dwelling people aged 75 years and older in Finland: repeated cross-sectional population studies. AB - BACKGROUND: Older people are at high risk of experiencing psychotropic-related adverse drug events. The objective of this study was to compare and contrast the use of psychotropic drugs among community-dwelling people aged >= 75 years in 1998 and 2004. METHODS: Comparable random samples of people aged >= 75 years were extracted from the population register in Kuopio, Finland, in 1998 (n = 700) and 2003 (n = 1000). In 1998 and 2004, 523 and 700 community-dwelling people respectively participated in nurse interviews, during which demographic, diagnostic and drug use data were elicited. Logistic regression was used to compute unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of psychotropic drug use in 2004 compared to 1998. RESULTS: The unadjusted prevalence of total psychotropic (37.3% and 38.4%, OR 1.05; 95% CI 0.83-1.33), anxiolytic, hypnotic and sedative (29.6% and 31.3%, OR 1.08, 95% CI 0.85-1.38), and antidepressant (10.7% and 11.9%, OR 1.12, 95% CI 0.78-1.61) use were similar in 1998 and 2004. There was a decrease in the unadjusted prevalence of antipsychotic use (9.2% and 5.7%, OR 0.60; 95% CI 0.39 0.93). After adjusting for socioeconomic and health status differences, there was an increase in the prevalence of total psychotropic (adjusted OR 1.31, 95% CI 1.01-1.70) and antidepressant (OR 1.59, 95% CI 1.06-2.40) use. CONCLUSION: The unadjusted prevalence of psychotropic drug use remained stable between 1998 and 2004. However, in adjusted analyses there was a small increase in the prevalence of any psychotropic drug use and antidepressant use specifically. PMID- 21554798 TI - Male wing fanning by the aphid parasitoid Aphidius ervi (Hymenoptera: Braconidae) produces a courtship song. AB - We, herein, report evidence that wing fanning by the aphid parasitoid Aphidius ervi Haliday (Hymenoptera: Braconidae) constitutes a courtship song. Complete removal of the forewings or only the distal half of them reduced male copulation success in comparison to intact males. Males that achieved copulation within the observation period produced wing fanning at a higher rate than males that did not copulate. Playback of wing fanning sound altered the behaviour of virgin females, increasing the time they devoted to grooming, as compared with subjects that were exposed to silence or white noise. Our findings contribute to the understanding of the acoustic dimension of the sensory modalities employed by this aphid parasitoid in sexual signalling. PMID- 21554799 TI - A quantitative comparison of frugivorous tephritids (Diptera: Tephritidae) in tropical forests and rural areas of the Democratic Republic of Congo. AB - Most of the current knowledge about African tephritids originates from studies performed in agricultural areas, while information about their distribution in pristine or moderately disturbed environments is extremely scarce. This study aims at (i) describing levels of spatial variability of frugivorous tephritids in tropical forests and small rural villages of the Congo River basin and (ii) verifying if human-mediated activities, such as small-scale agriculture and trade, can affect their distribution patterns. Four locations were sampled along a 250 km stretch of the Congo River. At each location, pristine and disturbed habitats (i.e. tropical forests and small rural villages, respectively) were sampled, with three replicate sites in each combination of habitat and location. Sampling with modified McPhail traps baited with four different attractants yielded 819 tephritid specimens of 29 species from seven genera (Bactrocera, Carpophthoromyia, Ceratitis, Dacus, Celidodacus, Perilampsis, Trirhithrum). The three most abundant species sampled (Dacus bivittatus, D. punctatifrons, Bactrocera invadens) showed significant variations in abundance across locations and sites and accounted for 98.29% of the overall dissimilarity between habitats. Assemblages differed among locations and sites while they showed significant differences between pristine and disturbed habitats in two out of the four locations. This study shows that frugivorous tephritids in central Congo have remarkably patchy distributions with differences among locations and sites representing the main source of variability. Our data show that, in rural villages of central Democratic Republic of Congo, human activities, such as small scale agriculture and local commerce, are not always sufficient to promote differences between the tephritid assemblages of villages and those of the surrounding tropical forests. PMID- 21554800 TI - Genetic differentiation among populations of Brachytrupes portentosus (Lichtenstein 1796) (Orthoptera: Gryllidae) in Thailand and the Lao PDR: the Mekong River as a biogeographic barrier. AB - The Mekong River is known to act as a boundary between a number of terrestrial and freshwater species, including various parasites and their intermediate hosts as well as endangered mammal species. Little information is available, however, on the genetic differentiation between terrestrial invertebrates to the east and the west of this wide river. The genetic diversity among eight natural populations of Brachytrupes portentosus (Lichtenstein, 1796) (Orthoptera: Gryllidae) collected from Thailand and the Lao People's Democratic Republic (PDR) were analyzed by multilocus enzyme electrophoresis. The allelic profiles of 20 enzymes encoding 23 loci were analyzed. An average of 41% fixed differences was detected between the populations from Thailand and Lao PDR, which are separated by the Mekong River. The percent fixed differences ranged between 4% and 26% within the populations from Thailand and between 4% and 22% within the populations from Lao PDR. A phenogram shows that the eight populations fell into two major clusters based on the Thai and Lao sampling sites. The genetic distance between the samples within Thailand and within Lao PDR was related to the distances between sampling areas. The genetic variability between populations of this cricket indicates that genetic relationships are influenced by a natural barrier as well as by the geographical distance between these allopatric populations. PMID- 21554801 TI - Insect food for astronauts: gas exchange in silkworms fed on mulberry and lettuce and the nutritional value of these insects for human consumption during deep space flights. AB - In this study, silkworm moth (Bombyx mori L.) larvae were regarded as an animal protein source for astronauts in the bioregenerative life support system during long-term deep space exploration in the future. They were fed with mulberry and stem lettuce leaves during the first three instars and the last two instars, respectively. In addition, this kind of environmental approach, which utilised inedible biomass of plants to produce animal protein of high quality, can likewise be applied terrestrially to provide food for people living in extreme environments and/or impoverished agro-ecosystems, such as in polar regions, isolated military bases, ships, submarines, etc. Respiration characteristics of the larvae during development under two main physiological conditions, namely eating and not-eating of leaves, were studied. Nutrient compositions of silkworm powder (SP), ground and freeze-dried silkworms on the 3rd day of the 5th instar larvae, including protein, fat, vitamins, minerals and fatty acids, were measured using international standard methods. Silkworms' respiration rates, measured when larvae were eating mulberry leaves, were higher than those of similar larvae that hadn't eaten such leaves. There was a significant difference between silkworms fed on mulberry leaves and those fed on stem lettuce in the 4th and 5th instars (P<0.01). Amounts of CO2 exhaled by the silkworms under the two physiological regimes differed from each other (P<0.01). There was also a significant difference between the amount of O2 inhaled when the insects were under the two physiological statuses (P<0.01). Moreover, silkworms' respiration quotient under the eating regime was larger than when under the not-eating regime. The SP was found to be rich in protein and amino acids in total; 12 essential vitamins, nine minerals and twelve fatty acids were detected. Moreover, 359 kcal could be generated per 100 gram of SP (dry weight). PMID- 21554802 TI - Hypocholesterolaemic effect of water-insoluble fish protein from Alaska pollock in ovariectomised rats is not abolished by methionine addition. AB - The present study investigated whether the hypocholesterolaemic effect of water insoluble fish protein (IFP) from Alaska pollock in ovariectomised (OVX) rats was affected by methionine (Met) addition. OVX rats (6 months old) were fed a cholesterol-free diet containing casein, IFP or IFP+Met as a protein source for 28 d. The ratio of Met:glycine was lower in the IFP and IFP+Met diets compared with the casein diet. Body-weight gain, food intake and liver lipids were not affected by the diet. Plasma total cholesterol concentration was lower in OVX rats fed the IFP diet compared with those fed the casein diet. The hypocholesterolaemic effect of the IFP diet was not abolished by Met addition. Amount of bile acids in the small-intestinal content and faecal excretion of bile acids were higher in OVX rats fed the IFP and IFP+Met diets compared with those fed the casein diet. Ileal bile acid transporter (IBAT) mRNA level and faecal excretion of bile acids were significantly lower and higher, respectively, in OVX rats fed the IFP diet compared with those fed the casein diet, but not in those fed the IFP+Met diet. Thus, the hypocholesterolaemic effect of the IFP diet seems to be mediated by increased faecal excretion of bile acids coupled with decreased reabsorption of bile acids from the ileum through a decrease in IBAT and the change in cholesterol metabolism linked to the amino acid profile. PMID- 21554803 TI - Effect of bariatric surgery on sulphur amino acids and glutamate. AB - Plasma total cysteine (tCys) concentrations are associated with BMI. To study the relationship between tCys and BMI, we monitored the changes in serum concentrations of tCys and metabolically related compounds in sixty obese patients (BMI 50-60 kg/m(2)) from before to 1 year after either gastric bypass surgery (mean 30 % weight loss) or duodenal switch surgery (mean 41 % weight loss). A total of fifty-eight healthy persons (BMI 17-31 kg/m(2)) served as controls. Before surgery, obese patients had modestly (approximately 17 %) higher mean serum tCys, and markedly (>2-fold) higher glutamate concentrations, than controls (P <= 0.001 for both). Serial examinations after surgery revealed that gastric bypass patients had no change in tCys concentrations (P = 0.22), while duodenal switch patients showed a modest (approximately 12 %) but significant decrease in tCys (P < 0.001). Total homocysteine concentrations increased in duodenal switch patients but not in gastric bypass patients. Independent of surgery type, serum concentrations of methionine and cystathionine decreased (P < 0.05 for both), while serum glutathione and taurine remained stable. Glutamate concentrations declined, as did gamma-glutamyltransferase activity (P < 0.001 for both). These results show that despite 30 % weight loss, and decreases in methionine, cystathionine and glutamate, there was no significant change in serum tCys in patients after gastric bypass surgery. The decrease in tCys in patients undergoing duodenal switch could be related to malabsorption. The present findings do not suggest that BMI is a causal determinant of plasma tCys. PMID- 21554804 TI - Effect of food form on postprandial plasma amino acid concentrations in older adults. AB - To assess the effect of food form (FF) on postprandial (PP) plasma amino acid (AA) concentrations, ten older adults (five men and five women, age 72 (sem 2) years, BMI 26.0 (sem 0.9) kg/m2) consumed, on separate days, energy and macronutrient-matched test meal replacement products (MRP) (approximately 25 % of the subject's daily energy need; approximately 54 % carbohydrate, 21 % protein, 25 % fat) in beverage and solid form. Blood samples were taken during fasting and throughout the 4 h PP period; plasma AA concentrations were assessed using HPLC. Consumption of each MRP led to an increase in total AA, branched-chain AA (BCAA), essential AA (EAA), non-essential AA (NEAA) and leucine concentrations (4 h area under the curve, AUC) (time effect; P < 0.05). The beverage MRP resulted in a greater initial (i.e. 30 min) and sustained (4 h AUC) increase in total AA, BCAA, EAA, NEAA and leucine concentrations compared with the solid MRP (each effect of FF; P < 0.05). Although there was no effect of FF on PP insulin response, glucose concentration was greater 1 and 2 h after the solid MRP was consumed (FF * time interaction; P < 0.05). For all PP time points combined, total AA concentration was positively associated with plasma insulin (r 0.25) and glucose (r 0.24) concentrations for the solid MRP but not for the beverage MRP. In conclusion, older adults can achieve higher plasma AA concentrations when a protein containing MRP is ingested in beverage form. The implications of the higher AA availability on anabolic processes warrant investigation. PMID- 21554805 TI - Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro opiomelanocortin gene. AB - Leptin supplementation of neonatal rats during the suckling period protects against being overweight in adulthood and ameliorates the control of food intake. This was associated with changes in the expression of hypothalamic genes involved in the central action of leptin: pro-opiomelanocortin (Pomc), leptin receptor (Lepr) and suppressor of cytokine signalling (Socs3). The purpose of the present study was to determine the methylation status within the promoter regions of these genes and to assess whether the observed changes in the expression levels of these genes could be explained by changes in their methylation status. Male rats were treated daily with an oral physiological dose of leptin or vehicle during the suckling period. After weaning, animals were fed with a normal-fat or a high-fat (HF) diet until aged 6 months. DNA was extracted from the hypothalamus and methylation within the promoter regions of the gene panel was measured by pyrosequencing. Pomc promoter methylation increased in control animals fed the HF diet but decreased in leptin-treated animals. In addition, there was a weak negative correlation between DNA methylation and POMC mRNA levels (P = 0.075). There were no changes in the methylation status of the CpG sites studied within the promoter regions of Lepr and Socs3 in response to leptin or HF treatments. This is the first demonstration that leptin treatment during lactation may programme methylation of an appetite-related gene in the hypothalamus of animals fed HF diets, with possible implications for gene expression and protection against the development of obesity. PMID- 21554806 TI - Antibacterial peptides derived from caprine whey proteins, by digestion with human gastrointestinal juice. AB - Peptides in caprine whey were identified after in vitro digestion with human gastrointestinal enzymes in order to determine their antibacterial effect. The digestion was performed in two continuing steps using human gastric juice (pH 2.5) and human duodenal juice (pH 8) at 37 degrees C. After digestion the hydrolysate was fractionated and 106 peptides were identified. From these results, twenty-two peptides, located in the protein molecules, were synthesised and antibacterial activity examined. Strong activity of the hydrolysates was detected against Escherichia coli K12, Bacillus cereus RT INF01 and Listeria monocytogenes, less activity against Staphylococcus aureus ATCC 25 923 and no effect on Lactobacillus rhamnosus GG. The pure peptides showed less antibacterial effect than the hydrolysates. When comparing the peptide sequences from human gastrointestinal enzymes with previously identified peptides from non-human enzymes, only two peptides, beta-lactoglobulin f(92-100) and beta-casein f(191 205) matched. No peptides corresponded to the antibacterial caprine lactoferricin f(14-42) or lactoferrampin C f(268-284). Human gastrointestinal enzymes seem to be more complex and have different cleavage points in their protein chains compared with purified non-human enzymes. Multiple sequence alignment of nineteen peptides showed proline-rich sequences, neighbouring leucines, resulting in a consensus sequence LTPVPELK. In such a way proline and leucine may restrict further proteolytic processing. The present study showed that human gastrointestinal enzymes generated different peptides from caprine whey compared with non-human enzymes and a stronger antibacterial effect of the hydrolysates than the pure peptides was shown. Antimicrobial activity against pathogens but not against probiotics indicate a possible host-protective activity of whey. PMID- 21554807 TI - Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality. AB - Refeeding syndrome is difficult to diagnose since the guidelines for identifying those at risk are largely based on subjective clinical parameters and there are no predictive biochemical markers. We examined the suitability of insulin-like growth factor 1 (IGF1) and leptin as markers to identify patients at risk of the refeeding syndrome before initiation of parenteral nutrition (PN). A total of thirty-five consecutive patients referred for commencement of PN were included. Serum leptin and IGF1 were measured before starting PN. Electrolytes, liver and renal function tests were conducted before and daily for 1 week after initiating PN. The primary outcome was a decrease in phosphate 12-36 h after initiating PN. 'Refeeding index' (RI) was defined as leptin * IGF1 divided by 2800 to produce a ratio of 1.0 in patients who are well nourished. RI had better sensitivity (78 %; 95 % CI 40, 97 %) and specificity (78 %; 95 % CI 40, 97 %) with a likelihood ratio of 3.4, at a cut-off value of 0.19 for predicting a >= 30 % decrease in phosphate concentration within 12-36 h after starting PN, compared with IGF1 or leptin alone. However, IGF1 was a better predictor of mortality than either leptin or the RI. The present study is the first to derive and test the 'RI', and find that it is a sensitive and specific predictor of the refeeding syndrome in hospitalised patients before starting PN. PMID- 21554808 TI - Association between parenting styles and own fruit and vegetable consumption among Portuguese mothers of school children. AB - The aim of the present study was to evaluate the association between parenting styles and own fruit and vegetable consumption among Portuguese mothers of school children. A cross-sectional study was performed in Portugal as part of the Pro Children cross-sectional European survey. Portuguese mothers (n 1601) of 11-13 year-old school children were included in the present study. A self-administered questionnaire was developed to assess fruit and vegetable consumption as well as the parenting styles. Fruit and vegetable consumption was assessed by a validated FFQ. Parenting styles based on two dimensions - strictness and involvement - were classified into authoritative, authoritarian, indulgent and neglectful. The higher mean intakes of fruit, vegetables and total fruit and vegetables were observed for mothers classified as indulgent, whereas the lower mean intakes were observed for mothers classified as neglectful. Differences in intake among parenting styles were significant for fruit, vegetables and total fruit and vegetables. When partial correlations were calculated between the two dimensions, strictness and involvement (controlled one for the other), and intakes, only involvement was positively associated with fruit, vegetables and total fruit and vegetable intake. Findings from the present study show that fruit and vegetable consumption of Portuguese mothers of school children seems to be related to their own parenting styles, especially with the dimension involvement. Future interventions to promote fruit and vegetable intake should take into account these variables. PMID- 21554809 TI - Effects of viscosity and fermentability of dietary fibre on nutrient digestibility and digesta characteristics in ileal-cannulated grower pigs. AB - Relative contributions of two functional properties, viscosity and fermentability of dietary fibre, on apparent ileal digestibility (AID), apparent total tract digestibility (ATTD), digesta passage rate, N retention and SCFA concentration have not been established. Thus, eight ileal-cannulated pigs randomised in a double 4 * 4 Latin square were fed four diets based on maize starch and casein supplemented with 5 % of actual fibre in a 2 * 2 factorial arrangement: low fermentable, low-viscous cellulose (CEL); low-fermentable, high-viscous carboxymethylcellulose (CMC); high-fermentable, low-viscous oat beta-glucan (LBG); high-fermentable, high-viscous oat beta-glucan (HBG). Viscosity and fermentability interacted to affect (P < 0.001) digesta viscosity and AID and ATTD of nutrients. These properties tended to interact to affect (P < 0.10) digesta passage rate and butyrate. Pigs fed the CMC diet had the lowest (P < 0.05) digesta passage rate and the highest (P < 0.001) AID of energy, crude protein and DM, and ATTD of energy and DM. Post-ileal DM digestibility was highest (P < 0.001) for pigs fed the CEL and HBG diets. Post-ileal DM digestibility had a negative, curvilinear relationship with the AID of energy and crude protein (R2 0.85 and 0.72, respectively; P < 0.001). Digesta viscosity had a less strong relationship with the AID of energy and crude protein (R2 0.45 and 0.36, respectively; P < 0.001). In conclusion, high-viscous, low-fermentable dietary fibre increases the proportion of a diet that is digested in the small intestine by reducing digesta passage rate. PMID- 21554810 TI - A grape polyphenol extract modulates muscle membrane fatty acid composition and lipid metabolism in high-fat--high-sucrose diet-fed rats. AB - Accumulation of muscle TAG content and modification of muscle phospholipid fatty acid pattern may have an impact on lipid metabolism, increasing the risk of developing diabetes. Some polyphenols have been reported to modulate lipid metabolism, in particular those issued from red grapes. The present study was designed to determine whether a grape polyphenol extract (PPE) modulates skeletal muscle TAG content and phospholipid fatty acid composition in high-fat-high sucrose (HFHS) diet-fed rats. Muscle plasmalemmal and mitochondrial fatty acid transporters, GLUT4 and lipid metabolism pathways were also explored. The PPE decreased muscle TAG content in HFHS/PPE diet-fed rats compared with HFHS diet fed rats and induced higher proportions of n-3 PUFA in phospholipids. The PPE significantly up-regulated GLUT4 mRNA expression. Gene and protein expression of muscle fatty acid transporter cluster of differentiation 36 (CD36) was increased in HFHS diet-fed rats but returned to control values in HFHS/PPE diet-fed rats. Carnitine palmitoyltransferase 1 protein expression was decreased with the PPE. Mitochondrial beta-hydroxyacyl CoA dehydrogenase was increased in HFHS diet-fed rats and returned to control values with PPE supplementation. Lipogenesis, mitochondrial biogenesis and mitochondrial activity were not affected by the PPE. In conclusion, the PPE modulated membrane phospholipid fatty acid composition and decreased muscle TAG content in HFHS diet-fed rats. The PPE lowered CD36 gene and protein expression, probably decreasing fatty acid transport and lipid accumulation within skeletal muscle, and increased muscle GLUT4 expression. These effects of the PPE are in favour of a better insulin sensibility. PMID- 21554811 TI - In silico exploration of the mechanisms that underlie parasite-induced anorexia in sheep. AB - A model was used to investigate two mechanisms describing reductions in food intake (anorexia) observed during gastrointestinal parasitism in lambs, and to explore relationships between anorexia and food composition. The mechanisms were either a reduction in intrinsic growth rate, leading to a consequent reduction in food intake (mechanism 1; M1), or a direct reduction in food intake (mechanism 2; M2). For both mechanisms, lambs growing from 2 to 6 months of age were modelled, with one of three levels of trickle challenge with Teladorsagia circumcincta. Scenarios were simulated for feeds varying in either protein or energy content, or both. Major differences were found between the predictions resulting from M1 and M2 on low-energy foods that constrained the intake of uninfected lambs through bulk. With M1, food intake was governed by the first operating constraint, whereas with M2 an additivity of constraints was observed. On the other foods, the duration of anorexia increased with increasing energy content of feed for M1, whilst the duration of anorexia decreased with increasing protein content of feed for M2.For foods that did not have an impact upon lambs' gastrointestinal tract capacity, published data were consistent with predictions of M2. Due to an absence of experimental data, no conclusions could be drawn for relationships between anorexia and food composition in the presence of other limiting constraints, such as bulk for low-energy foods. In conclusion, available experimental data and model predictions were consistent with anorexia having an impact directly on food intake, and with impacts of anorexia increasing with decreasing protein content. PMID- 21554812 TI - Phytosterol supplementation reduces metabolic activity and slows cell growth in cultured rat cardiomyocytes. AB - Besides being cholesterol-lowering agents, phytosterols (PS) can inhibit the growth and development of tumours. The anti-neoplastic activity is accounted for by PS incorporation into cell membranes, resulting in the interference of membrane functionality. The similarity between the PS cholesterol-lowering and anti-neoplastic effective doses deserves attention on the possible adverse effects even in non-neoplastic cells. To date, few studies have addressed the clarification of this important issue. In the present study, we supplemented primary, non-neoplastic neonatal rat cardiomyocytes with two different PS concentrations (3 or 6 MUg/ml), both within the range of human plasma concentration. Cardiac cells were chosen as an experimental model since the heart has been reported as the target organ for subchronic toxicity of PS. Following supplementation, a dose-dependent incorporation of PS and a decrease in cholesterol content were clearly evidenced. PS did not induce apoptosis but caused a reduction in metabolic activity (measured as 3-(4,5-dimethyldiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) conversion) and a slowing down of cell growth. The lower MTT conversion and the similar lactate dehydrogenase release could suggest that PS more efficiently target mitochondria than plasma membrane integrity. The replacement of cholesterol by PS could also have caused the observed slowing down of cell growth and the reduction in metabolic activity, which could rely on the PS increase, cholesterol decrease, or both. The present study is the first report on the effect of PS in cardiac cells, and although it is difficult to translate the obtained results to the health of heart tissue, it raises concerns about the safety of long-term exposure to physiologically relevant PS concentrations. PMID- 21554813 TI - Impact of phytosterols on mitochondrial functions. PMID- 21554814 TI - Ruminal methane inhibition potential of various pure compounds in comparison with garlic oil as determined with a rumen simulation technique (Rusitec). AB - Ruminants represent an important source of methane (CH(4)) emissions; therefore, CH(4) mitigation by diet supplementation is a major goal in the current ruminant research. The objective of the present study was to use a rumen simulation technique to evaluate the CH(4)-mitigating potential of pure compounds in comparison with that achieved with garlic oil, a known anti-methanogenic supplement. A basal diet (15 g DM/d) consisting of ryegrass hay, barley and soyabean meal (1:0.7:0.3) was incubated with the following additives: none (negative control); garlic oil (300 mg/l incubation liquid; positive control); allyl isothiocyanate (75 mg/l); lovastatin (150 mg/l); chenodeoxycholic acid (150 mg/l); 3-azido-propionic acid ethyl ester (APEE, 150 mg/l); levulinic acid (300 mg/l); 4-[(pyridin-2-ylmethyl)-amino]-benzoic acid (PABA, 300 mg/l). Fermentation profiles (SCFA, microbial counts and N turnover) and H(2) and CH(4) formation were determined. Garlic oil, allyl isothiocyanate, lovastatin and the synthetic compound APEE decreased the absolute daily CH(4) formation by 91, 59, 42 and 98 %, respectively. The corresponding declines in CH(4) emitted per mmol of SCFA were 87, 32, 40 and 99 %, respectively, compared with the negative control; the total SCFA concentration was unaffected. Garlic oil decreased protozoal numbers and increased bacterial counts, while chenodeoxycholic acid completely defaunated the incubation liquid. In vitro, neutral-detergent fibre disappearance was lower following chenodeoxycholic acid and PABA treatments (- 26 and - 18 %, respectively). In conclusion, garlic oil and APEE were extremely efficient at mitigating CH(4) without noticeably impairing microbial nutrient fermentation. Other promising substances were allyl isothiocyanate and lovastatin. PMID- 21554815 TI - An integrative in vitro approach to analyse digestion of wheat polysaccharides and the effect of enzyme supplementation. AB - The digestion of polysaccharides from the wheat cultivars Caphorn and Isengrain was investigated, and the efficiency of an enzyme preparation was tested using the TNO gastrointestinal model (TIM-1). The apparent digestibility (AD) of carbohydrates was determined based on the measurement of organic matter (OM), total monosaccharides, reducing ends (RE) and end products (EP: glucose, maltose and xylobiose). The AD of the OM from Caphorn and Isengrain measured using caecectomised cockerels did not differ from that measured using TIM-1: 72.0 (SD 2.6) v. 70.6 (SD 0.6) % for Caphorn (P = 0.580) and 73.0 (SD 2.3) v. 71.1 (SD 1.9) % for Isengrain (P = 0.252). After the 6 h TIM-1 digestion, 41.4-58.9 % of the OM, RE and EP were recovered from the jejunal compartment and 18.3-27.1 % from the ileal compartment, while ileal deliveries and digestive residues constituted the remainder. A commercial enzyme cocktail tested at 0.2 MUl/g of wheat improved TIM-1 digestibility of Caphorn and Isengrain polysaccharides: 3.9 % (P = 0.0203) and 3.4 % (P = 0.0058) based on the OM; 9.7 % (P < 0.0001) and 3.1 % (P = 0.031) based on the total glucose; 47.2 % (P < 0.0001) and 14.2 % (P = 0.0004) based on the RE, respectively. The enzyme cocktail improved the release of the EP for Caphorn (3.8 %, P = 0.008) but not for Isengrain ( - 0.8 %, P = 0.561). The higher efficiency of the enzyme supplementation on the digestion of Caphorn polysaccharides compared with Isengrain seems to be linked to the higher soluble carbohydrate contents and/or less ramified arabinoxylan of Caphorn. PMID- 21554816 TI - The oligosaccharide alpha-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults. AB - In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide alpha-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of alpha-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of alpha-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68-76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with (99m)Tc-sulphur colloid, with or without 10 g alpha-cyclodextrin. Gastric emptying was slowed slightly by alpha-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0.05) in distal stomach retention. After alpha-cyclodextrin, blood glucose was slightly less (P < 0.05) at 60 min, and serum insulin was less (P < 0.0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0.09) after alpha-cyclodextrin. We conclude that in a dose of 10 g, alpha-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption. PMID- 21554817 TI - Short-term effects of whole-grain wheat on appetite and food intake in healthy adults: a pilot study. AB - While it has been proposed, based on epidemiological studies, that whole grains may be beneficial in weight regulation, possibly due to effects on satiety, there is limited direct interventional evidence confirming this. The present cross-over study aimed to investigate the short-term effects on appetite and food intake of 48 g of whole-grain wheat (daily for 3 weeks) compared with refined grain (control). A total of fourteen healthy normal-weight adults consumed, within their habitual diets, either two whole-grain bread rolls (providing 48 g of whole grains over two rolls) or two control rolls daily for 3 weeks. Changes in food intake were assessed using 7 d diet diaries. Changes in subjective appetite ratings and food intake were also assessed at postprandial study visits. There were no significant differences between interventions in energy intake (assessed by the 7 d diet diaries and at the ad libitum test meal), subjective appetite ratings or anthropometric measurements. However, there was a significant difference between interventions for systolic blood pressure, which decreased during the whole-grain intervention and increased during the control intervention (-2 v. 4 mmHg; P = 0.015). The present study found no effect of whole grains on appetite or food intake in healthy individuals; however, 48 g of whole grain consumed daily for 3 weeks did have a beneficial effect on systolic blood pressure. The findings from the present study therefore do not support epidemiological evidence that whole grains are beneficial in weight regulation, although further investigation in other population groups (such as overweight and obese) would be required. PMID- 21554818 TI - Fatty acid intakes of children and adolescents are not in line with the dietary intake recommendations for future cardiovascular health: a systematic review of dietary intake data from thirty countries. AB - Fatty acid composition of the diet may influence cardiovascular risk from early childhood onwards. The objective of the present study was to perform a systematic review of dietary fat and fatty acid intakes in children and adolescents from different countries around the world and compare these with the population nutrient intake goals for prevention of chronic diseases as defined by the WHO (2003). Data on fat and fatty acid intake were mainly collected from national dietary surveys and from population studies all published during or after 1995. These were identified by searching PubMed, and through nutritionists at local Unilever offices in different countries. Fatty acid intake data from thirty countries mainly from developed countries were included. In twenty-eight of the thirty countries, mean SFA intakes were higher than the recommended maximum of 10 % energy, whereas in twenty-one out of thirty countries mean PUFA intakes were below recommended (6-10 % energy). More and better intake data are needed, in particular for developing regions of the world, and future research should determine the extent to which improvement of dietary fatty acid intake in childhood translates into lower CHD risk in later life. Despite these limitations, the available data clearly indicate that in the majority of the countries providing data on fatty acid intake, less than half of the children and adolescents meet the SFA and PUFA intake goals that are recommended for the prevention of chronic diseases. PMID- 21554819 TI - Cinnamaldehyde enhances in vitro parameters of immunity and reduces in vivo infection against avian coccidiosis. AB - The effects of cinnamaldehyde (CINN) on in vitro parameters of immunity and in vivo protection against avian coccidiosis were evaluated. In vitro stimulation of chicken spleen lymphocytes with CINN (25-400 ng/ml) induced greater cell proliferation compared with the medium control (P < 0.001). CINN activated cultured macrophages to produce higher levels of NO at 1.2-5.0 MUg/ml (P < 0.001), inhibited the growth of chicken tumour cells at 0.6-2.5 MUg/ml (P < 0.001) and reduced the viability of Eimeria tenella parasites at 10 and 100 MUg/ml (P < 0.05 and P < 0.001, respectively), compared with media controls. In chickens fed a diet supplemented with CINN at 14.4 mg/kg, the levels of IL-1beta, IL-6, IL-15 and interferon-gamma transcripts in intestinal lymphocytes were 2- to 47-fold higher (P < 0.001) compared with chickens given a non-supplemented diet. To determine the effect of CINN diets on avian coccidiosis, chickens were fed diets supplemented with CINN at 14.4 mg/kg (E. maxima or E. tenella) or 125 mg/kg (E. acervulina) from hatch for 24 d, and orally infected with 2.0 * 10(4) sporulated oocysts at age 14 d. CINN-fed chickens showed 16.5 and 41.6 % increased body-weight gains between 0-9 d post-infection (DPI) with E. acervulina or E. maxima, reduced E. acervulina oocyst shedding between 5-9 DPI and increased E. tenella-stimulated parasite antibody responses at 9 DPI compared with controls. PMID- 21554820 TI - Diet before pregnancy and the risk of hyperemesis gravidarum. AB - Hyperemesis gravidarum (hyperemesis), characterised by severe nausea and vomiting in early pregnancy, has an unknown aetiology. The aim of the present study was to investigate food and nutrient intake before pregnancy and the risk of developing hyperemesis in women participating in the Norwegian Mother and Child Cohort Study. From 1999 to 2002, a total of 7710 pregnant women answered a FFQ about their diet during the 12 months before becoming pregnant and a questionnaire about illnesses during pregnancy, including hyperemesis. Only women who were hospitalised for hyperemesis were included as cases. Nutrient intakes during the year before pregnancy did not differ between the ninety-nine women who developed hyperemesis and the 7611 who did not. However, the intake of seafood, allium vegetables and water was significantly lower among women who developed hyperemesis than among women in the non-hyperemesis group. Relative risks of hyperemesis were approximated as OR, and confounder control was performed with multiple logistic regression. Women in the upper tertile of seafood consumption had a lower risk of developing hyperemesis than those in the lower tertile (OR 0.56, 95 % CI 0.32, 0.98), and women in the second tertile of water intake had a lower risk of developing hyperemesis than those in the first tertile (OR 0.43, 95 % CI 0.25, 0.73). The findings suggest that a moderate intake of water and adherence to a healthy diet that includes vegetables and fish are associated with a lower risk of developing hyperemesis. PMID- 21554821 TI - Rhabdomyoma of the interventricular septum presenting as a Brugada phenocopy. AB - Brugada syndrome is a channelopathy characterised electrocardiographically by distinctive coved ST-segment elevation in the right precordial leads and is associated with a predisposition for sudden death secondary to ventricular arrhythmias in otherwise healthy patients. Previously known as Brugada-like patterns, Brugada phenocopies include agents and conditions that mimic true Brugada syndrome, presenting with an acquired Brugada Type-1 ECG pattern. We describe the first reported case of a 17-month-old female with an asymptomatic rhabdomyoma of the interventricular septum that presented as a Brugada phenocopy. PMID- 21554822 TI - Left cervical aortic arch associated with multiple vascular anomalies. AB - Cervical aortic arch is a rare anomaly occasionally associated with other cardiovascular abnormalities. We present a case of tortuous left cervical aortic arch associated with hypoplastic transverse arch, coarctation of the aorta, and right brachiocephalic arteries arising below the coarctation and stenotic origin of the left subclavian artery. These multiple anatomic anomalies, which are associated in our case, have not been described in a single patient previously. PMID- 21554823 TI - Early presentation of endomyocardial fibrosis. PMID- 21554824 TI - Flow-sensitive four-dimensional magnetic resonance imaging facilitates and improves the accurate diagnosis of partial anomalous pulmonary venous drainage. AB - OBJECTIVES: To assess if flow-sensitive four-dimensional velocity-encoded cine magnetic resonance imaging adds value in diagnosing patients with suspected partial anomalous pulmonary venous drainage. METHODS: In six patients with echocardiographically suspected partial anomalous pulmonary venous drainage, anatomy was evaluated using standard magnetic resonance imaging including angiography. Functional analysis included shunt calculations from flow measurements. We used four-dimensional velocity-encoded cine magnetic resonance imaging for visualisation of maldraining pulmonary veins and quantification of flow via the maldraining veins and interatrial communications, if present. RESULTS: In all patients, the diagnosis of partial anomalous pulmonary venous drainage was confirmed by standard magnetic resonance imaging. Shunt volumes ranged from 1.4:1 to 4.7:1. Drainage sites were the superior caval vein (n = 5) or the vertical vein (n = 1). Multiple maldraining pulmonary veins were found in three patients. Pulmonary arteries and veins could be clearly distinguished by selective visualisation using four-dimensional velocity-encoded cine magnetic resonance imaging. Flow measured individually in maldraining pulmonary veins in six patients and across the interatrial communication in three patients revealed a percentage of the overall shunt volume of 30-100% and 58-70%, respectively. CONCLUSION: Selective visualisation of individual vessels and their flow characteristics by four-dimensional velocity-encoded cine magnetic resonance imaging facilitates in distinguishing adjacent pulmonary arteries and veins and thus improves the accurate diagnosis of maldraining pulmonary veins. By detailed quantification of shunt volumes, additional information for planning of treatment strategies is provided. This method adds clinical value and might replace contrast-enhanced magnetic resonance angiography in these patients in the future. PMID- 21554825 TI - Assessment of resting electrocardiogram, P wave dispersion and duration in different genders applying for registration to the School of Physical Education and Sports - results of a single centre Turkish Trial with 2093 healthy subjects. AB - BACKGROUND: The 12-lead electrocardiogram shows a broad range of abnormal patterns in trained athletes. The primary end point of this study was to investigate P wave dispersion, and P wave durations and related factors in different genders applying for registration to the School of Physical Education and Sports. METHODS AND RESULTS: From 2006 to 2009, a total of 2093 students - 1674 boys with a mean age of 19.8 plus or minus 1.9 years and 419 girls with a mean age of 19.1 plus or minus 1.8 years - were included in the study. All 12 leads of the resting electrocardiogram were evaluated for P wave dispersion and electrocardiogram abnormalities. Baseline parameters such as age, body weight, body height, and body mass index, as well as electrocardiogram findings such as P wave maximal duration and P wave dispersion, were significantly higher in boys than in girls. Of all the parameters tested with correlation analysis, only gender (p = 0.03) (r = 0.04), body weight (p < 0.001) (r = 0.07), body height (p = 0.004) (r = 0.06), and body mass index (p = 0.01) (p = 0.05) were correlated with P wave dispersion. CONCLUSION: The frequencies of all electrocardiogram abnormalities, P wave dispersion, and P wave maximal duration were higher in boys as compared with girls in an unselected student population applying for registration to the School of Physical Education and Sports; in addition, P wave dispersion was correlated with gender, body weight, body height, and body mass index. PMID- 21554826 TI - The use of Arginine Vasopressin in neonates following the Norwood procedure. AB - BACKGROUND: Following the Norwood palliation, neonates may require an escalation of inotropic and vasoactive support. Arginine Vasopressin may be uniquely useful in supporting this population. MATERIALS AND METHODS: A retrospective evaluation of neonates at this institution between November, 2007 and October, 2010 who received Arginine Vasopressin following the Norwood procedure. Data were recorded from the patient records at one hour prior to, and then 1, 2, 3, 4, 6, and 24 hours following Arginine Vasopressin initiation. RESULTS: We included 28 neonates. The mean dose of Arginine Vasopressin was 0.0005 plus or minus 0.0003 units per kilogram per minute. There was an early response (less than 6 hours) characterised by an 8% increase in systolic blood pressure (p = 0.0004), a 100% increase in urine output (p = 0.02), and a 29% decrease in total fluid administration (p = 0.04). The late response (at 24 hours) revealed further increases in systolic blood pressure and urine output as well as a 53% decrease in serum lactate (p = 0.007) and increase in arterial pH from 7.36 to 7.45 (p less than 0.0001). These changes were not accompanied by increases in heart rate or inotrope score. CONCLUSIONS: The initiation of Arginine Vasopressin in post operative Norwood patients was temporally associated with an improvement in markers of perfusion including systolic blood pressure, urine output, lactate, and pH. Further studies are required to ascertain the efficacy of Arginine Vasopressin in this population. PMID- 21554827 TI - Comment on: Interest of b-blockers in patients with right ventricular systemic dysfunction. PMID- 21554828 TI - Infection and white matter injury in infants with congenital cardiac disease. AB - More than 60% of newborns with severe congenital cardiac disease develop perioperative brain injuries. Known risk factors include: pre-operative hypoxemia, cardiopulmonary bypass characteristics, and post-operative hypotension. Infection is an established risk factor for white matter injury in premature newborns. In this study, we examined term infants with congenital cardiac disease requiring surgical repair to determine whether infection is associated with white matter injury. Acquired infection was specified by site - bloodstream, pneumonia, or surgical site infection - according to strict definitions. Infection was present in 23 of 127 infants. Pre- and post-operative imaging was evaluated for acquired injury by a paediatric neuroradiologist. Overall, there was no difference in newly acquired post-operative white matter injury in infants with infection (30%), compared to those without (31%). When stratified by anatomy, infants with transposition of the great arteries, and bloodstream infection had an estimated doubling of risk of white matter injury that was not significant, whereas those with single ventricle anatomy had no apparent added risk. When considering only infants without stroke, the estimated association was higher, and became significant after adjusting for duration of inotrope therapy. In this study, nosocomial infection was not associated with white matter injury. Nonetheless, when controlling for risk factors, there was an association between bloodstream infection and white matter injury in selected sub populations. Infection prevention may have the potential to mitigate long-term neurologic impairment as a consequence of white matter injury, which underscores the importance of attention to infection control for these patients. PMID- 21554829 TI - Adolescents' drawings of their cardiac abnormality. AB - Following advances in overall management and improved outcomes, an increasing number of adolescents with cardiac disease are reaching adult age. Patients in general, including adolescents, seem to have a poor knowledge of their illness, which may further reflect in a less optimal quality of life. As a guide to their knowledge of their cardiac condition, adolescents were asked to draw a diagram of their cardiac abnormality. Relatively well adolescents aged 12-20 years with a cardiac abnormality were consecutively recruited from an ambulatory setting. All were asked to draw a picture of their cardiac abnormality and describe their condition. A total of 120 patients were recruited and had conditions varying from a hyperplastic right ventricle to a small ventricular septal defect. Only 60 (50%) of the patients completed a drawing, of which one-third did so at the time of attendance. Nevertheless, there was no difference between the accuracy of the adolescents' drawings completed at home or at the clinic. Only three patients drew an accurate diagram of their congenital cardiac abnormality. A further nine patients drew a reasonably correct diagram, 13 patients a partially correct diagram, whereas 35 patients submitted incorrect diagrams. Adolescents with congenital cardiac disease, many having been cared for since infancy with regular cardiological reviews, had a poor anatomical knowledge of their cardiac lesion, as reflected by their inability to correctly draw their abnormality. These findings suggest the need for improved strategies in developing appropriate education programmes for this patient population. PMID- 21554830 TI - An open-source engine for the processing of electron backscatter patterns: EBSD image. AB - An open source software package dedicated to processing stored electron backscatter patterns is presented. The package gives users full control over the type and order of operations that are performed on electron backscatter diffraction (EBSD) patterns as well as the results obtained. The current version of EBSD-Image (www.ebsd-image.org) offers a flexible and structured interface to calculate various quality metrics over large datasets. It includes unique features such as practical file formats for storing diffraction patterns and analysis results, stitching of mappings with automatic reorganization of their diffraction patterns, and routines for processing data on a distributed computer grid. Implementations of the algorithms used in the software are described and benchmarked using simulated diffraction patterns. Using those simulated EBSD patterns, the detection of Kikuchi bands in EBSD-Image was found to be comparable to commercially available EBSD systems. In addition, 24 quality metrics were evaluated based on the ability to assess the level of deformation in two samples (copper and iron) deformed using 220 grit SiC grinding paper. Fourteen metrics were able to properly measure the deformation gradient of the samples. PMID- 21554831 TI - Morphology of foliar trichomes of the Chinese cork oak Quercus variabilis by electron microscopy and three-dimensional surface profiling. AB - Morphology of foliar trichomes was analyzed in Quercus variabilis by electron microscopy and three-dimensional surface profiling. Leaves from suppressed or dominant sprouts of the oak species were collected after a forest fire to unravel the effects of the disturbance factor on sprouting of the oak species. Scanning electron microscopy revealed two types of trichomes depending on the leaf surface. The trichomes on the adaxial surface were branched and constricted, and possessed a single row of thin-walled cells with a collapsed morphology (glandular branched uniseriate trichomes). Meanwhile, the trichomes on the abaxial surface were star-shaped, unfused with each other, and had 6 to 10 rays (nonglandular simple stellate trichomes). An apparent proliferation of trichomes was evident on the adaxial surface of the dominant sprouts. Uniseriate trichomes could be discernable as an elevation from the surface by white light scanning interferometry. By transmission electron microscopy, thin and convoluted cell wall, degenerated cytoplasm, and a single row of cells were characteristic of the trichomes on the adaxial surface. The thick cell walls of the mature trichomes on the abaxial surface represented the nonglandular nature. This is the first report on the morphological and ultrastructural characterization of foliar trichomes of the oak species. PMID- 21554832 TI - Factors associated with contraceptive approval among religious leaders in Pakistan. AB - Research is needed to understand the role of religion in family planning dynamics, particularly in societies where the views of religious leaders can be an important influence on the reproductive decisions of individuals. This paper attempts to describe the factors associated with approval of contraception among religious leaders in Pakistan. The data are taken from the 1999-2000 Survey of Perception of Religious Leaders about Population Welfare. Regression modelling shows that whether or not religious leaders approve of family planning is associated with their views on the ideal family size, their level of religious education, the specific religious sect to which they belong, their own knowledge and use of family planning, their exposure to television and the region of the country in which they live. PMID- 21554833 TI - Determinants of territorial exogamy in Friuli (north-east Italy) in the second half of the nineteenth century. AB - The aim of this study was to identify the characteristics of individuals who formed exogamic marriages in the Friuli region (north-east Italy) during the second half of the 19th century. Logistic regression models were devised to measure the influence of the determinants of exogamic marriage, taking into account not only variables related to context but also spouses' economic, social and cultural characteristics. The determinants of exogamic marriage differ for men and women, and also vary by region due to differences in geographical mobility and size of the marriage market. The majority of exogamic spouses belong to one of two categories: either older individuals, often, especially in the case of men, with a previous marriage; or the upper social classes. PMID- 21554834 TI - First record of Neoxysomatium brevicaudatum through the non-invasive sampling of Anguis fragilis: complementary morphological and molecular detection. AB - Relatively few studies have examined the parasite fauna of British reptiles, partly due to the cryptic nature and low population density of these hosts. Here we examined 12 populations of the slow worm Anguis fragilis which, unlike other UK lizards, occurs at locally high population densities. Morphological examination of non-invasively collected faecal samples revealed the presence of Neoxysomatium brevicaudatum and a second unidentified nematode species. Although previously unrecorded from slow worms in the UK, N. brevicaudatum was present in 38% of animals (mean intensity 70.9, range 1-686). Morphological identification was confirmed by sequencing the 18S ribosomal gene. The use of the species specific, cytochrome oxidase I mitochondrial gene primers proved an efficient alternative to conventional, microscope screening for parasites, although the original identification of N. brevicaudatum was dependent upon morphological characters. Sequencing also identified the second, smaller nematode as belonging to the Rhabdiasidae family: this species was even more common at a prevalence of 83% (mean intensity 102.8, range 1-2000). While increasing our knowledge of the UK macroparasite fauna, this work demonstrates the benefits of a combined morphological-molecular approach. PMID- 21554835 TI - The life cycle of Gyliauchen volubilis Nagaty, 1956 (Digenea: Gyliauchenidae) from the Red Sea. AB - Although nothing is known about gyliauchenid life cycles, molecular phylogenetic studies have placed the Gyliauchenidae Fukui, 1929 close to the Lepocreadiidae Odhner, 1905. The gyliauchenid Gyliauchen volubilis Nagaty, 1956 was found in the intestine of its type-host, Siganus rivulatus, a siganid fish permanently resident in a lagoon within the mangrove swamps on the Egyptian coast of the Gulf of Aqaba. Larval forms of this trematode (mother sporocysts, rediae and cercariae) were found in the gonads and digestive gland of Clypeomorus clypeomorus (Gastropoda: Cerithiidae), a common snail in the same lagoon. So, this life cycle of G. volubilis was elucidated under natural conditions: eggs are directly ingested by the snail; mother sporocysts and rediae reach their maturity 3-6 and 11-13 weeks post-infection; rediae contain 23-29 developing cercariae; fully developed cercariae are gymnocephalus, without penetration glands, emerge from the snail during the night 16-18 weeks post-infection and rapidly encyst on aquatic vegetation (no second intermediate host); encysted metacercariae are not progenetic; 4-day-old metacercariae encysted on filamentous algae fed to S. rivulatus developed into fully mature worms 6-8 weeks post-infection. The cycle was completed in about 26 weeks and followed one of the three known patterns of lepocreadiid life cycles, and except for the gymnocephalus cercariae, the other larval stages are very similar to those of lepocreadiids. Generally, the life cycle of G. volubilis implicitly supports the phylogenetic relationship of Gyliauchenidae and Lepocreadiidae inferred from molecular phylogenetic studies. PMID- 21554836 TI - Assessing host-parasite specificity through coprological analysis: a case study with species of Corynosoma (Acanthocephala: Polymorphidae) from marine mammals. AB - In this paper we report an investigation of the utility of coprological analysis as an alternative technique to study parasite specificity whenever host sampling is problematic; acanthocephalans from marine mammals were used as a model. A total of 252 scats from the South American sea lion, Otaria flavescens, and rectal faeces from 43 franciscanas, Pontoporia blainvillei, from Buenos Aires Province, were examined for acanthocephalans. Specimens of two species, i.e. Corynosoma australe and C. cetaceum, were collected from both host species. In sea lions, 78 out of 145 (37.9%) females of C. australe were gravid and the sex ratio was strongly female-biased. However, none of the 168 females of C. cetaceum collected was gravid and the sex ratio was not female-biased. Conversely, in franciscanas, 14 out of 17 (82.4%) females of C. cetaceum were gravid, but none of 139 females of C. australe was, and the sex ratio of C. cetaceum, but not that of C. australe, was female-biased. In putative non-hosts, the size of worms was similar to that from specimens collected from prey. Results suggest that both acanthocephalans contact sea lions and franciscanas regularly. However, C. australe and C. cetaceum cannot apparently reproduce, nor even grow, in franciscanas and sea lions, respectively. Coprological analysis may represent a useful supplementary method to investigate parasite specificity, particularly when host carcasses are difficult to obtain. PMID- 21554837 TI - A visit to the Department of Otology and Neurotology, Toronto General Hospital, Ontario, Canada, March to April 2010. PMID- 21554838 TI - Comparison of auditory electrophysiological responses in normal-hearing patients with and without tinnitus. AB - INTRODUCTION: Tinnitus is a disturbing symptom and is often the main reason for otology referral. It is usually associated with hearing loss of varying aetiology, and is thought to begin in the cochlea, with later abnormal central activity. We hypothesise that tinnitus without hearing loss may be caused by central and subcortical abnormalities and altered outer hair cell function. AIM: To compare the auditory brainstem responses, middle latency responses and otoacoustic emissions in normal-hearing individuals with and without tinnitus. METHODOLOGY: The audiological test results of 25 normal hearing subjects with tinnitus (age 18-45 years) were determined, and compared with those of a control group. RESULTS: A statistically significant difference was found between study group tinnitus ears vs control group ears, as regards wave I latency prolongation, shortening of wave V and absolute I-III and I-V interpeak latency, enlargement of wave Na and Pa amplitude, and distortion product and transient evoked otoacoustic emission signal-to-noise ratios. There was no statistically significant difference between unilateral vs bilateral tinnitus ears. CONCLUSION: The pathogenesis and optimum management of tinnitus are still unclear. It often occurs with primary ear disease, usually associated with hearing loss, but may occur in patients with normal hearing. Observed changes in auditory brainstem and middle latency responses indicate central auditory alterations. Tinnitus involves both peripheral and central activity, and complete audiological and neurophysiological investigation is required. Management should be based on both audiological and neurophysiological findings. PMID- 21554839 TI - Incorporating parasite systematics in comparative analyses of variation in spleen mass and testes sizes of rodents. AB - Parasite diversity is hypothesized to act on host life-history traits through investment in immunity. In order to incorporate the diversity of the parasite community that an individual host or a host species may face, two indices can be used: Taxonomic Species Richness and Taxonomic Entropy, where the taxonomic information is incorporated with the taxonomic weight. We tested whether these indices correlate with several morphological traits potentially implicated in immune defence and in reproduction, using data on gastrointestinal helminths and their rodent hosts sampled in Southeast Asia. We found no relationship between parasite diversity indices and either spleen mass or testes size at the intraspecific level, i.e. at the level of individuals. At the interspecific level, we found no relationship between the parasite diversity indices and testes size. However, we found that female spleen mass is significantly influenced by the specific species richness of parasites, whereas male spleen mass is influenced by individual mean parasite diversity indices. We concluded that female spleen mass may have evolved in response to gastrointestinal helminth pressure acting at species levels, while in males, the individual spleen mass could be constrained by other factors, such as the blood storage function of the spleen. PMID- 21554840 TI - Estimating phylogenetic relationships despite discordant gene trees across loci: the species tree of a diverse species group of feather mites (Acari: Proctophyllodidae). AB - With the increased availability of multilocus sequence data, the lack of concordance of gene trees estimated for independent loci has focused attention on both the biological processes producing the discord and the methodologies used to estimate phylogenetic relationships. What has emerged is a suite of new analytical tools for phylogenetic inference--species tree approaches. In contrast to traditional phylogenetic methods that are stymied by the idiosyncrasies of gene trees, approaches for estimating species trees explicitly take into account the cause of discord among loci and, in the process, provides a direct estimate of phylogenetic history (i.e. the history of species divergence, not divergence of specific loci). We illustrate the utility of species tree estimates with an analysis of a diverse group of feather mites, the pinnatus species group (genus Proctophyllodes). Discord among four sequenced nuclear loci is consistent with theoretical expectations, given the short time separating speciation events (as evident by short internodes relative to terminal branch lengths in the trees). Nevertheless, many of the relationships are well resolved in a Bayesian estimate of the species tree; the analysis also highlights ambiguous aspects of the phylogeny that require additional loci. The broad utility of species tree approaches is discussed, and specifically, their application to groups with high speciation rates--a history of diversification with particular prevalence in host/parasite systems where species interactions can drive rapid diversification. PMID- 21554841 TI - Latent Trypanosoma brucei gambiense foci in Uganda: a silent epidemic in children and adults? AB - Trypanosoma brucei gambiense sleeping sickness follows a long asymptomatic phase and persists in ancient foci from which epidemic clinical disease arises. A putative focus of T. b. gambiense infections has been identified, initially in mothers and young children, on the Lake Albert shoreline of Western Uganda leading to mass screening of 6207 individuals in September 2008. T. b. gambiense infections were identified by Card Agglutination Test for Trypanosomiasis (CATT) and sub-species-specific PCR although parasitological methods failed to confirm any patent trypanosome infections. In April 2009, CATT positives were re-visited; diagnosis of individuals by CATT and PCR was unstable over the two time points and parasites remained undetected, even using mini Anion Exchange Centrifugation Technique (mAECT). These observations suggest the possibility of a silent focus of disease, where all infected individuals are in a latent stage, and highlight our limited understanding of the local natural history and disease progression of T. b. gambiense in children and adults. PMID- 21554842 TI - A novel neutralization sensitive and subdominant RAP-1-related antigen (RRA) is expressed by Babesia bovis merozoites. AB - OBJECTIVE: The Babesia bovis genome encodes a rap-1 related gene denominated RAP 1 related antigen (RRA). In this study, we analysed the pattern of expression, immunogenicity and functional relevance of RRA. METHODS: Phylogenetic analysis was performed using the program Phylip. Expression of rra was analysed by Northern blots, RT-PCR, immunoprecipitation, Western blots and immunofluorescence. RRA antigenicity was tested by T-cell proliferation and Western blot analysis, and functional relevance was determined in an in vitro neutralization assay. RESULTS: RRA is more closely related to RAP-1b of Babesia bigemina than to B. bovis RAP-1, and it is highly conserved among distinct strains. Transcriptional analysis suggests lower numbers of rra transcripts compared to rap-1. Immunoprecipitation of metabolically labelled B. bovis proteins with antibodies against synthetic peptides representing predicted antigenic regions of RRA confirmed the expression of a ~43 kDa RRA in cultured merozoites. Antibodies present in B. bovis hyperimmune sera, but not in field infected cattle sera, reacted weakly with recombinant RRA, and no significant stimulation was obtained using recombinant RRA as antigen in T-cell proliferation assays, indicating that RRA is a subdominant antigen. Antibodies against RRA synthetic peptides reacted with merozoites using immunofluorescence, and were able to significantly inhibit erythrocyte invasion in in vitro neutralization tests, suggesting functional relevance for parasite survival. CONCLUSION: B. bovis express a novel subdominant RAP-1-like molecule that may contribute to erythrocyte invasion and/or egression by the parasite. PMID- 21554843 TI - Trypanosomatids are common and diverse parasites of Drosophila. AB - Drosophila melanogaster is an important model system of immunity and parasite resistance, yet most studies use parasites that do not naturally infect this organism. We have studied trypanosomatids in natural populations to assess the prevalence and diversity of these gut parasites. We collected several species of Drosophila from Europe and surveyed them for trypanosomatids using conserved primers for two genes. We have used the conserved GAPDH sequence to construct a phylogenetic tree and the highly variable spliced leader RNA to assay genetic diversity. All 5 of the species that we examined were infected, and the average prevalence ranged from 1 to 6%. There are several different groups of trypanosomatids, related to other monoxenous Trypanosomatidae. These may represent new trypanosomatid species and were found in different species of European Drosophila from different geographical locations. The detection of a little studied natural pathogen in D. melanogaster and related species provides new opportunities for research into both the Drosophila immune response and the evolution of hosts and parasites. PMID- 21554844 TI - Intensity-dependent host mortality: what can it tell us about larval growth strategies in complex life cycle helminths? AB - Complex life cycle helminths use their intermediate hosts as both a source of nutrients and as transportation. There is an assumed trade-off between these functions in that parasite growth may reduce host survival and thus transmission. The virulence of larval helminths can be assessed by experimentally increasing infection intensities and recording how parasite biomass and host mortality scale with intensity. I summarize the literature on these relationships in larval helminths and I provide an empirical example using the nematode Camallanus lacustris in its copepod first host. In all species studied thus far, including C. lacustris, overall parasite volume increases with intensity. Although a few studies observed host survival to decrease predictably with intensity, several studies found no intensity-dependent mortality or elevated mortality only at extreme intensities. For instance, no intensity-dependent mortality was observed in male copepods infected with C. lacustris, whereas female survival was reduced only at high intensities (>3) and only after worms were fully developed. These observations suggest that at low, natural intensity levels parasites do not exploit intermediate hosts as much as they presumably could and that increased growth would not obviously entail survival costs. PMID- 21554845 TI - Characterization of acid phosphatases from marine scuticociliate parasites and their activation by host's factors. AB - Scuticociliates are histophagous marine parasites that cause mortality in fish. Acid phosphatases (AcPs) are considered virulence factors and they are used by different parasites to dephosphorylate host molecules. The aim of this work was to characterize the AcPs from 3 scuticociliate species, Uronema marinum, Miamiensis avidus and Parauronema virginianum, which parasitize marine finfish species. We identified AcP activity (pH 5.2) with differential cellular distribution in the 3 parasite species. Native gel electrophoresis of ciliate lysates revealed the presence of 1 high molecular weight AcP activity band in M. avidus (tartrate-sensitive), several low molecular weight AcPs in U. marinum and 1 low molecular weight band only in P. virginianum (tartrate-resistant). Scuticociliate AcP was inhibited by specific inhibitors of tyrosine protein phosphatases. AcP decreased upon starvation but rapid reactivation occurred following exposure to skin mucus. Groper (Polyprion oxygeneios) peripheral blood leucocytes (PBLs) and, to a lesser extent, red blood cells, also increased AcP activity. Protein tyrosine phosphatase PTP1b was primarily detected in the plasma membrane of M. avidus and ingestion of groper PBLs upregulated its expression. M. avidus recovered from experimentally infected groper had greater levels of PTP1b expression than the injected suspension. The present results highlight the importance of PTPs in histophagous parasites and their interaction with fish host's factors. PMID- 21554846 TI - Open abdomen management: why, when and how? PMID- 21554847 TI - Laparoscopic appendectomy for complicated acute appendicitis. AB - The role of laparoscopic appendectomy in complicated appendicitis is still not widely accepted. The authors report their retrospective study performed to evaluate the effectiveness of the laparoscopic approach in the management of complicated appendicitis. From January 2003 to October 2008, 552 patients underwent appendectomy in our surgical department. Among these, 358 were not complicated appendicitis while 194 were complicated. Of the 194 cases of complicated appendicitis, 121 patients underwent laparoscopic appendectomy while the remaining 73 cases were treated by conventional open surgery. The average length of hospital stay was 5.7 days, with a range from 4 to 13 days. Post operative complications were observed in a total 11 patients (9.1%), including 3 cases of intra abdominal abscess (2.5%), 2 cases of umbilical wound infection (1.6%) and 6 cases of prolonged ileus (4.9%). Our experience suggests that the laparoscopic procedure is a valid, safe and feasible option to manage acute complicated appendicitis. PMID- 21554848 TI - Multifocal pyomyositis and meningitis after bone marrow biopsy in a diabetic patient. AB - Primary or tropical pyomyositis is a subacute infection of the skeletal muscle complicated by abscess formation. The disease is rare in the temperate climates and often misdiagnosed because of the vague clinical presentation. We herein report a case of a 38-year-old diabetic patient with a history of recent bone marrow biopsy presented multifocal primary pyomyositis complicated by meningitis. PMID- 21554849 TI - Management of corrosive injuries of the upper gastrointestinal tract. Our experience in 58 patients. AB - BACKGROUND: The ingestion of caustic substances is one of the most difficult conditions to be treated in Emergency Department. PATIENTS AND METHODS: The medical records of patients with caustic ingestion and hospitalized from 2003 to 2008 at the Division of General Emergency Surgery with Polyspecialistic Observation of AORN "A. Cardarelli "in Naples, have been revalued. RESULTS: From 2003 to 2008, 58 patients with caustic ingestion were admitted to our Division. Ten of these patients (17.24%) underwent surgery. Six patients underwent oesophageal and gastric resection with cervical esophagostomy and alimentary digiunostomy in emergency; two underwent exploratory laparotomy, two had gastroenteroanastomosis for antropyloric stenosis. One patient underwent new operation for a complication. In total, three reconstructions of oesophagus with colon were performed . Of the six patients undergoing esofagogastrectomy, two died in the first postoperative day, but four have passed the acute phase. CONCLUSIONS: There is no universally accepted diagnostic and therapeutic procedure for the management of these patients, who are often left - as it appears in literature - to the personal experience of the surgeon who is dealing with this situation. PMID- 21554850 TI - Breast cancer metastatic to the submandibular gland. Case report. AB - Metastatic disease in the major salivary glands is rare and the parotid gland is most frequently involved. Secondary deposits in the submandibular gland are very uncommon. We report a case of a 50-year-old woman who developed a metastasis from breast cancer in the right submandibular gland, 9 years after primary surgery for G3 T1c N0 ipsilateral breast carcinoma. The peculiarity of the case was the unusual site of the metastatic disease and the difficulty in differential diagnosis with primitive ductal salivary carcinoma. PMID- 21554851 TI - [Inguinal endometriosis. Case report and review of the literature]. AB - Endometriosis is a common gynaecological condition which affects women during their reproductive years. It is characterized by ectopic endometrial tissue responding to hormonal changes associated with menstrual cycle. Aetiology is unknown and symptoms are quite aspecific (dysmenorrhoea, pelvic pain, infertility or pelvic mass). Ultrasonography (US) and Magnetic Resonance Imaging (MRI) are accurate diagnostic exams but laparoscopy represents the gold standard in diagnosis and therapy (excision or ablation). Medical treatment pre or postoperatively may be useful prolonging the symptom free interval. In this paper we report the case of a young woman affected by an inguinal mass: diagnostic examinations and histological specimen revealed to be an endometrial focus. We review the literature focusing the diagnostic techniques and relationships between endometriosis and ovarian cancer (endometrioid and clear cell subtypes). PMID- 21554852 TI - Bleeding control by radiofrequency in penetrating trauma of the liver. AB - Termocoagulation by radiofrequency (RF) is widely used for ablation of liver neoplasms. Recently, innovative uses of RF were proposed, as to assist liver resection, to help partial splenectomy, or to treat ruptured hepatocellular carcinoma. A 21 years old man was admitted for massive haemorrhage from a right thoraco-abdominal knife wound. Massive haemothorax was drained but arterial bleeding was caused by a deep penetrating wound on liver segment VIII. During operation, considering the difficult exposure of the source of bleeding, it was taught to stop haemorrhage using RF termocoagulation, under ultrasonographic guidance. Termocoagulation of the pedicle of the liver segment VIII was performed. In this patient with haemorrhagic shock the RF method for bleeding control was very easy and effective, and avoided risks of morbidity due to a major procedure. PMID- 21554853 TI - [Venous thromboembolism prophylaxis after general surgery: where are we now?]. AB - Venous thromboembolism (VTE) is a frequent complication in patients undergoing major surgery, with the possibility of long-term disability or fatal outcome. The rationale of the thromboprophylaxis in all patients can be summarized in three points: 1) the VTE is common in some types of surgery; 2) the VTE can be fatal; 3) thromboprophylaxis is highly effective and safe and, besides these clinical benefits, leads to lower total costs of treatment without further diagnostic and a new shelter for treating venous thrombosis. The surgical patients may present at admission one or more risk factors for VTE, The effect of this risk is cumulative, it is important to stratify the risk and to established an adequate prophylactic strategy. Today there is a unanimous consensus that the low molecular weight heparins are both effective and safe in preventing VTE in surgical patients. Unanimously approved guidelines can help surgeons in making decisions regarding VTE prophylaxis. PMID- 21554854 TI - [Treatment of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. AB - Pinto Peritoneal carcinomatosis (PC) had for long been regarded as a terminal disease, characterized by a very poor survival and worthy of being treated with palliative therapy only. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide a promising additional treatment option for patients with peritoneal carcinomatosis, resulting in recently published series enable to obtain long-term survival. In spite of the need for more high quality studies, there is now a consensus among many international experts about the use of this new strategy as gold standard for treating with intent of cure selected patients with PC. We summarized the present status and possible future progress of this treatment modality, in particular outlining its rationale, current practice and general outcomes. PMID- 21554855 TI - A pragmatic single-blind randomised controlled trial and economic evaluation of the use of leukotriene receptor antagonists in primary care at steps 2 and 3 of the national asthma guidelines (ELEVATE study). PMID- 21554856 TI - The effect of aliphatic alcohols on fluid bilayers in unilamellar DOPC vesicles- a small-angle neutron scattering and molecular dynamics study. AB - Small-angle neutron scattering and coarse-grained molecular dynamics simulations have been used to determine the structural parameters (bilayer thickness D, polar region thickness D(H), interfacial lateral area of the unit cell A(UC) and alcohol partial interfacial area A(CnOH)) of fluid dioleoylphosphatidylcholine:dioleoylphosphatidylserine (PCPS, DOPC:DOPS=24.7mol:mol) bilayers in extruded unilamellar vesicles with incorporated aliphatic alcohols (CnOH, n=8-18 is the even number of carbons in alkyl chain). External ((2))H(2)O/H(2)O contrast variation experiments revealed that D(H) decreases as a function of alkyl chain length and CnOH:PCPS molar ratio. Using measurements at single 100% ((2))H(2)O contrast we found that (i) D decreases with CnOH:PCPS molar ratio and increases with CnOH chain length (at 0.4 molar ratio); (ii) A(UC) significantly increases already in the presence of shortest CnOH studied (at 0.4 molar ratio), further increase is observed with longer CnOHs and at higher molar ratios; (iii) A(CnOH) of alcohol molecules in PCPS bilayer increases linearly with the alkyl chain length, A(CnOH) obtained for CnOHs with n<=10 corresponds to A(CnOH)<=20A(2) - a value specific for the crystalline or solid rotator phase of alkanes. All these structural modifications induced by studied CnOHs were reproduced in MD simulations. The computational results give an accurate description of the alcohol effects at the molecular level, explaining the experimental data. The anomaly in A(CnOH) is discussed via the "umbrella" effect described for cholesterol. PMID- 21554857 TI - Accessible chromatin structure permits factors Sp1 and Sp3 to regulate human TGFBI gene expression. AB - Transforming growth factor beta 1-induced (TGFBI) protein is an extracellular matrix (ECM) protein that is associated with other ECM proteins and functions as a ligand for various types of integrins. In this study, we investigated how human TGFBI expression is regulated in lung and breast cancer cells. We observed that the TGFBI promoter in A549 and MBA-MD-231 cells, which constitutively express TGFBI, existed in an open chromatin conformation associated with transcriptionally permissive histone modifications. Moreover, we found that TGFBI expression required Sp1 transcription elements that can bind transcription factors Sp1 and Sp3 in vitro. Occupancy of the TGFBI promoter by Sp1 and Sp3 in vivo was only observed in TGFBI-expressing cells, indicating that open chromatin conformation might facilitate the binding of Sp1 and Sp3 to the TGFBI promoter region. TGFBI promoter activity was impaired when Sp1 elements were mutated, but was increased when Sp1 or Sp3 factors was overexpressed. Furthermore, Sp1 inhibition in vivo by mithramycin A, as well as knockdown of Sp1 and/or Sp3 expression by short interfering RNA, significantly reduced TGFBI mRNA and protein levels. Thus, our data demonstrated that the expression of TGFBI is well correlated with chromatin conformation at the TGFBI promoter, and that factors Sp1 and Sp3 are the primary determinants for the control of constitutive expression of TGFBI gene. PMID- 21554858 TI - Goose parvovirus structural proteins expressed by recombinant baculoviruses self assemble into virus-like particles with strong immunogenicity in goose. AB - Goose parvovirus (GPV), a small non-enveloped ssDNA virus, can cause Derzsy's disease, and three capsid proteins of VP1, VP2, and VP3 are encoded by an overlapping nucleotide sequence. However, little is known on whether recombinant viral proteins (VPs) could spontaneously assemble into virus-like particles (VLPs) in insect cells and whether these VLPs could retain their immunoreactivity and immunogenicity in susceptible geese. To address these issues, genes for these GPV VPs were amplified by PCR, and the recombinant VPs proteins were expressed in insect cells using a baculovirus expression system for the characterization of their structures, immunoreactivity, and immunogenicity. The rVP1, rVP2, and rVP3 expressed in Sf9 cells were detected by anti-GPV sera, anti-VP3 sera, and anti His antibodies, respectively. Electron microscopy revealed that these rVPs spontaneously assembled into VLPs in insect cells, similar to that of the purified wild-type GPV virions. In addition, vaccination with individual types of VLPs, particularly with the rVP2-VLPs, induced higher titers of antibodies and neutralized different strains of GPVs in primary goose and duck embryo fibroblast cells in vitro. These data indicated that these VLPs retained immunoreactivity and had strong immunogenicity in susceptible geese. Therefore, our findings may provide a framework for development of new vaccines for the prevention of Derzsy's disease and vehicles for the delivery of drugs. PMID- 21554859 TI - Increased number of Arginine-based salt bridges contributes to the thermotolerance of thermotolerant acetic acid bacteria, Acetobacter tropicalis SKU1100. AB - Thermotolerant acetic acid bacteria (AAB), Acetobacter tropicalis SKU1100, can grow above 40 degrees C. To investigate the basis of its thermotolerance, we compared the genome of A. tropicalis SKU1100 with that of mesophilic AAB strain Acetobacter pasteurianus IFO3283-01. The comparative genomic study showed that amino acid substitutions from large to small residue and Lys to Arg occur in many orthologous genes. Furthermore, comparative modeling study was carried out with the orthologous proteins between SKU1100 and IFO3283-01 strains, indicating that the number of Arg-based salt bridges increased in protein models. Since it has been reported that Arg-based salt bridges are important factor for thermo stability of protein structure, our results strongly suggest that the increased number of Arg-based salt bridges may contributes to the thermotolerance of A. tropicalis SKU1100 (the thermo-stability of proteins in A. tropicalis SKU1100). PMID- 21554860 TI - The deltaA isoform of calmodulin kinase II mediates pathological cardiac hypertrophy by interfering with the HDAC4-MEF2 signaling pathway. AB - Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a new promising target for prevention and treatment of cardiac hypertrophy and heart failure. There are three delta isoforms of CaMKII in the heart and previous studies focused primarily on deltaB and deltaC types. Here we report the deltaA isoform of CaMKII is also critically involved in cardiac hypertrophy. We found that deltaA was significantly upregulated in pathological cardiac hypertrophy in both neonatal and adult models. Upregulation of deltaA was accompanied by cell enlargement, sarcomere reorganization and reactivation of various hypertrophic cardiac genes including atrial natriuretic factor (ANF) and beta-myocin heavy chain (beta-MHC). Studies further indicated the pathological changes were largely blunted by silencing the deltaA gene and an underlying mechanism indicated selective interference with the HDAC4-MEF2 signaling pathway. These results provide new evidence for selective interfering cardiac hypertrophy and heart failure when CaMKII is considered as a therapeutic target. PMID- 21554861 TI - The effect of sphingomyelin synthase 2 (SMS2) deficiency on the expression of drug transporters in mouse brain. AB - Sphingomyelin synthase (SMS), the last enzyme involved in the biosynthesis of sphingomyelin (SM), plays a critical role in the constitution of cell membrane and has impact on the expression of membrane proteins. SMS2, one of two SMS enzymes, is predominantly located in the plasma membrane, and is mainly expressed in the brain. Therefore, it is conceivable that SMS2 deficiency may have impact on expression of some membrane proteins, such as membrane-bound drug transporters. Using SMS2 gene deficient mouse brain tissues, we studied the gene and protein expression profiles of drug transporters, ERM proteins (ezrin/radixin/moesin) and the cytoskeleton protein, beta-actin, in mouse brain by RT-PCR, western blot and immunohistochemistry analysis. We found that the mRNA expression of Mdr1 rather than the other drug transporters was significantly decreased in the SMS2 deficient brain. Accordingly, the expression and the function of Pgp (Mdr1/P-glycoprotein) were significantly downregulated in brain. In addition, the substantially downregulated expression of ezrin and beta-actin was also observed in the SMS2 deficient brain. The immunohistochemistry analysis further revealed the suppressed expression of Pgp, ezrin and beta-actin in both cortex and paraventricular areas of SMS2 knockout mice. Furthermore, both Pgp and beta-actin were found to be co-immunoprecipitated with ezrin from the total brain lysate, suggesting the association between Pgp, ezrin and beta-actin in the brain. These results indicate that SMS2 participates in the expression regulation of drug transporters, particularly Pgp, and suggest that SMS2 may be a potential target for enhancing drug access to the brain. PMID- 21554862 TI - Review of the Churchill County, NV ALL cluster, 1997-2004. AB - Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who either lived in Churchill County, Nevada at the time of diagnosis or had lived in the county before their diagnosis. The cases were characterized as a cluster of like illnesses and the probability of having such a cluster occur by chance was estimated to be very small (approximately one in 2.33*10(8)). This suggested that the cluster could be linked to one or more physical, limnological, chemical, or biological agents. This review discusses the setting in which the cluster took place, the epidemiological investigations carried out by the Nevada Bureau of Health Protection Services, the National Center for Environmental Health Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry, and subsequent investigations supported by a special allocation of federal funds through the US Environmental Protection Agency's Region IX office in San Francisco, CA. This review is meant as background for the papers in this special issue that report results from multi- and interdisciplinary research into environmental and biological factors potentially related to the Churchill County leukemia cluster. PMID- 21554863 TI - Methylated chrysin induces co-ordinated attenuation of the canonical Wnt and NF kB signaling pathway and upregulates apoptotic gene expression in the early hepatocarcinogenesis rat model. AB - Hepatocellular carcinoma (HCC), a highly aggressive form of solid tumor, has been increasing in South East Asia. The lack of effective therapy necessitates the introduction of novel chemopreventive strategies to counter the substantial morbidity and mortality associated with the disease. Recently, we reported that dimethoxy flavone (DMF), a methylated flavone derived from chrysin, significantly suppressed the development of preneoplastic lesions induced by N nitrosodiethylamine (DEN) in rats, although the mechanism of action was not known. In the present study, we have investigated the effects of DMF administration on gene expression changes related to the inflammation-mediated NF kB pathway, Wnt pathway and apoptotic mediators in DEN-induced preneoplastic nodules. There was a significant increase in inflammatory markers like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and a decrease in apoptotic mediators like p53, caspase-3 and bax in DEN-treated rats when compared to the control group. Activation of NF-kB was noticed by an elevated expression of nuclear protein expression of NF-kB and cytoplasmic phospho-IkBalphaSer(32/36) in the same animals. Likewise, upregulation of canonical Wnt pathway was noticed by elevated expression of nuclear protein levels of phospho-beta-cateninThr(393) and cytoplasmic casein kinase-2 (CK2), Dvl2 and cyclin D1 levels, along with a simultaneous decrease in expression of phospho-GSK3beta(Ser9). Dietary DMF (100mg/kg) administration inhibited liver nodule incidence and multiplicity by 82% and 78%, respectively. DMF also reversed the activation of NF-kB and Wnt pathway as shown by the decrease in protein expression of several proteins. Results of the present investigation provide evidence that attenuation of Wnt pathway and suppression of inflammatory response mediated by NF-kB could be implicated, in part, in the chemopreventive effects of methylated flavone. Therefore, the present findings hold great promise for the utilization of DMF as an effective chemotherapeutic agent in treating early stages of liver cancer. PMID- 21554864 TI - Chemical synthesis of the (25R)- and (25S)-epimers of 3alpha,7alpha,12alpha trihydroxy-5alpha-cholestan-27-oic acid as well as their corresponding glycine and taurine conjugates. AB - The (25R)- and (25S)-epimers of C(27) 3alpha,7alpha,12alpha-trihydroxy-5alpha cholestan-27-oic acid as well as their corresponding N-acylamidate conjugates with glycine or taurine were prepared starting from cholic acid in 14 steps. The principal reactions involved were (1) reduction of a key intermediary C(24)allo cholic acid performate with NaBH(4)/triethylamine/ethyl chloroformate, (2) iodination of the resulting 3,7,12-triformyloxy-5alpha-cholan-24-ol with I(2)/triphenylphosphine; (3) nucleophilic substitution of the iodo derivative with diethylmethyl malonate/NaH; and (4) hydrolysis of the resulting 3,7,12 triformyloxy-25-methyl-26,27-diethyl ester with KOH, followed by decarboxylation of the geminal dicarboxylic acid with LiCl. N-Acylamidation of the resulting (25R)/(25S)-3alpha,7alpha,12alpha-trihydroxy-5alpha-cholestan-27-oic acid mixture with glycine or taurine afforded the corresponding epimeric mixtures of the glycine and taurine conjugates. The (25R)- and (25S)-epimers of the three variants of unconjugated and conjugated 3alpha,7alpha,12alpha-trihydroxy-5alpha cholestan-27-oic acid were efficiently separated by HPLC on a reversed-phase C(18) column and their structural characteristics, particularly the chiral center at C-25, delineated using (1)H and (13)C NMR. These synthetic compounds should be useful as authentic reference standards for establishing their presence in bile as well as being useful in studies on the biosynthesis of allo-bile acids from cholesterol. PMID- 21554865 TI - Hemoglobin Seville [alpha2 beta2 81(EF5) Leu->Phe] a silent phenotypic variant that interferes in hemoglobin A1c measurement by ion-exchange HPLC method. AB - OBJECTIVES: The aim of the study was to investigate hemoglobin (Hb) species in a 61 year-old male with diabetes mellitus type II and a low value of Hb A(1c). DESIGN AND METHODS: Hb species were analyzed by electrophoresis and chromatography methods. Functional properties were determined by oxygen equilibrium studies. beta-globin gene was amplified by PCR and sequenced. RESULTS AND CONCLUSIONS: A novel clinically silent Hb (Hb Seville), that results in falsely low Hb A(1c) measurement, was detected. This Hb variant presented a single base mutation at codon 81 (C->T) of the beta-globin gene. This case points out the necessity of careful inspection of the chromatograms and the use of additional methods to Hb A(1c) measurement when the presence of aberrant peaks is detected. PMID- 21554866 TI - Porcupine homolog is required for canonical Wnt signaling and gastrulation in mouse embryos. AB - Wnt signaling plays important roles in development and disease. The X-chromosomal Porcupine homolog gene (Porcn) encodes an evolutionary conserved member of the membrane bound O-acyl transferase (MBOAT) superfamily that has been shown to be required for the palmitoylation and secretion of Wnt3a, a mechanism that has been suggested to be conserved for all mammalian Wnt ligands. PORCN mutations in humans cause Focal Dermal Hypoplasia (FDH), a disorder causing developmental defects in heterozygous females and embryonic lethality in hemizygous males. In this study, Porcn mutant mouse embryonic stem (ES) cells were used to analyze the role of Porcn in mammalian embryonic development. In vitro, we show an exclusive requirement for Porcn in Wnt secreting cells and further, that any of the four Porcn isoforms is sufficient to allow for the secretion of functional Wnt3a. Embryos generated by aggregation of Porcn mutant ES cells with wildtype embryos fail to complete gastrulation in vivo, but remain in an epiblast-like state, similar to Wnt3 and Gpr177/Wls mutants. Consistent with this phenotype, in vitro differentiated mutant ES cells fail to generate endoderm and mesoderm derivatives. Taken together, these data confirm the importance of Porcn for Wnt secretion and gastrulation and suggest that disruption of early development underlies the male lethality of human PORCN mutants. PMID- 21554867 TI - Developmental transition of touch response from slow muscle-mediated coilings to fast muscle-mediated burst swimming in zebrafish. AB - It is well known that slow and fast muscles are used for long-term sustained movement and short bursts of activity, respectively, in adult animal behaviors. However, the contribution of the slow and fast muscles in early animal movement has not been thoroughly explored. In wild-type zebrafish embryos, tactile stimulation induces coilings consisting of 1-3 alternating contractions of the trunk and tail at 24 hours postfertilization (hpf) and burst swimming at 48 hpf. But, embryos defective in flightless I homolog (flii), which encodes for an actin regulating protein, exhibit normal coilings at 24 hpf that is followed by significantly slower burst swimming at 48 hpf. Interestingly, actin fibers are disorganized in mutant fast muscle but not in mutant slow muscle, suggesting that slower swimming at 48 hpf is attributable to defects of the fast muscle tissue. In fact, perturbation of the fast muscle contractions by eliminating Ca(2+) release only in fast muscle resulted in normal coilings at 24 hpf and slower burst swimming at 48 hpf, just as flii mutants exhibited. In contrast, specific inactivation of slow muscle by knockdown of the slow muscle myosin genes led to complete loss of coilings at 24 hpf, although normal burst swimming was retained by 48 hpf. These findings indicate that coilings at 24 hpf is mediated by slow muscle only, whereas burst swimming at 48 hpf is executed primarily by fast muscle. It is consistent with the fact that differentiation of fast muscle follows that of slow muscle. This is the first direct demonstration that slow and fast muscles have distinct physiologically relevant contribution in early motor development at different stages. PMID- 21554868 TI - PASS assisted prediction and pharmacological evaluation of novel nicotinic analogs for nootropic activity in mice. AB - The aim of present study is to predict the probable nootropic activity of novel nicotine analogues with the help of computer program, PASS (prediction of activity spectra for substances) and evaluate the same. Two compounds from differently substituted pyridines were selected for synthesis and evaluation of nootropic activity based on their high probable activity (Pa) value predicted by PASS computer program. Evaluation of nootropic activity of compounds after acute and chronic treatment was done with transfer latency (TL) and step down latency (SDL) methods which showed significant nootropic activity. The effect on scopolamine induced amnesia was also observed along with their acetylcholine esterase inhibitory activity which also showed positive results which strengthened their efficacy as nootropic agents through involvement of cholinergic system. This nootropic effect was similar to the effect of nicotine and donepezil used as standard drugs. Muscle coordination and locomotor activity along with their addiction liability, safety and tolerability studies were also evaluated. These studies showed that these compounds are well tolerable and safe over a wide range of doses tested along with the absence of withdrawal effect which is present in nicotine due to its addiction liability. The study showed that these compounds are true nicotine analogs with desirable efficacy and safety profile for their use as effective nootropic agents. PMID- 21554869 TI - Tempol, a membrane-permeable radical scavenger, ameliorates lipopolysaccharide induced acute lung injury in mice: a key role for superoxide anion. AB - Acute lung injury or acute respiratory distress syndrome is a serious clinical problem with high mortality. Oxidative stress was found to play a major role in mediating lung injury and antioxidants have been shown to be effective in attenuating acute lung injury. In this study, we determine the effects of tempol, a membrane-permeable radical scavenger, in lipopolysaccharide (LPS)-induced acute lung injury and the underlying mechanism. Acute lung injury was induced by intraperitoneal injection of LPS (1mg/kg) and mice were treated with tempol 30min before injection of LPS. One hour later, bronchoalveolar lavage fluid was collected and subjected to estimation of total and differential cell counts as well as the proinflammatory cytokines; tumor necrosis factor-alpha(TNF-alpha), interleukin-1beta(IL-1beta) and interferon-gamma (IFN-gamma). Lung tissue damage was confirmed by histopathological changes and by immunohistochemical analysis of myeloperoxidase (MPO). Moreover, lipid peroxidation, reduced glutathione (GSH) and nitric oxide (NO) were investigated in the lung tissue. Pretreatment with tempol produced significant attenuation of LPS-induced lung injury as well as inhibition of LPS mediated increase in MPO immunostaining, MDA and NO levels in lung tissue. Elevated cytokines levels in both bronchoalveolar lavage fluid and lung tissue homogenates of acute lung injury mice were significantly decreased after administration of tempol. These findings confirmed significant protection by tempol against LPS-induced acute lung injury and that superoxide anion scavenging appears to be a potential target for new potential therapy in pulmonary disorders. PMID- 21554870 TI - Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro. AB - Cordycepin, (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological actions, such as anti-inflammatory, antioxidative and anticancer activities. Little is known about the neuroprotective action of cordycepin as well as its molecular mechanisms. In this study, cordycepin was investigated for its neuroprotective potential in mice with ischemia following 15 min of the bilateral common carotid artery occlusion and 4h of reperfusion. The effect of cordycepin was also studied in mice brain slices treated with oxygen-glucose deprivation (OGD) injury. Our results showed that cordycepin was able to prevent postischemic neuronal degeneration and brain slice injury. Excitatory amino acids such as glutamate and aspartate in brain homogenized supernatant, which were increased in ischemia/reperfusion group, were detected by high performance liquid chromatography (HPLC). The results showed that cordycepin was able to decrease the extracellular level of glutamate and aspartate significantly. Moreover, cordycepin was able to increase the activity of superoxide dismutase (SOD) and decrease the level of malondialdehyde (MDA), ameliorating the extent of oxidation. Furthermore, matrix metalloproteinase-3(MMP 3), a key enzyme involved in inflammatory reactions, was markedly increased after ischemia reperfusion, whereas cordycepin was able to inhibit its expression obviously. In conclusion, our in vivo and in vitro study showed that cordycepin was able to exert a potent neuroprotective function after cerebral ischemia/reperfusion. PMID- 21554871 TI - Potentiation of the actions of acetylcholine, epibatidine, and nicotine by methyllycaconitine at fetal muscle-type nicotinic acetylcholine receptors. AB - Methyllycaconitine (MLA) is a norditerpenoid alkaloid found in high abundance in toxic Delphinium (larkspur) species. It is a potent and selective antagonist of alpha(7)-nicotinic acetylcholine receptors, but has not been well investigated for activity aside from receptor antagonism. The aim of this study was to investigate the effects of MLA alone and in combination with acetylcholine, epibatidine, nicotine, and neostigmine for actions other than receptor antagonism in TE-671 cells expressing (alpha(1))(2)beta(1)gammadelta nicotinic acetylcholine receptors. Ligand activity was assessed through measurements of membrane potential changes in TE-671 cells using a fluorescent membrane potential sensitive dye and normalized to the maximum response to epibatidine (10MUM). MLA was ineffective in changing cell membrane potential in the absence of other receptor agonists. However at nanomolar concentrations, it acted as a co-agonist to potentiate TE-671 cell responses to acetylcholine, epibatidine, nicotine, and neostigmine. These results suggest that the poisoning of cattle by norditerpenoid alkaloids found in larkspur may be more complex than previously determined. PMID- 21554872 TI - Regulation mechanism of ABCA1 expression by statins in hepatocytes. AB - ATP-binding cassette transporter A1 (ABCA1) is predicted to be involved in the control of apolipoprotein AI-mediated cholesterol efflux: biosynthesis of high density lipoprotein (HDL). However, the effects of HMG-CoA reductase inhibitors (statins) on ABCA1 in the liver and the precise mechanisms of their actions have been obscure. The aims of this study were to determine whether statins (atorvastatin (Ato) and pitavastatin (Pit)) affect hepatic ABCA1 expression and to clarify the mechanisms of their actions using HepG2 cells and the rat liver. We examined alterations in mRNA and protein levels of ABCA1 and peroxisome proliferator-activated receptors (PPARs) by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. In vitro and in vivo studies suggested that Pit increases ABCA1 mRNA level, but not Ato. Pit greatly increased Abca1 mRNA level and also increased the amount of plasma HDL and the mRNA level of PPARalpha. Clofibrate (PPARalpha agonist) increased ABCA1 expression in HepG2 cells and rat primary hepatocytes more than did PPAR beta/delta and gamma agonists. Pit-induced ABCA1 expression alteration was blocked by GW6471 (PPARalpha antagonist) and by PPARalpha knockdown. In this study, we demonstrated that Pit affect ABCA1 expression via PPARalpha in hepatocytes. The strategy to target a PPARalpha agonist in the liver can lead to increases in ABCA1 expression and HDL level. PMID- 21554873 TI - Development of non-antibiotic macrolide that corrects inflammation-driven immune dysfunction in models of inflammatory bowel diseases and arthritis. AB - Inflammation-driven immune dysfunction supports the development of several chronic human disorders including inflammatory bowel diseases and rheumatoid arthritis. Macrolides are effective antibiotics endowed with immunomodulatory effects. In this study we report the chemical synthesis and the pharmacological characterization of CSY0073, a non-antibiotic derivative of azithromycin. CSY0073 was tested for efficacy in two experimental models of colitis induced by administering mice with dextran sulfate (DSS) and trinitrobenzene sulphonic acid (TNBS) and in collagen induced arthritis. Like azithromycin, CSY0073 improved clinical, macroscopic and histopathological scores in mice administered DSS (12.5MUmol/kg/day p.o.) and TNBS (45MUmol/kg/day p.o.). When administered to TNBS treated mice, CSY0073 effectively attenuated influx of neutrophils and macrophages into the colonic mucosa and reduced the intestinal expression pro inflammatory cytokines TNFalpha, IL-2 and IFNgamma. CSY0073 (0.1 to 10MUM) counter-regulated TNFalpha, IFNgamma, IL-12 and IL-23 release caused by exposure of mouse spleen monocytes and CD11b+ cells isolated from the colonic lamina propria to endotoxin. CSY0073 (25MUmol/kg/day) reduced clinical scores in the collagen induced murine model of rheumatoid arthritis. In myeloid cells, CSY0073 (10MUM) prevented the nuclear translocation of the p65 subunit of NF-kappaB and its binding to canonical NF-kappaB responsive elements. In summary, we report a novel class of non-antibiotic 14-member macrocycles with anti-inflammatory and immune-modulatory effects. CSY0073, the prototype of this new class of macrolides exerts counter-regulatory activity on NF-kappaB signaling. This study suggests the exploitation of non-antibiotic macrolides in the treatment of inflammatory disorders characterized by immune dysfunction. PMID- 21554874 TI - The effect of pentoxifylline and its metabolite-1 on inflammation and fibrosis in the TNBS model of colitis. AB - TNBS-induced colitis has characteristics resembling human Crohn's disease including transmural inflammation, ulceration, and fibrosis. Current treatments target acute symptoms but do not necessarily prevent fibrotic complications of the disease. The aim of this study was to determine the effect of pentoxifylline and its primary metabolite (M-1) on fibrosis in the TNBS-induced colitis model. Myeloperoxidase activity and interleukin-18 are indicators of inflammation and were elevated in the TNBS model. The morphology damage score assesses colon damage and was also elevated in the TNBS model. Collagen as the indicator of fibrosis was quantified and visualized by the Sirius Red/Fast Green staining technique and collagen type I was assessed by Western analysis. Collagen was elevated in the TNBS-induced model. Pentoxifylline and M-1 treatment significantly attenuated colon damage and inflammation in TNBS-colitis (P<0.05). M-1 treatment significantly reduced the TNBS-induced increase in colon weight, colon thickness and total collagen content (P<0.05). Results suggest that pentoxifylline and M-1 inhibit intestinal fibrosis in this experimental model and may prove beneficial in the treatment of intestinal fibrosis associated with human Crohn's disease with the added benefit of inhibiting inflammation and ulceration. This is the first study to examine the effects of racemic M-1 in vivo and one of the few studies to examine the effect of drugs on both inflammation and fibrosis in an experimental model of colitis. PMID- 21554875 TI - Commentary on chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Merja H. Voutilainen et al. PMID- 21554876 TI - Combination of CpG-oligodeoxynucleotides with recombinant ROP2 or GRA4 proteins induces protective immunity against Toxoplasma gondii infection. AB - Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) have been characterized as Th1-promoting immunopotentiators, an adjuvant activity desirable for vaccination against intracellular parasites like Toxoplasma gondii. In an attempt to find new antigen-adjuvant combinations that enhance the immunogenicity of antigen candidates for toxoplasma vaccines, we analyzed the extent of protection in mice immunized with ROP2 and GRA4 recombinant proteins when co-administered with CpG-ODN. Both GRA4+CpG-ODN and ROP2+CpG-ODN formulations were shown to induce a strong humoral Th1-biased response characterized by a high IgG(2a) to IgG(1) antibody ratio. Both vaccination regimens led to increased secretion of IFN-gamma and IL-10, and negligible amounts of IL-4, upon specific re-stimulation of spleen cells from these groups of mice. After a non-lethal challenge with tissue cysts of a moderately virulent strain, only the brains from mice vaccinated with ROP2 or GRA4 in combination with CpG-ODN showed a significant reduction (63% and 62%, respectively) in their parasite load compared to the controls. The rate of protection obtained with GRA4+ROP2+CpG-ODN resulted equivalent (66%) to those achieved with the single antigens plus CpG-ODN. Taken together, these results indicate that CpG-ODN is an important candidate adjuvant for use in potential multicomponent anti-T. gondii vaccines for animals and humans. PMID- 21554877 TI - Development of the reproductive system of Echinostoma paraensei in Mesocricetus auratus analyzed by light and confocal scanning laser microscopy. AB - This study was performed to gain insight into the maturation of the reproductive system of Echinostoma paraensei worms grown in an early infection of Mesocricetus auratus. Hamsters were infected with 100 metacercariae and necropsied on days 3, 5, 7, 10 and 14 post infection (dpi). Recovered flukes stained with hydrochloric carmine were preserved as whole mounts and analyzed by light and confocal scanning laser microscopy. The average worm recovery was 43.7 per host. Images of the male and female reproductive systems were taken. The ovary and anterior and posterior testis were evidenced on day 3, while the ootype and cirrus sac were present on day 5. Confocal imaging showed primordium testis and ovary as a cluster of primordial cells from day 3 onward. The testes, ovary, cirrus sac and uterus organs were already present during the first week of life. The two testes were seen as individual structures on 7 dpi while the cirrus sac and vitelline glands were in development. The ovary was connected to the uterus while the ootype was adjacent to it. Both testes were larger than the ovary, showing cells at different stages of development, but with few bundles of functional spermatozoa in 10 day-old worms. On day 14, eggs and spermatozoa were seen in the uterus and seminal vesicle, respectively, while oocytes appeared in the ootype as fertilized eggs. We conclude that the reproductive system of E. paraensei was functional on 14 dpi in the hamsters. PMID- 21554878 TI - Trichobilharzia regenti: host immune response in the pathogenesis of neuroinfection in mice. AB - Besides their natural bird hosts, Trichobilharzia regenti cercariae are able to penetrate skin of mammals, including humans. Experimental infections of mice showed that schistosomula of this species are able to avoid the immune response in skin of their non-specific mammalian host and escape the skin to migrate to the CNS. Schistosomula do not mature in mammals, but can survive in nervous tissue for several days post infection. Neuroinfections of specific bird hosts as well as accidental mammalian hosts can lead to neuromotor effects, for example, leg paralysis and thus this parasite serves as a model of parasite invasion of the CNS. Here, we show by histological and immunohistochemical investigation of CNS invasion of immunocompetent (BALB/c) and immunodeficient (SCID) mice by T. regenti schistosomula that the presence of parasites in the nervous tissue initiated an influx of immune cells, activation of microglia, astrocytes and development of inflammatory lesions. Schistosomula elimination in the tissue depended on the host immune status. In the absence of CD3+ T-cells in immunodeficient SCID mice, parasite destruction was slower than that in immunocompetent BALB/c mice. Axon injury and subsequent secondary demyelination in the CNS were associated with mechanical damage due to migration of schistosomula through the nervous tissue, and not by host immune processes. Immunoreactivity of the parasite intestinal content for specific antigens of oligodendrocytes/myelin and neurofilaments showed for the first time that schistosomula ingest the nervous tissue components during their migration. PMID- 21554879 TI - Human NK receptors: from the molecules to the therapy of high risk leukemias. AB - Natural killer cells are important players of the innate immunity. In humans, they express HLA-class I-specific inhibitory receptors including the allotypic specific KIR and various activating receptors. In most instances, in an autologous setting NK cells do not kill self cells. In contrast, in an allogeneic setting as the haploidentical hematopoietic stem cell transplantation to cure high risk leukemias, donor-derived NK cells may express inhibitory KIR that are not engaged by the HLA-class I alleles (KIR ligands) expressed by recipient cells. Such "alloreactive" NK cells may be responsible for the eradication of leukemia blasts escaping the preparative regimen, residual host dendritic cells and T lymphocytes, thus preventing leukemia relapse, GvHD and graft rejection, respectively. These NK-mediated effects result in a sharp improvement of the estimated 5 years survival. PMID- 21554880 TI - FEBS Letters. Turin special issue: Biochemistry for tomorrow's medicine. PMID- 21554881 TI - Vasopressin needs an audience: neuropeptide elicited stress responses are contingent upon perceived social evaluative threats. AB - The nonapeptide arginine vasopressin (AVP) plays an important role in hypothalamus-pituitary-adrenal axis regulation and also functions as a social hormone in a wide variety of species, from voles to humans. In the current report we use a variety of stress inducing tasks, including the Trier Social Stress Test (TSST) and intranasal administration of AVP to show that intranasal administration of this neuropeptide leads to a significant increase in salivary cortisol and pulse rate, specifically in conditions where subjects perform tasks in the presence of a social evaluative threat (task performance could be negatively judged by others). In contrast, in conditions without a social evaluative threat (no task condition, modified TSST without audience and bike ergometry), subjects receiving AVP did not differ from subjects receiving placebo. Thus exogenous AVP's influence is contingent upon a circumscribed set of initial conditions that constitute a direct threat to the maintenance of our social selves. Stress evoked by social threat is an integral part of social life and is related to self-esteem and in extreme forms, to poor mental health (e.g., social phobia). Our findings suggest that AVP is a key component in the circuit that interlaces stress and social threat and findings offer inroads to our understanding of individual differences in sociability and in stress response elicited in threatening social situations. PMID- 21554882 TI - Changes in CNS response to neurotensin accompany the postpartum period in mice. AB - Neurotensin (NT) is a highly conserved neuropeptide in mammals. Recent studies suggest that altered NT neurotransmission in postpartum females could promote the emergence of some maternal behaviors, including offspring protection. Here we evaluated how virgin and postpartum brains from mice selected for high maternal defense differ in response to NT. Virgin and postpartum mice were injected with either vehicle or 0.1 MUg NT icv and brains were evaluated for c-Fos immunoreactivity, an indirect marker of neuronal activity. Using ANOVA analysis, common significant responses to NT were found in both female groups in four brain regions, including supraoptic nucleus, ventromedial nucleus, bed nucleus of stria terminalis dorsal, and a subregion of lateral septum (LS). For postpartum mice, only one additional region showed a significant response to NT relative to vehicle, whereas for virgin mice seven unique brain regions showed a significant c-Fos response: nucleus accumbens shell, paraventricular nucleus, central amygdala, and substantia nigra. Using a principal components analysis of c-Fos, we identified regions within each group with highly correlated activity. As expected, virgin and postpartum mice (vehicle conditions) showed different activity hubs and in the postpartum group the hubs matched regions linked to maternal care. The response to injected NT was different in the maternal and virgin groups with maternal mice showing a stronger coordinated activity in periaqueductal gray whereas virgin mice showed a stronger septal and amygdala linking of activity. Together, these results indicate neuronal responses of virgin and postpartum mice to NT and highlight pathways by which NT can alter maternal responses. PMID- 21554883 TI - Neonatal agonism of ERbeta impairs male reproductive behavior and attractiveness. AB - The organization of the developing male rodent brain is profoundly influenced by endogenous steroids, most notably estrogen. This process may be disrupted by estrogenic endocrine disrupting compounds (EDCs) resulting in altered sex behavior and the capacity to attract a mate in adulthood. To better understand the relative role each estrogen receptor (ER) subtype (ERalpha and ERbeta) plays in mediating these effects, we exposed male Long Evans rats to estradiol benzoate (EB, 10 MUg), vehicle, or agonists specific for ERbeta (DPN, 1 mg/kg) or ERalpha (PPT, 1 mg/kg) daily for the first four days of life, and then assessed adult male reproductive behavior and attractiveness via a partner preference paradigm. DPN had a greater adverse impact than PPT on reproductive behavior, suggesting a functional role for ERbeta in the organization of these male-specific behaviors. Therefore the impact of neonatal ERbeta agonism was further investigated by repeating the experiment using vehicle, EB and additional DPN doses (0.5 mg/kg, 1 mg/kg, and 2 mg/kg bw). Exposure to DPN suppressed male reproductive behavior and attractiveness in a dose dependent manner. Finally, males were exposed to EB or an environmentally relevant dose of genistein (GEN, 10 mg/kg), a naturally occurring xenoestrogen, which has a higher relative binding affinity for ERbeta than ERalpha. Sexual performance was impaired by GEN but not attractiveness. In addition to suppressing reproductive behavior and attractiveness, EB exposure significantly lowered the testis to body weight ratio, and circulating testosterone levels. DPN and GEN exposure only impaired behavior, suggesting that disrupted androgen secretion does not underlie the impairment. PMID- 21554884 TI - Schistosome I/Lamides--a new family of bioactive helminth neuropeptides. AB - Here we report the identification of a new family of helminth neuropeptides with members in both nematodes and flatworms, and include preliminary cell biological and functional characterisation of one of the peptides from the trematode parasite of humans, Schistosoma mansoni. Bioinformatics and Rapid Amplification of cDNA Ends (RACE)-PCR were used to identify the complete S. mansoni neuropeptide precursor gene Sm-npp-1, which encodes three pentapeptides bearing the motif (A/G)FVR(I/L).NH(2). Similar peptides were identified in three other flatworm species and in 15 nematode species. Quantitative PCR (qPCR) and immunocytochemical (ICC) analyses showed that Sm-npp-1 is constitutively expressed in larval and adult worms. ICC and confocal microscopy were employed to localise one of the schistosome NPP-1 peptides (GFVRIamide) in adult worms and schistosomules; antibodies labelled a pair of neurones in the cerebral ganglia that extend posteriorly along the main nerve cords. GFVRIamide displayed no detectable co-localisation with FMRFamide-like peptides (FLPs), nor was it detectable in muscle innervation. Exogenously applied peptide had a significant inhibitory effect on the mobility of whole adult worm pairs at 10(-5)M (n = 9). Finally, we explored Sm-npp-1 function in schistosomules using RNA interference (RNAi); we successfully achieved specific knockdown of the Sm-npp-1 transcript (54.46 +/- 10.41% knockdown, n = 3), but did not detect any clear, aberrant mobility or morphological phenotypes. NPP-1-like peptides are a new family of helminth peptides with a cell-specific expression pattern distinct from FLPs and a modulatory effect on schistosome muscular activity. PMID- 21554885 TI - Immunoassay for the discrimination of free prostate-specific antigen (fPSA) forms with internal cleavages at Lys(145) or Lys(146) from fPSA without internal cleavages at Lys(145) or Lys(146). AB - Total levels of circulating prostate-specific antigen (tPSA) are strongly associated with prostate cancer (PCa) risk and outcome but benign prostate disease is the most frequent cause of a moderately elevated PSA level. Free PSA (fPSA) forms are independently associated with PCa risk and contribute modest diagnostic enhancements above and beyond tPSA alone. We developed an immunoassay for fPSA subfractions containing internal cleavages at Lys(145) or Lys(146) (fPSA N). The assay was based on blocking intact single-chain fPSA (fPSA-I) with antibody 4D4 which does not detect PSA containing internal cleavages at Lys(145) or Lys(146). We also measured fPSA-N in blood from healthy volunteers and in anti coagulated plasma from 76 men with or without evidence of PCa at biopsy. The analytical and functional detection limits of this assay were 0.016 ng/mL and 0.10 ng/mL, respectively. The median recovery of male fPSA-N from female plasma was 95.0%. All 12 female samples (average age 28 years) had fPSA-N concentrations at or below the analytical detection limit. The median fPSA-N concentration (0.050 ng/mL) in 9 healthy male volunteers (age<40 years) was below the functional detection limit, 0.420 ng/mL in 27 patients with benign prostate conditions and 0.239 ng/mL in 49 patients with PCa. Deming regression analysis of the patient samples showed that the measured fPSA-N concentrations were generally 23% lower than the previously calculated (fPSA minus fPSA-I) concentrations, likely due to differences in the antibody combinations used. In conclusion, we have developed a sensitive, specific and direct immunoassay for fPSA-N which can be used to study the clinical relevance of this PSA isoform. PMID- 21554886 TI - Coordinated movements of the head and body during orienting behaviour in the praying mantis Tenodera aridifolia. AB - The visual orienting behaviour towards prey in the free-moving mantis was investigated with a high-speed camera. The orienting behaviour consisted of head, prothorax, and abdomen rotations. Coordinated movements of these body parts in the horizontal plane were analysed frame-by-frame. Rotations of these body parts were initiated with no or slight (<=40 ms) differences in timing. The initiation timing of prothorax-abdomen rotation was affected by its initial angle before the onset of orienting. There were positive correlations in amplitude among head prothorax, prothorax-abdomen, and abdomen rotations. The ratio of these rotations to total gaze rotation was affected by the initial prothorax-abdomen angle before the onset of orienting. Our data suggest that coordinated movements of the head, prothorax, and abdomen during orienting are ballistic events and are pre determined according to visual and proprioceptive information before the onset of orienting. PMID- 21554887 TI - Bursicon-expressing neurons undergo apoptosis after adult ecdysis in the mosquito Anopheles gambiae. AB - Neuropeptides are important regulators of diverse processes during development. The insect neuropeptide bursicon, a 30 kDa heterodimer, controls the hardening of the new cuticle after the shedding of the old one (ecdysis) and the inflation and maturation of adult wings. Given this specific functional role, its expression should only be required transiently because adult insects no longer undergo ecdysis. Here we report the transient expression of bursicon in the mosquito, Anopheles gambiae. Quantitative RT-PCR revealed that transcription of the bursicon monomers, burs and pburs, steadily increases through the larval stages, peaks in the black pupa stage, and decreases to below detectable levels by 8 h after adult ecdysis (eclosion). Immunohistochemistry on the adult nervous system showed that bursicon is co-expressed with crustacean cardioactive peptide (CCAP) in specific neurons of the abdominal ganglia, but that labeling intensity wanes by 14 h post-eclosion. Finally, detection of disintegrating DNA by TUNEL labeling demonstrated that the bursicon expressing neurons successively undergo apoptosis following eclosion. Taken altogether, these data describe A. gambiae as another holometabolous insect in which bursicon ceases to be produced in adults, and in which the bursicon expressing neurons are removed from the ventral nerve cord. PMID- 21554888 TI - Crucial points within the pore as determinants of K+ channel conductance and gating. AB - While selective for K+, K+ channels vary significantly among their rate of ion permeation. Here, we probe the effect of steric hindrance and electrostatics within the ion conduction pathway on K+ permeation in the MthK K+ channel using structure-based mutagenesis combined with single-channel electrophysiology and X ray crystallography. We demonstrate that changes in side-chain size and polarity at Ala88, which forms the constriction point of the open MthK pore, have profound effects on single-channel conductance as well as open probability. We also reveal that the negatively charged Glu92s at the intracellular entrance of the open pore form an electrostatic trap, which stabilizes a hydrated K+ and facilitates ion permeation. This electrostatic attraction is also responsible for intracellular divalent blockage, which renders the channel inward rectified in the presence of Ca2+. In light of the high structural conservation of the selectivity filter, the size and chemical environment differences within the portion of the ion conduction pathway other than the filter are likely the determinants for the conductance variations among K+ channels. PMID- 21554889 TI - Microsecond subdomain folding in dihydrofolate reductase. AB - The characterization of microsecond dynamics in the folding of multisubdomain proteins has been a major challenge in understanding their often complex folding mechanisms. Using a continuous-flow mixing device coupled with fluorescence lifetime detection, we report the microsecond folding dynamics of dihydrofolate reductase (DHFR), a two-subdomain alpha/beta/alpha sandwich protein known to begin folding in this time range. The global dimensions of early intermediates were monitored by Forster resonance energy transfer, and the dynamic properties of the local Trp environments were monitored by fluorescence lifetime detection. We found that substantial collapse occurs in both the locally connected adenosine binding subdomain and the discontinuous loop subdomain within 35 MUs of initiation of folding from the urea unfolded state. During the fastest observable ~550 MUs phase, the discontinuous loop subdomain further contracts, concomitant with the burial of Trp residue(s), as both subdomains achieve a similar degree of compactness. Taken together with previous studies in the millisecond time range, a hierarchical assembly of DHFR--in which each subdomain independently folds, subsequently docks, and then anneals into the native conformation after an initial heterogeneous global collapse--emerges. The progressive acquisition of structure, beginning with a continuously connected subdomain and spreading to distal regions, shows that chain entropy is a significant organizing principle in the folding of multisubdomain proteins and single-domain proteins. Subdomain folding also provides a rationale for the complex kinetics often observed. PMID- 21554890 TI - Quantum-like model of brain's functioning: decision making from decoherence. AB - We present a quantum-like model of decision making in games of the Prisoner's Dilemma type. By this model the brain processes information by using representation of mental states in a complex Hilbert space. Driven by the master equation the mental state of a player, say Alice, approaches an equilibrium point in the space of density matrices (representing mental states). This equilibrium state determines Alice's mixed (i.e., probabilistic) strategy. We use a master equation in which quantum physics describes the process of decoherence as the result of interaction with environment. Thus our model is a model of thinking through decoherence of the initially pure mental state. Decoherence is induced by the interaction with memory and the external mental environment. We study (numerically) the dynamics of quantum entropy of Alice's mental state in the process of decision making. We also consider classical entropy corresponding to Alice's choices. We introduce a measure of Alice's diffidence as the difference between classical and quantum entropies of Alice's mental state. We see that (at least in our model example) diffidence decreases (approaching zero) in the process of decision making. Finally, we discuss the problem of neuronal realization of quantum-like dynamics in the brain; especially roles played by lateral prefrontal cortex or/and orbitofrontal cortex. PMID- 21554891 TI - Loss of p120 catenin upregulates transcription of pro-inflammatory adhesion molecules in human endothelial cells. AB - P120 catenin (p120ctn) is an adherens junction protein recognized to regulate barrier function, but emerging evidence indicates that p120ctn may also exert control on other cellular functions such as transcriptional suppression of genes. We investigated the hypothesis that loss of p120ctn in human endothelial cells activates transcription of pro-inflammatory adhesion molecules. For study, siRNA targeted to p120ctn was transfected into brain microvascular (HBMECs) or pulmonary artery endothelial cells (HPAECs) for 24-120h, which depleted 50-80% of endogenous p120ctn. This loss of p120ctn resulted in increased promoter reporter activity of transcription factors, NFkappaB, AP-1, and Kaiso, as well as of target genes, MMP-1 and ICAM-1. Real-time RT-PCR analysis indicated that the mRNA for ICAM-1, VCAM-1, and E- and P-selectins were all upregulated during the period of 24-120h of p120ctn depletion, although the time-course and extent of the expression profiles differed. The upregulated mRNA of adhesion molecules corresponded with increased PMN adhesion to the EC surface and elevated ICAM-1 protein expression. We further explored the role of ERK1/2 as a potential signaling mechanism responsible for regulation of transcriptional activities by p120ctn. Results indicated that loss of p120ctn increased phosphorylated ERK1/2, and a MEK1 inhibitor (PD98059) prevented NFkappaB nuclear translocation. This implicates ERK1/2 in signaling the NFkappaB activation induced by p120ctn loss. The findings provide strong evidence that deficiency in p120ctn expression in endothelial cells is a potent stimulus for transcriptional upregulation of multiple adhesion molecules. We conclude that p120ctn functions to suppress transcription, which is an important and novel regulation in vascular endothelium. PMID- 21554892 TI - Number reading in pure alexia--a review. AB - It is commonly assumed that number reading can be intact in patients with pure alexia, and that this dissociation between letter/word recognition and number reading strongly constrains theories of visual word processing. A truly selective deficit in letter/word processing would strongly support the hypothesis that there is a specialized system or area dedicated to the processing of written words. To date, however, there has not been a systematic review of studies investigating number reading in pure alexia and so the status of this assumed dissociation is unclear. We review the literature on pure alexia from 1892 to 2010, and find no well-documented classical dissociation between intact number reading and impaired letter identification in a patient with pure alexia. A few studies report strong dissociations, with number reading less impaired than letter reading, but when we apply rigorous statistical criteria to evaluate these dissociations, the difference in performance across domains is not statistically significant. There is a trend in many cases of pure alexia, however, for number reading to be less affected than letter identification and word reading. We shed new light on this asymmetry by showing that, under conditions of brief exposure, normal participants are also better at identifying digits than letters. We suggest that the difference observed in some pure alexic patients may possibly reflect an amplification of this normal difference in the processing of letters and digits, and we relate this asymmetry to intrinsic differences between the two types of symbols. PMID- 21554893 TI - The role of taste in food acceptance at the beginning of complementary feeding. AB - Introduction of solid foods is a major step in the establishment of eating behavior and is likely to affect children's health. However, the role of taste in acceptance of new foods, in particular in the first months of complementary feeding, is not fully understood and was the aim of the present study. Infants had to be in good health to participate (N=74). First, the infants' reactions to new foods were recorded by their parents between the ages of 5 and 7 months using a 4-point-scale ranging from very negative to very positive. Taste intensities of infant foods were scored by a trained panel and foods were clustered into groups showing similar taste profiles. Infants' reactions were used to calculate new food acceptance (NFA) defined as the average reaction towards a group of foods showing a similar taste profile. Second, preferences for the five basic tastes over water were measured using a 4-bottle test at 6 months old comparing intake of tastant solutions to water. Taste acceptance was evaluated through ingestion ratio (IR=intake of tastant solutions/intake of tastant solutions and water). NFAs were compared across food groups. Kendall correlations were calculated between NFA and IR. Most reactions (88%) to new foods were positive. However, NFA varied according to the taste profile of the foods: vegetables in which salt or a salty ingredient was added were more accepted than plain vegetables (P<0.01). On average no rejection of basic tastes was observed. For sweet, sour and umami tastes, significant positive correlations were observed between NFA and IR. Healthy foods like vegetables could be easily introduced in the diet of most, but not all infants. The role of taste preferences in new food acceptance was highlighted: a higher acceptance for a taste was associated to an enhanced acceptance of foods bearing this taste. PMID- 21554894 TI - Serotonergic system involvement in the inhibitory action of estrogen on induced sodium appetite in female rats. AB - This study of the participation of the serotonergic system in the inhibitory effect of estrogen on induced sodium appetite in female rats explores sodium appetite induced by Furosemide and low sodium diet treatment (DEP) in normally cycling rats and in ovariectomized rats with and without estradiol replacement (OVX, OVX+E(2)). We also analyzed the neural activity of serotonergic neurons of the dorsal raphe nucleus (DRN) as well as the activity of other brain nuclei previously found to be involved in sodium and water balance in sodium depleted animals without access to the intake test. For this purpose, we examined the brain Fos, Fos-serotonin and Fos-vasopressin immunoreactivity patterns in diestrus (D), estrus (E), OVX and OVX+E(2) rats subjected to DEP. Female rats in E and OVX+E(2) exhibited a significant decrease in induced sodium intake compared with females in D and OVX. This estrogen-dependent inhibition on induced sodium appetite (approximately 50% reduction) can be correlated with changes in Fos activation observed in the organum vasculosum of the lamina terminalis (OVLT) and DRN, in response to sodium depletion. Given our previous observations in males, the expected sodium depletion-induced activity of the OVLT was found to be absent in OVX+E(2) females, while the usual inhibitory tonic activity of serotonergic neurons of the DRN, instead of decreasing after sodium depletion, increases or remains unchanged in OVX+E(2)-DEP and E-DEP females, respectively. Regarding urinary water and sodium excretion 3h after furosemide treatment, E-DEP and OVX+E(2)-DEP animals excreted smaller volumes of more highly concentrated urine than depleted D and OVX rats. Twenty hours after sodium depletion, the same groups of animals also showed a significant increase in the number of Fos-AVP immunoreactive neurons within the supraoptic nucleus, compared with D-DEP. In summary, our results demonstrate an estrogen-dependent inhibition of induced sodium appetite in normally cycling rats and ovariectomized animals with estradiol replacement, which may involve an interaction between excitatory neurons of the OVLT and inhibitory serotonergic cells of the DRN. The main finding is thus serotonergic system involvement as a possible mechanism in the inhibitory action of estrogen on induced sodium appetite. PMID- 21554895 TI - Sex, drugs and gluttony: how the brain controls motivated behaviors. AB - Bart Hoebel has forged a view of an integrated neural network that mediates both natural rewards and drug use. He pioneered the use of microdialysis, and also effectively used electrical stimulation, lesions, microinjections, and immunohistochemistry. He found that feeding, stimulant drug administration, and electrical stimulation of the lateral hypothalamus (LH) all increased dopamine (DA) release in the nucleus accumbens (NAc). However, whereas DA in the NAc enhanced motivation, DA in the LH inhibited motivated behaviors. The Hull lab has pursued some of those ideas. We have suggested that serotonin (5-HT) in the perifornical LH inhibits sexual behavior by inhibiting orexin/hypocretin neurons (OX/HCRT), which would otherwise excite neurons in the mesocorticolimbic DA tract. We have shown that DA release in the medial preoptic area (MPOA) is very important for male sexual behavior, and that testosterone, glutamate, nitric oxide (NO) and previous sexual experience promote MPOA DA release and mating. Future research should follow Bart Hoebel's emphasis on neural systems and interactions among brain areas and neurotransmitters. PMID- 21554896 TI - Ghrelin, peptide YY and their hypothalamic targets differentially regulate spontaneous physical activity. AB - Recent studies suggest that spontaneous physical activity (SPA) may be under the non-conscious control of neuroendocrine circuits that are known to control food intake. To further elucidate endocrine gut-brain communication as a component of such circuitry, we here analyzed long-term and acute effects of the gastrointestinal hormones ghrelin and PYY 3-36 as well as their hypothalamic neuropeptide targets NPY, AgRP and POMC (alpha-MSH), on locomotor activity and home cage behaviors in rats. For the analysis of SPA, we used an automated infrared beam break activity measuring system, combined with a novel automated video-based behavior analysis system (HomeCageScan (HCS)). Chronic (one-month) peripheral infusion of ghrelin potently increased body weight and fat mass in rats. Such positive energy balance was intriguingly not due to an overall increased caloric ingestion, but was predominantly associated with a decrease in SPA. Chronic intracerebroventricular infusion (7 days) of ghrelin corroborated the decrease in SPA and suggested a centrally mediated mechanism. Central administration of AgRP and NPY increased food intake as expected. AgRP administration led to a delayed decrease in SPA, while NPY acutely (but transiently) increased SPA. Behavioral dissection using HCS corroborated the observed acute and transient increases of food intake and SPA by central NPY infusion. Acute central administration of alpha-MSH rapidly decreased food intake but did not change SPA. Central administration of the NPY receptor agonist PYY 3 36 transiently increased SPA. Our data suggest that the control of spontaneous physical activity by gut hormones or their neuropeptide targets may represent an important mechanistic component of energy balance regulation. PMID- 21554897 TI - Self-administered and yoked nicotine produce robust increases in blood pressure and changes in heart rate with modest effects of behavioral contingency in rats. AB - Experimenter-administered nicotine produces reliable increases in blood pressure and changes in heart rate. However, an extensive literature demonstrates that the effects of psychoactive drugs are dependent on whether administration is contingent on behavior. The present study assessed the cardiovascular effects of nicotine and whether those effects vary as a function of whether nicotine was self-administered or response-independent. Rats were divided into three groups according to a yoked design. The pattern of infusions for each triad was determined by the animal self-administering nicotine; the other two animals received either yoked nicotine or saline. Heart rate and blood pressure were measured during eighteen daily, 1h drug sessions by radiotelemetry. Each session was preceded and followed by a 20 minute period during which cardiovascular function was monitored in the operant chambers, but drug was not available. Acute exposure to yoked nicotine produced a rapid rise in blood pressure that was larger than the increase observed with self-administered nicotine. Additional infusions during the first session resulted in a similar sustained elevation in blood pressure in the nicotine groups. Over subsequent sessions, self administered nicotine produced a larger effect on systolic blood pressure particularly early in each session, although for both self-administered and yoked nicotine the hypertensive effects waned partially with repeated test sessions. This decrease was fully accounted for by a pre-session decrease in pressure; relative to pre-session levels the strong hypertensive effects of nicotine persisted. Initial exposure to nicotine produced a short-lived bradycardia that in subsequent sessions was replaced with a longer-lasting nicotine-induced tachycardia; neither effect was related to the behavioral contingency of nicotine delivery. Together, these data provide a rich picture of the cardiovascular effects of nicotine. Effects of behavioral contingency were observed, but differences were limited. Other non-pharmacological factors such as baseline shifts potentially related to nicotine-associated cues deserve further attention. PMID- 21554898 TI - Another major function of the anterior cingulate cortex: the representation of requirements. AB - The anterior cingulate cortex (ACC) is a ubiquitously active brain region, doubtless reflecting a multiplicity of functions. Improved knowledge of such functions should progress understanding of disorders with established ACC involvement, including depression, apathy, and addiction. This theoretical paper proposes a hypothesis concerning an original and important ACC function, namely that the ACC operates as part of distributed networks to which it contributes the representation of requirements. Such requirements are further suggested to proactively coordinate and organize processing in effector regions to achieve consummation, thereby implementing an optimal strategy. The ACC (predominantly Brodmann's areas 24 and 32) is activated during states characterized by active requirements such as homeostatic perturbations, pain, desire, addiction, and cognition, and this is evidenced by systematic reviews of neuroimaging studies, and by neuropsychological findings. Further, ACC activity commences early in processing, and proactively influences processing in effector regions, further supporting the hypothesis. Thus, this hypothesis accounts for some ACC findings that are otherwise unexplained, and proposes novel testable predictions offering new insights into ACC functional organization. PMID- 21554900 TI - Assessment of surface electromyographic clinical analysis of selective femoral neurotomy on cerebral palsy with stiff knee. AB - This study aimed to explore the role of surface electromyography (sEMG) on the changes of myoelectric activities of quadriceps femoris and the assessment of its clinical effect before and after selective femoral neurotomy on spastic cerebral palsy with stiff knee. Selective femoral neurotomy was carried out in 15 patients on 26 sides. The electromyography of quadriceps femoris was recorded before and after the operation. Passive and voluntary movements were performed during recording. The root mean square (RMS) and integrated electromyography (iEMG) was calculated by time domain analysis. Meanwhile, the range of the patients' knee joint motion (ROM) was measured by a joint goniometer. The RMS and iEMG of the quadriceps femoris during passive movement was significantly decreased post operation when compared to those pre-operation (both P<0.05, n=26). Meanwhile, the RMS and iEMG of the quadriceps femoris during voluntary movement post operation was significantly reduced than those pre-operation (both P<0.05, n=26). Additionally, total excursion on the sagittal plane and the peak knee flexion in the swing phase were significantly raised post-operation than those pre-operation (both P<0.05, n=26). The spasms in the quadriceps femoris in spastic cerebral palsy patients with stiff knee was clearly improved, and the ROM of the knee was significantly enhanced after the selective femoral neurotomy. Importantly, surface EMG can objectively evaluate the clinical therapeutic effect of spastic cerebral palsy stiff knee as a noninvasive detection method. PMID- 21554901 TI - TLRs, NLRs and RLRs: innate sensors and their impact on allergic diseases--a current view. AB - Charles Janeway first wrote 1989 about how important recognition of "certain characteristics or patterns common on infectious agents but absent from the host" would be for our immune response [1]. Surprisingly, it almost took 10 years before his ideas would lead to the revolutionary findings that fundamentally changed the view of the innate immune system over the past decade. Recognition of invading microorganisms belongs to the primary tasks of the innate immune system and is achieved through different families of innate immune sensors. Among these, Toll-like receptors (TLRs), nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) and Rig-I-like receptors (RLRs) have drawn major interests over the last decade. These receptor families are targeted by overlapping classes of pathogens and share functional domains and signal transduction pathways (see Fig. 1 and Table 1 for an overview of their structural organization, ligands, adaptors and activated pathways). This current view describes our present knowledge about these three main innate immune receptor families and their importance for adaptive immune responses such as asthma and allergy. PMID- 21554899 TI - Promise of resveratrol for easing status epilepticus and epilepsy. AB - Resveratrol (RESV; 3,5,4'-tri-hydroxy stilbene), a naturally occurring phytoalexin, is found at a high concentration in the skin of red grapes and red wine. RESV mediates a wide-range of biological activities, which comprise an increased life span, anti-ischemic, anti-cancer, antiviral, anti-aging and anti inflammatory properties. Studies in several animal prototypes of brain injury suggest that RESV is an effective neuroprotective compound. Ability to enter the brain after a peripheral administration and no adverse effects on the brain or body are other features that are appealing for using this compound as a therapy for brain injury or neurodegenerative diseases. The goal of this review is to discuss the promise of RESV for treating acute seizures, preventing the acute seizure or status epilepticus induced development of chronic epilepsy, and easing the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction. First, the various beneficial effects of RESV on the normal brain are discussed to provide a rationale for considering RESV treatment in the management of acute seizures and epilepsy. Next, the detrimental effects of acute seizures or status epilepticus on the hippocampus and the implications of post status epilepticus changes in the hippocampus towards the occurrence of chronic epilepsy and cognitive dysfunction are summarized. The final segment evaluates studies that have used RESV as a neuroprotective compound against seizures, and proposes studies that are critically needed prior to the clinical application of RESV as a prophylaxis against the development of chronic epilepsy and cognitive dysfunction after an episode of status epilepticus or head injury. PMID- 21554902 TI - Inhibition of porcine reproductive and respiratory syndrome virus infection in piglets by a peptide-conjugated morpholino oligomer. AB - Porcine reproductive and respiratory syndrome (PRRS) causes substantial economic losses to the swine industry in many countries, and current control strategies are inadequate. Previously, we explored the strategy of using peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to inhibit PRRS virus (PRRSV) replication. PPMOs are nuclease-resistant and single-stranded DNA analogs containing a modified backbone conjugated to a cell-penetrating peptide and can act as antisense agents through steric blockade of complementary messenger RNA. A PPMO (designated 5UP2) targeting highly conserved sequence in the 5'-terminal region of the PRRSV genome was found to produce multi-log10 inhibition of PRRSV replication in cultured cells. To evaluate 5UP2 in vivo, we here administrated the PPMO to 3-week-old piglets via intranasal instillation at 24h before, and 2 and 24h after infection with PRRSV (strain VR2385). Blood samples were collected at 6, 10 and 14 days post-infection (dpi) for detection of PRRSV RNA and antibodies. Necropsy was performed at 14 dpi. Monitoring weight gain in all piglet groups throughout the experiment indicated that PPMO was well tolerated at the doses used. PPMO 5UP2 treatment significantly reduced PRRSV viremia at 6 dpi. On day 14, piglets receiving 5UP2 had significantly less interstitial pneumonia and lower level of anti-PRRSV antibodies than untreated piglets. In alveolar macrophages isolated at the time of necropsy, the expression of antiviral genes in PPMO-treated piglets was elevated in comparison with untreated. This study provides further data indicating that the 5UP2 PPMO can be considered a candidate component for a novel PRRS control strategy. PMID- 21554903 TI - Treatment of spatial memory impairment in hamsters infected with West Nile virus using a humanized monoclonal antibody MGAWN1. AB - In addition to functional disorders of paresis, paralysis, and cardiopulmonary complications, subsets of West Nile virus (WNV) patients may also experience neurocognitive deficits and memory disturbances. A previous hamster study has also demonstrated spatial memory impairment using the Morris water maze (MWM) paradigm. The discovery of an efficacious therapeutic antibody MGAWN1 from pre clinical rodent studies raises the possibility of preventing or treating WNV induced memory deficits. In the current study, hamsters were treated intraperitoneally (i.p.) with 32 mg/kg of MGAWN1 at 4.5 days after subcutaneously (s.c.) challenging with WNV. As expected, MGAWN1 prevented mortality, weight loss, and improved food consumption of WNV-infected hamsters. The criteria for entry of surviving hamsters into the study were that they needed to have normal motor function (forelimb grip strength, beam walking) and normal spatial reference memory in the MWM probe task. Twenty-eight days after the acute phase of the disease had passed, MGAWN1- and saline-treated infected hamsters were again trained in the MWM. Spatial memory was evaluated 48 h after this training in which the hamsters searched for the location where a submerged escape platform had been positioned. Only 56% of infected hamsters treated with saline spent more time in the correct quadrant than the other three quadrants, as compared to 92% of MGAWN1-treated hamsters (P?0.05). Overall these studies support the possibility that WNV can cause spatial memory impairment and that therapeutic intervention may be considered. PMID- 21554904 TI - Cardioprotection by ischemic postconditioning is lost in isolated perfused heart from diabetic rats: Involvement of transient receptor potential vanilloid 1, calcitonin gene-related peptide and substance P. AB - We previously found that the expression of transient receptor potential vanilloid 1 (TRPV1) and contents of calcitonin gene-related peptide (CGRP) and substance P (SP), two main neuropeptides released from TRPV1, were decreased in diabetic hearts. This study aimed to test whether decreased TRPV1, CGRP and SP levels were responsible for the loss of cardioprotection by ischemic postconditioning (IPostC) in isolated perfused heart from streptozotocin-induced diabetic rats. IPostC effectively protected non-diabetic hearts against ischemia/reperfusion injury by improving cardiac function and lowering creatine kinase (CK) and cardiac troponin I (cTnI) release, which could be abolished by inhibiting TRPV1, CGRP receptor or SP receptor. However, IPostC had no effect on cardiac function and the release of CK and cTnI in diabetic hearts regardless of whether TRPV1, CGRP receptor or SP receptor were inhibited. CGRP or SP-induced postconditioning significantly prevented both non-diabetic and diabetic hearts from ischemia/reperfusion injury by improving cardiac function and lowering CK and cTnI release. Additionally, IPostC markedly increased CGRP and SP release in non diabetic hearts, which could be reversed with TRPV1 inhibition, but not CGRP receptor or SP receptor inhibition. However, IPostC failed to affect CGRP and SP release in diabetic hearts in the presence or absence of TRPV1, CGRP receptor or SP receptor inhibition. These results indicate that the loss of cardioprotection by IPostC during diabetes is partly associated with a failure to increase CGRP and SP release, likely due to decreased TRPV1 expression and CGRP and SP contents in diabetic hearts. PMID- 21554905 TI - A simplified touch tape preparation from tube cultures for microscopic examination of filamentous fungi. AB - Cellophane touch tape preparation provides reproducible results in minimal time when compared to tease mount and slide culture techniques for the identification of fungi from culture plates, but it is difficult to perform from tube cultures. Here, we describe an easy to perform touch tape preparation method that provided a better result from fungal tube culture. PMID- 21554906 TI - Efficient implementation of RNA interference in the pathogenic yeast Cryptococcus neoformans. AB - An improved method has been developed for RNA interference in Cryptococcus neoformans, using opposing promoters to facilitate cloning and RNA interference targeting URA5 to allow selection of cells in which silencing is most effective. These advances significantly reduce the variability of silencing and the effort required for interference plasmid construction. PMID- 21554907 TI - Focus. PMID- 21554908 TI - Layer-by-layer capsules for magnetic resonance imaging and drug delivery. AB - Layer-by-layer (LbL) self-assembled polyelectrolyte capsules have demonstrated their unique advantages and capability in drug delivery applications. These ordered micro/nano-structures are also promising candidates as imaging contrast agents for diagnostic and theranostic applications. Magnetic resonance imaging (MRI), one of the most powerful clinical imaging modalities, is moving forward to the molecular imaging field and requires the availability of advanced imaging probes. In this review, we are focusing on the design of MRI visible LbL capsules, which incorporate either paramagnetic metal-ligand complexes or superparamagnetic iron oxide (SPIO) nanoparticles. The design criteria cover the topics of probe sensitivity, biosafety, long-circulation property, targeting ligand decoration, and drug loading strategies. Examples of MRI visible LbL capsules with paramagnetic or superparamagnetic moieties were given and discussed. This carrier platform can also be chosen for other imaging modalities. PMID- 21554909 TI - Front-of-pack nutrition labels. Their effect on attention and choices when consumers have varying goals and time constraints. AB - Although front-of-pack nutrition labeling can help consumers make healthier food choices, lack of attention to these labels limits their effectiveness. This study examines consumer attention to and use of three different nutrition labeling schemes (logo, multiple traffic-light label, and nutrition table) when they face different goals and resource constraints. To understand attention and processing of labels, various measures are used including self-reported use, recognition, and eye-tracking measures. Results of two experiments in different countries show that although consumers evaluate the nutrition table most positively, it receives little attention and does not stimulate healthy choices. Traffic-light labels and especially logos enhance healthy product choice, even when consumers are put under time pressure. Additionally, health goals of consumers increase attention to and use of nutrition labels, especially when these health goals concern specific nutrients. PMID- 21554910 TI - A cafeteria-based tasting program increased liking of fruits and vegetables by lower, middle and upper elementary school-age children. AB - This study aimed to increase 1st, 3rd, and 5th grade children's liking for fruits and vegetables by offering repeated opportunities to taste selected items. Tastes of four fruits or four vegetables were offered to children (51% boys; 32% 1st graders and 34% 3rd graders) on alternate weeks for 8 weeks. Two-week follow-up tastings occurred 4 months and 10 months post-intervention. Children who began the program disliking the targeted fruits and vegetables improved liking for all items after 8 weeks and maintained higher scores at both follow-up assessments. Grade and gender differences in liking were observed but were not consistent at each time point. PMID- 21554911 TI - Time-dependent changes in the serum levels of prolactin, nesfatin-1 and ghrelin as a marker of epileptic attacks young male patients. AB - A relationship between hormones and seizures has been reported in animals and humans. Therefore, the purpose of this study was to investigate the association between serum levels of prolactin, nesfatin-1 and ghrelin measured different times after a seizure or non-epileptic event and compared with controls. The study included a total of 70 subjects, and of whom 18 patients had secondary generalized epilepsy (SGE), 16 patients had primary generalized epilepsy (PGE), 16 patients exhibited paroxysmal event (psychogenic) and 20 healthy males were control subjects. The first sample was taken within 5min of a seizure, with further samples taken after 1, 24, and 48h so long as the patient did not exhibit further clinically observable seizures; blood samples were taken once from control subjects. Prolactin was measured immediately using TOSOH Bioscience hormone assays. Nesfatin-1 and ghrelin peptides were measured using a commercial immunoassay kit. Patients suffering from focal epilepsy with secondary generalization and primary generalized epilepsy presented with significantly higher levels of serum prolactin and nesfatin-1 and lower ghrelin levels 5min, 1 and 24h after a seizure than patients presenting with paroxysmal events (psychogenic) and control subjects; the data were similar but not statistically significant after 48h. The present study suggests that increased serum prolactin and nesfatin-1 concentrations, decreased ghrelin concentrations could be used as markers to identify patients that have suffered a recent epileptic seizure or other paroxysmal event (psychogenic). PMID- 21554912 TI - Targeting of HIV-p24 particle-based vaccine into differential skin layers induces distinct arms of the immune responses. AB - Skin routes of immunization such as subcutaneous (SC), intradermal (ID) and transcutaneous (TC) administration are utilized for vaccination against various pathogens, without understanding their potential impact on the outcome of immune responses. We demonstrated that SC immunization induced HIV-1 p24 specific IgG in absence of antigen-specific CD8 T cells, whereas the ID route induced both cellular and humoral responses. Interestingly, TC application through empty hair follicular ducts, targeting epidermal Langerhans Cells (LCs), induced major CD8 effector cells, in the absence of IgG. However, high levels of mucosal IgA, were localized in the stratified epithelium of the vagina after TC prime. We propose that re-directing the immune responses by targeting differential skin immunization routes, offers enormous potential for innovative vaccination strategies, especially against HIV. PMID- 21554913 TI - Characterization of antigenic regions in the porcine reproductive and respiratory syndrome virus by the use of peptide-specific serum antibodies. AB - The porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus that causes reproductive failure in sows and boars, and respiratory disease in pigs of all ages. Antibodies against several viral envelope proteins are produced upon infection, and the glycoproteins GP4 and GP5 are known targets for virus neutralization. Still, substantial evidence points to the presence of more, yet unidentified neutralizing antibody targets in the PRRSV envelope proteins. The current study aimed to identify and characterize linear antigenic regions (ARs) within the entire set of envelope proteins of the European prototype PRRSV strain Lelystad virus (LV). Seventeen LV-specific antisera were tested in pepscan analysis on GP2, E, GP3, GP4, GP5 and M, resulting in the identification of twenty-one ARs that are capable of inducing antibodies upon infection in pigs. A considerable number of these ARs correspond to previously described epitopes in different European- and North-American-type PRRSV strains. Remarkably, the largest number of ARs was found in GP3, and two ARs in the GP3 ectodomain consistently induced antibodies in a majority of infected pigs. In contrast, all remaining ARs, except for a highly immunogenic epitope in GP4, were only recognized by one or a few infected animals. Sensitivity to antibody-mediated neutralization was tested for a selected number of ARs by in vitro virus neutralization tests on alveolar macrophages with peptide-purified antibodies. In addition to the known neutralizing epitope in GP4, two ARs in GP2 and one in GP3 turned out to be targets for virus-neutralizing antibodies. No virus-neutralizing antibody targets were found in E, GP5 or M. Since the neutralizing AR in GP3 induced antibodies in a majority of infected pigs, the immunogenicity of this AR was studied more extensively, and it was demonstrated that the corresponding region in GP3 of virus strains other than LV also induces virus-neutralizing antibodies. This study provides new insights into PRRSV antigenicity, and contributes to the knowledge on protective immunity and immune evasion strategies of the virus. PMID- 21554914 TI - Immune responses in Atlantic salmon (Salmo salar) following protective vaccination against infectious salmon anemia (ISA) and subsequent ISA virus infection. AB - Infectious salmon anemia (ISA) is an orthomyxoviral disease that has had devastating effects on farmed Atlantic salmon. ISA is still a disease resulting in continued loss of revenues and therefore development of effective vaccines is of great importance. Commercial vaccines against ISA are available, but the efficacy is poorly described. There is little information about vaccine-induced immune factors preventing ISA virus (ISAV) infection today. In this study we assessed the protective effects and immunogenicity of vaccines containing three different quantities of the inactivated ISAV antigen. Our findings indicated that immunization induced effective protection in Atlantic salmon with a relative percent survival (RPS) as high as 86. The level of protection was correlated to the amount of ISAV antigen in the vaccine, and fish immunized with high antigen amounts produced detectable ISAV-specific and neutralizing antibodies. While ISAV infection was detectable in non-vaccinated control fish challenged by cohabitation, no infection was detected in fish immunized with high antigen amounts. After challenge, transcriptional analysis of selected immune-related genes demonstrated activation of innate immune responses in ISAV-infected control fish, but not in vaccine protected fish. This study furthers the knowledge about vaccine efficacy and vaccine-induced immunity to ISAV challenge in Atlantic salmon. PMID- 21554915 TI - Immunological priming induced by a two-dose series of H5N1 influenza antigen, administered alone or in combination with two different formulations of AS03 adjuvant in adults: results of a randomised single heterologous booster dose study at 15 months. AB - One influenza pandemic preparedness strategy involves priming a population with a pre-pandemic subtype-specific vaccine and boosting the immunological response at the time of the pandemic with a strain-matched vaccine. In the current study, adults (n=469) randomised 15 months previously to receive an A/Indonesia/5/2005 (H5N1) influenza vaccine (3.75 MUg haemagglutinin antigen [HA]) administered alone or in combination with an oil-in-water emulsion based Adjuvant System containing 11.86 mg (AS03(A)) or 5.93 mg (AS03(B)) tocopherol per dose, received one booster dose of A/turkey/Turkey/1/2005 (H5N1) vaccine (3.75 MUg HA) with or without AS03(A). An anamnestic antibody response that met US regulatory acceptance criteria was observed 15 months after priming. Although superior immunogenicity of AS03-adjuvanted compared to unadjuvanted priming was not demonstrated, higher antibody titres which persisted longer were seen when both priming and boosting regimens were adjuvanted. This may affect duration of response or heterologous immunity. The booster vaccines had a clinically acceptable safety/reactogenicity profile after adjuvanted or unadjuvanted priming. This study has been registered at www.clinicaltrials.gov NCT00771615. PMID- 21554916 TI - Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors. AB - Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP+/MPP+) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (beta-carboline), 9-methylnorharman (9-methyl-beta-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP+/MPP+, in human mitochondria (IC50 of 0.18, 3.1, 9.9, 7.3, and 12.6 MUM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC50 of 0.15 MUM), a known neuroprotectant. The naturally-occurring beta-carbolines, harmine, harmaline and tetrahydro-beta-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5 nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC50 of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9 methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species. PMID- 21554917 TI - E. coli Lipopolysaccharide: acute oral toxicity study in mice. AB - A single dose of endotoxin (lipopolysaccharide) from a common laboratory cloning and expression strain (Escherichia coli BL21[DE3]) was administered to groups of male and female CD-1 mice (n=5/group) at doses up to 1,000,000 endotoxin units (EU) per mouse by oral gavage. The mice were observed for mortality, body weight effects, and clinical signs for 14 days after which they were sacrificed for gross organ necropsy. All mice survived until the scheduled sacrifice, no clinical signs of toxicity were observed, no test substance-related body weight losses occurred and no gross lesions were present at necropsy. Under the conditions of this study, oral administration of E. coli BL21(DE3) endotoxin to mice at a dose of up to 1,000,000 EU/mouse produced no evidence of toxicity. PMID- 21554918 TI - Eupatilin, a dietary flavonoid, induces G2/M cell cycle arrest in human endometrial cancer cells. AB - This study is the first to investigate the antiproliferative effect of eupatilin in human endometrial cancer cells. Eupatilin, a naturally occurring flavonoid isolated from Artemisia princeps, has anti-inflammatory, anti-oxidative, and anti tumor activities. In the present study, we investigated the potential effect of eupatilin on cell growth and its molecular mechanism of action in human endometrial cancer cells. Eupatilin was more potent than cisplatin in inhibiting cell viability in the human endometrial cancer cell lines Hec1A and KLE. Eupatilin showed relatively low cytotoxicity in normal human endometrial cells HES and HESC cells when compared to cisplatin. Eupatilin induced G2/M phase cell cycle arrest in a time- and dose-dependent manner, as indicated by flow cytometry analysis. In addition, treatment of Hec1A cells with eupatilin resulted in a significant increase in the expression of p21(WAF1/CIP1) and in the phosphorylation of Cdc25C and Cdc2. Knockdown of p21 using specific siRNAs significantly compromised eupatilin-induced cell growth inhibition. Interestingly, levels of mutant p53 in Hec1A cells decreased markedly upon treatment with eupatilin, and p53 siRNA significantly increased p21 expression. Moreover, eupatilin modulated the phosphorylation of protein kinases ERK1/2, Akt, ATM, and Chk2. These results suggest that eupatilin inhibits the growth of human endometrial cancer cells via G2/M phase cell cycle arrest through the up regulation of p21 by the inhibition of mutant p53 and the activation of the ATM/Chk2/Cdc25C/Cdc2 checkpoint pathway. PMID- 21554919 TI - Dietary fluoride intake from infant and toddler formulas in Poland. AB - Risk of enamel fluorosis associated with excessive fluoride intake during infancy and early childhood has been widely reported in literature. Results of several studies indicate that infant formula consumption, especially in the form of powdered concentrate, may appreciably increase children's fluoride exposure in optimally fluoridated communities. The aim of the study was to measure fluoride content of infant and toddler formulas available in Poland and to discuss implications of the results. Twenty nine brands of powdered formulas were evaluated. Analyzes were performed with the use of ionselective fluoride electrode (09-37 type) and a RAE 111 chloride-silver reference electrode (MARAT). Results revealed that concentration of fluoride in all products was low (mean 29.0 MUg/100 g), and that the formula itself is not a significant source of fluoride exposure. However, when reconstituted with water containing more than 0.5 ppm of fluoride, starting formulas and follow-on formulas may provide a daily fluoride intake of above the suggested threshold for fluorosis. Thus, fully formula-fed infants consuming mother milk substitutes prepared with optimally fluoridated water may be at increased risk of dental fluorosis. PMID- 21554920 TI - Clinical study of indirect composite resin inlays in posterior stress-bearing cavities placed by dental students: results after 4 years. AB - OBJECTIVES: This longitudinal randomized controlled clinical trial evaluated the longevity of composite resin inlays in single- or multi-surface cavities up to 4 years. METHODS: 21 dental students placed 75 Artglass and 80 Charisma composite resin inlays in class I and II cavities in posterior teeth (89 adult patients) luted with dual-curing resin cements. Clinical evaluation was performed up to 4 years using modified USPHS criteria. RESULTS: 87.2% of Artglass and 76.6% of Charisma inlays were assessed to be clinically excellent or acceptable. Up to the 4-year recall 5 Artglass and 11 Charisma inlays failed mainly because of postoperative symptoms, bulk fracture, and loss of marginal integrity. No significant differences between both composite resin materials could be detected at 4 years for all clinical criteria (Mann-Whitney U-test, p>0.05). The comparison of restoration performance with time yielded a significant increase in marginal discolouration and postoperative symptoms (p<0.05), deterioration of surface texture quality, marginal and restoration integrity (p<0.05) for both inlay systems. However, the changes were mainly effects of scoring shifts from alfa to bravo. Small inlays compared to large inlays and premolar restorations compared to molar restorations showed significant better outcome for some of the tested clinical parameters for the Artglass inlays (p<0.05). For Charisma inlays no such influences were revealed. CONCLUSIONS: Clinical assessment of Artglass and Charisma composite resin inlays exhibited an annual failure rate of 3.2% and 5.9% that is within the range of published data. Within the limitations of this study indirect composite inlays are a competitive restorative procedure in stress bearing preparations. PMID- 21554921 TI - MMP-2 assay within the hybrid layer created by a two-step etch-and-rinse adhesive: biochemical and immunohistochemical analysis. AB - OBJECTIVE: Degradation of hybrid layers (HLs) within resin-infiltrated dentine results from multiple degradation factors, including collagenolytic activity of specific matrix metalloproteinases (MMPs). Inhibition of host-derived MMPs may, therefore, slow the degradation of HL. The null hypothesis tested is that the presence of MMP-2 is similar regardless of chlorhexidine (CHX) pre-treatment or the use of an adhesive. METHODS: Powdered dentine prepared from extracted human teeth was divided into 4 groups: (G1) mineralised powder (control group); (G2) dentine powder treated with 1% phosphoric acid for 1 min; (G3) 1% phosphoric acid etched dentine treated with Adper Scotchbond 1 XT (SB1XT; 3M ESPE); (G4) 1% phosphoric acid-etched dentine treated with 0.2% CHX followed by SB1XT. The concentration of detectable pro-MMP-2 and MMP-2 was assayed using a colorimetric assay system (QuantiSir). In addition, the presence of MMP-2 in the HL was assessed in 1 year-aged adhesive-dentine interfaces using an immunohistochemical approach under FEI-SEM/TEM. RESULTS: In dentine powder treated with 1% phosphoric acid (G2), MMP-2 level decreased compared to controls (G1); the application of SB1XT (G3) resulted in an increase of MMP-2, whilst 0.2% CHX before SB1XT application (G4), reduced MMP-2. The FEI-SEM/TEM analysis revealed MMP-2 distribution within the HL of aged interfaces showing increase MMP-2 patterns in the control group and minor labelling in the CHX-pretreated specimens. CONCLUSION: The results of this study support the use of non-toxic MMPs inhibitors, such as CHX, as an appropriate additional step in bonding procedures in order to increase the longevity of the adhesive restorations. PMID- 21554922 TI - p21Waf1 is required for complete oncogenic transformation of mouse embryo fibroblasts by E1Aad5 and c-Ha-ras oncogenes. AB - Cyclin-dependent kinase inhibitor p21(Waf1) is known to have alternative functions associated with positive regulation of proliferation, actin cytoskeleton remodeling and suppression of apoptosis. The goal of the present study was to assess the role of p21(Waf1) in the establishment of the transformed phenotype of mouse embryo fibroblasts with stable expression of E1Aad5 and c-Ha ras complementary oncogenes. Herein, we demonstrate that E1A/c-Ha-Ras-transformed p21(Waf1)-null fibroblasts possess some characteristic features of transformed cells, such as loss of contact inhibition, high saturation density, shortened cell cycle, inability to undergo cell-cycle arrest after DNA damage and serum deprivation, but, at the same time, they are not completely transformed in that they are unable to proliferate at clonal density, are anchorage-dependent, retain a fibroblast-like morphology with pronounced actin cytoskeleton and show reduced migration and invasion. Our data support the concept of p21(Waf1) "tumor suppressor" having alternative oncogenic functions in the cytoplasm and for the first time indicate that p21(Waf1) can be indispensable for complete oncogenic transformation. PMID- 21554924 TI - Gene environment interactions with a novel variable Monoamine Oxidase A transcriptional enhancer are associated with antisocial personality disorder. AB - Monoamine Oxidase A (MAOA) is a critical enzyme in the catabolism of monoaminergic neurotransmitters. MAOA transcriptional activity is thought to be regulated by a well characterized 30 base pair (bp) variable nucleotide repeat (VNTR) that lies approximately ~1000 bp upstream of the transcriptional start site (TSS). However, clinical associations between this VNTR genotype and behavioral states have been inconsistent. Herein, we describe a second, 10 bp VNTR that lies ~1500 bp upstream of the TSS. We provide in vitro and in silico evidence that this new VNTR region may be more influential in regulating MAOA transcription than the more proximal VNTR and that methylation of this CpG-rich VNTR is genotype dependent in females. Finally, we demonstrate that genotype at this new VNTR interacts significantly with history of child abuse to predict antisocial personality disorder (ASPD) in women and accounts for variance in addition to that explained by the prior VNTR. PMID- 21554925 TI - T cells expressing the activating NK-cell receptors KIR2DS4, NKG2C and NKG2D are elevated in paroxysmal nocturnal hemoglobinuria and cytotoxic toward hematopoietic progenitor cell lines. AB - OBJECTIVE: To investigate the presence of T cells with natural killer cell receptors (NKR) in paroxysmal nocturnal hemoglobinuria (PNH), and their potential involvement in clonal expansion of glycosylphosphatidylinositol (GPI)-deficient hematopoietic stem cells by selective immune attack to normal and not GPI deficient hematopoietic stem cells. MATERIALS AND METHODS: By flow cytometry, the frequency and number of T cells expressing NKR was evaluated in 39 PNH patients and compared to healthy controls. Elevated T cell subsets in PNH were assessed for differential cytotoxic lysis of GPI(+) and GPI(-) CD34(+) hematopoietic progenitor cell lines. RESULTS: In PNH patients, the frequency (p < 0.001) and absolute number of T cells expressing the NKR CD56 (p = 0.01) were significantly increased. Furthermore, a higher percentage of T cells expressed the activating NKR NKG2D (p < 0.01), NKG2C (p < 0.01), and KIR2DS4 (p = 0.01). Further characterization showed that these populations predominantly consist of CD8(+) effector memory CD45RA(+) T cells (T(EMRA)). NKR(+) cytotoxic T-lymphocyte lines isolated from PNH patient peripheral blood and bone marrow displayed high cytotoxicity towards CD34(+) hematopoietic progenitor cell lines and K562 cells, suggesting major histocompatibility complex class I-independent cytotoxicity. These cytotoxic T lymphocyte (CTL) lines are capable of differential lysis of GPI(+) and GPI(-) hematopoietic cell lines, however, not in all cases. This suggests that multiple factors, such as the highly activated status of in vitro cultured CTLs, influence whether GPI-dependent lysis occurs. CONCLUSIONS: The increased frequency of CD8(+) effector-memory T cells with activating NKR and cytotoxicity toward hematopoietic cell lines suggests involvement in bone marrow failure and clonal expansion in PNH. PMID- 21554923 TI - Biomarkers in frontotemporal lobar degenerations--progress and challenges. AB - Neuronal and glial changes associated with tau, TAR DNA binding protein of ~43 kDa (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice. PMID- 21554926 TI - Tools-4-Metatool (T4M): online suite of web-tools to process stoichiometric network analysis data from Metatool. AB - Tools-4-Metatool (T4M) is a suite of web-tools, implemented in PERL, which analyses, parses, and manipulates files related to Metatool. Its main goal is to assist the work with Metatool. T4M has two major sets of tools: Analysis and Compare. Analysis visualizes the results of Metatool (convex basis, elementary flux modes, and enzyme subsets) and facilitates the study of metabolic networks. It is composed of five tools: MDigraph, MetaMatrix, CBGraph, EMGraph, and SortEM. Compare was developed to compare different Metatool results from different networks. This set consists of: Compara and ComparaSub which compare network subsets providing outputs in different formats and ComparaEM that seeks for identical elementary modes in two metabolic networks. The suite T4M also includes one script that generates Metatool input: CBasis2Metatool, based on a Metatool output file that is filtered by a list of convex basis' metabolites. Finally, the utility CheckMIn checks the consistency of the Metatool input file. T4M is available at http://solea.quim.ucm.es/t4m. PMID- 21554927 TI - A conserved isoleucine in the LOV1 domain of a novel phototropin from the marine alga Ostreococcus tauri modulates the dark state recovery of the domain. AB - BACKGROUND: Phototropins are UV-A/blue light receptor proteins with two LOV (Light-Oxygen-Voltage) sensor domains at their N terminus and a kinase domain at the C-terminus in photoautotrophic organisms. This is the first research report of a canonical phototropin from marine algae Ostreococcus tauri. METHODS: We synthesized core LOV1 (OtLOV1) domain-encoding portion of the phototropin gene of O. tauri, the domain was heterologously expressed, purified and assessed for its spectral properties and dark recovery kinetics by UV-Visible, fluorescence spectroscopy and mutational studies. Quaternary structure characteristics were studied by SEC and glutaraldehyde crosslinking. RESULTS: The absorption spectrum of OtLOV1 lacks the characteristic 361nm peak shown by other LOV1 domains. It undergoes a photocycle with a dark state recovery time of approximately 30min (tau=300.35s). Native OtLOV1 stayed as dimer in aqueous solution and the dimer formation was light and concentration independent. Mutating isoleucine at 43rd position to valine accelerated the dark recovery time by more than 10-fold. Mutating it to serine reduced sensitivity to blue light, but the dark recovery time remained unaltered. I43S mutation also destabilized the FMN binding to a great extent. CONCLUSION: The OtLOV1 domain of the newly identified OtPhot is functional and the isoleucine at position 43 of OtLOV1 is the key residue responsible for fine-tuning the domain properties. GENERAL SIGNIFICANCE: This is the first characterized LOV1 domain of a canonical phototropin from a marine alga and spectral properties of the domain are similar to that of the LOV1 domain of higher plants. PMID- 21554928 TI - Brazilian propolis-derived components inhibit TNF-alpha-mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. AB - BACKGROUND: Previous reports suggest that Brazilian propolis has multiple biological functions and may help to restore adiponectin expression and insulin sensitivity. However, little is known about the molecular mechanisms by which these compounds inhibit the downregulation of adiponectin. METHODS: The effect of various Brazilian propolis-derived components on inhibition of tumor necrosis factor-alpha (TNF-alpha)-mediated downregulation of adiponectin expression in 3T3 L1 adipocytes and molecular mechanism was investigated. RESULTS AND CONCLUSIONS: Pretreatment with either artepillin C (C3) or its derivative (C4) significantly inhibited TNF-alpha-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes. Interestingly, C3 strongly activated peroxisome proliferator activated receptor gamma (PPARgamma) transcriptional activity. Treatment of adipocytes with C3 resulted in the upregulation of adiponectin and fatty acid binding protein 4 expression, but C4 did not significantly induce PPARgamma transactivation. C4 did, however, inhibit the TNF-alpha-induced c-Jun-NH(2) terminal kinase (JNK) signaling that is involved in adiponectin expression. Molecular docking studies based on hPPARgamma with C3 and JNK1 with C4 clearly supported our experimental results. These data demonstrate that 1) both C3 and C4 significantly inhibit the TNF-alpha-mediated downregulation of adiponectin in adipocytes, 2) C3 functions as a PPARgamma agonist, and its inhibition of the effect of TNF-alpha is due to this PPARgamma transactivation, and 3) C4 is an effective inhibitor of JNK activation, thus inhibiting the TNF-alpha-mediated downregulation of adiponectin. GENERAL SIGNIFICANCE: Brazilian propolis-derived components (C3 and C4) can significantly inhibit TNF-alpha-mediated downregulation of adiponectin in adipocytes, although they do so via different mechanisms. PMID- 21554929 TI - Ganglioside GD1a negatively regulates hepatocyte growth factor expression through caveolin-1 at the transcriptional level in murine osteosarcoma cells. AB - BACKGROUND: Hepatocyte growth factor (HGF) is a mesenchyme-derived, multifunctional protein that is implicated in tumor growth and invasive behavior. Some tumor cells express both HGF and its receptor MET, forming an autocrine loop that permanently activates it. Ganglioside GD1a suppresses metastatic capacity in murine FBJ osteosarcoma cells and MET phosphorylation activated by HGF binding, but the signaling pathway controlling HGF production has not been fully explored. METHODS: Expression of HGF, caveolins, or MET of the cells that had been transfected with siRNA or cDNA directed to GM2/GD2 synthase, caveolin-1 or HGF was determined by semi-quantitative RT-PCR and Western blots. RESULTS: HGF expression in highly metastatic, GD1a-deficient FBJ-LL cells was higher than that in the poorly metastatic, GD1a-rich FBJ-S1 cells. Transfection with GM2/GD2 synthase cDNA increased GD1a levels in FBJ-LL cells and suppressed HGF expression. Treatment with siRNAs directed toward GM2/GD2 synthase in FBJ-S1 cells reduced gangliosides and augmented HGF expression. GD1a was found to be the only ganglioside species suppressing HGF expression upon addition to FBJ-LL cells. HGF expression was decreased by GD1a addition to FBJ-LL cells after 48h, enough to induce caveolin-1 expression. Silencing caveolin-1 up-regulated HGF, and the re-introduction of caveolin-1 cDNA decreased HGF expression. Caveolin-1 suppressed MET phosphorylation. We also found GD1a regulation of HGF in Lewis lung carcinoma cells. CONCLUSIONS: HGF expression was negatively regulated by GD1a through caveolin-1 at the transcriptional level via the suppression of MET phosphorylation. GENERAL SIGNIFICANCE: This is the first report that ganglioside GD1a negatively regulates HGF expression through caveolin-1. PMID- 21554930 TI - Selective constraints in yeast genes with differential expressivity: codon pair usage and mRNA stability perspectives. AB - Protein translation has been elucidated to be dictated by evolutionary constraints, namely, variations in tRNA availabilities and/or variations in codon anticodon binding that is manifested in biased codon usage. Taking advantage of publicly available mRNA expression and protein abundance data for Saccharomyces cerevisiae, we have performed a comprehensive analysis of the diverse factors guiding translation leading to desired protein levels irrespective of the corresponding high or low mRNA levels. It has been elucidated in this study that different combinations of most abundant/non abundant tRNA isoacceptors are selected for in S. cerevisiae that helps in achieving the optimum speed and accuracy in the protein translation process. This is also accompanied by the strategic location of codon pairs in coherence to mRNA secondary structure folding stability for the above mentioned combinations of tRNA isoacceptors. We thus find that codon pair contextual effects; in addition to tRNA abundance and mRNA folding stability during translation elongation process play plausible roles in maintaining translation accuracy and speed that can achieve desired protein levels. PMID- 21554931 TI - Fluoxetine induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats. AB - Fluoxetine (FLX) is a drug commonly used as antidepressant. However, its effects on tumorigenesis remain controversial. Aiming to evaluate the effects of FLX treatment on early malignant changes, we analyzed serotonin (5-HT) metabolism and recognition, aberrant crypt foci (ACF), proliferative process, microvessels, vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) expression in colon tissue. Male Wistar rats received a daily FLX-gavage (30mgkg( 1)) and, a single dose of 1,2 dimethylhydrazine (DMH; i.p., 125mgkg(-1)). After 6 weeks of FLX-treatment, our results revealed that FLX and nor-fluoxetine (N-FLX) are present in colon tissue, which was related to significant increase in serotonin (5-HT) levels (P<0.05) possibly through a blockade in SERT mRNA (serotonin reuptake transporter; P<0.05) resulting in lower 5-hydroxyindoleacetic acid (5-HIAA) levels (P<0.01) and, 5-HT2C receptor mRNA expressions. FLX treatment decreased dysplastic ACF development (P<0.01) and proliferative process (P<0.001) in epithelia. We observed a significant decrease in the development of malignant microvessels (P<0.05), VEGF (P<0.001), and COX-2 expression (P<0.01). These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue, probably due to its modulatory activity on 5-HT metabolism and/or its ability to reduce colonic malignant events. PMID- 21554932 TI - In vitro study of intestinal transport of arsenite, monomethylarsonous acid, and dimethylarsinous acid by Caco-2 cell line. AB - Arsenic is a pollutant widely distributed in the environment. There are numerous studies on the toxicity of trivalent arsenic forms As(III), MMA(III), and DMA(III), but few data are available on the processes of digestion and absorption of these arsenic species and the mechanisms involved are unknown. The present study evaluated the processes involved in intestinal absorption of trivalent arsenic species, using the Caco-2 cell model as system. The apparent permeability values obtained for As(III) in apical-basolateral direction (4.6+/-0.3)*10( 6)cm/s, showing moderate intestinal absorption. Transport of MMA(III) [P(app)=(7.0+/-0.9)*10(-6)cm/s] and DMA(III) [P(app)=(10.6+/-1.4)*10(-6)cm/s] is greater than that of As(III). The cellular retention of As(III) (0.9-2.4%) was less than that observed for MMA(III) (30%) and DMA(III) (35%). A substantial paracellular component was observed in transport of As(III) and MMA(III), whereas DMA(III) does not use this pathway for its absorption. For all the trivalent species, transport depends on temperature, with an active transcellular component for MMA(III) and DMA(III). Variations in pH do not affect transport of these species. The presence of GSH and green tea extract significantly alters transport of As(III) across Caco-2 cells. PMID- 21554933 TI - Non-enzymatic pretreatment of nerve agent (soman) poisoning: a brief state-of-the art review. AB - The rapid onset of toxic signs following nerve agent intoxication and the apprehension that current therapy (atropine, oxime, diazepam) may not prevent brain damage, requires supportive pretreatment. Since the current pretreatment drug pyridostigmine fails in protecting brain-AChE, more effective pretreatment is necessary. A main focus of present-day pretreatment research is on bioscavengers, another is on centrally active reversible AChE-inhibitors combined with drugs showing anti-cholinergic, anti-glutamatergic, neuroprotective and non sedating GABA-ergic activity. Strategies aimed at improving efficacy of pharmacological pretreatment will briefly be discussed. Galantamine, given as a pretreatment or stand-alone therapy, emerged as one of the best medical countermeasures against nerve agent poisoning in guinea pigs. Other preclinical studies demonstrated effective pretreatment consisting of physostigmine combined with procyclidine, scopolamine or bupropion (all single injections), against nerve agent poisoning in guinea pigs. A long sign-free pretreatment with physostigmine (Alzet pump), combined with single injection of procyclidine just before soman poisoning, enhanced the efficacy of a post-poisoning therapy consisting of 3 autoinjector equivalents of HI-6, atropine and diazepam, considerably. PMID- 21554934 TI - Aristolochic acid I and ochratoxin A differentially regulate VEGF expression in porcine kidney epithelial cells--the involvement of SP-1 and HIFs transcription factors. AB - Aristolochic acid I (AAI) and ochratoxin A (OTA) cause chronic kidney diseases. Recently, the contribution of hypoxic injuries and angiogenic disturbances to nephropathies has been suggested, but underlying mechanisms have not been fully clarified yet. In porcine kidney epithelial cell line, LLC-PK1 cells, treatment with non-toxic doses of AAI increased whereas with OTA decreased production of vascular endothelial growth factor (VEGF), the angiogenic factor with well defined functions in kidney. Moreover, the activity of transcription factors regulating VEGF expression was differentially affected by examined compounds. Activity of hypoxia inducible factors (HIFs) and SP-1 was increased by AAI but diminished by OTA. Interestingly, AP-1 activity was inhibited while NFkappaB was not influenced by both toxins. Mithramycin A, a SP-1 inhibitor, as well as chetomin, an inhibitor of HIFs, reversed AAI-induced up-regulation of VEGF synthesis, indicating the importance of SP-1 and HIFs in this effect. Additionally, adenoviral overexpression of HIF-2alpha but not HIF-1alpha prevented OTA-diminished VEGF production suggesting the protective effect of this isoform towards the consequences exerted by OTA. These observations provide new insight into complex impact of AAI and OTA on angiogenic gene regulation. Additionally, it adds to our understanding of hypoxia influence on nephropathies pathology. PMID- 21554935 TI - Ferrociphenol lipid nanocapsule delivery by mesenchymal stromal cells in brain tumor therapy. AB - The prognosis of patients with malignant glioma remains extremely poor despite surgery and improvements in radio- and chemo-therapies. Thus, treatment strategies that specifically target these tumors have the potential to greatly improve therapeutic outcomes. "Marrow-isolated adult multilineage inducible" cells (MIAMI cells) are a subpopulation of mesenchymal stromal cells (MSCs) which possess the ability to migrate to brain tumors. We have previously shown that MIAMI cells were able to efficiently incorporate lipid nanocapsules (LNCs) without altering either their stem cell properties or their migration capacity. In this study, we assessed whether the cytotoxic effects of MIAMI cells loaded with LNCs containing an organometallic complex (ferrociphenol or Fc-diOH) could be used to treat brain tumors. The results showed that MIAMI cells internalized Fc-diOH-LNCs and that this internalization did not induce MIAMI cell death. Furthermore, Fc-diOH-LNC-loaded MIAMI cells produced a cytotoxic effect on U87MG glioma cells in vitro. This cytotoxic effect was validated in vivo after intratumoral injection of Fc-diOH-LNC-loaded MIAMI cells in a heterotopic U87MG glioma model in nude mice. These promising results open up a new field of treatment in which cellular vehicles and nanoparticles can be combined to treat brain tumors. PMID- 21554936 TI - Production of monodisperse epigallocatechin gallate (EGCG) microparticles by spray drying for high antioxidant activity retention. AB - Epigallocatechin gallate (EGCG) originated from green tea is well-known for its pharmaceutical potential and antiproliferating effect on carcinoma cells. For drug delivery, EGCG in a micro-/nanoparticle form is desirable for their optimized chemopreventive effect. In this study, first time reports that EGCG microparticles produced by low temperature spray drying can maintain high antioxidant activity. A monodisperse droplet generation system was used to realize the production of EGCG microparticles. EGCG microparticles were obtained with narrow size distribution and diameter of 30.24 +/- 1.88 MUM and 43.39 +/- 0.69 MUM for pure EGCG and lactose-added EGCG, respectively. The EC50 value (the amount of EGCG necessary to scavenge 50% of free radical in the medium) of spray dried pure EGCG particles obtained from different temperature is in the range of 3.029-3.075 MUM compared to untreated EGCG with EC50 value of 3.028 MUM. Varying the drying temperatures from 70 degrees C and 130 degrees C showed little detrimental effect on EGCG antioxidant activity. NMR spectrum demonstrated the EGCG did not undergo chemical structural change after spray drying. The major protective mechanism was considered to be: (1) the use of low temperature and (2) the heat loss from water evaporation that kept the particle temperature at low level. With further drier optimization, this monodisperse spray drying technique can be used as an efficient and economic approach to produce EGCG micro /nanoparticles. PMID- 21554937 TI - Smart gelation of chitosan solution in the presence of NaHCO3 for injectable drug delivery system. AB - In situ gelling systems are attractive as injectable vehicles for drug delivery. The present work described a novel gelation process of acidic chitosan solution in the presence of sodium bicarbonate (NaHCO(3)). The NaHCO(3) concentration played an important role in this gelling system. When it came within the appropriate range, the chitosan/NaHCO(3) system would stay at sol state in certain condition and showed sol-gel transition from the top to the bottom after heating. The rheological properties of the gelling system, as well as the morphology and erosion behavior of the formed chitosan hydrogels were evaluated as a function of the NaHCO(3) concentration in sols. The hydrogels showed porous morphologies with some diversification depending on the NaHCO(3) concentration, which also affected their erosion behaviors and drug release rates. Moreover, the gelation mechanism of such chitosan/NaHCO(3) system was studied and proposed as the formation of three-dimensional chitosan network with physical junctions thanks to the deprotonation of -NH(3)(+) in chitosan accompanying with the gradual neutralization between HCO(3)(-) and acid. In vivo gelation test was also performed by the dorsal subcutaneous injection of chitosan/NaHCO(3) solution in rat. The formation of in situ gels suggested such system promising applications in injectable drug delivery system. PMID- 21554938 TI - Single shot tetanus vaccine manufactured by a supercritical fluid encapsulation technology. AB - Single shot vaccines of tetanus toxoid (TT) were manufactured using the NanoMix process - a low temperature solvent free encapsulation technology using supercritical fluids. The formulations were injected into mice, and compared to multiple injections of a commercially available alum adsorbed TT vaccine. After 5 months the antibody titres were found to be similar for both the alum adsorbed and microparticle formulations, demonstrating for the first time the potential of formulating antigens in PLA microparticles using the supercritical fluid (NanoMix) technique to produce single shot vaccines. The results are likely to be due to the maintenance of toxoid bioactivity and some degree of sustained release of the encapsulated antigens, resulting in repeated stimulation of antigen presenting cells eliminating the need for multiple immunisations. This demonstrates the potential of this supercritical fluid processing technique to reduce the need for booster doses in a vaccine regimen. PMID- 21554939 TI - Use of remote film loading methodology to entrap sirolimus into liposomes: preparation, characterization and in vivo efficacy for treatment of restenosis. AB - The main objective of this study was to formulate an effective controlled-release liposomal drug delivery system for sirolimus (SIR), a potent antiproliferative and anti-inflammatory drug, to be used for the treatment of restenosis following local vascular delivery. Liposomes were prepared using remote film loading method and characterized with regard to entrapment efficiency (EE), size distribution and zeta potential. The effects of key formulation and proceeding variables on both EE and drug release were studied using a fractional factorial design. By means of this entrapment technique, 98% SIR incorporation was achieved. Nanoliposomes were found to have average size of 110 nm and zeta potential of -9 mV. Developed formulations were found to have prolonged drug release for up to 3 weeks in vitro; this was best fitted by the Higuchi model. Other scopes of this work were to determine the applicability of sirolimus-loaded nanoliposomes (SIR L) as drug carriers for the treatment of restenosis and to evaluate the effect of the presence of rigid lipids on the in vivo efficacy of the liposomal carrier of SIR. In vivo studies in balloon injured rat carotid arteries revealed the potential of SIR-loaded liposomes as efficient local and controlled drug delivery systems to reduce restenosis. PMID- 21554940 TI - First explanations for differences in electrotransfection efficiency in vitro and in vivo using spheroid model. AB - Electro-gene-therapy is a promising technique for cancer treatment. However, knowledge about mechanism of gene transfer with electric field in tumor is limited. Whereas in vitro electrotransfection is efficient, gene expression in tumoral cells in vivo is weak. To determine reasons for this difference and unravel gene transfer mechanisms, we propose to use multicellular tumor spheroid as a tridimensional model ex vivo. Comparison of efficiency between cell in suspension and cells in spheroid allow highlighting fundamental differences. For classical electrical conditions (consisting in 10 pulses of 500V/cm, 5ms, 1Hz), suspension cells present a transfection rate of 23.75%+/-2.450 SEM. In the same conditions on spheroid, although plasmid DNA coding GFP interact with half of electrically permeabilized cells, less than 1% of cells are expressing the transgene. First answers to in vivo electrotransfection failure are given: cell mortality due to electric field is responsible of this low transfection rate, as tridimensional and multicellular structure that prevents DNA passage. These results show that spheroid is reproducing in vivo situation. Validation of spheroid as a relevant model for electrotransfection study opens ex vivo optimization possibility before in vivo assay. PMID- 21554941 TI - Finite element analysis of the coupling between ossicular chain and mass loading for evaluation of implantable hearing device. AB - Finite element (FE) model is used to analyze the coupling effects between ossicular chain and transducer of implantable middle-ear hearing devices. The mass loading of the transducer is attached to the long process of the incus in the form of floating mass transducer (FMT) or applied near the incus-stapes joint by a magnet of contactless electromagnetic transducer (CLT). By changing placement of the transducer, crimping connection and damping parameter of the crimping mechanism, theoretical performances of the transducers were investigated on mechanical characteristics in two aspects: (1) displacement change at the stapes footplate, which describes the change in hearing due to placement of the transducer; (2) the equivalent pressure output of the transducer, which relates the footplate displacement driven by transducer to the sound pressure applied to a normal ear to produce that displacement. For the FMT with a less tight crimping connection or low supporting rigidity, a large drop of the sound-induced stapes displacement occurs at a specific frequency, with a peak reduction about 25.8 dB. A tight connection or high supporting rigidity shifts the drop of the stapes displacement to higher frequency. For the CLT, an electromagnetic transducer of 25 mg placed near the incus-stapes joint produces a maximum decrease of the stapes displacement around 16.5 dB. The equivalent sound pressure output and electromagnetic force requirement are proposed to produce the stapes displacement equivalent to that ear canal sound stimulus. The drop of the footplate displacement caused by mass loading effect can be recovered by the transducer stimulation over frequency range from 1500 Hz to 4000 Hz. The FE analysis reveals that enhancing the coupling stiffness between the clip and the ossicular chain is much helpful for maximizing the efficiency of the transducer stimulation. PMID- 21554943 TI - Expression of a collagenase that enables blood-brain barrier penetration for Salmonella implicated in bovine encephalopathies. AB - Recent studies identified strains of Salmonella that induce encephalopathies in calves exposed to stressful situations. In order to cause neurologic signs (such as ataxia, head tilt, and partial blindness), the strain must be able to cross the blood-brain barrier (BBB). One possible way is through the break down of tight junctions, which regulate the permeability of the BBB and can be weakened by enzymes such as collagenases. Salmonella and other Gram-negative bacteria contain a collagenase gene (clg) that is silenced in vitro but inducibly expressed in vivo. We hypothesized that the neuropathic strains of Salmonella express clg in response to neuroendocrine factors in the host and that the expressed collagenase perturbs the BBB allowing for CNS invasion by Salmonella. Our in vitro results revealed that clg is derepressed in serum obtained from stressed cattle. Derepression is relegated to the neuropathic Salmonella strains. In vivo studies indicated that clg expression is required for neuropathogenicity and that pharmacologic maintenance of the BBB prevents both the Salmonella invasion into the brain and the resulting neurologic signs. These studies identify a host-induced Salmonella collagenase that facilitates neuropathogenicity at the level of the BBB. PMID- 21554942 TI - Activity of all JNK isoforms contributes to neurite growth in spiral ganglion neurons. AB - Jun N-terminal kinase (JNK) is a multifunctional protein kinase crucial for neuronal apoptosis as well as neurite growth. We have previously shown that JNK activity is correlated with spiral ganglion neuron (SGN) apoptosis following hair cell loss in rats (Alam et al., 2007) implying that JNK inhibition may have therapeutic potential to protect SGNs in deaf individuals. Here we investigated the role of JNK in neurite outgrowth from cultured neonatal rat and mouse SGNs. We show that JNK is required for initial growth of neurites and for continued extension of already established neurites. The effect of JNK inhibition on neurite growth is rapid and is also rapidly reversible after washout of the inhibitor. Using phosphoJNK immunoreactivity as an indicator, we show that JNK is activated in growth cones within 30 min after transfer to medium lacking neurotrophic stimuli (5 K medium) but activation in the nucleus and soma requires hours. By transfecting epitope-tagged JNK1, JNK2, or JNK3 isoforms into SGNs, we found that all are present in the nucleus and cytoplasm and that there is no preferential redistribution to the nucleus after transfer to 5 K medium. Cotransfection of dominant-negative (dn) JNK1 and JNK2 into SGNs reduced neurite growth, although transfection of dnJNK1 or dnJNK2 alone had no significant effect. SGNs cultured from JNK3(-/-) mice showed reduced neurite growth that was further reduced by transfection of dnJNK1 and dnJNK2. This indicates that all three JNK isoforms promote SGN neurite growth although there may be functional redundancy between JNK1 and JNK2. PMID- 21554944 TI - BapC autotransporter protein is a virulence determinant of Bordetella pertussis. AB - A protein designated Bap-5 (GenBank accession no. AF081494) or BapC (GenBank accession no. AJ277634) has been identified as a member of the Bordetella pertussis autotransporter family and the present work suggests that this protein, like the previously characterised BrkA, is a Bvg-regulated serum resistance factor and virulence determinant. B. pertussis bapC and brkA, bapC mutants were created and, like a brkA mutant, showed greater sensitivity to killing by normal human serum than their parent strains but they were not as sensitive as a bvg mutant. Competition assays also showed an important role for BapC, like BrkA, in virulence of B. pertussis in mice after intranasal infection. Moreover, the bapC and brkA, bapC mutants, like the brkA mutant, were found to be more sensitive to the antimicrobial peptide cecropin P1 than the parent strains. In the genome sequence of B. pertussis strain Tohama, bapC is designated as a pseudogene due, in part, to a frameshift in a poly(C) tract near the 5' end of the gene which creates a truncated BapC protein. Sequence analyses of the bapC region spanning the poly(C) tract of a number of B. pertussis strains showed minor nucleotide and amino acid polymorphisms but it appeared that all had an ORF that would be able to produce BapC. PMID- 21554945 TI - Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease. AB - OBJECTIVE: To assess serum brain derived neurotrophic factor (BDNF) concentrations as a correlate of cardiopulmonary fitness and as a predictor of cognitive performance in subjects with coronary artery disease (CAD). METHODS: Serum BDNF concentrations were assayed by ELISA and fitness was assessed using a standardized exercise stress test. The Mini Mental Status Examination (MMSE), California Verbal Learning Test 2nd Ed., Stroop, Trail Making Test B and the Digit Symbol-Coding task were administered. The val66met BDNF genotype and serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) concentrations were determined as potential confounders. RESULTS: In subjects with CAD (n=88; 85.2% male, mean age 62.8+/-10.5 yr), cardiopulmonary fitness was associated with higher serum BDNF concentrations (beta=.305, p=.013). Higher serum BDNF concentrations were associated with higher MMSE scores (F(1,87)=15.406, p<.0005) and better performance on the Digit Symbol-Coding task (F(1,87)=9.620, p=.003). IL-6, TNF-alpha and the val66met genotype did not influence these results. CONCLUSION: Serum BDNF concentrations were associated with cardiopulmonary fitness, psychomotor processing speed and overall cognition in subjects with CAD. PMID- 21554946 TI - Trait anger, cynical hostility and inflammation in Latinas: variations by anger type? AB - Anger and hostility are psychological factors that appear to play a salient role in relation to cardiovascular disease (CVD) risk; however, their association with risk within the Latino population remains relatively unexplored. The current study examined associations between overall trait anger, anger subdimensions (i.e., anger temperament and anger reaction) and cynical hostility with sICAM-1, a marker of cellular adhesion and systemic inflammation related to CVD risk, in a sample of 294 middleaged Mexican-American women. Results showed no association between trait anger or anger temperament and sICAM-1. Anger reaction was marginally associated with sICAM-1 (beta=4.77, p=.06). Cynical hostility was significantly associated with sICAM-1 (beta=5.89, p=.04) even after controlling for demographic, biological and behavioral covariates. The current study provides evidence that specific aspects of anger and hostility relate to physiological pathways that potentially influence CVD risk. Findings are discussed in light of contextual cultural factors. PMID- 21554947 TI - Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo. AB - NADPH oxidase-4 (Nox4) is an important modulator of redox signaling that is inducible at the level of transcriptional expression in multiple cell types. By contrast to other Nox enzymes, Nox4 is continuously active without requiring stimulation. We reported recently that expression of Nox4 is induced in the adult heart as an adaptive stress response to pathophysiological insult. To elucidate the potential downstream target(s) regulated by Nox4, we performed a microarray screen to assess the transcriptomes of transgenic (tg) mouse hearts in which Nox4 was overexpressed. The screen revealed a significant increase in the expression of many antioxidant and detoxifying genes regulated by Nrf2 in tg compared to wild-type (wt) mouse hearts, and this finding was subsequently confirmed by Q PCR. Expression of glutathione biosynthetic and recycling enzymes was increased in tg hearts and associated with higher levels of both GSH and the ratio of reduced:oxidised GSH, compared to wt hearts. The increases in expression of the antioxidant genes and the changes in glutathione redox effected by Nox4 were ablated in an Nrf2-null genetic background. These data therefore demonstrate that Nox4 can activate the Nrf2-regulated pathway, and suggest a potential role for Nox4 in the regulation of GSH redox in cardiomyocytes. PMID- 21554948 TI - Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production. AB - Xanthine oxidase (XO) is a critical source of reactive oxygen species (ROS) that contribute to vascular inflammation. Binding of XO to vascular endothelial cell glycosaminoglycans (GAGs) results in significant resistance to inhibition by traditional pyrazolopyrimidine-based inhibitors such as allopurinol. Therefore, we compared the extent of XO inhibition (free and GAG-bound) by allopurinol to that by febuxostat, a newly approved nonpurine XO-specific inhibitor. In solution, febuxostat was 1000-fold more potent than allopurinol at inhibiting XO dependent uric acid formation (IC50= 1.8 nM vs 2.9 MUM). Association of XO with heparin-Sepharose 6B (HS6B-XO) had minimal effect on the inhibition of uric acid formation by febuxostat (IC50= 4.4 nM) while further limiting the effect of allopurinol (IC50= 64 MUM). Kinetic analysis of febuxostat inhibition revealed K(i) values of 0.96 (free) and 0.92 nM (HS6B-XO), confirming equivalent inhibition for both free and GAG-immobilized enzyme. When XO was bound to endothelial cell GAGs, complete enzyme inhibition was observed with 25 nM febuxostat, whereas no more than 80% inhibition was seen with either allopurinol or oxypurinol, even at concentrations above those tolerated clinically. The superior potency for inhibition of endothelium-associated XO is predictive of a significant role for febuxostat in investigating pathological states in which XO derived ROS are contributive and traditional XO inhibitors are only slightly effective. PMID- 21554949 TI - Arsenic-induced oxidative stress and its reversibility. AB - This review summarizes the literature describing the molecular mechanisms of arsenic-induced oxidative stress, its relevant biomarkers, and its relation to various diseases, including preventive and therapeutic strategies. Arsenic alters multiple cellular pathways including expression of growth factors, suppression of cell cycle checkpoint proteins, promotion of and resistance to apoptosis, inhibition of DNA repair, alterations in DNA methylation, decreased immunosurveillance, and increased oxidative stress, by disturbing the pro/antioxidant balance. These alterations play prominent roles in disease manifestation, such as carcinogenicity, genotoxicity, diabetes, cardiovascular and nervous systems disorders. The exact molecular and cellular mechanisms involved in arsenic toxicity are rather unrevealed. Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation. Arsenic forms oxygen based radicals (OH(*), O(2)(*-)) under physiological conditions by directly binding with critical thiols. As a carcinogen, it acts through epigenetic mechanisms rather than as a classical mutagen. The carcinogenic potential of arsenic may be attributed to activation of redox-sensitive transcription factors and other signaling pathways involving nuclear factor kappaB, activator protein 1, and p53. Modulation of cellular thiols for protection against reactive oxygen species has been used as a therapeutic strategy against arsenic. N acetylcysteine, alpha-lipoic acid, vitamin E, quercetin, and a few herbal extracts show prophylactic activity against the majority of arsenic-mediated injuries in both in vitro and in vivo models. This review also updates the reader on recent advances in chelation therapy and newer therapeutic strategies suggested to treat arsenic-induced oxidative damage. PMID- 21554950 TI - AMPK-mediated autophagy is a survival mechanism in androgen-dependent prostate cancer cells subjected to androgen deprivation and hypoxia. AB - The present study was designed to investigate (i) the role of AMPK activation in inducing autophagy in androgen-dependent prostate cancer cells subjected to androgen deprivation and hypoxia, and (ii) whether autophagy offers a survival advantage under these harsh conditions. Low androgen and low oxygen are two co existing conditions frequently found in prostate cancer tissue following surgical or medical castration. In LNCaP cells, androgen deprivation and hypoxia together boosted AMPK activation to a higher level than that seen with either condition alone. The augmented AMPK response was associated with improved viability and the induction of autophagy. These observations suggest that a threshold of AMPK activity has to be attained in order to trigger autophagy, since neither androgen deprivation nor hypoxia by itself was capable of pushing AMPK activity past that threshold. Beclin-1 was identified as a potential downstream target of AMPK in turning on the autophagic cascade. If autophagy was blocked by chemical inhibition or RNA interference of key regulators, e.g., AMPK or beclin-1, more cells would die by apoptosis. The occurrence of autophagy is thus a survival mechanism for androgen-dependent prostate cancer cells to escape from an androgen deprived and hypoxic subsistence. PMID- 21554951 TI - Modulation of Pseudomonas aeruginosa surface-associated group behaviors by individual amino acids through c-di-GMP signaling. AB - To colonize the cystic fibrosis lung, Pseudomonas aeruginosa establishes sessile communities referred to as biofilms. Although the signaling molecule c-di-GMP governs the transition from motile to sessile growth, the environmental signal(s) required to modulate biofilm formation remain unclear. Using relevant in vivo concentrations of the 19 amino acids previously identified in cystic fibrosis sputum, we demonstrated that arginine, ornithine, isoleucine, leucine, valine, phenylalanine and tyrosine robustly promoted biofilm formation in vitro. Among the seven biofilm-promoting amino acids, only arginine also completely repressed the ability of P. aeruginosa to swarm over semi-solid surfaces, suggesting that arginine may be an environmental cue favoring a sessile lifestyle. Mutating two documented diguanylate cyclases required for biofilm formation (SadC and RoeA) reduced biofilm formation and restored swarming motility on arginine-containing medium. Growth on arginine increased the intracellular levels of c-di-GMP, and this increase was dependent on the SadC and RoeA diguanylate cyclases. Strains mutated in sadC, roeA or both also showed a reduction in biofilm formation when grown with the other biofilm-promoting amino acids. Taken together, these results suggest that amino acids can modulate biofilm formation and swarming motility, at least in part, by controlling the intracellular levels of c-di-GMP. PMID- 21554952 TI - Influence of aging and hemorrhage injury on Sirt1 expression: possible role of myc-Sirt1 regulation in mitochondrial function. AB - Trauma-hemorrhage (T-H) causes hypoxia and organ dysfunction. Mitochondrial dysfunction is a major factor for cellular injury due to T-H. Aging also has been known to cause progressive mitochondrial dysfunction. In order to study the effect of aging on T-H-induced mitochondrial dysfunction, we recently developed a rodent mitochondrial genechip with probesets representing mitochondrial and nuclear genes contributing to mitochondrial structure and function. Using this chip we recently identified signature mitochondrial genes altered following T-H in 6 and 22 month old rats; augmented expression of the transcription factor c myc was the most pronounced. Based on reports of c-myc-IL6 collaboration and c myc-Sirt1 negative regulation, we further investigated the expression of these regulatory factors with respect to aging and injury. Rats of ages 6 and 22 months were subjected to T-H or sham operation and left ventricular tissues were tested for cytosolic cytochrome c, mtDNA content, Sirt1 and mitochondrial biogenesis factors Foxo1, Ppara and Nrf-1. We observed increased cardiac cytosolic cytochrome c (sham vs T-H, p<0.03), decreased mitochondrial DNA content (sham vs T-H, p<0.05), and decreased Sirt1 expression (sham vs TH, p<0.05) following T-H and with progressing age. Additionally, expression of mitochondrial biogenesis regulating transcription factors Foxo1 and Nrf-1 was also decreased with T-H and aging. Based upon these observations we conclude that Sirt1 expression is negatively modulated by T-H causing downregulation of mitochondrial biogenesis. Thus, induction of Sirt1 is likely to produce salutary effects following T-H induced injury and hence, Sirt1 may be a potential molecular target for translational research in injury resolution. PMID- 21554954 TI - A coordinated expression of biosynthetic enzymes controls the flux of juvenile hormone precursors in the corpora allata of mosquitoes. AB - Juvenile hormone (JH) is a key regulator of metamorphosis and ovarian development in mosquitoes. Adult female Aedes aegypti mosquitoes show developmental and dynamically regulated changes of JH synthesis. Newly emerged females have corpora allata (CA) with low biosynthetic activity, but they produce high amounts of JH a day later; blood feeding results in a striking decrease in JH synthesis, but the CA returns to a high level of JH synthesis three days later. To understand the molecular bases of these dynamic changes we combined transcriptional studies of 11 of the 13 enzymes of the JH pathway with a functional analysis of JH synthesis. We detected up to a 1000-fold difference in the levels of mRNA in the CA among the JH biosynthetic enzymes studied. There was a coordinated expression of the 11 JH biosynthetic enzymes in female pupae and adult mosquito. Increases or decreases in transcript levels for all the enzymes resulted in increases or decreases of JH synthesis; suggesting that transcript changes are at least partially responsible for the dynamic changes of JH biosynthesis observed. JH synthesis by the CA was progressively increased in vitro by addition of exogenous precursors such as geranyl-diphosphate, farnesyl-diphosphate, farnesol, farnesal and farnesoic acid. These results suggest that the supply of these precursors and not the activity of the last 6 pathway enzymes is rate limiting in these glands. Nutrient reserves play a key role in the regulation of JH synthesis. Nutritionally deficient females had reduced transcript levels for the genes encoding JH biosynthetic enzymes and reduced JH synthesis. Our studies suggest that JH synthesis is controlled by the rate of flux of isoprenoids, which is the outcome of a complex interplay of changes in precursor pools, enzyme levels and external regulators such as nutrients and brain factors. Enzyme levels might need to surpass a minimum threshold to achieve a net flux of precursors through the biosynthetic pathway. In glands with low synthetic activity, the flux of isoprenoids might be limited by the activity of enzymes with low levels of expression. PMID- 21554953 TI - Antiviral, anti-parasitic, and cytotoxic effects of 5,6-dihydroxyindole (DHI), a reactive compound generated by phenoloxidase during insect immune response. AB - Phenoloxidase (PO) and its activation system are implicated in several defense responses of insects. Upon wounding or infection, inactive prophenoloxidase (proPO) is converted to active PO through a cascade of serine proteases and their homologs. PO generates reactive compounds such as 5,6-dihydroxyindole (DHI), which have a broad-spectrum antibacterial and antifungal activity. Here we report that DHI and its spontaneous oxidation products are also active against viruses and parasitic wasps. Preincubation of a baculovirus stock with 1.25 mM DHI for 3 h near fully disabled recombinant protein production. The LC50 for lambda bacteriophage and eggs of the wasp Microplitis demolitor were 5.6 +/- 2.2 and 111.0 +/- 1.6 MUM, respectively. The toxicity of DHI and related compounds also extended to cells derived from insects that serve as hosts for several of the aforementioned pathogens. Pretreatment of Sf9 cells with 1.0 mM DHI for 4 h resulted in 97% mortality, and LC50 values of 20.3 +/- 1.2 MUM in buffer and 131.8 +/- 1.1 MUM in a culture medium. Symptoms of DHI toxicity in Sf9 cells included DNA polymerization, protein crosslinking, and lysis. Taken together, these data showed that proPO activation and DHI production is strongly toxic against various pathogens but can also damage host tissues and cells if not properly controlled. PMID- 21554955 TI - The role of IkappaB kinase complex in the neurobiology of Huntington's disease. AB - The IkappaB kinase beta (IKKbeta) is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington's disease (HD). Inflammatory mediators accumulate in the serum and CNS of premanifest and manifest HD patients, and cytokine levels correlate with disease progression. IKKbeta may also directly regulate the neurotoxicity of huntingtin (Htt). Activation of IKKbeta by DNA damage triggers caspase-dependent cleavage of WT and mutant Htt and enhances the accumulation of oligomeric fragments. Moreover, the N terminal fragments of mutant Htt (HDx1) directly bind to and activate IKKbeta. Thus, the IKKbeta-dependent cleavage of full-length mutant Htt and the buildup of HDx1 could form a deleterious feed-forward loop. Elevated IKKbeta activity is present throughout the CNS in a symptomatic mouse model of HD expressing HDx1, whereas in asymptomatic mice with full-length mutant Htt, it is confined to the striatum. IKKbeta could also influence the phosphorylation of Htt at Ser13 and Ser16, which is linked to HD pathology. IKKbeta inhibitors ameliorate the toxicity of mutant Htt in striatal neurons and prevent DNA damage-induced Htt cleavage. Inhibition of IKKbeta in the CNS also reduces neuroinflammation and imparts neuroprotection in a chemical model of HD. These findings support an active role for IKKbeta in HD pathogenesis and represent an example of how gene environment (exemplified by DNA damage and inflammation) interactions can influence Htt neurotoxicity. We will summarize these findings and describe the therapeutic potentials of IKKbeta for HD. PMID- 21554956 TI - Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain. AB - Preconditioning-induced ischemic tolerance has been documented in the newborn brain, however, the signaling mechanisms of this preconditioning require further elucidation. The aims of this study were to develop a hypoxic-preconditioning (PC) model of ischemic tolerance in the newborn piglet, which emulates important clinical similarities to human situation of birth asphyxia, and to characterize some of the molecular mechanisms shown to be implicated in PC-induced neuroprotection in rodent models. One day old piglets were subjected to PC (8% O2/92% N2) for 3 h and 24 h later were exposed to hypoxia-ischemia (HI) produced by a combination of hypoxia (5% FiO2) for a period of 30 min and ischemia induced by a period of hypotension (10 min of reduced mean arterial blood pressure; <=70% of baseline). Neuropathologic analysis and unbiased stereology, conducted at 24 h, 3 and 7 days of recovery following HI, indicated a substantial reduction in the severity of brain damage in PC piglets compared to non-PC piglets (P<0.05). PC significantly increased the mRNA expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and its target gene, vascular endothelial growth factor (VEGF) at 0 h, 6h, 24 h, 3 and 7 days of recovery. Immunoblot analysis demonstrated that PC resulted in HIF-1alpha protein stabilization and accumulation in nuclear extracts of cerebral cortex of newborn piglet brain compared to normoxic controls. Protein levels of VEGF increased in a time-dependent manner in both cortex and hippocampus following PC. Double-immunolabeling indicated that VEGF is mainly expressed in neurons, endothelial cells and astroglia. Our study demonstrates for the first time the protective efficacy of PC against hypoxic-ischemic injury in newborn piglet model, which recapitulates many pathophysiological features of asphyxiated human neonates. Furthermore, as has been shown in rodent models of preconditioning, our results suggest that PC-induced protection in neonatal piglets may involve upregulation of VEGF. PMID- 21554957 TI - Excitatory amplification through divergent-convergent circuits: the role of the midline thalamus in limbic seizures. AB - INTRODUCTION: The midline thalamic nuclei are an important component of limbic seizures. Although the anatomic connections and excitatory influences of the midline thalamus are well known, its physiological role in limbic seizures is unclear. We examined the role of the midline thalamus on two circuits that are involved in limbic seizures: (a) the subiculum-prefrontal cortex (SB-PFC), and (b) the piriform cortex-entorhinal cortex (PC-EC). METHODS: Evoked field potentials for both circuits were obtained in anesthetized rats, and the likely direct monosynaptic and polysynaptic contributions to the responses were identified. Seizures were generated in both circuits by 20 Hz stimulus trains. Once stable seizures and evoked potentials were established, the midline thalamus was inactivated through an injection of the sodium channel blocker tetrodotoxin (TTX), and the effects on the evoked responses and seizures were analyzed. RESULTS: Inactivation of the midline thalamus suppressed seizures in both circuits. Seizure suppression was associated with a significant reduction in the late thalamic component but no significant change in the early direct monosynaptic component. Injections that did not suppress the seizures did not alter the evoked potentials. CONCLUSIONS: Suppression of the late thalamic component of the evoked potential at the time of seizure suppression suggests that the thalamus facilitates seizure induction by extending the duration of excitatory drive through a divergent-convergent excitatory amplification system. This work may have broader implications for understanding signaling in the limbic system. PMID- 21554958 TI - Elevation of p-NR2A(S1232) by Cdk5/p35 contributes to retinal ganglion cell apoptosis in a rat experimental glaucoma model. AB - Glaucoma, mainly caused by high intraocular pressure (IOP), is characterized by apoptotic death of retinal ganglion cells (RGCs). We investigated the possible involvement of cyclin-dependent kinase 5 (Cdk5) and its activator p35, which have been implicated in a variety of neurological disorders, in RGC apoptosis in a rat experimental glaucoma model reproduced by blocking episcleral veins. Cholera toxin B subunit (CTB) retrogradely labeled RGCs displayed a dramatic reduction in number both in the central and peripheral retina on day 14 (D14) (P<0.05 vs. control), D21 (P<0.01 vs. control) and D28 (P<0.001 vs. control) after operation. Terminal dUTP nick end labeling (TUNEL)-positive cells were detected on D14 both in the central and peripheral regions, and numerous TUNEL-positive cells were found on D21 and D28 in both the regions (P all<0.001 vs. control). As compared with the control eyes, the expression level of Cdk5 was significantly increased on D21 (P<0.001), whereas that of p35 displayed a marked increase on D14 (P<0.01) and D21 (P<0.001). Meanwhile, both NR2A and p-NR2A(S1232) increased from D14 onwards (P<0.01 to 0.001). Co-immunoprecipitation indicated a direct interaction between Cdk5 and p-NR2A(S1232). Intraperitoneal injection of the Cdk5 inhibitor roscovitine remarkably inhibited RGC apoptosis (P<0.001 vs. vehicle group) and increased the number of CTB-labeled RGCs (P<0.05 to 0.01 vs. vehicle group) in whole flat-mounted retinas, which was accompanied by a significant decrease in expression levels of p35 and p-NR2A(S1232) (P all<0.01 vs. vehicle group). Our results suggest that elevation of p-NR2A(S1232) by Cdk5/p35 contributes to RGC apoptotic death in experimental glaucoma rats, which could be effectively ameliorated by inhibiting Cdk5/p35. PMID- 21554959 TI - Priming the prophenoloxidase system of Artemia franciscana by heat shock proteins protects against Vibrio campbellii challenge. AB - Like other invertebrates, the brine shrimp Artemia franciscana relies solely on innate immunity, which by definition lacks adaptive characteristics, to combat against invading pathogens. One of the innate mechanisms is melanisation of bacteria mediated by the activation of the prophenoloxidase (proPO) system. The 70 kDa heat shock proteins (Hsp70) derived from either prokaryote (Escherichia coli) or eukaryote (Artemia), well conserved and immune-dominant molecules, protect Artemia against Vibrio campbellii. However, the molecular mechanisms by which these proteins protect Artemia against Vibrio campbellii infection are unknown. Here we demonstrated that feeding gnotobiotically grown Artemia with either Artemia Hsp70 or the E. coli Hsp70 equivalent DnaK, each overproduced in E. coli, followed by V. campbellii challenge enhanced the proPO system, at both mRNA and protein activity levels. Additionally, the Artemia fed with these proteins survived well in a Vibrio challenge assay. These results indicated that Hsp70s derived from either prokaryotic or eukaryotic sources generate protective immunity in the crustacean Artemia against V. campbellii infection by priming the proPO system. This is apparently the first in vivo report on priming activity of Hsp70 in an invertebrate. PMID- 21554960 TI - Conflict, error likelihood, and RT: Response to Brown & Yeung et al. PMID- 21554961 TI - Dissociable brain networks involved in development of fairness considerations: understanding intentionality behind unfairness. AB - In this functional magnetic resonance imaging study, we examined developmental changes in the brain regions involved in reactions to unfair allocations. Previous studies on adults suggested that reactions to unfairness are not only affected by the distribution itself but also by the ascribed intentionality of the proposer. In the current study, we employed the mini Ultimatum Game (Falk, Fehr, & Fischbacher, 2003) to examine responder behavior to unfair offers of varying degrees of intentionality. Sixty-eight participants from four age groups (10-, 13-, 15-, and 20-year-olds) carried out the task while fMRI data were acquired. Participants of all ages showed activation in the bilateral insula and dorsal anterior cingulate cortex (dACC) during rejection of unintentional but acceptance of intentional unfair offers. Rejection of unintentional unfair offers further involved increasing activation with age in the temporoparietal junction and the dorsolateral prefrontal cortex. These findings provide evidence for an early developing insula-dACC network involved in detecting personal norm violations and gradually increasing involvement of temporal and prefrontal brain regions related to intentionality considerations in social reasoning. The results are discussed in light of recent findings on the development of the adolescent social brain network. PMID- 21554962 TI - Penalized functional regression analysis of white-matter tract profiles in multiple sclerosis. AB - Diffusion tensor imaging (DTI) enables noninvasive parcellation of cerebral white matter into its component fiber bundles or tracts. These tracts often subserve specific functions, and damage to the tracts can therefore result in characteristic forms of disability. Attempts to quantify the extent of tract specific damage have been limited in part by substantial spatial variation of imaging properties from one end of a tract to the other, variation that can be compounded by the effects of disease. Here, we develop a "penalized functional regression" procedure to analyze spatially normalized tract profiles, which powerfully characterize such spatial variation. The central idea is to identify and emphasize portions of a tract that are more relevant to a clinical outcome score, such as case status or degree of disability. The procedure also yields a "tract abnormality score" for each tract and MRI index studied. Importantly, the weighting function used in this procedure is constrained to be smooth, and the statistical associations are estimated using generalized linear models. We test the method on data from a cross-sectional MRI and functional study of 115 multiple-sclerosis cases and 42 healthy volunteers, considering a range of quantitative MRI indices, white-matter tracts, and clinical outcome scores, and using training and testing sets to validate the results. We show that attention to spatial variation yields up to 15% (mean across all tracts and MRI indices: 6.4%) improvement in the ability to discriminate multiple sclerosis cases from healthy volunteers. Our results confirm that comprehensive analysis of white matter tract-specific imaging data improves with knowledge and characterization of the normal spatial variation. PMID- 21554963 TI - Dysfunctions of cerebral networks precede recognition memory deficits in early Parkinson's disease. AB - We aimed to investigate changes in the verbal recognition memory network in patients with early Parkinson's disease (PD) without overt recognition memory alteration. Verbal recognition memory was assessed in 24 PD patients in early stages of the disease and a control group of 24 healthy subjects during fMRI data acquisition. Participants were presented with a list of 35 words before imaging, and later during fMRI scanning they were required to recognize these previously presented words. Both model-based (FEAT) and model-free (MELODIC) analyses of the fMRI data were carried out with FSL software. Memory was also assessed by means of Rey's Auditory Verbal Learning Test (RAVLT). PD patients showed no difference in the fMRI recognition memory task and recognition memory assessed by the RAVLT compared to healthy controls. Model-based analysis did not show significant differences between groups. On the other hand, model-free analysis identified components that fitted the task-model and were common to all the participants, as well as components that differed between PD and healthy controls. PD patients showed decreased task-related activations in areas involved in the recognition memory network and decreased task-related deactivations in the default mode network in comparison with controls. In conclusion, model-free fMRI analysis detected alterations in functional cerebral networks involved in a verbal memory task in PD patients without evident recognition memory deficit. PMID- 21554964 TI - Syntactic and auditory spatial processing in the human temporal cortex: an MEG study. AB - Processing syntax is believed to be a higher cognitive function involving cortical regions outside sensory cortices. In particular, previous studies revealed that early syntactic processes at around 100-200 ms affect brain activations in anterior regions of the superior temporal gyrus (STG), while independent studies showed that pure auditory perceptual processing is related to sensory cortex activations. However, syntax-related modulations of sensory cortices were reported recently, thereby adding diverging findings to the previous studies. The goal of the present magnetoencephalography study was to localize the cortical regions underlying early syntactic processes and those underlying perceptual processes using a within-subject design. Sentences varying the factors syntax (correct vs. incorrect) and auditory space (standard vs. change of interaural time difference (ITD)) were auditorily presented. Both syntactic and auditory spatial anomalies led to very early activations (40-90 ms) in the STG. Around 135 ms after violation onset, differential effects were observed for syntax and auditory space, with syntactically incorrect sentences leading to activations in the anterior STG, whereas ITD changes elicited activations more posterior in the STG. Furthermore, our observations strongly indicate that the anterior and the posterior STG are activated simultaneously when a double violation is encountered. Thus, the present findings provide evidence of a dissociation of speech-related processes in the anterior STG and the processing of auditory spatial information in the posterior STG, compatible with the view of different processing streams in the temporal cortex. PMID- 21554965 TI - Strategy-effects in prefrontal cortex during learning of higher-order S-R rules. AB - All of us regularly face situations that require the integration of the available information at hand with the established rules that guide behavior in order to generate the most appropriate action. But where individuals differ from one another is most certainly in terms of the different strategies that are adopted during this process. A previous study revealed differential brain activation patterns for the implementation of well established higher-order stimulus response (S-R) rules depending on inter-individual strategy differences (Wolfensteller and von Cramon, 2010). This raises the question of how these strategies evolve or which neurocognitive mechanisms underlie these inter individual strategy differences. Using functional magnetic resonance imaging (fMRI), the present study revealed striking strategy-effects across regions of the lateral prefrontal cortex during the implementation of higher-order S-R rules at an early stage of learning. The left rostrolateral prefrontal cortex displayed a quantitative strategy-effect, such that activation during rule integration based on a mismatch was related to the degree to which participants continued to rely on rule integration. A quantitative strategy ceiling effect was observed for the left inferior frontal junction area. Conversely, the right inferior frontal gyrus displayed a qualitative strategy-effect such that participants who at a later point relied on an item-based strategy showed stronger activations in this region compared to those who continued with the rule integration strategy. Together, the present findings suggest that a certain amount of rule integration is mandatory when participants start to learn higher-order rules. The more efficient item-based strategy that evolves later appears to initially require the recruitment of additional cognitive resources in order to shield the currently relevant S-R association from interfering information. PMID- 21554966 TI - Continuous theta-burst stimulation (cTBS) over the lateral prefrontal cortex alters reinforcement learning bias. AB - The prefrontal cortex is known to play a key role in higher-order cognitive functions. Recently, we showed that this brain region is active in reinforcement learning, during which subjects constantly have to integrate trial outcomes in order to optimize performance. To further elucidate the role of the dorsolateral prefrontal cortex (DLPFC) in reinforcement learning, we applied continuous theta burst stimulation (cTBS) either to the left or right DLPFC, or to the vertex as a control region, respectively, prior to the performance of a probabilistic learning task in an fMRI environment. While there was no influence of cTBS on learning performance per se, we observed a stimulation-dependent modulation of reward vs. punishment sensitivity: Left-hemispherical DLPFC stimulation led to a more reward-guided performance, while right-hemispherical cTBS induced a more avoidance-guided behavior. FMRI results showed enhanced prediction error coding in the ventral striatum in subjects stimulated over the left as compared to the right DLPFC. Both behavioral and imaging results are in line with recent findings that left, but not right-hemispherical stimulation can trigger a release of dopamine in the ventral striatum, which has been suggested to increase the relative impact of rewards rather than punishment on behavior. PMID- 21554967 TI - Object representations in ventral and dorsal visual streams: fMRI repetition effects depend on attention and part-whole configuration. AB - The effects of attention and object configuration on the neural responses to short-lag visual image repetition were investigated with fMRI. Attention to one of two object images in a prime display was cued spatially. The images were either intact or split vertically; a manipulation that negates the influence of view-based representations. A subsequent single intact probe image was named covertly. Behavioural priming observed as faster button presses was found for attended primes in both intact and split configurations, but only for uncued primes in the intact configuration. In a voxel-wise analysis, fMRI repetition suppression (RS) was observed in a left mid-fusiform region for attended primes, both intact and split, whilst a right intraparietal region showed repetition enhancement (RE) for intact primes, regardless of attention. In a factorial analysis across regions of interest (ROIs) defined from independent localiser contrasts, RS for attended objects in the ventral stream was significantly left lateralised, whilst repetition effects in ventral and dorsal ROIs correlated with the amount of priming in specific conditions. These fMRI results extend hybrid theories of object recognition, implicating left ventral stream regions in analytic processing (requiring attention), consistent with prior hypotheses about hemispheric specialisation, and implicating dorsal stream regions in holistic processing (independent of attention). PMID- 21554969 TI - Evolutionary trends of GC/AT distribution patterns in promoters. AB - Nucleotide distributions in genomes is known not to be random, showing the presence of specific motifs, long and short range correlations, periodicities, etc. Particularly, motifs are critical for the recognition by specific proteins affecting chromosome organization, transcription and DNA replication but little is known about the possible functional effects of nucleotide distributions on the conformational landscape of DNA, putatively leading to differential selective pressures throughout evolution. Promoter sequences have a fundamental role in the regulation of gene activity and a vast literature suggests that their conformational landscapes may be a critical factor in gene expression dynamics. On these grounds, with the aim of investigating the putative existence of phylogenetic patterns of promoter base distributions, we analyzed GC/AT ratios along the 1000 nucleotide sequences upstream of TSS in wide sets of promoters belonging to organisms ranging from bacteria to pluricellular eukaryotes. The data obtained showed very clear phylogenetic trends throughout evolution of promoter sequence base distributions. Particularly, in all cases either GC-rich or AT-rich monotone gradients were observed: the former being present in eukaryotes, the latter in bacteria along with strand biases. Moreover, within eukaryotes, GC-rich gradients increased in length from unicellular organisms to plants, to vertebrates and, within them, from ancestral to more recent species. Finally, results were thoroughly discussed with particular attention to the possible correlation between nucleotide distribution patterns, evolution, and the putative existence of differential selection pressures, deriving from structural and/or functional constraints, between and within prokaryotes and eukaryotes. PMID- 21554968 TI - Handedness-dependent and -independent cerebral asymmetries in the anterior intraparietal sulcus and ventral premotor cortex during grasp planning. AB - When planning grasping actions, right-handers show left-lateralized responses in the anterior intraparietal sulcus (aIPS) and ventral premotor cortex (vPMC), two areas that are also implicated in sensorimotor control of grasp. We investigated whether a similar cerebral asymmetry is evident in strongly left-handed individuals. Fourteen participants were trained to grasp an object appearing in a variety of orientations with their left and right hands and with a novel mechanical tool (operated with either hand). BOLD fMRI data were then acquired while they decided prospectively whether an over- or under-hand grip would be most comfortable for grasping the same stimulus set while remaining still. Behavioral performances were equivalent to those recorded previously in right handers and indicated reliance on effector-specific internal representations. In left-handers, however, grip selection decisions for both sides (left, right) and effectors (hand, tool) were associated with bilateral increases in activity within aIPS and vPMC. A direct comparison between left- and right-handers did reveal equivalent increases in left vPMC regardless of hand dominance. By contrast, aIPS and right vPMC activity were dependent on handedness, showing greater activity in the motor-dominant hemisphere. Though showing bilateral increases in both left- and right-handers, greater increases in the motor dominant hemisphere were also detected in the caudal IPS (cIPS), superior parietal lobule (SPL) and dorsal premotor cortex (dPMC). These findings provide further evidence that regions involved in the sensorimotor control of grasp also participate in grasp planning, and that for certain areas hand dominance is a predictor of the cerebral organization of motor cognitive functions. PMID- 21554970 TI - Molecular phylogenetics and character evolution of the "sacaca" clade: novel relationships of Croton section Cleodora (Euphorbiaceae). AB - Phylogenetic relationships of Croton section Cleodora (Klotzsch) Baill. were evaluated using the nuclear ribosomal ITS and the chloroplast trnL-F and trnH psbA regions. Our results show a strongly supported clade containing most previously recognized section Cleodora species, plus some other species morphologically similar to them. Two morphological synapomorphies that support section Cleodora as a clade include pistillate flowers in which the sepals overlap to some degree, and styles that are connate at the base to varying degrees. The evolution of vegetative and floral characters that have previously been relied on for taxonomic decisions within this group are evaluated in light of the phylogenetic hypotheses. Within section Cleodora there are two well supported clades, which are proposed here as subsections (subsection Sphaerogyni and subsection Spruceani). The resulting phylogenetic hypothesis identifies the closest relatives of the medicinally important and essential oil-rich Croton cajucara Benth. as candidates for future screening in phytochemical and pharmacological studies. PMID- 21554971 TI - S-nitrosylation of proteins: a new insight into endothelial cell function regulated by eNOS-derived NO. AB - Nitric oxide (NO) is a messenger molecule that is highly diffusible and short lived. Despite these two characteristics, seemingly unsuitable for intracellular reactions, NO modulates a variety of cellular processes via the mechanism of S nitrosylation. An important factor that determines the specificity of S nitrosylation as a signaling mechanism is the compartmentalization of nitric oxide synthase (NOS) with its target proteins. Endothelial NOS (eNOS) is unique among the NOS family members by being localized mainly near specific intracellular membrane domains including the cytoplasmic face of the Golgi apparatus and plasma membrane caveolae. Nitric oxide produced by eNOS localized on the Golgi apparatus can react with thiol groups on nearby Golgi proteins via a redox mechanism resulting in S-nitrosylation of these proteins. This modification influences their function as regulators of cellular processes such as protein trafficking (e.g., exocytosis and endocytosis), redox state, and cell cycle. Thus, eNOS-derived NO regulates a wide range of endothelial cell functions, such as inflammation, apoptosis, permeability, migration, and cell growth. PMID- 21554972 TI - Insights into the effect of nitric oxide and its metabolites nitrite and nitrate at inhibiting neointimal hyperplasia. AB - OBJECTIVE: Periadventitial delivery of the nitric oxide (NO) donor PROLI/NO following arterial injury effectively inhibits neointimal hyperplasia. Given the short half-life of NO release from PROLI/NO, our goal was to determine if inhibition of neointimal hyperplasia by PROLI/NO was due to NO, or its metabolites nitrite and nitrate. METHODS AND RESULTS: In vitro, the NO donor DETA/NO inhibited proliferation of rat aortic vascular smooth muscle cells (RASMC), but neither nitrite nor nitrate did. In vivo, following rat carotid artery balloon injury or injury plus the molar equivalents of PROLI/NO, nitrite, or nitrate (n=8-11/group), PROLI/NO was found to provide superior inhibition of neointimal hyperplasia (82% inhibition of intimal area, and 44% inhibition of medial area, p<0.001). Only modest inhibition was noted with nitrite or nitrate (45% and 41% inhibition of intimal area, and 31% and 29% inhibition of medial area, respectively, p<0.001). No effects on blood pressure were noted with any treatment groups. In vivo, only PROLI/NO inhibited cellular proliferation and increased arterial lumen area compared to injury alone (p<0.001). However, all three treatments inhibited inflammation (p<0.001). CONCLUSIONS: PROLI/NO was more effective at inhibiting neointimal hyperplasia following arterial injury than nitrite or nitrate. However, modest inhibition of neointimal hyperplasia was observed with nitrite and nitrate, likely secondary to anti-inflammatory actions. In conclusion, we have demonstrated that the efficacy of NO donors is primarily due to NO production and not its metabolites, nitrite and nitrate. PMID- 21554973 TI - Neuropeptide Y effect on food intake in broiler and layer chicks. AB - Broiler chicks eat more food than layer chicks. In this study, we examined the involvement of orexigenic peptide neuropeptide Y (NPY) in the difference in food intake between broiler and layer chicks (Gallus gallus). First, we compared the hypothalamic mRNA levels of NPY and its receptors (Y1 and Y5 receptors) between these strains at 1, 2, 4, and 8 days of age. Daily food intake was significantly higher in broiler chicks than layer chicks after 2 days of age. However, the hypothalamic NPY mRNA level was significantly lower in broiler chicks than layer chicks except at 8 days of age. In addition, the mRNA levels of NPY receptors were also significantly lower in broiler chicks than layer chicks at 2 and 4 days of age (Y1 receptor) or 2 days of age (Y5 receptor). These results suggest that the differences in the expressions of hypothalamic NPY and its receptors do not cause the increase in food intake in broiler chicks. To compare the orexigenic effect of NPY between broiler and layer chicks, we next examined the effects of central administration of NPY on food intake in these strains. In both strains, central administration of NPY significantly increased food intake at 2, 4 and 8 days of age. All our findings demonstrated that the increase in food intake in broiler chicks is not accompanied with the over-expression of NPY or its receptor. PMID- 21554974 TI - Calreticulin is crucial for calcium homeostasis mediated adaptation and survival of thick ascending limb of Henle's loop cells under osmotic stress. AB - The thick ascending limb of Henle's loop (TALH) is normally exposed to variable and often very high osmotic stress and involves different mechanisms to counteract this stress. ER resident calcium binding proteins especially calreticulin (CALR) play an important role in different stress balance mechanisms. To investigate the role of CALR in renal epithelial cells adaptation and survival under osmotic stress, two-dimensional fluorescence difference gel electrophoresis combined with mass spectrometry and functional proteomics were performed. CALR expression was significantly altered in TALH cells exposed to osmotic stress, whereas renal inner medullary collecting duct cells and interstitial cells exposed to hyperosmotic stress showed no significant changes in CALR expression. Moreover, a time dependent downregulation of CALR was accompanied with continuous change in the level of free intracellular calcium. Inhibition of the calcium release, through IP3R antagonist, prevented CALR expression alteration under hyperosmotic stress, whereas the cell viability was significantly impaired. Overexpression of wild type CALR in TALH cells resulted in significant decrease in cell viability under hyperosmotic stress. In contrast, the hyperosmotic stress did not have any effect on cells overexpressing the CALR mutant, lacking the calcium-binding domain. Silencing CALR with siRNA significantly improved the cell survival under osmotic stress conditions. Taken together, our data clearly highlight the crucial role of CALR and its calcium binding role in TALH adaptation and survival under osmotic stress. PMID- 21554975 TI - Editorial for the directed issue: "Metabolic pathways in cancer". PMID- 21554976 TI - The large GTPase dynamin2: a new player in connexin 43 gap junction endocytosis, recycling and degradation. AB - Connexins (Cx) are key regulators of cell proliferation, differentiation and apoptosis. Cx trafficking and endocytosis need interactions with a large number of signaling and scaffolding proteins. We demonstrate herein that Cx43-GFP gap junction plaque endocytosis was blocked in cells transfected by the dominant negative form of dynamin2 (Dyn2K44A) and by dynasore, an inhibitor of dynamin GTPase activity, which reduced the association between dynamin2 and Cx43. Our data also reveal that recruitment of the GTPase at the plasma membrane and its activation by c-Src are key events for Cx43 internalization. In addition they show that dynamin2 participated in internalization and degradation of the gap junction plaque but also in recycling of Cx43 to the plasma membrane through respectively Rab5/Rab7 and Rab11 pathways. These results demonstrate for the first time that dynamin2 is a new Cx partner and report an innovating mechanistic model by which dynamin2 may control Cx43 gap junction plaque invagination, endocytosis, recycling and degradation. These processes are magnified in response to carcinogen exposure underlining their potential importance during carcinogenesis. PMID- 21554977 TI - Mutual regulation of hypoxic and retinoic acid related signalling in tubular proximal cells. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) and all-trans retinoic acid (ATRA) afford protection in several experimental models of kidney disease. HIF-1alpha protein is degraded under normoxia but stabilized by hypoxia, which activates its transcription factor function. ATRA activates another set of transcription factors, the retinoic acid receptors (RAR) alpha, beta and gamma, which mediate its effects on target genes. ATRA also up-regulates the expression of RAR alpha, beta and gamma at the transcriptional level. Here we demonstrate the presence of mutual regulation of hypoxic and retinoic acid related signalling in tubular proximal cells. In human proximal tubular HK-2 cells we have found that: (i) ATRA treatment induces HIF-1alpha under normoxic conditions and also synergizes with hypoxia leading to the over-expression of HIF-1alpha and vascular endothelial growth factor-A, a HIF-1alpha-regulated renal protector. ATRA-induced HIF-1alpha expression involved stabilization of HIF-1alpha mRNA but not of HIF-1alpha protein. (ii) Expression of HIF-1alpha is an absolute requirement for the transcriptional up-regulation of RARbeta by ATRA. Transfection with HIF-1alpha siRNA abolished the induction by ATRA of the expression of both RARbeta mRNA and protein while treatment with HIF-1alpha inhibitor YC-1 results in the abolishment of ATRA-induced activity of a retinoic acid-response element (RARE) construct from the RARbeta promoter. (iii) Hypoxia up-regulates RARbeta through HIF-1alpha since this effect was inhibited by HIF-1alpha knockdown. In contrast to ATRA induced RARbeta up-regulation, induction of RARbeta expression by ATRA did not involve transcriptional up-regulation as hypoxia did not increase the expression of RARbeta mRNA or the activity of the RARE construct. These results suggest the presence of crosstalk between hypoxia/HIF-1alpha and ATRA/RARbeta that may be physiologically and pharmacologically relevant. PMID- 21554978 TI - Rendezvous in chemical space? Comparing the small molecule compound libraries of Bayer and Schering. AB - Here, we compare the entire compound collections of Bayer HealthCare and Schering AG with respect to structural identities, similarities and physico-chemical properties. We discuss possible consequences stemming from unexpected findings in light of new collaborative models in pharmaceutical research. PMID- 21554979 TI - Utility of protein structures in overcoming ADMET-related issues of drug-like compounds. AB - The number of solved X-ray structures of proteins relevant for ADMET processes of drug molecules has increased remarkably over recent years. In principle, this development offers the possibility to complement the quantitative structure property relationship (QSPR)-dominated repertoire of in silico ADMET methods with protein-structure-based approaches. However, the complex nature and the weak nonspecific ligand-binding properties of ADMET proteins take structural biology methods and current docking programs to the limit. In this review we discuss the utility of protein-structure-based design and docking approaches aimed at overcoming issues related to plasma protein binding, active transport via P glycoprotein, hERG channel mediated cardiotoxicity and cytochrome P450 inhibition, metabolism and induction. PMID- 21554980 TI - Comprehensive assessment of the photomutagenicity, photogenotoxicity and photo(cyto)toxicity of azulene. AB - The polycyclic aromatic hydrocarbon azulene and its naturally occurring derivative guaiazulene (1,4-dimethyl-7-isopropylazulene) are known to absorb light in the UV-vis region of the spectrum. Both compounds were reported to be mutagenic in the Salmonella typhimurium bacterial mutagenicity assay (Ames test) in strain TA102, and to cause DNA damage in the comet assay in vitro upon exposure to UVA light. In contrast, another study reported a photoprotective effect in vitro of guaiazulene. We present here a comprehensive assessment of the photo(cyto)toxicity (3T3 fibroblast Neutral Red uptake test), the photomutagenicity (Ames test) and photogenotoxicity (comet assay and micronucleus test in L5178Y cells in vitro) of azulene. In the Ames test, the mutagenicity of azulene was assessed in the presence and absence of UV light by use of the Salmonella strains TA102, TA104, TA2638 and E. coli WP2. Azulene was irradiated before being plated with bacteria (pre-irradiation), or concomitantly with the bacteria either after plating or while in suspension. Guaiazulene was included in some of the experiments. Neither in the photo-Ames test nor in the other photogenotoxicity tests, azulene or guaiazulene showed any photomutagenic or photogenotoxic activity. Weak photo(cyto)toxicity (estimate of PIF>=1.67) was observed with azulene in the 3T3 NRU test, the Alamar Blue test and the relative cell count, which may be due to the generation of reactive oxygen species, as reported recently. PMID- 21554981 TI - Comparative analysis of micronuclei and DNA damage induced by Ochratoxin A in two mammalian cell lines. AB - The fungal toxin, Ochratoxin A (OTA), is a common contaminant in human food and animal feed. The present study evaluated micronucleus (MN) induction by OTA in comparison with its ability to induce cytotoxicity and DNA damage in two mammalian cell lines, CHO-K1-BH(4) Chinese hamster ovary cells and TK6 human lymphoblastoid cells. Micronuclei were evaluated by flow cytometry, cytotoxicity was estimated by relative population doubling (RPD), while direct DNA damage and oxidative DNA damage were measured with the Comet assay, performed without and with digestion by formamidopyrimidine-DNA glycosylase (fpg). For the MN and cytotoxicity measurements, the cell lines were treated for 24h (CHO cells) or 27h (TK6 cells) with 5-25MUM OTA in the absence of exogenous metabolic activation. The OTA treatments resulted in concentration-responsive increases in cytotoxicity, with higher concentrations of the agent being more cytotoxic in CHO cells than TK6 cells. 15MUM OTA produced positive responses for MN induction and hypodiploid events (a measure of aneugenicity) in both cell lines; this concentration of OTA also produced cytotoxicity near to the recommended limit for the assay (45+/-5% RPD). A time course assay with TK6 cells indicated that at least 4h of OTA treatment were required to produce a positive MN response. For the Comet assay DNA damage assessments, the cell lines were treated with 5-50MUM OTA for 4h. Direct DNA damage was detected in TK6 cells, but not CHO cells, while concentration-related increases in fpg-sensitive sites were detected for both cell lines. The consistent association of oxidative DNA damage with OTA exposure suggests its involvement in producing OTA-induced clastogenicity and aneugenicity; however, based on its detection in TK6 cells direct DNA damage could be involved in any human risk posed by OTA exposure. PMID- 21554982 TI - Bis (monoacylglycero) phosphate interfacial properties and lipolysis by pancreatic lipase-related protein 2, an enzyme present in THP-1 human monocytes. AB - The interfacial physical properties of bis(monoacylglycero)phosphate (BMP) and its derivatives with three oleoyl chains (hemi-BDP) and four oleoyl chains (bis(diacylglycero)phosphate, BDP) were investigated using Langmuir monomolecular films. The mean molecular area of BMP at the collapse surface pressure (45mN m( 1)) was similar to those measured with other phospholipids bearing two acyl chains (66 and 59.6A(2) molecule(-1) at pH 5.5 and 8.0, respectively). In Hemi BDP and BDP, the mean molecular area increased by 26 and 35A(2) molecule(-1) per additional acyl chain at pH 5.5 and 8.0, respectively. When BMP was added to a phospholipid mixture mimicking late endosome membrane composition at pH 8.0, the mean phospholipid molecular area increased by 7% regardless of the surface pressure. In contrast, the variation in molecular area was surface pressure dependent at pH 5.5, a pH value close to that of intra-endosomal content. BMP and hemi-BDP, but not BDP, were hydrolyzed by pancreatic lipase-related protein 2 (PLRP2), which exhibits phospholipase A(1) activity. At pH 5.5, the maximum activities of PLRP2 on BMP were recorded at high surface pressures (25-35mN/m). At pH 8.0, the PLRP2 activity vs. surface pressure showed a bell-shaped curve with maximum activities at 15mN/m for both BMP and hemi-BDP. This is a new activity for this enzyme which could degrade cellular BMP since both human PLRP2 (HPLRP2) and BMP were localized in human monocytic THP-1 cells. This is the first report on the cellular localization of HPLRP2 in human monocytes. PMID- 21554983 TI - Retinoid chemistry: synthesis and application for metabolic disease. AB - In this review a discussion of the usual procedures used to synthesize retinoids is followed by an overview of the structure-activity relationships of these molecules. The discussion is then focused on the role and impact of retinoids on metabolic disorders with a particular emphasis on obesity, diabetes, and the metabolic syndrome. In these areas, both natural and synthetic retinoids that are being studied are reviewed and areas where likely future research will occur are suggested. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism. PMID- 21554984 TI - Biomedical complexity and error. PMID- 21554985 TI - Mutual information-based template matching scheme for detection of breast masses: from mammography to digital breast tomosynthesis. AB - Development of a computational decision aid for a new medical imaging modality typically is a long and complicated process. It consists of collecting data in the form of images and annotations, development of image processing and pattern recognition algorithms for analysis of the new images and finally testing of the resulting system. Since new imaging modalities are developed more rapidly than ever before, any effort for decreasing the time and cost of this development process could result in maximizing the benefit of the new imaging modality to patients by making the computer aids quickly available to radiologists that interpret the images. In this paper, we make a step in this direction and investigate the possibility of translating the knowledge about the detection problem from one imaging modality to another. Specifically, we present a computer aided detection (CAD) system for mammographic masses that uses a mutual information-based template matching scheme with intelligently selected templates. We presented principles of template matching with mutual information for mammography before. In this paper, we present an implementation of those principles in a complete computer-aided detection system. The proposed system, through an automatic optimization process, chooses the most useful templates (mammographic regions of interest) using a large database of previously collected and annotated mammograms. Through this process, the knowledge about the task of detecting masses in mammograms is incorporated in the system. Then, we evaluate whether our system developed for screen-film mammograms can be successfully applied not only to other mammograms but also to digital breast tomosynthesis (DBT) reconstructed slices without adding any DBT cases for training. Our rationale is that since mutual information is known to be a robust inter-modality image similarity measure, it has high potential of transferring knowledge between modalities in the context of the mass detection task. Experimental evaluation of the system on mammograms showed competitive performance compared to other mammography CAD systems recently published in the literature. When the system was applied "as-is" to DBT, its performance was notably worse than that for mammograms. However, with a simple additional preprocessing step, the performance of the system reached levels similar to that obtained for mammograms. In conclusion, the presented CAD system not only performed competitively on screen film mammograms but it also performed robustly on DBT showing that direct transfer of knowledge across breast imaging modalities for mass detection is in fact possible. PMID- 21554986 TI - Biliary stricture and negative cytology: what next? PMID- 21554987 TI - Early fluid resuscitation reduces morbidity among patients with acute pancreatitis. AB - BACKGROUND & AIMS: Early fluid resuscitation is recommended to reduce morbidity and mortality among patients with acute pancreatitis, although the impact of this intervention has not been quantified. We investigated the association between early fluid resuscitation and outcome of patients admitted to the hospital with acute pancreatitis. METHODS: Nontransfer patients admitted to our center with acute pancreatitis from 1985-2009 were identified retrospectively. Patients were stratified into groups on the basis of early (n = 340) or late resuscitation (n = 94). Early resuscitation was defined as receiving >=one-third of the total 72 hour fluid volume within 24 hours of presentation, whereas late resuscitation was defined as receiving <=one-third of the total 72-hour fluid volume within 24 hours of presentation. The primary outcomes were frequency of systemic inflammatory response syndrome (SIRS), organ failure, and death. RESULTS: Early resuscitation was associated with decreased SIRS, compared with late resuscitation, at 24 hours (15% vs 32%, P = .001), 48 hours (14% vs 33%, P = .001), and 72 hours (10% vs 23%, P = .01), as well as reduced organ failure at 72 hours (5% vs 10%, P < .05), a lower rate of admission to the intensive care unit (6% vs 17%, P < .001), and a reduced length of hospital stay (8 vs 11 days, P = .01). Subgroup analysis demonstrated that these benefits were more pronounced in patients with interstitial rather than severe pancreatitis at admission. CONCLUSIONS: In patients with acute pancreatitis, early fluid resuscitation was associated with reduced incidence of SIRS and organ failure at 72 hours. These effects were most pronounced in patients admitted with interstitial rather than severe disease. PMID- 21554988 TI - Patients with clinically significant portal hypertension caused by hepatitis C virus cirrhosis respond poorly to antiviral therapy. PMID- 21554989 TI - Cholecystocolonic fistula. PMID- 21554990 TI - Natural history of potential celiac disease. PMID- 21554991 TI - The GiSAS study: rationale and design of a pragmatic randomized controlled trial on aripiprazole, olanzapine and haloperidol in the long-term treatment of schizophrenia. AB - Given the controversy about the comparative efficacy of first- compared with second-generation antipsychotics in the treatment of schizophrenia, more large scale evidence is needed to guide clinicians in their prescriptions. Most randomized controlled trials (RCTs) were conducted in centers of excellence on highly selected samples, poorly representative of real-world patients, and often suffered conflicts of interest as they were sponsored by drug companies. The primary aim of the present study is to compare the effectiveness of haloperidol, olanzapine and aripiprazole in a representative sample of schizophrenia patients. The GiSAS trial is an open-label, independent, pragmatic RCT in Italian community based public psychiatric services. At least 260 patients meeting the DSM-IV criteria for schizophrenia will be randomly allocated to one of the study drugs and followed up for one year. A two-year observational phase will follow. The primary outcome for tolerability will be the onset of metabolic syndrome. The primary endpoint for effectiveness will be discontinuation of antipsychotic monotherapy. Secondary measures include global functioning, time to discontinuation due to side-effects, change of lipid profile, extrapyramidal symptoms and other adverse effects. In the last four years, the GiSAS study group has been working to implement this multicenter RCT. The trial mechanism is now fully functional and working. As of end of February 2011, 260 subjects were randomized by 54 study investigators in 33 out of 43 participating centers. PMID- 21554992 TI - The relative efficiency of time-to-threshold and rate of change in longitudinal data. AB - Randomized, placebo-controlled trials often use time-to-event as the primary endpoint, even when a continuous measure of disease severity is available. We compare the power to detect a treatment effect using either rate of change, as estimated by linear models of longitudinal continuous data, or time-to-event estimated by Cox proportional hazards models. We propose an analytic inflation factor for comparing the two types of analyses assuming that the time-to-event can be expressed as a time-to-threshold of the continuous measure. We conduct simulations based on a publicly available Alzheimer's disease data set in which the time-to-event is algorithmically defined based on a battery of assessments. A Cox proportional hazards model of the time-to-event endpoint is compared to a linear model of a single assessment from the battery. The simulations also explore the impact of baseline covariates in either analysis. PMID- 21554993 TI - A wide-spectrum paired comparison of the properties of the Rolling 6 and 3+3 Phase I study designs. AB - The recently proposed Rolling 6 Phase I study design is an alternative to the standard 3+3 patient cohort design. It was proposed as a way to reduce the time necessary to complete a trial by reducing the downtime during which Phase I trials are suspended for evaluation of dose-limiting toxicity (DLT). We performed a paired comparison of the Rolling 6 and 3+3 designs via a large simulation study over a wide spectrum of conditions defined by inter-patient arrival time, number of doses, DLT dose response slope, DLT dose response shape, and starting dose. Our results in general confirm that, on average, trials will be completed more quickly with the Rolling 6, with negligible penalty in terms of patient safety during the trial or as a result of the selected MTD, although the Rolling 6 on average will require more patients and thus will incur higher research costs. While the reduction in average trial duration with the Rolling 6 can be notable in absolute terms, in relative terms the reduction may be modest, in contrast to the relative increase in numbers of patients treated, which can be substantial. For identical sequences of patients, the difference between the two designs in trial duration and numbers of patients treated is highly variable. Therefore it is not so predictable whether the Rolling 6 will result in more rapid completion of a single trial or of a small series of trials. PMID- 21554994 TI - A values-based Motivational Interviewing (MI) intervention for pediatric obesity: study design and methods for MI Values. AB - To reduce pediatric obesity in clinical settings, multidisciplinary behaviorally based treatment programs are recommended. High attrition and poor compliance are two difficulties frequently encountered in such programs. A brief, empathic and directive clinical intervention, Motivational Interviewing (MI), might help address these motivational and behavioral issues, ultimately resulting in more positive health outcomes. The efficacy of MI as an adjunct in the treatment of pediatric obesity remains relatively understudied. MI Values was developed to implement within an existing multidisciplinary treatment program for obese, ethnically diverse adolescents, the T.E.E.N.S. Program (Teaching, Encouragement, Exercise, Nutrition, Support). T.E.E.N.S. participants who consent to MI Values are randomized to either MI or an education control condition. At weeks 1 and 10 of T.E.E.N.S. participation, the subset of participants assigned to the MI condition engages in individual MI sessions and control participants view health education videos. All MI sessions are audiotaped and coded to monitor treatment fidelity, which has been satisfactory thus far. Participants complete comprehensive assessments at baseline, 3- and 6-month follow-ups. We hypothesize that MI participants will demonstrate greater reductions in Body Mass Index (BMI) percentile, improved diet and physical activity behaviors, better compliance with T.E.E.N.S., and lower attrition than participants in the control group. We present study design and methods for MI Values as well as data on feasibility of recruitment methods and treatment integrity. At study completion, findings will contribute to the emerging literature examining the efficacy of MI in the treatment of pediatric obesity. PMID- 21554995 TI - Analysis of trematode parasite communities in fish eye lenses by pyrosequencing of naturally pooled DNA. AB - Infections by multiple parasite species are common in nature and have important consequences for between-species interactions and coevolutionary dynamics with the host populations. For example, ecological and evolutionary factors underlying the structure of parasite communities determine the range of hosts a parasite can infect and set the basis for both evolution of host defences and parasite virulence, as well as management of diseases. Studies investigating these factors have been facilitated in the recent past by genetic methods, which surmount difficulties of traditional morphological taxonomy in identifying individual parasite species. Here we take a step further and present a novel methodological approach to analyze parasite communities as a whole. We determined the relative frequencies of interspecific SNP alleles by pyrosequencing naturally pooled samples of closely related Diplostomum spp. trematodes infecting eye lenses of freshwater fish. Pyrosequencing allowed us to use naturally pooled community samples (lenses) to increase the sample size and statistical power, without sequencing single parasite specimens. In a case study, we applied this method to analyze the community structure of the eye flukes across fish host species of a freshwater system in Finland. We found that the fish species harboured significantly different parasite communities and that multiple species infections were common. Our study provides an example of how quantitative pyrosequencing can be used to answer evolutionary and ecological questions in natural communities of parasites. PMID- 21554996 TI - High baseline interleukine-8 level is an independent risk factor for the achievement of sustained virological response in chronic HCV patients. AB - Hepatitis C virus (HCV), a major cause of liver disease throughout the world, is difficult to treat with interferon (IFN) (and various formulations and combinations thereof) being the only approved molecule available. It has been investigated recently that proinflammatory chemokine interleukin-8 (IL-8) induced by HCV partially inhibits the antiviral IFN-alpha therapy. Therefore, the current study was aimed to prospectively utilize the baseline IL-8 levels in the HCV infected serum and predicts its role in sustained virological response (SVR) to IFN-alpha+ribavirin therapy, in chronic HCV patients in Pakistan. One hundred and ten hepatitis C patients without any other infections underwent IFN alpha+ribavirin combination treatment. Baseline IL-8 levels were determined before starting of the therapy for all these patients. Fifteen normal volunteers negative for HCV were kept as control. The baseline IL-8 levels were found significantly higher in all HCV positive patients as compared to normal healthy volunteers (1083.54 +/- 85.72 pg/ml versus 6.99 +/- 1.05 pg/ml [mean +/- SEM], p<0.01) and were also significantly higher in non-responders than responders (p<0.05). Comparatively higher mean baseline IL-8 levels were observed in non responders (2442.02 +/- 159.92 pg/ml), than late (1009.31 +/- 45.31) and rapid (540.91 +/- 27.06 pg/ml) responders. Significant relation was observed between baseline IL-8 level and response to IFN therapy (p<0.01). Results of this study suggest that increased levels of IL-8 in HCV infection might be involved in pathogenesis, persistence and resistance to IFN-alpha+ribavirin combination therapy. PMID- 21554997 TI - Widespread carbapenem resistant Acinetobacter baumannii clones in Italian hospitals revealed by a multicenter study. AB - Population diversity, susceptibility to antibiotics including carbapenems of 277 Acinetobacter baumannii strains collected in 17 Italian hospitals over a 6 months' period was assessed. Semi-automated rep-PCR was used for screening strains for genotypic relatedness. AFLP analysis and MLST were used as definitive methods for strain, species and/or clone identification. Among the 277 strains, 49 rep-PCR types were distinguished with four types (1-4) predominant, indicating both intra- and interhospital spread. AFLP analysis allowed to distinguish 51 types and largely confirmed rep-typing results. Isolates with predominant rep types 1 and 2 (in 3 and 9 hospitals) were allocated to EU clones I and II, respectively. Rep-type 3 (8 hospitals) belonged to a new clone ("Italian clone"). Rep-type 4 was found in 2 neighbouring hospitals. Two isolates from 2 locations belonged to EU clone III. Twenty-five isolates were identified by AFLP-analysis to A. pittii, emphasizing misidentification by phenotypic methods. MLST confirmed clone identification by AFLP; demonstrating also that the "Italian clone" was ST78, recently detected in different Mediterranean countries. Multidrug resistance, defined as resistance to 9 out of the 11 drugs tested, was common in 10 out of 17 hospitals. The high prevalence of carbapenem resistance was associated with OXA-58 found in 9 out of the 10 hospitals. A high percentage of noted very major errors in susceptibility testing, especially for amikacin and meropenem, was probably due to heteroresistant strains. The occurrence of carbapenem and multidrug resistance in A. baumannii was mainly confined to a limited number of clonal lineages of A. baumannii. PMID- 21554998 TI - Genetic diversity of Plasmodium vivax Duffy Binding Protein II (PvDBPII) under unstable transmission and low intensity malaria in Sri Lanka. AB - Elucidating the genetic diversity of the Duffy Binding Protein II (PvDBPII), a leading vaccine candidate for vivax malaria, in different geographical settings is vital. In Sri Lanka malaria transmission is unstable with low intensity. A relatively high level of allelic diversity, with 27 polymorphic nucleotides and 33 (aa) haplotypes was detected among the PvdbpII gene in 100 local Plasmodium vivax isolates collected from two hypoendemic areas, and from a non endemic area of the country. Mutations, recombination and balancing selection seem to maintain the observed local allelic diversity of PvdbpII. Lack of gene flow was evidenced by high Fst values between the two endemic study sites. Some of the aa polymorphisms may alter the binding and expression capacity of predicted T cell epitopes in PvDBPII. Of the 8 binding inhibitory linear B cell epitopes, 2 (H2 and M1) in the vicinity of the exact binding region of PvDBPII appeared to be highly conserved in Sri Lankan, Iran and Colombian isolates, while H3, M2, M3 and L3 neutralizing epitopes seem to be polymorphic globally, with H1 and L2 conserved in Colombian, South Korean and Iran isolates. In comparison to the reference Sal-1 strain, among 402 world-wide isolates (302 global and 100 local), 121 aa polymorphisms and 138 haplotypes were recorded of which 3 aa polymorphisms and 21 haplotypes seem to be unique to Sri Lanka. PvdbpII phylogeny suggests that local P. vivax parasites represent a sample of the global population. The ubiquitous presence of some PvDBPII aa haplotypes among both local and global P. vivax isolates may aid future vaccination strategies based on PvDBPII. PMID- 21554999 TI - Polymorphism of 3'UTR region of TNFR2 coding gene and its role in clinical tuberculosis in Han Chinese pediatric population. AB - Genetic factors of human susceptibility to tuberculosis (TB) are multiple and their effect may be ethnic- and age-dependent. TNFR2 encoded by the TNFRSF1B gene is one of the important TNF-alpha receptors; its polymorphisms were previously suggested as potential markers of host susceptibility to TB. Here, genotyping of three SNPs in TNFRSF1B 3'UTR (rs1061624, rs5030792, rs3397) was performed in Han Chinese pediatric population (229 TB patients and 233 control subjects). rs5030792 was found homozygous (TT genotype) in all studied individuals. The rs3397-T allele was almost equally represented in both gender groups in this study; in particular, it was detected in 33.9% and 35.2% in female cases and controls, respectively (P=0.8). This latter result differs strikingly from an African study where rs3397-T was found in only 12.8 and 16.2% of Ghanaian female cases and controls, respectively (P=0.007 [Moller et al., 2010. Am. J. Respir. Crit. Care. Med. 181, 388-393]). In contrast, rs1061624-A allele, acting recessively, was found to be a possible risk factor for clinical TB in females (P=0.03). The rs1061624 heterozygotes were overdominant in controls versus patients (P=0.015) that warrants further study of their hypothetical advantage in TB. Neither of the common haplotypes was associated with susceptibility to TB. Compared to the published contrasting data on African (7-15%) and European (57%) populations, GTT haplotype was found in an intermediate frequency (26%). Further studies on both adult and pediatric populations in ethnically diverse settings are needed to elucidate the functionality of these 3'UTR SNPs of the TNFR2 gene. PMID- 21555000 TI - Morphological differences of the carotid body among C57/BL6 (B6), A/J, and CSS B6A1 mouse strains. AB - The C57/BL6 (B6) mouse strain exhibits post-hypoxic frequency decline and periodic breathing, as well as greater amount of irregular breathing during rest in comparison to the A/J and to the B6a1, a chromosomal substitution strain whereby the A/J chromosome 1 is bred onto the B6 background (Han et al., 2002; Yamauchi et al., 2008a,b). The hypothesis was that morphological differences in the carotid body would associate with such trait variations. After confirming strain differences in post-hypoxic ventilatory behavior, histological examination (n=8 in each group) using hematoxylin and eosin (H&E) staining revealed equivalent, well-defined tissue structure at the bifurcation of the carotid arteries, an active secretory parenchyma (type I cells) from the supportive stromal tissue, and clustering of type I cells in all three strains. Tyrosine hydroxylase (TH) immunohistochemical staining revealed a typical organization of type I cells and neurovascular components into glomeruli in all three strains. Image analysis from 5 MUm sections from each strain generated a series of cytological metrics. The percent carotid body composition of TH+ type I cells in the A/J, B6 and B6a1 was 20+/-4%, 39+/-3%, and 44+/-3%, respectively (p=0.00004). However, cellular organization in terms of density and ultrastructure in the B6a1 is more similar to the B6 than to the A/J. These findings indicate that genetic mechanisms that produce strain differences in ventilatory function do not associate with carotid body structure or tyrosine hydroxylase morphology, and that A/J chromosome 1 does not contribute much to B6 carotid body morphology. PMID- 21555001 TI - Proteomic identification of binding targets of isothiocyanates: A perspective on techniques. AB - Intake of cruciferous vegetable is inversely associated with the risk of several cancer types. Isothiocyanates (ITCs) are believed to be important constituents contributing to these cancer-preventive effects. Although several mechanisms, including induction of apoptosis, have been proposed for the anti-carcinogenesis activities of ITCs, detailed upstream triggering events are still not fully understood. Identification of ITC binding targets in cellular proteins is crucial for not only mechanistic studies but also future drug screening and design. In this review, we summarize recent progress in discovery of ITC protein targets from a technical perspective. The advantages and limitations of each method are discussed to facilitate future studies on target discovery of ITCs and perhaps other compounds. PMID- 21555002 TI - EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1. AB - EVI1 (Ecotropic Viral Integration site I), which was originally identified as a site of viral integration in murine myeloid tumors, encodes a complex protein required for embryogenesis. The gene is known to express inappropriately in many types of human myeloid leukemias and solid tumors. Forced expression of EVI1 in murine hematopoietic precursor cells lead to abnormal differentiation and increased proliferation. EVI1 encodes two sets of zinc finger domains due to which it behaves as a transcriptional factor. However, except a few, the targets of EVI1 are not well understood and hence also the mechanism by which it initiates oncogenesis is not very clear. In this report, we show that SIRT1, a histone deacetylase is a direct target of EVI1. In vivo chromatin immunoprecipitation assay revealed that EVI1 binds to the promoter region of SIRT1 approximately 1kb upstream of the transcription start site. The functionality of the site was deduced by luciferase assay which showed that EVI1 significantly increases the SIRT1 promoter activity. SIRT1 was also found to be up regulated in cell lines and in chronic myeloid leukemia patient samples where EVI1 was detected. Over expression of SIRT1 in cells shows that it interacts with EVI1 and this interaction lead to the deacetylation of the protein. Upon deacetylation the stability of EVI1 was found to be affected which was negatively regulated by nicotinamide (NAM). Our results thus identify an EVI1-SIRT1 axis in the regulation of EVI1 activity suggesting a possible role of SIRT1 in EVI1 positive neoplasms. PMID- 21555003 TI - Bisphosphonates: the first 40 years. AB - The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40years to review the history of their development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from 'bench to bedside'. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural 'water softener' in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (gammadelta) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved 'block-buster' status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New 'designer' BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over. PMID- 21555004 TI - Osteoblast/osteocyte-specific inactivation of Stat3 decreases load-driven bone formation and accumulates reactive oxygen species. AB - Signal transducers and activators of transcription 3 (Stat3) is a transcription factor expressed in many cell types including osteoblasts, osteocytes, and osteoclasts. STAT3 mutations cause a rare human immunodeficiency disease that presents reduced bone mineral density and recurrent pathological fractures. To investigate the role of Stat3 in load-driven bone metabolism, two strains of osteoblast/osteocyte-selective Stat3 knockout (KO) mice were generated. Compared to age-matched littermate controls, this selective inactivation of Stat3 significantly lowered bone mineral density (7-12%, p<0.05) as well as ultimate force (21-34%, p<0.01). In ulna loading (2.50-2.75N with 120 cycles/day at 2Hz for 3 consecutive days), Stat3 KO mice were less responsive than littermate controls as indicated by reduction in relative mineralizing surface (rMS/BS, 47 59%, p<0.05) and relative bone formation rate (rBFR/BS, 64-75%, p<0.001). Furthermore, inactivation of Stat3 suppressed load-driven mitochondrial activity, which led to an elevated level of reactive oxygen species (ROS) in cultured primary osteoblasts. Taken together, the results support the notion that the loss of-function mutation of Stat3 in osteoblasts and osteocytes diminishes load driven bone formation and impairs the regulation of oxidative stress in mitochondria. PMID- 21555005 TI - The devil is in the details: methodological reviews - a new JMCC initiative. PMID- 21555006 TI - Endocrine assessment of prepubertal boys with a history of cryptorchidism and/or hypospadias: a pilot study. AB - PURPOSE: Four disorders, including poor semen quality, testicular cancer, cryptorchidism and hypospadias, are thought to represent testicular dysgenesis syndrome and have been hypothesized to share a common etiology. We predicted testicular function in prepubertal boys with a history of cryptorchidism and/or hypospadias by measuring serum hormone levels. MATERIALS AND METHODS: A total of 82 prepubertal boys who underwent orchiopexy and/or hypospadias repair in childhood were enrolled in the study. Patients were surgically treated for cryptorchidism (23 in group 1), hypospadias (49 in group 2), cryptorchidism and hypospadias (10 in group 3), and hydrocele testis (7 in control group 4). Serum hormones, including luteinizing hormone, follicle-stimulating hormone and total testosterone, were measured separately by age less than 12.5, 12.5 to 13.5 and greater than 13.5 years, and by Tanner pubertal stage. RESULTS: Follicle stimulating hormone in group 3 was significantly higher than in groups 1, 2 and 4 at ages 12.5 to 13.5 and greater than 13.5 years, and for Tanner stages 2 and 3 (p <0.05). However, luteinizing hormone and testosterone did not differ among the groups regardless of age or Tanner stage. Group 3 patients had significantly higher follicle-stimulating hormone regardless of the severity of cryptorchidism or hypospadias. CONCLUSIONS: Data suggest that testicular function in patients with cryptorchidism plus hypospadias is more severely impaired than that in patients with cryptorchidism or hypospadias, lending clinical support to the testicular dysgenesis syndrome hypothesis of a common origin. PMID- 21555007 TI - Editorial comment. PMID- 21555009 TI - Evolution of single practice trends in the surgical approach to the undescended testicle. AB - PURPOSE: The surgical approach to palpable and nonpalpable testicles has changed with increasing use of a single scrotal incision and laparoscopy, respectively. We identified current trends in the surgical approach to undescended testicles in the practice of a single surgeon at our institution. MATERIALS AND METHODS: A total of 580 orchiopexies were performed in 554 patients by a single surgeon between January 2002 and July 2009. Study inclusion criteria were palpable and nonpalpable primary undescended testicles. Patients were stratified into groups based on the date of the initial procedure by year. A retrospective chart review was performed and the surgical approach in each patient was recorded as laparoscopic, transinguinal abdominal, inguinal or scrotal. RESULTS: During the 7 year period the percent of orchiopexies performed through a single scrotal incision increased from approximately 15% to a high of 63%. The overall percent of cases performed through a standard inguinal incision decreased from 65% to 17% and the percent performed through a transinguinal abdominal approach decreased from 15% to 0% in the 2 most recent years tabulated. The use of laparoscopy increased from 3% to 17%. CONCLUSIONS: Substantial trends were observed among the 3 groups. The percent of procedures performed through a scrotal incision increased during the 7-year period while the percent of inguinal and transinguinal abdominal procedures decreased concomitantly with no increase in morbidity. Selected use of scrotal approach orchiopexy is safe and effective for palpable undescended testicles. PMID- 21555010 TI - Editorial comment. PMID- 21555012 TI - Management of the looping vas deferens during laparoscopic orchiopexy. AB - PURPOSE: A number of variables should be assessed during laparoscopic orchiopexy, including vas anatomy. A looping vas deferens enters the inguinal canal and loops back to the abdominal cavity. This anatomical variant is not uncommonly encountered. Some groups considered this condition in their laparoscopic classification of nonpalpable testis. We present our experience with managing the looping vas during laparoscopic orchiopexy. MATERIALS AND METHODS: We identified this condition in 18 procedures. In 14 cases it was possible to bring the vas back to the abdominal cavity. In 3 cases the loop could not be brought back laparoscopically and an inguinal incision was used. After the vas was dissected free and dropped into the abdominal cavity pneumoperitoneum was resumed and the procedure was completed laparoscopically. A Web based survey was done to test the value of this method. RESULTS: A total of 17 procedures were completed successfully with preservation of the vas deferens while in 1 the vas was inadvertently cut. A looping vas did not significantly affect operative time. All 18 testes were viable and retained the scrotal position on followup scrotal Doppler ultrasound. CONCLUSIONS: Verification of vasal anatomy is a crucial step that should be completed before any dissection. Bringing a looping vas back to the abdominal cavity is usually feasible laparoscopically but in a few cases this may require a small incision to dissect the vasal loop from its inguinal attachments. PMID- 21555014 TI - Editorial comment. PMID- 21555015 TI - Salvage of bilateral asynchronous perinatal testicular torsion. AB - PURPOSE: Current management strategies for prenatal torsion include observation alone, delayed contralateral orchiopexy and emergent contralateral orchiopexy. Bilateral torsion is now being reported with more frequency and approximately a third of these patients have asynchronous torsion. We highlight the role of scrotal exploration in neonates diagnosed with bilateral asynchronous testicular torsion. MATERIALS AND METHODS: We reviewed the clinical experience from 2000 to present of 2 senior pediatric urologists to identify cases of bilateral perinatal testicular torsion. Asynchronous torsion was identified by the varying physical findings of each testicle at exploration. A literature review was done to evaluate the evolving management of perinatal testicular torsion. RESULTS: Six cases of bilateral perinatal torsion were identified since 2000. In 3 of the 6 cases extravaginal torsion of the contralateral testis was incidentally identified at surgical exploration. All 3 testes had normal Doppler flow before exploration. Testicular salvage was not successful in the 2 patients with bilaterally absent blood flow on newborn ultrasound. The 3 cases of incidentally diagnosed contralateral torsion and 1 of preoperatively diagnosed contralateral torsion were successfully salvaged. Thus, 4 of 6 patients with bilateral torsion were left with 1 viable testis. CONCLUSIONS: Physical examination findings and radiography can be inaccurate to assess the contralateral testis in males born with prenatal torsion. We have adopted the strategy of emergent surgical exploration in cases of prenatal torsion. Using this approach anorchia was minimized in patients with bilateral asynchronous torsion. PMID- 21555016 TI - Editorial comment. PMID- 21555017 TI - Familial testicular torsion. AB - PURPOSE: Isolated reported cases of familial torsion yield modest information on incidence, genetics or clinical features. We present what is to our knowledge the largest series of familial torsion, including the first 3 generation case and a review of the literature. MATERIALS AND METHODS: Since 2006, we have questioned the presence of a positive family history in all patients with torsion at the initial consultation. We compiled data on familial relationship, laterality, age and outcomes of the proband and affected relatives. We collected previously published cases to better understand clinical features and genetics. RESULTS: Eight of 70 boys (11.4%) with torsion had affected family members. Another 2 families were included from a historical perspective. One relative was affected in 7 families, 2 were affected in 2 and 3 were affected in 1. First degree relatives were most commonly affected. In 1 family torsion occurred in 3 consecutive generations. Despite a family history 50% of patients experienced testicular loss. Brothers were affected in each of the 10 previously reported cases. In 3 families fathers were also affected. There were 3 sets of monozygotic twins. We noted laterality concordance 5 times and discordance 6 times. Age at torsion in probands was adolescence except in 2 with neonatal torsion. No clear inheritance mode was found. CONCLUSIONS: Familial torsion occurs in about 10% of probands and can affect multiple relatives and generations. A positive family history may be useful for torsion diagnosis and management. Relatives of affected patients need education on the signs and symptoms of torsion, and the importance of early presentation to improve outcome. PMID- 21555018 TI - Editorial comment. PMID- 21555019 TI - Outcomes of hypospadias repair in older children: a prospective study. AB - PURPOSE: The American Academy of Pediatrics recommendation is to perform hypospadias repair at age 6 to 12 months. However, our patient population included a significant proportion of patients in adolescence and beyond undergoing primary repair. We report a comparison of outcomes in patients in different age groups. MATERIALS AND METHODS: We prospectively report on patients with distal hypospadias who underwent primary repair at our institution during 7 months. Study parameters included age, degree of hypospadias, surgical technique and the complications rate. RESULTS: A total of 61 patients were included in analysis. All cases underwent repair using the tubularized incised plate technique. More proximal hypospadias and different repair techniques were excluded from study. Patients were classified by age, including group 1-25 (40%) 6 months to 2 years old, group 2-17 (28%) 2.2 to 3.7 years old and group 3-19 (32%) 4 years old or older. Only 6 patients (9.8%) had postoperative complications and all were in groups 2 and 3. In group 2 there were 3 complications (17.6%), including loss of repair, meatal stenosis and hematoma in 1 case each. In group 3 there were 3 cases (15.8%) of postoperative fistula. The fistula incidence was higher in group 3 (p = 0.032). CONCLUSIONS: Despite previous reports suggesting a much higher incidence of complications in older children the complication rate is within the acceptable range for infant hypospadias repair in some series. However, these complications were statistically significantly different between the older groups when compared with the recommended age group under American Academy of Pediatrics guidelines. PMID- 21555021 TI - Editorial comment. PMID- 21555022 TI - Posterior urethral valves: multivariate analysis of factors affecting the final renal outcome. AB - PURPOSE: Posterior urethral valves represent the most common obstructive uropathy in children with a broad spectrum of clinical severity. We evaluated prognostic variables affecting the outcome of renal function in such children. MATERIALS AND METHODS: Between 1987 and 2004, 120 patients with a mean age of 2 years with posterior urethral valves were treated initially with valve ablation at our center. We studied certain parameters, including age at presentation, serum creatinine (initial and nadir), initial creatinine clearance, renal ultrasound findings (hydronephrosis and renal parenchymal echogenicity), vesicoureteral reflux on initial voiding cystourethrogram, bladder dysfunction and popoff mechanisms such as the syndrome of large vesical diverticulum, urinoma and ascites. Long-term renal outcome was assessed. RESULTS: Followup was 2 to 16 years (median 3.6). Renal insufficiency developed at the end of followup in 44 patients (36.5%). Serum creatinine at hospital admission, nadir serum creatinine, initial creatinine clearance and renal parenchymal echogenicity were significant predictors of the final renal outcome (p < 0.05). Patient age at diagnosis (2 or less vs greater than 2 years), upper tract dilatation, the presence or absence of vesicoureteral reflux, popoff mechanisms and bladder dysfunction had no significant impact on future renal function. On multivariate analysis nadir serum creatinine was the only independent prognostic factor. CONCLUSIONS: Our data confirm the high prognostic value of nadir creatinine after primary valve ablation. Also, initial serum creatinine, creatinine clearance and renal parenchymal echogenicity on initial renal ultrasound correlate significantly with long-term renal function in children with posterior urethral valves. PMID- 21555023 TI - Editorial comment. PMID- 21555024 TI - Setting the speed limit: a pilot study of the rate of serum creatinine decrease after endoscopic valve ablation in neonates. AB - PURPOSE: In neonates with a posterior urethral valve serum creatinine is increased. It decreases after successful relief of obstruction. Clinicians consider urinary diversion if serum creatinine remains increased. However, the optimal rate of decrease of serum creatinine is not defined. We generated useful data on the rate of serum creatinine decrease in neonates with a posterior urethral valve by introducing the idea of a prediction curve. MATERIALS AND METHODS: We reviewed the medical charts of 15 consecutive children treated for a posterior urethral valve in the neonatal period at our institute between 2002 and 2007. The 11 children with a delayed diagnosis of a posterior urethral valve were excluded from analysis. Serial serum creatinine levels in the cohort of 15 patients were analyzed to estimate 1) the rate of decrease after valve ablation and 2) the time needed to achieve a nadir. RESULTS: One child died of renal insufficiency on day 10 of life and was excluded from study. Serum creatinine attained a nadir at about age 6 months but 73% of the total decrease occurred within the first 2 months of life, which was also equal to a 45% decrease from the peak values recorded soon after birth. The rate of decrease did not appear to be influenced by the peak values. Children with normal peak creatinine or intercurrent problems did not follow the trend. CONCLUSIONS: The rate of decrease in serum creatinine in the first few months of life may provide useful information on the adequacy of valve ablation. PMID- 21555025 TI - Editorial comment. PMID- 21555027 TI - Comparison of the learning curve and outcomes of robotic assisted pediatric pyeloplasty. AB - PURPOSE: We compared the learning curve and outcomes in children undergoing robotic assisted laparoscopic pyeloplasty during the initiation of a robotic surgery program compared to the benchmark of open pyeloplasty. MATERIALS AND METHODS: The records of our first consecutive 33 children undergoing robotic assisted laparoscopic pyeloplasty from 2006 to 2009 were retrospectively reviewed and compared to those of age and gender matched children who underwent open repair done by senior faculty surgeons before the initiation of our robotic surgery program. We compared operative time, complications, postoperative pain, length of stay and surgical success for 2 surgeons who adopted the robotic approach at an academic teaching institution. RESULTS: We found no significant differences in length of stay, pain score or surgical success at a median followup of 16 months. The number of complications was similar and they tended to be early and technical in the robotic assisted laparoscopic pyeloplasty group. Overall average operative time was 90 minutes longer (38%) for robotic assisted laparoscopic pyeloplasty (p <0.004). When evaluated chronologically, there was evidence of a learning curve. After 15 to 20 robotic cases overall operative times for robotic assisted laparoscopic cases was consistently within 1 SD of our average open pyeloplasty time with no significant difference in overall operative time (p = 0.23). Of the decrease in overall operative time 70% was due to decreased pyeloplasty time rather than peripheral time. CONCLUSIONS: There was similar safety and efficacy with robotic assisted laparoscopic pyeloplasty, although complications tended to be technical and early in our initial experience. Operative time decreased with experience and after 15 to 20 cases it was similar to that of open pyeloplasty with similar outcomes and surgical success. PMID- 21555028 TI - Editorial comment. PMID- 21555029 TI - Salvage dextranomer-hyaluronic acid copolymer for persistent reflux after ureteral reimplantation: early success rates. AB - PURPOSE: Endoscopic injection of dextranomer-hyaluronic acid copolymer is an accepted initial procedure to correct vesicoureteral reflux. Less data are available on its role in treating failed ureteral reimplantation. MATERIALS AND METHODS: We retrospectively reviewed the charts from 2002 to 2008 and identified 21 patients (26 ureteral units) with persistent reflux after reimplantation. RESULTS: Mean age was 7 years (range 2 to 13). Mean followup was 2 years (range 10 to 46 months). Of the 17 patients with a single system ureteral reimplantation was extravesical in 9 and intravesical in 8 with tapering performed in 5. Three patients underwent reimplantation of duplex systems and 1 underwent reimplantation due to ureterocele. Residual reflux grade was 1 to 4 in 3 (11%), 17 (65%), 3 (11%) and 3 ureteral units (11%), respectively. Dextranomer hyaluronic acid copolymer was injected transurethrally. The mean volume injected was 1.2 ml (range 0.7 to 3). After 1 injection reflux resolved in 15 patients (71%) or a total of 20 ureteral units (77%), including 12 of 14 (86%) extravesically and 8 of 12 (66%) intravesically reimplanted units. The resolution rate improved to 84% after multiple injections. Two of the 6 patients with reflux after 1 injection had a single system, 2 had an obstructive megaureter with tapered reimplantation, 1 had a duplicated system and 1 had a ureterocele. Three of the 5 patients with persistent reflux underwent revision surgery. Ureteral abnormalities other than reflux and tapered reimplantation were associated with a statistically significant inferior success rate. CONCLUSIONS: Dextranomer hyaluronic acid copolymer injection is an efficacious salvage procedure for persistent reflux after ureteral reimplantation. The success rate is inferior for ureteral abnormalities other than primary vesicoureteral reflux and after tapering. PMID- 21555030 TI - Editorial comment. PMID- 21555031 TI - Can we rely on the presence of dextranomer-hyaluronic acid copolymer mounds on ultrasound to predict vesicoureteral reflux resolution after injection therapy? AB - PURPOSE: We determined whether the presence or absence of dextranomer-hyaluronic acid copolymer mounds on bladder ultrasound coincides with voiding cystourethrogram results after injection therapy in children with primary vesicoureteral reflux. MATERIALS AND METHODS: We retrospectively reviewed consecutive cases of dextranomer-hyaluronic acid copolymer injection for primary vesicoureteral reflux. The primary outcome investigated was the appearance of dextranomer-hyaluronic acid copolymer mounds on ultrasound and their association with voiding cystourethrogram results postoperatively. An intramural dextranomer hyaluronic acid copolymer mound on ultrasound was considered a negative test result for vesicoureteral reflux. RESULTS: A total of 187 cases were identified, of which 132 had imaging available for evaluation. Intramural mounds were seen on ultrasound in 86 cases postoperatively, of which 34 (40%) had a positive voiding cystourethrogram. Of 46 cases in which no mound was identified 21 (46%) had a positive voiding cystourethrogram. The sensitivity of ultrasound to determine the presence or absence of vesicoureteral reflux was 38%, specificity was 67%, accuracy was 55%, the positive predictive value was 46% and the negative predictive value was 60%. CONCLUSIONS: Our results indicate poor correlation of dextranomer-hyaluronic acid copolymer mound appearance on ultrasound with voiding cystourethrogram results after injection. To adequately evaluate for the resolution of vesicoureteral reflux a voiding cystogram or nuclear medicine cystogram needs to be performed after injection therapy. PMID- 21555032 TI - Editorial comment. PMID- 21555033 TI - Editorial comment. PMID- 21555034 TI - The efficacy of oral midazolam for decreasing anxiety in children undergoing voiding cystourethrogram: a randomized, double-blind, placebo controlled study. AB - PURPOSE: Voiding cystourethrogram is an invasive test that evokes anxiety. Our primary aim was to determine whether midazolam is beneficial in decreasing anxiety in children who undergo voiding cystourethrogram. Secondary aims were an examination of parent anxiety, health care professional perceptions and post procedure behavioral outcomes in children after voiding cystourethrogram. MATERIALS AND METHODS: A total of 44 children were randomized to placebo or oral midazolam before voiding cystourethrogram in double-blind fashion. The Modified Yale Preoperative Anxiety Scale was used to evaluate child behavior before and during voiding cystourethrogram, and the Post Hospitalization Behavior Questionnaire was used to investigate any short-term and intermediate-term behavioral outcomes. The State-Trait Anxiety Inventory was used to evaluate parent personal anxiety during voiding cystourethrogram. A separate questionnaire was administered to radiology staff. Statistical analysis included the 2-sample t and Fisher exact tests. RESULTS: There was no difference in Modified Yale Preoperative Anxiety Scale scores in children randomized to midazolam or placebo. There was also no significant difference in parent anxiety. Radiology care providers identified no reliable benefit when blinded to sedation vs placebo. We did not note any post-procedural behavior issues after voiding cystourethrogram at up to 6 months of followup. CONCLUSIONS: Midazolam may not significantly help with child or parent anxiety during voiding cystourethrogram. No reliable benefit was noted according to radiology health care provider perception and there was no significant post-procedural behavior benefit. Midazolam may not provide a significant benefit in decreasing anxiety during voiding cystourethrogram. PMID- 21555035 TI - Editorial comment. PMID- 21555036 TI - Bladder neck reconstruction is often necessary after complete primary repair of exstrophy. AB - PURPOSE: A major goal of bladder exstrophy management is urinary continence, often using bladder neck reconstruction. We report our experience with bladder neck reconstruction after complete primary repair of exstrophy. MATERIALS AND METHODS: Patient history, ultrasound, voiding cystourethrogram, examination using anesthesia and urodynamics were performed during a prospective evaluation. Continence was assessed using the International Children's Continence Society classification and the dry interval. Bladder capacity was measured by examination using anesthesia, voiding cystourethrogram and/or urodynamics. Urodynamics were also done to assess bladder compliance and detrusor muscle function. RESULTS: From 1994 to 2010 we treated 31 male and 15 female patients with bladder exstrophy after complete primary repair of exstrophy. Of patients 5 years old or older bladder neck reconstruction was performed after complete primary repair in 9 of 21 males (43%) and in 3 of 11 females (27%) at a mean age of 6.3 and 8.1 years, respectively. By the International Children's Continence Society classification 6 of 12 patients (50%) were continent less than 1.5 years after bladder neck reconstruction and 2 of 9 (23%) were evaluable 1.5 years or greater after reconstruction. Median bladder capacity was 100 ml before, 50 ml less than 1.5 years after and 123 ml 1.5 years or greater after bladder neck reconstruction. Three males and 2 females emptied via an appendicovesicostomy. Two boys underwent augmentation. CONCLUSIONS: In our experience most patients with bladder exstrophy require bladder neck reconstruction after complete primary repair of exstrophy. The need for reconstruction is more common in males. Our rates of bladder neck reconstruction after complete primary repair of exstrophy and of continence after bladder neck reconstruction are similar to those in other reports. PMID- 21555037 TI - Editorial comment. PMID- 21555038 TI - Extravesical implantation of a continent catheterizable channel. AB - PURPOSE: Extravesical ureteral reimplantation provides results equivalent to those of the open technique with the advantage of less postoperative morbidity from a large cystotomy. Surgical series describing the technique and efficacy of extravesical implantation of continent catheterizable channel are lacking. We reviewed our results to determine the efficacy of this technique with an emphasis on continence and the need for revision. MATERIALS AND METHODS: We reviewed the records of 394 patients who underwent a bladder continent catheterizable channel procedure from 1999 to 2009. Operative records describing an extravesical technique were noted. Briefly, a 3 to 6 cm incision is made in the detrusor and seromuscular flaps are created. The continent catheterizable channel is laid in the tunnel and the flaps are brought anterior to the channel and sutured to each other. Fixation of the bladder wall to the abdominal wall preserves tunnel length and minimizes the risk of angulation. The type of continent catheterizable channel, stomal continence and the need for revision were recorded. RESULTS: The extravesical implantation technique of a continent catheterizable channel was done in 84 of 394 patients (21%). The channel was an appendix in 47 cases and Monti ileovesicostomy in 37. Stomal continence was achieved in 79 of 84 cases (94%). At a mean followup of 45 months 22 patients (26%) required a total of 30 surgical revisions, of which most were skin level or endoscopic procedures at a mean of 26 months after channel creation. CONCLUSIONS: The extravesical technique for continent catheterizable channel implantation is effective. If intravesical surgery is not necessary, avoidance of a large cystotomy and longer operative time may expedite postoperative recovery when using an extravesical implantation technique to create a continent catheterizable channel. PMID- 21555039 TI - Editorial comment. PMID- 21555040 TI - Territorial impact assessment: integrating territorial aspects in sectoral policies. AB - Territorial impact assessment has recently gained attention as a tool to improve the coherence of sector policies with territorial cohesion objectives. The paper presents a method for territorial impact assessment and the results of applying this method on Slovenian energy policy. A two phase approach first disaggregates the problem into a three-dimensional matrix, consisting of policy measures, territorial objectives and territorial units. The synthesis phase aggregates measures and objectives in physical, economic or socio-cultural groups and observes their interrelation through an input-output matrix. The results have shown that such a two level approach is required to obtain complete and useful information for policy developers. In contrast to the relatively favourable evaluation of individual measures on the first level of assessment, the synthesis has revealed substantial and systemic weaknesses: considerable imbalance of energy policy favouring territorial effectiveness and mainly neglecting territorial identity as well as its counterproductiveness in reducing regional disparities. PMID- 21555041 TI - Application of logic models in a large scientific research program. AB - It is the purpose of this article to discuss the development and application of a logic model in the context of a large scientific research program within the Commonwealth Scientific and Industrial Research Organisation (CSIRO). CSIRO is Australia's national science agency and is a publicly funded part of Australia's innovation system. It conducts mission-driven scientific research focussed on delivering results with relevance and impact for Australia, where impact is defined and measured in economic, environmental and social terms at the national level. The Australian Government has recently signalled an increasing emphasis on performance assessment and evaluation, which in the CSIRO context implies an increasing emphasis on ensuring and demonstrating the impact of its research programs. CSIRO continues to develop and improve its approaches to impact planning and evaluation, including conducting a trial of a program logic approach in the CSIRO Preventative Health National Research Flagship. During the trial, improvements were observed in clarity of the research goals and path to impact, as well as in alignment of science and support function activities with national challenge goals. Further benefits were observed in terms of communication of the goals and expected impact of CSIRO's research programs both within CSIRO and externally. The key lesson learned was that significant value was achieved through the process itself, as well as the outcome. Recommendations based on the CSIRO trial may be of interest to managers of scientific research considering developing similar logic models for their research projects. The CSIRO experience has shown that there are significant benefits to be gained, especially if the project participants have a major role in the process of developing the logic model. PMID- 21555042 TI - Enabling multi-faceted measures of success for protected area management in Trinidad and Tobago. AB - A key challenge has been to define and measure "success" in managing protected areas. A case study was conducted of efforts to evaluate the new protected area management system in Trinidad and Tobago using a participatory approach. The aim of the case study was to (1) examine whether stakeholder involvement better captures the multi-faceted nature of success and (2) identify the role and influence of various stakeholder groups in this process. An holistic and systematic framework was developed with stakeholder input that facilitated the integration of expert and lay knowledge, a broad emphasis on ecological, socio economic, and institutional aspects, and the use of both quantitative and qualitative data allowing the evaluation to capture the multi-faceted nature and impacts of protected area management. Input from primary stakeholders, such as local communities, was critical as they have a high stake in protected area outcomes. Secondary and external stakeholders, including government agencies, non governmental organizations, academia and the private sector, were also important in providing valuable technical assistance and serving as mediators. However, a lack of consensus over priorities, politics, and limited stakeholder capacity and data access pose significant barriers to engaging stakeholders to effectively measure the management success of protected areas. PMID- 21555043 TI - The evaluation of the PACA regional public health plan: reconciling the managerial, scientific and democratic finalities. AB - For more than a decade now, evaluation has developed considerably in France, thanks in particular to the Societe Francaise de l'Evaluation, whose charter sets out a number of principles designed to guide the work of evaluators. This article examines how the evaluation process surrounding a regional public health plan (referred to as PRSP)--itself being a new instrument for regional planning in France--accords with one of these principles, which specifies that evaluation must be framed according to "a three-fold logic involving public management, democracy and scientific debate." Our analysis shows that while this evaluation was driven primarily by managerial concerns (i.e., assessing the capacity of the plan to structure health policy in a region), it also provided an Opportunity for restoring dialogue with a range of actors by opening up a space of cooperation and consultation. In addition, in order to ensure the legitimacy of the evaluation's conclusions, the knowledge produced by the evaluators had to rest on an irreproachable methodology. This example illustrates how evaluation, in the French tradition, is a process that strives to reconcile the viewpoints and expectations of managers, scientists and the general public; it is also a process that brings out lines of tension and areas of complementariness between these three logics. PMID- 21555044 TI - Self-evaluation of assessment programs: a cross-case analysis. AB - The goal of this article is to contribute to the validation of a self-evaluation method, which can be used by schools to evaluate the quality of their Competence Assessment Program (CAP). The outcomes of the self-evaluations of two schools are systematically compared: a novice school with little experience in competence based education and assessment, and an innovative school with extensive experience. The self-evaluation was based on 12 quality criteria for CAPs, including both validity and reliability, and criteria stressing the importance of the formative function of assessment, such as meaningfulness and educational consequences. In each school, teachers, management and examination board participated. Results show that the two schools use different approaches to assure assessment quality. The innovative school seems to be more aware of its own strengths and weaknesses, to have a more positive attitude towards teachers, students, and educational innovations, and to explicitly involve stakeholders (i.e., teachers, students, and the work field) in their assessments. This school also had a more explicit vision of the goal of competence-based education and could design its assessments in accordance with these goals. PMID- 21555045 TI - A mixed method study of propensity for participatory evaluation. AB - One way to increase the use of evaluation results is practical participatory evaluation (PPE), which enables non-evaluator participants to join the evaluation process in a participatory mode. We examined the propensity for PPE of health professionals by focusing on four components: learning, working in groups, using judgment and using systematic methods. We interviewed the professionals at a Haitian health institution to determine their positioning on a scale of propensity (low, medium and high) for the four components. The professionals defined each component in relation to the energy puts into them, being more or less proactive. Facilitating elements for all three levels of propensity integration included past positive experiences, external pressure and a desire for better individual and organizational performance. Impeding factors included a lack of available resources perceived responsibilities and commitments toward private patients. The reported advantages included improved organizational performance and idea sharing, and the disadvantages included availability of, difficulty implementing solutions and altered human relationships. PMID- 21555046 TI - Using hybrid models to support the development of organizational evaluation capacity: a case narrative. AB - The ongoing need for public sector organizations to enhance their internal evaluation capacity is increasingly resulting in the use of hybrid evaluation project models, where internal evaluators work with external contracted evaluators to complete evaluative work. This paper first seeks to identify what is currently known about internal evaluation through a synthesis of the literature in this area. It then presents a case narrative illustrating how internal and external evaluation approaches may be used together to strengthen an evaluation project and to develop the evaluation capacity of the organization. Lessons learned include the need to integrate internal and external resources throughout the evaluation and to clarify expectations at the outset of the project. PMID- 21555047 TI - Survival of the fittest: capacity building for small nonprofit organizations. AB - This paper discusses capacity building activities designed for small nonprofits who are members of the Second Harvest Food Bank of Central Florida's ADEPT program. The Second Harvest Food Bank of Central Florida (SHFBCF) is a nonprofit organization that collects, stores and distributes donated food to more than 450 nonprofit partners in Brevard, Lake, Orange, Osceola, Seminole and Volusia counties. This project sought to delineate, design, and implement the capacity building trainings desired by ADEPT member agencies. It also analyzed the relationship between the number of clients served, number of staff, number of volunteers, and the training needs. At the conclusion of the capacity building trainings, data was collected to gauge participants' perceptions of the capacity building trainings and their perceived impact on the effectiveness of the ADEPT Program and its member agencies. The generalizability and applicability of the research results to other small community-based organizations providing social and human services is also discussed. PMID- 21555048 TI - The role of community context in planning and implementing community-based health promotion projects. AB - The current study examines how community context affected collaborative planning and implementation in eight sites participating in a healthy cities and communities initiative in California. Data are from 23 focus groups conducted with coalition members, and 76 semi-structured interviews with local coordinators and community leaders. Multiple case study methods were used to identify major themes related to how five contextual domains influenced collaborative planning and implementation. Results showed that history of collaboration can influence resources and interpersonal and organizational connections available for planning and implementation, as well as priorities selected for action. Community politics and history can affect which segments of the community participate in a planning process and what issues are prioritized, as well as the pool of partners willing to aid in implementation. Some community norms and values bring people together and others appear to limit involvement from certain groups. Community demographics and economic conditions may shape outreach strategies for planning and implementation, and may also shape priorities. Geography can play a role in assessment methods, priority selection, partners available to aid in implementation, and participation in activities and events. Results suggest that community context plays a substantive role in shaping how community-based health promotion projects unfold. PMID- 21555049 TI - Traditional birth attendant training and local birthing practices in India. AB - Training birth attendants (TBAs) provide essential maternal and infant health care services during delivery and ongoing community care in developing countries. Despite inadequate evidence of relevance and effectiveness of TBA training programmes, there has been a policy shift since the 1990s in that many donor agencies funding TBA training programmes redirected funds to providing skilled attendants during delivery. This study aimed to assess the ways in which a TBA training programme in India has been successful in disseminating evidence-based knowledge on birthing practices. TBAs practicing within 16 villages targeted by training programme initiatives were administered with structured questionnaires. The post training birthing practices of trained (24) and untrained (14) TBAs was compared and birthing practices adopted by women assisted by trained (16) and untrained (9) TBAs was analysed. Positive post training practices were hand washing, use of a clean blade for cutting the cord, immediate breastfeeding and weighing of babies. Nevertheless, the training could be further improved with up to date and evidence-based information and more comprehensive instructions. The findings suggest an integration of local and evidence-based knowledge is needed to improve the training. Raising community awareness of public health measures related to maternal and child health is also recommended. PMID- 21555050 TI - Childhood moyamoya disease and moyamoya syndrome: a pictorial review. AB - Moyamoya disease is an uncommon chronic cerebrovasculopathy, characterized by progressive stenosis of the terminal portion of the internal carotid artery and its main branches, in association with the development of compensatory collateral vessels at the base of the brain. The etiology is unknown, and was originally considered exclusive to East Asia, with particular prevalence in Japan. Moyamoya disease is increasingly diagnosed throughout the world, and represents an important cause of childhood stroke in Western countries. In some cases, similar angiographic features are evident in children with other medical conditions, such as sickle cell disease and Down syndrome. In these instances, the term "moyamoya syndrome" is used. Diagnosing the vasculopathy, excluding possible associated conditions, and planning treatment and follow-up imaging comprise important aspects of clinical management. We review the key imaging features of childhood moyamoya disease and syndrome, present examples of its associations, and discuss new neuroradiologic methods that may be useful in management. PMID- 21555051 TI - Experience with lacosamide in a series of children with drug-resistant focal epilepsy. AB - We report our pediatric experience with lacosamide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n=3), vagus nerve stimulation (n=9), and ketogenic diet (n=3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n=10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P<0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (>=50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with >=50% seizure reduction) without severe adverse events. PMID- 21555052 TI - Corpus callosum anomalies: birth prevalence and clinical spectrum in Hungary. AB - Data regarding the epidemiology of callosal anomalies are contradictory. We performed a population-based retrospective survey to study the birth prevalence and clinical features of agenesis/hypoplasia of the corpus callosum and accompanying central nervous system and somatic abnormalities in southeastern Hungary between July 1, 1992 and June 30, 2006. Among 185,486 live births, 38 patients (26 boys and 12 girls) manifested agenesis/hypoplasia of the corpus callosum, corresponding to a prevalence of 2.05 per 10,000 live births (95% confidence interval, 1.4-2.7). Callosal anomalies were isolated in 18 patients, and were associated with other central nervous system malformations in five children. Both central nervous system and noncentral nervous system abnormalities were evident in seven patients, whereas callosal dysgenesis was accompanied only by somatic anomalies in eight children. Five of 18 patients with isolated agenesis/hypoplasia of the corpus callosum remained asymptomatic. Developmental delay, intellectual disability, or epilepsy occurred in all patients, except one, when callosal anomalies were combined with other brain or somatic abnormalities. Five patients with multiplex malformations died. Callosal anomalies form a clinically significant and relatively frequent group of central nervous system malformations. PMID- 21555053 TI - Electroencephalogram monitoring during intracranial surgery for moyamoya disease. AB - We describe our experience with intraoperative electroencephalography in moyamoya surgery, a method to monitor for ischemic changes during the procedure and to minimize the risk of intraoperative and perioperative stroke. Case records and intraoperative electroencephalography recordings of all patients (n=220) treated with surgical revascularization for moyamoya (pial synangiosis) performed for 14 years (1994-2008) were reviewed. Electroencephalographic slowing occurred in 100 cases (45.5%), and was persistent in nine cases (9%). Slowing coincided with specific operative manipulations, most commonly while suturing the donor vessel to the pia, and during closure of the craniotomy. Slowing generally occurred bilaterally, independently of the side of intervention. The presence, length, and severity of slowing were not predictive of perioperative ischemic events. We present additional data on intraoperative electroencephalography with a modified montage to accommodate the craniotomy. Although not predictive of perioperative ischemic events in this series, electroencephalographic changes were correlated with specific operative interventions, and revealed global responses to unilateral manipulation. These findings suggest that prospective analyses of this technique may elucidate additional methods of predicting (and possibly preventing) perioperative ischemic events. PMID- 21555054 TI - Clinical features of encephalopathy in children with cancer requiring cranial magnetic resonance imaging. AB - We analyzed acute neurotoxic problems attributable to chemotherapy or immunosuppression in the context of childhood neoplastic diseases, based on clinical and neuroradiologic findings. This retrospective single-center study reviewed the acute neurologic complications of 62 children receiving conventional chemotherapy or hematopoietic stem cell transplantation from July 2005-July 2008. We excluded patients with central nervous system metastasis and various neurotoxic manifestations not usually requiring cranial magnetic resonance imaging. Of 62 patients, 12 (19.3%) developed acute neurologic complications. The most common complications included posterior reversible encephalopathy syndrome in six of 12 (50%) patients, and Wernicke's encephalopathy in three of 12 (25%) patients. Other complications included chemical arachnoiditis, grey matter injury induced by postchemotherapeutic angiopathy, and leukoencephalopathy. Posterior reversible encephalopathy syndrome was accompanied by hypertensive episodes in most patients (5/6), and Wernicke's encephalopathy was evident with altered mental status in malnourished children. These data indicate that posterior reversible encephalopathy syndrome and Wernicke's encephalopathy are the predominant complications in children undergoing chemotherapy or hematopoietic stem cell transplantation. Early radiologic and clinical evaluation and prompt treatment for these complications are necessary to prevent their progression to irreversible brain damage. PMID- 21555055 TI - Topiramate for the treatment of neonatal seizures. AB - Therapeutic options for treating neonatal seizures, such as phenobarbital and phenytoin, lack efficacy and are potentially harmful to the developing brain. Topiramate appears effective as both an antiseizure and neuroprotective agent in animal models of newborn brain injury. Although topiramate is a common add-on agent in newborns, its use in this population has not yet been reported. We performed a retrospective cohort study of clinical topiramate use in newborns with acute symptomatic seizures that were refractory to standard agents. In four of six newborns, apparent reduction or no further seizures occurred. None of the children experienced side effects resulting in discontinuation of the drug, either during the hospital admission or after discharge. Prospective studies evaluating the safety and efficacy of topiramate for both seizures and neuroprotection will be important in determining whether it deserves widespread use in clinical practice. PMID- 21555056 TI - Clinical outcomes in bilateral Sturge-Weber syndrome. AB - Approximately 15% of patients with Sturge-Weber syndrome demonstrate bilateral intracranial involvement, and the prognosis of these patients is considered particularly unfavorable. We reviewed the clinical and neuroimaging features of patients with Sturge-Weber syndrome and bilateral intracranial involvement. Seizure variables, the presence of hemiparesis, and the degree of developmental impairment at most recent follow-up were compared with imaging abnormalities. Of 110 Sturge-Weber syndrome patients, 14 demonstrated bilateral brain involvement, with an asymmetric pattern on glucose metabolism positron emission tomography. Although most patients manifested frequent seizures initially, associated with frontal hypometabolism on positron emission tomography, six (43%) had achieved good seizure control during follow-up. Bilateral frontal hypometabolism was associated with severe developmental impairment. Two children with bitemporal hypometabolism exhibited autistic features. Hemiparesis was associated with superior frontal (motor cortex) hypometabolism. Three patients underwent resective surgery, resulting in improved seizure control and developmental outcomes. The severity of neurologic complications and clinical course depend on the extent of cortical dysfunction in bilateral Sturge-Weber syndrome. Bilateral frontal and temporal hypometabolism is associated with poor developmental outcomes. Good seizure control and only mild/moderate developmental impairment can be achieved in about 50% of patients with bilateral Sturge-Weber syndrome, with or without resective surgery. PMID- 21555057 TI - Molecular genetic studies in Indian patients with megalencephalic leukoencephalopathy. AB - Mutations in the MLC1 gene cause megalencephalic leukoencephalopathy with subcortical cysts. We sought to identify mutations in the MLC1 gene, to evaluate the genotype-phenotype correlation, and to develop a strategy for diagnosing Indian patients with megalencephalic leukoencephalopathy. Forty patients were enrolled. We developed a rapid restriction fragment length polymorphism method to screen a common mutation, c.135_136insC. Rare and novel mutations were screened by conformation-sensitive gel electrophoresis, followed by sequencing. Three previously reported and two novel mutations were identified in 37 patients. The presence of the c.135_136insC mutation in 29 patients of the Agarwal community suggests a founder effect. The mutation c.959C>A was evident in four patients, and appears to be the second commonest mutation. Genotype could not predict phenotype. We recommend screening for the commonest mutation (c.135_136insC), followed by the next commonest mutation (c.959C>A), and then other rare mutations, using conformation-sensitive gel electrophoresis analysis or direct sequencing. PMID- 21555058 TI - Acquired infantile abducens palsy associated with anti-GM2 antibodies. AB - Anti-ganglioside antibodies have been associated with acquired neuropathies, including Guillain-Barre syndrome. We describe a case of acute abducens nerve palsy acquired 2 weeks after symptoms of upper respiratory tract infection and rash in a 6-month-old. Elevated anti-GM2 ganglioside immunoglobulin M antibodies were detected in the serum. The palsy slowly improved over time, although eventually surgical intervention was required. Elevated anti-GM2 immunoglobulin M antibodies have previously been reported in Guillain-Barre syndrome variants involving sensory and cranial neuropathies, but never in isolated unilateral cranial nerve VI mononeuropathy. Anti-ganglioside antibodies may play a role in the pathogenesis of postinfectious isolated abducens palsy in young children. PMID- 21555059 TI - Sellar-suprasellar tuberculomas in children: 2 cases and literature review. AB - Sellar and suprasellar tuberculomas are rare. Patients with these lesions usually experience headache, vomiting, and hypofunction of pituitary gland; imaging reveals an enhancing sellar-suprasellar mass. We report 2 rare cases of sellar suprasellar tuberculomas in children aged 8 and 6 years. One child presented with features of headache and vomiting, and the other presented with posterior pituitary dysfunction. In both cases, imaging revealed sellar-suprasellar masses. Both cases were multidrug-resistant tuberculomas. We discuss sellar-suprasellar tuberculomas, a rare form of neurotuberculosis in the background of an overall increase in multidrug-resistant tuberculosis, especially in children. PMID- 21555060 TI - Measles-vaccinated Israeli boy with subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis is a rare neurologic disorder of childhood and adolescence. We describe a 16-year-old boy who manifested the disease despite proper vaccinations. He was hospitalized because of bedwetting, involuntary limb movements, abnormal speech, and balance disturbances. Immunoglobulin G antibodies against measles were strongly positive, with a high relative cerebrospinal fluid/serum ratio. Polymerase chain reaction for measles produced negative results. Electroencephalography registered slow activity with high voltage discharges every few seconds, and with triphasic complex morphology. Magnetic resonance imaging revealed diffuse white matter changes, mostly around the posterior regions and lateral ventricles. Treatment with valproic acid, levetiracetam, carbamazepine, and intravenous immunoglobulin G was ineffective. Inosiplex and interferon-beta-1a were also administrated. The patient became comatose, with generalized myoclonic jerks, and died 1 year later. An autopsy was not performed. This patient illustrates that subacute sclerosing panencephalitis should be suspected among young vaccinated subjects. PMID- 21555061 TI - Unusual clinical course in pediatric Tolosa-Hunt syndrome. AB - We report on a 7-year-old immunocompetent boy initially presenting with right sided frontal cephalalgia, painful ophthalmoplegia, and ptosis for 1 month. Initial cerebrospinal fluid analysis produced normal results. Magnetic resonance imaging revealed an inflammatory pseudotumor of the right cavernous sinus after intravenous gadolinium administration, indicating a rare idiopathic inflammatory disorder of the cavernous sinus, i.e., Tolosa-Hunt syndrome. Ptosis and cephalalgia resolved after steroid treatment, although right-sided ophthalmoplegia remained. Breakthrough headache, associated with signs of meningeal irritation, developed 6 weeks later. Follow-up contrast-enhanced computed tomography revealed no enhancing cavernous soft tissue mass. A further lumbar puncture disclosed central nervous system infection with Staphylococcus saprophyticus. After 6 weeks of vancomycin, the headache resolved completely, and neuroimaging produced normal results. A diagnosis of Tolosa-Hunt syndrome should be rendered cautiously, because the etiology may involve a rare but not "idiopathic" infection. Moreover, if clinical signs are not fully responsive to steroid treatment, the underlying problems should receive careful investigation. PMID- 21555062 TI - Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation. AB - Lafora disease is a fatal, autosomal recessive form of progressive myoclonus epilepsy. Patients characteristically exhibit myoclonic and tonic-clonic seizures and cognitive impairment, beginning in their second decade. Alterations in two genes were identified as the cause of the disease. Mutations in the NHL repeat containing 1 (NHLRC1) gene were described in association with a more benign clinical course and later age of death, compared with epilepsy progressive myoclonus type 2A (EPM2A) mutations. We describe a rapidly progressive phenotype of Lafora disease in an adolescent patient with a novel NHLRC1 mutation. He developed severe disability and dementia less than 2 years after the onset of signs. PMID- 21555063 TI - Tolosa-Hunt syndrome preceded by facial palsy in a child. PMID- 21555065 TI - Are polyglutamine diseases expanding? AB - It remains a matter of speculation as to whether the sense CUG-containing RNA and/or the antisense CAG-encoding polyglutamine peptide serves as the pathogenic moiety in Huntington's disease like-2 (HDL2). In this issue of Neuron, Wilburn et al. show that in a HDL2 mouse model, the polyglutamine peptide drives disease progression. PMID- 21555066 TI - Transsynaptic coordination of presynaptic and postsynaptic modifications underlying enduring synaptic plasticity. AB - Neurexins and neuroligins are cell adhesion molecules that form transsynaptic interactions. In this issue of Neuron, Choi et al. report that neurexin neuroligin signaling plays a critical role in functional and structural synaptic plasticity underlying memory formation in Aplysia. PMID- 21555067 TI - Making choices between rules or between actions. AB - A new study by Klaes et al. in this issue of Neuron shows that the brain can simultaneously apply two rules to the same sensory information in order to specify two parallel potential action goals, which then compete for execution in the sensorimotor system. PMID- 21555069 TI - The many faces of tau. AB - While the microtubule-binding capacity of the protein tau has been known for many years, new functions of tau in signaling and cytoskeletal organization have recently emerged. In this review, we highlight these functions and the potential roles of tau in neurodegenerative disease. We also discuss the therapeutic potential of drugs targeting various aspects of tau biology. PMID- 21555068 TI - GABAA receptor trafficking-mediated plasticity of inhibitory synapses. AB - Proper developmental, neural cell-type-specific, and activity-dependent regulation of GABAergic transmission is essential for virtually all aspects of CNS function. The number of GABA(A) receptors in the postsynaptic membrane directly controls the efficacy of GABAergic synaptic transmission. Thus, regulated trafficking of GABA(A) receptors is essential for understanding brain function in both health and disease. Here we summarize recent progress in the understanding of mechanisms that allow dynamic adaptation of cell surface expression and postsynaptic accumulation and function of GABA(A) receptors. This includes activity-dependent and cell-type-specific changes in subunit gene expression, assembly of subunits into receptors, as well as exocytosis, endocytic recycling, diffusion dynamics, and degradation of GABA(A) receptors. In particular, we focus on the roles of receptor-interacting proteins, scaffold proteins, synaptic adhesion proteins, and enzymes that regulate the trafficking and function of receptors and associated proteins. In addition, we review neuropeptide signaling pathways that affect neural excitability through changes in GABA(A)R trafficking. PMID- 21555070 TI - An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. AB - Huntington's disease-like-2 (HDL2) is a phenocopy of Huntington's disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology, and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein. Importantly, BAC HDL2 mice, but not control BAC mice, accumulate polyQ-containing NIs in a pattern strikingly similar to those in the patients. Furthermore, BAC mice with genetic silencing of the expanded CUG transcript still express HDL2-CAG transcript and manifest polyQ pathogenesis. Finally, studies of HDL2 mice and patients revealed CBP sequestration into NIs and evidence for interference of CBP-mediated transcriptional activation. These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2. PMID- 21555071 TI - Mechanistic logic underlying the axonal transport of cytosolic proteins. AB - Proteins vital to presynaptic function are synthesized in the neuronal perikarya and delivered into synapses via two modes of axonal transport. While membrane anchoring proteins are conveyed in fast axonal transport via motor-driven vesicles, cytosolic proteins travel in slow axonal transport via mechanisms that are poorly understood. We found that in cultured axons, populations of cytosolic proteins tagged to photoactivatable GFP (PAGFP) move with a slow motor-dependent anterograde bias distinct from both vesicular trafficking and diffusion of untagged PAGFP. The overall bias is likely generated by an intricate particle kinetics involving transient assembly and short-range vectorial spurts. In vivo biochemical studies reveal that cytosolic proteins are organized into higher order structures within axon-enriched fractions that are largely segregated from vesicles. Data-driven biophysical modeling best predicts a scenario where soluble molecules dynamically assemble into mobile supramolecular structures. We propose a model where cytosolic proteins are transported by dynamically assembling into multiprotein complexes that are directly/indirectly conveyed by motors. PMID- 21555072 TI - Activity-dependent transcription of BDNF enhances visual acuity during development. AB - In the developing Xenopus tadpole, conditioning with 20 min of visual stimulation leads to increased proBDNF protein levels in the tectum measured 4 hr later. Following conditioning, the ability to induce direction selectivity in tectal neurons, as well as both retinotectal long-term potentiation and depression, thought to underlie this phenomenon, was strongly facilitated. This facilitation was blocked by knockdown of BDNF expression in tectal neurons. Animals that had been exposed to visual conditioning and subsequently received normal visual input for 7-11 hr exhibited higher spatial frequency thresholds of tectal cell responses to counterphasing gratings than nonconditioned control animals. An improvement in visual acuity was confirmed by enhanced sensitivity to counterphasing gratings in a behavioral test. These results indicate that brief sensory stimulation, by initiating nuclear transcription and de novo protein synthesis of BDNF, can facilitate the refinement of response properties in the developing visual system. PMID- 21555073 TI - Neurexin-neuroligin transsynaptic interaction mediates learning-related synaptic remodeling and long-term facilitation in aplysia. AB - Neurexin and neuroligin, which undergo heterophilic interactions with each other at the synapse, are mutated in some patients with autism spectrum disorder, a set of disorders characterized by deficits in social and emotional learning. We have explored the role of neurexin and neuroligin at sensory-to-motor neuron synapses of the gill-withdrawal reflex in Aplysia, which undergoes sensitization, a simple form of learned fear. We find that depleting neurexin in the presynaptic sensory neuron or neuroligin in the postsynaptic motor neuron abolishes both long-term facilitation and the associated presynaptic growth induced by repeated pulses of serotonin. Moreover, introduction into the motor neuron of the R451C mutation of neuroligin-3 linked to autism spectrum disorder blocks both intermediate-term and long-term facilitation. Our results suggest that activity-dependent regulation of the neurexin-neuroligin interaction may govern transsynaptic signaling required for the storage of long-term memory, including emotional memory that may be impaired in autism spectrum disorder. PMID- 21555074 TI - TRPM3 is a nociceptor channel involved in the detection of noxious heat. AB - Transient receptor potential melastatin-3 (TRPM3) is a broadly expressed Ca(2+) permeable nonselective cation channel. Previous work has demonstrated robust activation of TRPM3 by the neuroactive steroid pregnenolone sulfate (PS), but its in vivo gating mechanisms and functions remained poorly understood. Here, we provide evidence that TRPM3 functions as a chemo- and thermosensor in the somatosensory system. TRPM3 is molecularly and functionally expressed in a large subset of small-diameter sensory neurons from dorsal root and trigeminal ganglia, and mediates the aversive and nocifensive behavioral responses to PS. Moreover, we demonstrate that TRPM3 is steeply activated by heating and underlies heat sensitivity in a subset of sensory neurons. TRPM3-deficient mice exhibited clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia. These experiments reveal an unanticipated role for TRPM3 as a thermosensitive nociceptor channel implicated in the detection of noxious heat. PMID- 21555075 TI - TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. AB - HCN1 channel subunits, which contribute to the hyperpolarization-activated cation current (Ih), are selectively targeted to distal apical dendrites of hippocampal CA1 pyramidal neurons. Here, we addressed the importance of the brain-specific auxiliary subunit of HCN1, TRIP8b, in regulating HCN1 expression and localization. More than ten N-terminal splice variants of TRIP8b exist in brain and exert distinct effects on HCN1 trafficking when overexpressed. We found that isoform-wide disruption of the TRIP8b/HCN1 interaction caused HCN1 to be mistargeted throughout CA1 somatodendritic compartments. In contrast, HCN1 was targeted normally to CA1 distal dendrites in a TRIP8b knockout mouse that selectively lacked exons 1b and 2. Of the two remaining hippocampal TRIP8b isoforms, TRIP8b(1a-4) promoted HCN1 surface expression in dendrites, whereas TRIP8b(1a) suppressed HCN1 misexpression in axons. Thus, proper subcellular localization of HCN1 depends on its differential additive and subtractive sculpting by two isoforms of a single auxiliary subunit. PMID- 21555076 TI - Maturation of a recurrent excitatory neocortical circuit by experience-dependent unsilencing of newly formed dendritic spines. AB - Local recurrent excitatory circuits are ubiquitous in neocortex, yet little is known about their development or architecture. Here we introduce a quantitative technique for efficient single-cell resolution circuit mapping using 2-photon (2P) glutamate uncaging and analyze experience-dependent neonatal development of the layer 4 barrel cortex local excitatory circuit. We show that sensory experience specifically drives a 3-fold increase in connectivity at postnatal day (P) 9, producing a highly recurrent network. A profound dendritic spinogenesis occurs concurrent with the connectivity increase, but this is not experience dependent. However, in experience-deprived cortex, a much greater proportion of spines lack postsynaptic AMPA receptors (AMPARs) and synaptic connectivity via NMDA receptors (NMDARs) is the same as in normally developing cortex. Thus we describe a approach for quantitative circuit mapping and show that sensory experience sculpts an intrinsically developing template network, which is based on NMDAR-only synapses, by driving AMPARs into newly formed silent spines. PMID- 21555077 TI - Aversion to nicotine is regulated by the balanced activity of beta4 and alpha5 nicotinic receptor subunits in the medial habenula. AB - Nicotine dependence is linked to single nucleotide polymorphisms in the CHRNB4 CHRNA3-CHRNA5 gene cluster encoding the alpha3beta4alpha5 nicotinic acetylcholine receptor (nAChR). Here we show that the beta4 subunit is rate limiting for receptor activity, and that current increase by beta4 is maximally competed by one of the most frequent variants associated with tobacco usage (D398N in alpha5). We identify a beta4-specific residue (S435), mapping to the intracellular vestibule of the alpha3beta4alpha5 receptor in close proximity to alpha5 D398N, that is essential for its ability to increase currents. Transgenic mice with targeted overexpression of Chrnb4 to endogenous sites display a strong aversion to nicotine that can be reversed by viral-mediated expression of the alpha5 D398N variant in the medial habenula (MHb). Thus, this study both provides insights into alpha3beta4alpha5 receptor-mediated mechanisms contributing to nicotine consumption, and identifies the MHb as a critical element in the circuitry controlling nicotine-dependent phenotypes. PMID- 21555078 TI - Choosing goals, not rules: deciding among rule-based action plans. AB - In natural situations, movements are often directed toward locations different from that of the evoking sensory stimulus. Movement goals must then be inferred from the sensory cue based on rules. When there is uncertainty about the rule that applies for a given cue, planning a movement involves both choosing the relevant rule and computing the movement goal based on that rule. Under these conditions, it is not clear whether primates compute multiple movement goals based on all possible rules before choosing an action, or whether they first choose a rule and then only represent the movement goal associated with that rule. Supporting the former hypothesis, we show that neurons in the frontoparietal reach areas of monkeys simultaneously represent two different rule based movement goals, which are biased by the monkeys' choice preferences. Apparently, primates choose between multiple behavioral options by weighing against each other the movement goals associated with each option. PMID- 21555079 TI - Perceptual learning and decision-making in human medial frontal cortex. AB - The dominant view that perceptual learning is accompanied by changes in early sensory representations has recently been challenged. Here we tested the idea that perceptual learning can be accounted for by reinforcement learning involving changes in higher decision-making areas. We trained subjects on an orientation discrimination task involving feedback over 4 days, acquiring fMRI data on the first and last day. Behavioral improvements were well explained by a reinforcement learning model in which learning leads to enhanced readout of sensory information, thereby establishing noise-robust representations of decision variables. We find stimulus orientation encoded in early visual and higher cortical regions such as lateral parietal cortex and anterior cingulate cortex (ACC). However, only activity patterns in the ACC tracked changes in decision variables during learning. These results provide strong evidence for perceptual learning-related changes in higher order areas and suggest that perceptual and reward learning are based on a common neurobiological mechanism. PMID- 21555080 TI - Triangulating the neural, psychological, and economic bases of guilt aversion. AB - VIDEO ABSTRACT: Why do people often choose to cooperate when they can better serve their interests by acting selfishly? One potential mechanism is that the anticipation of guilt can motivate cooperative behavior. We utilize a formal model of this process in conjunction with fMRI to identify brain regions that mediate cooperative behavior while participants decided whether or not to honor a partner's trust. We observed increased activation in the insula, supplementary motor area, dorsolateral prefrontal cortex (PFC), and temporal parietal junction when participants were behaving consistent with our model, and found increased activity in the ventromedial PFC, dorsomedial PFC, and nucleus accumbens when they chose to abuse trust and maximize their financial reward. This study demonstrates that a neural system previously implicated in expectation processing plays a critical role in assessing moral sentiments that in turn can sustain human cooperation in the face of temptation. PMID- 21555081 TI - Privatisation in health systems in developing countries: what's in a name? PMID- 21555082 TI - Affordability of emergency obstetric and neonatal care at public hospitals in Madagascar. AB - Timely access to emergency obstetric care is necessary to save the lives of women experiencing complications at delivery, and for newborn babies. Out-of-pocket costs are one of the critical factors hindering access to such services in low- and middle-income countries. This study measured out-of-pocket costs for caesarean section and neonatal care at an urban tertiary public hospital in Madagascar, assessed affordability in relation to household expenditure and investigated where families found the money to cover these costs. Data were collected for 103 women and 73 newborns at the Centre Hospitalier Universitaire de Mahajanga in the Boeny region of Madagascar between September 2007 and January 2008. Out-of-pocket costs for caesarean section were catastrophic for middle and lower socio-economic households, and treatment for neonatal complications also created a big financial burden, with geographical and other financial barriers further limiting access to hospital care. This study identified 12 possible cases where the mother required an emergency caesarean section and her newborn required emergency care, placing a double burden on the household. In an effort to make emergency obstetric and neonatal care affordable and available to all, including those living in rural areas and those of medium and lower socio-economic status, well-designed financial risk protection mechanisms and a strong commitment by the government to mobilise resources to finance the country's health system are necessary. PMID- 21555083 TI - The sexual and reproductive health care market in Bangladesh: where do poor women go? AB - In Bangladesh, the formal public health system provides few services for common sexual and reproductive health problems such as white discharge, fistula, prolapse, menstrual problems, reproductive and urinary tract infections, and sexual problems. Recent research has found that poor women and men resort to informal providers for these problems instead. This paper draws on interviews with 303 providers and 312 women from two rural and one urban area of Bangladesh from July 2008 to January 2009. Both informal and formal markets played an important role in treating these problems, including for the poor, but the treatments were often unlikely to resolve the problems. Providers ranged from village doctors without formal training to qualified private practitioners. The health system is heavily marketised and boundaries between "public" and "private" are blurred. There exists a huge, neglected domain of sexual and reproductive health needs which are a source of silent suffering and for which there are no trained health staff providing treatment in government facilities. The complexity of this situation calls for engaged debate in Bangladesh on how to improve the quality of existing services, discourage or prevent obviously harmful practices, and develop financing mechanisms to enable women to access effective treatment, regardless of the source, for these neglected problems. PMID- 21555084 TI - Poor standards of care in small, private hospitals in Maharashtra, India: implications for public-private partnerships for maternity care. AB - The private health sector in India is generally unregulated. Maharashtra is among the few states which require registration of private hospitals. This paper reports on a study of standards of care in small, private hospitals (less than 30 beds) in Maharashtra state, India, with a focus on maternity care, based on interviews with the hospitals' owners or senior staff, and observation. In the absence of reliable information on the number of private hospitals in the state, a physical listing was carried out in 11 districts and an estimate drawn up; 10% of hospitals found in each location were included in the study sample. We found poor standards of care in many cases, and few or no qualified nurses or a duty medical officer in attendance. Of the 261 hospitals visited, 146 provided maternity services yet 137 did not have a qualified midwife, and though most claimed they provided emergency care, including caesarean section, only three had a blood bank and eight had an ambulance. Government plans to promote public private partnerships with such hospitals, including for maternity services, create concern, given our findings. The need to enforce existing regulations and collect information on health outcomes and quality of care before the state involves these hospitals further in provision of maternity care is called for. PMID- 21555085 TI - Prevalence of hysterectomy among rural and urban women with and without health insurance in Gujarat, India. AB - This paper presents findings on hysterectomy prevalence from a 2010 cross sectional household survey of 2,214 rural and 1,641 urban, insured and uninsured women in low-income households in Ahmedabad city and district in Gujarat, India. The study investigated why hysterectomy was a leading reason for use of health insurance by women insured by SEWA, a women's organisation that operates a community-based health insurance scheme. Of insured women, 9.8% of rural women and 5.3% of urban women had had a hysterectomy, compared to 7.2% and 4.0%, respectively, of uninsured women. Approximately one-third of all hysterectomies were in women younger than 35 years of age. Rural women used the private sector more often for hysterectomy, while urban use was almost evenly split between the public and private sectors. SEWA's community health workers suggested that such young women underwent hysterectomies due to difficulties with menstruation and a range of gynaecological morbidities. The extent of these and of unnecessary hysterectomy, as well as providers' attitudes, require further investigation. We recommend the provision of information on hysterectomy as part of community health education for women, and better provision of basic gynaecological care as areas for advocacy and action by SEWA and the public health community in India. PMID- 21555086 TI - Quality of reproductive health services at commune health stations in Viet Nam: implications for national reproductive health care strategy. AB - This paper presents a qualitative study conducted in 2009 of provider and patient perceptions of primary level reproductive health services provided by commune health stations (CHSs), and the implications for Viet Nam's 2011-2020 National Strategy for Reproductive Health Care. In the three provinces of Thai Nguyen, Thua Thien Hue, and Vinh Long, we interviewed the heads of CHSs, held focus group discussions with midwives and women patients, and observed facilities. Half the 30 CHSs visited were in poor physical condition; the rest were newly renovated. However, the model of service delivery was largely unchanged from ten years before. Many appeared to fall short in meeting patient expectations in terms of modern medical equipment and technology, range of drug supplies, and levels of staff expertise. As a result, many women were turning to private doctors and public hospitals, at least in urban areas, or seeking medication from pharmacies. To make CHS clinics sustainable, promotion of access to reproductive health services should be undertaken concurrently with quality improvement. A responsive payment scheme must also be developed to generate revenues. Efforts should be made to reduce the unnecessary use of more costly services from private clinics and higher level public facilities. PMID- 21555087 TI - Assessing public and private sector contributions in reproductive health financing and utilization for six sub-Saharan African countries. AB - The present study provides evidence to support enhanced attention to reproductive health and comprehensive measures to increase access to quality reproductive health services. We compare and contrast the financing and utilization of reproductive health services in six sub-Saharan African countries using data from National Health Accounts and Demographic and Health Surveys. Spending on reproductive health in 2006 ranged from US$4 per woman of reproductive age in Ethiopia to US$17 in Uganda. These are below the necessary level for assuring adequate services given that an internationally recommended spending level for family planning alone was US$16 for 2006. Moreover, reproductive health spending shows signs of decline in tandem with insufficient improvement in service utilization. Public providers played a predominant role in antenatal and delivery care for institutional births, but home deliveries with unqualified attendants dominated. The private sector was a major supplier of condoms, oral pills and IUDs. Private clinics, pharmacies and drug vendors were important sources of STI treatment. The findings highlight the need to commit greatly increased funding for reproductive health services as well as more policy attention to the contribution of public, private and informal providers and the role of collaboration among them to expand access to services for under-served populations. PMID- 21555088 TI - Trends and inequities in where women delivered their babies in 25 low-income countries: evidence from Demographic and Health Surveys. AB - In low-income countries, the coverage of institutional births is low. Using data from the two most recent Demographic and Health Surveys (1995-2001 and 2001-2006) for 25 low-income countries, this study examined trends in where women delivered their babies--public or private facilities or non-institutional settings. More than half of deliveries were in institutional settings in ten countries, mostly public facilities. In the other 15 countries, the majority of births were in women's homes, which was often their only option. Between the two survey periods, all five Asian countries studied (except Bangladesh) had an increase of 10-20 percentage points in institutional coverage, whereas none of the 19 sub-Saharan African countries saw an increase of more than 10 percentage points. More urban women and more in the richest (least poor) quintile gave birth in public or private facilities than rural and poorest quintile women. The rich-poor gap of institutional births was wider than the urban-rural gap. Inadequate public investment in health system infrastructure in rural areas and lack of skilled health professionals are major obstacles in reducing maternal mortality. Governments in low-income countries must invest more, especially in rural maternity services. Strengthening private, for-profit providers is not a policy choice for poor, rural communities. PMID- 21555089 TI - Equity of access to and utilization of reproductive health services in Thailand: national Reproductive Health Survey data, 2006 and 2009. AB - This study assessed trends in equity of access to reproductive health services and service utilization in terms of coverage of family planning, antenatal care and skilled birth attendance in Thailand. Two health indicators were measured: the prevalence of low birthweight and exclusive breastfeeding. Equity was measured against the combined urban-rural areas and geographic regions, women's education level and quintiles of household assets index. The study used data from two nationally representative household surveys, the 2006 and 2009 Reproductive Health Surveys. Very high coverage of family planning (79.6%), universal antenatal care (98.9%) and skilled birth attendance (99.7%), with very small socioeconomic and geographic disparities, were observed. The public sector played a dominant role in maternity care (90.9% of all deliveries in 2009). The private sector also had a role among the higher educated, wealthier women living in urban areas. Public sector facilities, followed by drug stores, were a major supplier of contraception, which had a high use rate. High coverage and low inequity were the result of extensive investment in the health system by successive governments, in particular primary health care at district and sub-district levels, reaching universality by 2002. While maintaining these achievements, methodological improvements in measuring low birthweight and exclusive breastfeeding for future reproductive health surveys are recommended. PMID- 21555090 TI - Stigmatisation and commercialisation of abortion services in Poland: turning sin into gold. AB - This paper is about the economic consequences of the stigmatisation and illegality of abortion and its almost complete removal from public health services in Poland since the late 1980s. Once abortion left the public sphere, it entered the grey zone of private arrangements, in which a woman's private worries became someone else's private gain, and her sin turned into gold. The most important consequence was social inequality, as the right to health, life, information and safety became commodities on the free market. Women with money, who are more likely to have political influence, find this bearable, while working class women lack the political capital to protest. In the private sector, there are no government controls on price, quality of care or accountability, and almost no prosecutions. With an estimated 150,000 abortions per year, a rough estimate of US$ 95 million is being generated annually for doctors, unregistered and tax-free. Thus, the combined forces of right-wing ideology and neoliberal economic reforms have created reproductive and social injustice. To address this, stigmatisation of abortion must be countered. But a change in the political climate, a less restrictive interpretation of the law, or even a new law would not resolve the problem. Given reductions in public health care spending, abortion would remain excluded from state coverage unless neoliberal health care reforms could be reversed. PMID- 21555091 TI - Cross-border assisted reproduction care in Asia: implications for access, equity and regulations. AB - This paper gives an overview of the global commercialised market in assisted reproduction treatment in low-resource countries in Asia and raises concerns about access and equity, the potential commercial exploitation of the bodies of subaltern women to service the demand for donated ova and surrogate pregnancy, and the need for protections through regulations. A lack of systematic data about cross-border reproductive care is a significant obstacle to debate and policy intervention. Little is known about the extent, experience or conditions of cross border reproductive care outside of Europe and the United States. Further research is needed in Asia on the local effects of this trade upon local health systems, couples seeking care, and those women whose body tissues and nurturing capacities facilitate it. More attention needs to be paid to the provision of publicly funded reproductive health services to address the inequitable distribution of treatment and to investigate means to regulate this trade by governments, international NGOs, professional organisations and civil society groups in developing countries. The global trade in assisted reproduction challenges us to balance the rights of individuals to pursue health care across national borders with the rights of those providing services to meet their needs, especially vulnerable groups in situations of economic disparity. PMID- 21555092 TI - New estimates of maternal mortality and how to interpret them: choice or confusion? AB - Two independent exercises to estimate levels of maternal mortality took place during 2010, one published by the Institute for Health Metrics and Evaluation in Seattle, USA, the other published by four UN agencies (UNICEF, UNFPA, World Bank and World Health Organization). Although both approaches are based on similar sets of empirical country data, their statistical methods differ in important respects--with implications for the resulting global, regional and country estimates. This paper examines the differences, discusses both the value and inherent limitations in such exercises, proposes ways of interpreting the different estimates and suggests how such exercises could be made more relevant to the needs of country-level decision-makers. It calls on the global community to invest seriously in working with countries to generate primary data on maternal mortality using measurement methods that reduce uncertainty and generate data on a continuing basis. The best routine source of data on maternal deaths is a civil registration system that assures permanent, compulsory and universal recording of the occurrence and characteristics of vital events, including births and deaths, and causes of death. The record of deaths among women of reproductive age derived from civil registration is often the first step in conducting a confidential enquiry into and preventing maternal deaths. PMID- 21555093 TI - Repeated pregnancy in a woman with uterine prolapse from a rural area in Nepal. AB - Pelvic organ prolapse is common in rural women in Nepal. Pregnancy in a woman with pelvic organ prolapse is uncommon and rarely continues beyond the second trimester. If it proceeds after that, the uterus usually ascends with progression of pregnancy and becomes abdominal, leaving little trace of prolapse. Pregnancy continuing to term with uterine prolapse is very rare. The case reported here is of a pregnant woman from a remote district in Nepal who had nine pregnancies and at 38 weeks of pregnancy presented at the district hospital with severe uterine prolapse, a large cervical ulcer and the baby's foot protruding from the cervix. Air transport was the only means of reaching the nearest hospital with emergency obstetric care, 200 km away. The baby was delivered stillborn at the airport by the auxiliary nurse-midwife who accompanied her. Her husband was counselled for and had a vasectomy. The woman was fitted with a ring pessary but could not afford to go to the nearest town for surgery for the prolapse. People in remote areas of Nepal often seek medical advice very late. This and the lack of education, low utilisation of family planning services, and lack of skilled birth attendance and safe delivery centres at local level contribute to high maternal morbidity and mortality. PMID- 21555094 TI - A strategic assessment of unsafe abortion in Malawi. AB - As part of efforts to achieve Millennium Development Goal 5--to reduce maternal mortality by 75% and achieve universal access to reproductive health by 2015--the Malawi Ministry of Health conducted a strategic assessment of unsafe abortion in Malawi. This paper describes the findings of the assessment, including a human rights-based review of Malawi's laws, policies and international agreements relating to sexual and reproductive health and data from 485 in-depth interviews about sexual and reproductive health, maternal mortality and unsafe abortion, conducted with Malawians from all parts of the country and social strata. Consensus recommendations to address the issue of unsafe abortion were developed by a broad base of local and international stakeholders during a national dissemination meeting. Malawi's restrictive abortion law, inaccessibility of safe abortion services, particularly for poor and young women, and lack of adequate family planning, youth-friendly and post-abortion care services were the most important barriers. The consensus reached was that to make abortion safe in Malawi, there were four areas for urgent action--abortion law reform; sexuality education and family planning; adolescent sexual and reproductive health services; and post-abortion care services. PMID- 21555095 TI - Severe maternal morbidity among immigrant women in the Netherlands: patients' perspectives. AB - This 2006 study investigated ethnicity-related factors contributing to sub standard maternity care and the effects on severe maternal morbidity among immigrant women in the Netherlands. In-depth interviews were carried out with 40 immigrant and 10 native Dutch women. The immigrant women reported that health care providers often paid insufficient attention to their pregnancy-related complaints, especially in cases of pre-eclampsia. They also reported delays in receiving information about diagnosis and treatment. Obstetricians who reviewed 20 of these cases judged sub-standard care to have played a role in the development of complications in 16 of them. The women themselves had problems identifying medically significant complications, presenting their complaints to health care providers effectively, and taking an active role as patients. Even highly educated migrant women showed low health literacy skills in their interaction with doctors. Patients' perspectives are valuable as one of the tools to evaluate the quality of maternity care. Communication by maternal health professionals can be improved through more sensitivity to social factors that affect immigrant women's health problems. Women with limited health literacy should be empowered through education about danger signs in pregnancy and information about preferences and policies in obstetrics in the Netherlands. They should also be invited to participate in medical decision-making. PMID- 21555096 TI - Using the Internet and social media to promote condom use in Turkey. AB - Condoms are an important contraceptive method in Turkey, used by one in three couples using modern methods. However, withdrawal remains the most common form of contraception, resulting in many unwanted pregnancies. To address this issue and increase condom use in Turkey, DKT International, a social marketing enterprise, leveraged the high use of the Internet and social networking to help build Fiesta, a premium condom brand, and promote sales and condom use. By utilising a wide range of digital platforms--a new website, Facebook page, Google Adwords, an e-newsletter, viral marketing, banner ads and involving bloggers--Fiesta achieved strong recognition among the target audience of sexually active young people, though far more men than women. Retail audits, Internet analysis and sales performance suggest that using the Internet was instrumental in establishing Fiesta. Sales reached 4.3 million condoms (of which 8% were sold online) in the first 18 months. In contrast, Kiss, a far more inexpensive DKT condom, launched at the same time but with no digital campaign, sold 2.6 million. With the growing availability and use of the Internet and social media globally, family planning organizations should consider incorporating these technologies into their educational, outreach and marketing programmes. PMID- 21555097 TI - Does condom social marketing improve health outcomes and increase usage and equitable access? AB - Condom social marketing (CSM) has increased condom supplies, broadened commercial markets for condoms and introduced marketing innovations in developing countries. Yet rigorous and reliable evidence of the impact on condom usage and disease prevention is limited, as is evidence of the impact on equity of access to condoms for poor populations, women and people living with HIV. One strand of research on CSM reports mostly on output (e.g. sales and processes) and market growth; but these have been found to be highly unreliable measures of condom usage. Another strand of research reports primarily on changes in sexual behaviour, attitude or condom usage, using survey data. While random sampling is rare, these studies often use representative samples, which provide some measure of validity. There have been attempts to improve the reliability or results to good effect, but challenges remain for researchers, scholars and donors, including the need to supplement output data with measures of behaviour change, use rigorous designs which are built into programmes a priori, report on equity measures, report on potential harms of CSM programmes, and encourage external and systematic reviews. PMID- 21555098 TI - Youth-friendly services in two rural districts of West Bengal and Jharkhand, India: definite progress, a long way to go. AB - It is a continuing challenge to reach rural youth in India with sexual and reproductive health services. Drawing on a large survey among 6,572 young people aged 15-24 and 264 rural health providers accessed by them in rural West Bengal and Jharkhand, we witnessed a long-awaited response to national efforts to promote birth spacing. That 31% of young, married women without children were using contraception to delay a first birth was evidence of cracks in the persistent tradition of demonstrating fertility soon after marriage. The coverage of public sector services for reproductive and sexual health is highly variable and the scope largely restricted to married women, with unmarried young women and men relying mainly on the informal private sector, and seriously underserved. Strong social norms proscribing pre-marital sexual relationships perpetuate barriers in meeting their needs. Access to contraception is affected by negative provider attitudes and reluctance to report having sex underestimates the real scale of unmet need. Yet, 30% of providers reported unmarried young women seeking abortion services. To address the needs of all rural youth, the public sector needs to expand its remit or engage with informal providers, train them to deliver youth-friendly services and give them a recognised role in abortion referral. PMID- 21555099 TI - Sexual relations and childbearing decisions of HIV-discordant couples: an exploratory study in South Africa and Tanzania. AB - This article reports on the influence of HIV on sexual relations and childbearing decisions of 36 HIV-discordant couples, 26 in South Africa and 10 in Tanzania, recruited into an exploratory study through hospital antiretroviral treatment clinics and civil society organisations working with people living with HIV. Self administered questionnaires were used to obtain social and demographic information, while couples' sexual relations and childbearing decisions were explored through in-depth, semi-structured individual and couple interviews. The majority of the HIV-positive partners were women, who were on antiretroviral treatment. Almost one-third of South African respondents and half of those in Tanzania reported experiences of tension related to HIV-discordance, while more than half of the South Africans and almost three-quarters of the Tanzanians reported that intimacy had been affected by their discordant status. Those without children were more likely to desire children (17/23) than those who already had children (16/44), although this desire was influenced by fear of HIV transmission to the negative partner and medical professional advice. The study points to the need for targeted information for HIV discordant couples, as well as couple counselling and support services. PMID- 21555100 TI - The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011). PMID- 21555101 TI - New technology in urology: balancing risk and reward. PMID- 21555102 TI - Predictors of costs for robotic-assisted laparoscopic radical prostatectomy. AB - OBJECTIVES: Information on the association of perioperative parameters with costs for robotic-assisted laparoscopic radical prostatectomy (RALP) is lacking. Understanding factors that impact cost may allow reduction in cost of prostate cancer care. We identified factors associated with higher costs in a contemporary series of RALP. MATERIALS AND METHODS: Total direct cost and clinicopathologic data were available for 264 patients who underwent RALP at our institution between May 2005 and April 2008. We performed linear regression analyses to identify predictors of direct cost using preoperative, intraoperative, and postoperative variables. RESULTS: On univariable analyses, operating room (OR) time, placement of a pelvic drain (both P<0.001), complications during surgery (P=0.002) or hospitalization, blood transfusion, and length of stay (all P<0.001) were associated with higher direct costs. On multivariable analysis, none of the preoperative features were found to predict direct costs. Of the intraoperative factors, OR time (P<0.001) and pelvic drain placement (P=0.006) were associated with higher direct costs. A longer OR time, length of stay, and usage of transfusions (all P<0.001) during the postoperative course were independently associated with higher direct costs. CONCLUSIONS: Of factors that are available preoperatively, none seems to be useful to predict added costs for individual patients undergoing RALP. Higher costs for RALP are driven by events occurring during the procedure or postoperative hospital stay. PMID- 21555103 TI - The application of natural orifice surgery for adenocarcinoma of the prostate. AB - Prostate cancer remains the most common solid organ malignancy in men. Unfortunately, surgical management of this disease is often associated with significant morbidity. In an effort to decrease the invasiveness and deleterious impact on quality of life associated with prostate cancer surgery, minimally invasive techniques have been applied to this disease. At present, the robotic assisted laparoscopic radical prostatectomy has become the most commonly performed surgical treatment modality for adenocarcinoma of the prostate. Recently, several centers within the United States have begun to evaluate the feasibility of applying natural orifice translumenal endoscopic surgery to prostate cancer. This review article details the initial work done on cadaveric and canine models to develop the transurethral radical prostatectomy procedure. Potential advantages and disadvantages of this modality, as well as challenges facing its continued development, are highlighted. PMID- 21555104 TI - Clinical application of a 3D ultrasound-guided prostate biopsy system. AB - OBJECTIVES: Prostate biopsy (Bx) has for 3 decades been performed in a systematic, but blind fashion using 2D ultrasound (US). Herein is described the initial clinical evaluation of a 3D Bx tracking and targeting device (Artemis; Eigen, Grass Valley, CA). Our main objective was to test accuracy of the new 3D method in men undergoing first and follow-up Bx to rule out prostate cancer (CaP). MATERIALS AND METHODS: Patients in the study were men ages 35-87 years (66.1 +/- 9.9), scheduled for Bx to rule out CaP, who entered into an IRB approved protocol. A total of 218 subjects underwent conventional trans-rectal US (TRUS); the tracking system was then attached to the US probe; the prostate was scanned and a 3D reconstruction was created. All Bx sites were visualized in 3D and tracked electronically. In 11 men, a pilot study was conducted to test ability of the device to return a Bx to an original site. In 47 men, multi parametric 3 Tesla MRI, incorporating T2-weighted images, dynamic contrast enhancement, and diffusion-weighted imaging, was performed in advance of the TRUS, allowing the stored MRI images to be fused with real-time US during biopsy. Lesions on MRI were delineated by a radiologist, assigned a grade of CaP suspicion, and fused into TRUS for biopsy targeting. RESULTS: 3D Bx tracking was completed successfully in 180/218 patients, with a success rate approaching 95% among the last 50 men. Average time for Bx with the Artemis device was 15 minutes with an additional 5 minutes for MRI fusion and Bx targeting. In the tracking study, an ability to return to prior Bx sites (n=32) within 1.2 +/- 1.1 mm SD was demonstrated and was independent of prostate volume or location of Bx site. In the MRI fusion study, when suspicious lesions were targeted, a 33% Bx-positivity rate was found compared with a 7% positivity rate for systematic, nontargeted Bx (19/57 cores vs. 9/124 cores, P=0.03). CONCLUSION: Use of 3D tracking and image fusion has the potential to transform MRI into a clinical tool to aid biopsy and improve current methods for diagnosis and follow-up of CaP. PMID- 21555105 TI - Imaging guidance in minimally invasive prostatectomy. AB - Minimally invasive prostatectomy, such as laparoscopic and robot-assisted prostatectomy, has become more popular, with similar short-term outcomes as open radical retropubic prostatectomy series. The purpose of this article is to review different imaging modalities that have been developed with a goal of further improving the surgical outcomes in minimally invasive prostatectomy. PMID- 21555112 TI - X-ray crystallography marries spectroscopy to unveil structure and function of biological macromolecules. PMID- 21555113 TI - Internal auditory canal lipoma. PMID- 21555114 TI - Design and validation of an improved graphical user interface with the 'Tool ball'. AB - The purpose of this research is introduce the design of an improved graphical user interface (GUI) and verifies the operational efficiency of the proposed interface. Until now, clicking the toolbar with the mouse is the usual way to operate software functions. In our research, we designed an improved graphical user interface - a tool ball that is operated by a mouse wheel to perform software functions. Several experiments are conducted to measure the time needed to operate certain software functions with the traditional combination of "mouse click + tool button" and the proposed integration of "mouse wheel + tool ball". The results indicate that the tool ball design can accelerate the speed of operating software functions, decrease the number of icons on the screen, and enlarge the applications of the mouse wheel. PMID- 21555115 TI - Effect of iron on enamel demineralization and remineralization in vitro. AB - OBJECTIVE: To evaluate the effect of ferrous sulphate on enamel demineralization and remineralization, using pH-cycling models. DESIGN: Fifty blocks were selected by their initial surface hardness and subjected to a pH-cycling demineralization process. Artificially demineralized lesions were produced in 60 blocks; out of these blocks, the surface hardness of 50 blocks and the cross-sectional hardness of 10 blocks were determined. The 50 blocks were then subjected to a remineralization pH-cycling process. Treatments were carried out using ferrous sulphate solutions of different concentrations (0.333, 0.840, 18.0, and 70.0 MUg Fe/mL) and a control group (deionized water). The final surface hardness (SH(2)) was determined, and the integrated subsurface hardness (DeltaKHN) was calculated. The enamel blocks were analysed for fluoride, calcium, phosphorus, and iron. The obtained data were distributed heterogeneously and were analysed using the Kruskal-Wallis test (p<0.05). RESULTS: In demineralization pH cycling, the group treated with the 18.0 MUg Fe/mL solution had higher secondary surface hardness and lower integrated subsurface hardness (DeltaKHN) than the other groups. In remineralization pH cycling, the control group showed the lowest value of DeltaKHN. A decline in Ca and P concentration was observed when the Fe concentration increased (p<0.05). There was no significant difference in the F concentration (p>0.05) and an increase in Fe concentration (p<0.05) in the enamel was observed when the Fe concentration increased in both the demineralization and remineralization experiments. CONCLUSION: The results suggest that iron reduces demineralization but does not allow remineralization to occur. PMID- 21555116 TI - Localization of nesfatin-1 neurons in the mouse brain and functional implication. AB - Nesfatin-1 reduces food intake when injected centrally in rodents. We recently described wide distribution of nucleobindin2 (NUCB2)/nesfatin-1 immunoreactivity in rat brain autonomic nuclei activated by various stressors. We used C57BL/6 mice to localize brain NUCB2/nesfatin-1 immunoreactivity and assessed activation of NUCB2/nesfatin 1 neurons after water avoidance stress (WAS). Gastric emptying of a non-nutrient liquid was also determined. NUCB2/nesfatin-1 immunoreactivity was detected in cortical areas including piriform, insular, cingulate and somatomotor cortices, the limbic system including amygdaloid nuclei, hippocampus and septum, the basal ganglia, bed nucleus of the stria terminalis, the thalamus including paraventricular and parafascicular nuclei, the hypothalamus including supraoptic, periventricular, paraventricular (PVN), arcuate nuclei and ventromedial and lateral hypothalamic areas. Intensely labeled NUCB2/nesfatin-1 neurons were detected in a previously undefined region which we named intermediate dorsomedial hypothalamus. In the brainstem, NUCB2/nesfatin-1 immunoreactivity was detected in the raphe nuclei, Edinger-Westphal nucleus, locus coeruleus (LC), lateral parabrachial nucleus, ventrolateral medulla (VLM) and dorsal vagal complex. WAS induced Fos expression in 35% of NUCB2/nesfatin-1 immunoreactive neurons in the PVN, 50% in the LC, 54% in the rostral raphe pallidus, 58% in the VLM, 39% in the middle part of the nucleus of the solitary tract (NTS) and 33% in the caudal NTS. Nesfatin-1 injected intracerebroventricularly significantly decreased gastric emptying. These data showed that NUCB2/nesfatin-1 immunoreactivity is distributed in mouse brain areas involved in the regulation of stress response and visceral functions activated by an acute psychological stressor suggesting that nesfatin-1 might play a role in the efferent component of the stress response. PMID- 21555117 TI - Rifampicin inhibits microglial inflammation and improves neuron survival against inflammation. AB - Microglial activation plays an important role in the pathophysiology of neurodegenerative diseases, and suppression of microglial activation prevents the progression of neurodegeneration. Rifampicin, a bacteriocidal antibiotic, induces immunosuppression. We hypothesized that rifampicin might be neuroprotective by inhibiting the production of pro-inflammatory mediators, thereby suppressing microglial activation. In the present study, we examined the effects of rifampicin on the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators and their signaling pathways in BV2 microglia. We also assessed the neuroprotective effects of rifampicin using a co-culture of microglia and neurons. Our results showed that rifampicin inhibited the LPS-stimulated expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-alpha, and interleukin-1beta, as well as the production of nitric oxide and prostaglandin E2. Moreover, rifampicin suppressed LPS-induced nuclear factor kappa B activation by blocking the degradation of the inhibitor of the nuclear transcription factor NF-kappa B. Rifampicin inhibited the phosphorylation of mitogen activated protein kinases, although protein kinase B was not inhibited. Preincubation of microglia with rifampicin reduced neurotoxicity and improved neuron survival in a microglia-neuronal co-culture system. Taken together, these findings suggest that rifampicin, with its anti-inflammatory properties, might be a novel treatment for neurodegenerative diseases. PMID- 21555118 TI - Motor imagery facilitates force field learning. AB - Humans have the ability to produce an internal reproduction of a specific motor action without any overt motor output. Recent findings show that the processes underlying motor imagery are similar to those active during motor execution and both share common neural substrates. This suggests that the imagery of motor movements might play an important role in acquiring new motor skills. In this study we used haptic robot in conjunction with motor imagery technique to improve learning in a robot-based adaptation task. Two groups of subjects performed reaching movements with or without motor imagery in a velocity-dependent and position-dependent mixed force field. The groups performed movements with motor imagery produced higher after effects and decreased muscle co-contraction with respect to no-motor imagery group. These results showed a positive influence of motor imagery on acquiring new motor skill and suggest that motor learning can be facilitated by mental practice and could be used to increase the rate of adaptation. PMID- 21555119 TI - Differential expression of pro-inflammatory cytokines, endothelin-1 and nitric oxide synthases in the rat carotid body exposed to intermittent hypoxia. AB - The enhanced carotid body (CB) chemosensory response to hypoxia induced by chronic intermittent hypoxia (CIH) has been attributed to oxidative stress, which is expected to increase the expression of chemosensory modulators including chemoexcitatory pro-inflammatory cytokines in the CB. Accordingly, we studied the time-course of the changes in the immunohistological expression of TNF-alpha, IL 1beta, IL-6, ET-1, iNOS, eNOS and 3-nitrotyrosine in the CB, along with the progression of enhanced CB chemosensory responses to acute hypoxia in male Sprague-Dawley rats exposed to CIH (5%O2, 12 times/h per 8h) for 7, 14 and 21 days. Exposure to CIH for 7 days resulted in a sustained potentiation of CB chemosensory responses to acute hypoxia, which persisted until 21 days of CIH. The chemosensory potentiation was paralleled by an increased 3-nitrotyrosine expression in the CB. On the contrary, CIH produced a transient 2-fold increase of ET-1 immunoreactivity at 7 days, a decrease in eNOS immunoreactivity, and a delayed but progressive increase of TNF-alpha, IL-1beta and iNOS immunoreactivity, which was not associated with changes in systemic plasma levels or immune cell invasion within the CB. Thus, present results suggest that the local expression of chemosensory modulators and pro-inflammatory cytokines in the CB may have different temporal contribution to the CB chemosensory potentiation induced by CIH. PMID- 21555120 TI - Vomifoliol 9-O-alpha-arabinofuranosyl (1->6)-beta-D-glucopyranoside from the leaves of Diospyros Kaki stimulates the glucose uptake in HepG2 and 3T3-L1 cells. AB - A novel alpha-glucosidase inhibitor, vomifoliol 9-O-alpha-arabinofuranosyl (1->6) beta-D-glucopyranoside, was isolated for the first time from leaves of Diospyros Kaki and its bioactivity analyzed. This inhibitor exhibited strong anti-alpha glucosidase activity with an IC50 value of 170.62nM and stimulated a dose dependent increase in the uptake of a fluorescent d-glucose analog, 2-[N-(7 nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), in HepG2 cells at a rate higher than that of insulin controls. It was also found to be associated with adipocyte differentiation and moderate increases in 2-NBDG uptake by 3T3-L1 cells. These findings suggest that vomifoliol 9-O-alpha arabinofuranosyl (1->6)-beta-D-glucopyranoside could augment peripheral glucose as an insulin-sensitizing agent against Type 2 diabetes mellitus. PMID- 21555122 TI - Reproductive outcomes among former Love Canal residents, Niagara Falls, New York. AB - Love Canal, located in Niagara Falls, NY, and among the earliest and most significant hazardous waste sites in the United States, first came to public attention in 1978. In this study, researchers evaluated 1,799 live births from 1960 through 1996 to 980 women who formerly lived in the Love Canal Emergency Declaration Area and were of reproductive age sometime during that time period. Using Upstate New York and Niagara County as external comparison populations, standardized incidence ratios with 95% confidence intervals were calculated for low birth weight, preterm birth, small for gestational age, and congenital malformations, and unadjusted proportions of male to female births were calculated. Internal comparisons among the infants were also performed according to several measures of potential exposure using generalized estimating equations. The results indicated a statistically significant elevated risk of preterm birth among children born on the Love Canal prior to the time of evacuation and relocation of residents from the Emergency Declaration Area, using Upstate New York as the standard population (standardized incidence ratio=1.40; 95% confidence interval: 1.01, 1.90). Additionally, the ratio of male to female births was lower for children conceived in the Emergency Declaration Area (sex ratio=0.94 versus sex ratio=1.05 in the standard population) and the frequency of congenital malformations was greater than expected among Love Canal boys born from 1983 to 1996 (standardized incidence ratio=1.50 when compared to Upstate New York), although in both cases the 95% confidence interval included the null value. Finally, increased risk for low birth weight infants among mothers who lived closest to the Canal as children was found (odds ratio=4.68; 95% confidence interval: 1.24, 17.66), but this estimate was limited due to small numbers (n=4). The study adds to the knowledge of the possible reproductive effects from exposure to chemicals arising from hazardous waste; however, given the small number of some events, the qualitative nature of the exposure assessment, and possibility of spurious associations due to multiple comparisons, the findings should be interpreted cautiously. PMID- 21555123 TI - Tracing patterns of activity in the human skeleton: an overview of methods, problems, and limits of interpretation. AB - Studies of patterns of activity in human skeletal remains have grown in number over the last few years. Different methods have been used to reconstruct activity patterns in past populations. In this review of the available literature the common themes of these studies have been isolated in order to show that many studies do not truly conform to the standards of the field. Inadequate sample size, too far-reaching conclusions and neglect of other possible explanations are among the problems easily recognised in the literature. Many assumptions are lacking a sound experimental basis, and it becomes increasingly evident that there are many more problems and limits of interpretations than have been usually acknowledged in the recent past. It also appears that many results, which have been interpreted in terms of sexual division of labour may, in fact, be expressions of the intrinsic sexual dimorphism of Homo sapiens and not culture- or population-specific peculiarities. Acknowledging the results of many studies from the field of sports medicine it appears doubtful that adult patterns of activity can truly be isolated from those which stem from the formative years of the human skeleton during the subadult growth period. A more cautious approach to the interpretation of data and a return to more basic research are needed to adequately address all the possibly confounding issues when trying to reconstruct patterns of activity from archaeological skeletal remains. PMID- 21555124 TI - Early results after vertebral body stenting for fractures of the anterior column of the thoracolumbar spine. AB - INTRODUCTION: Vertebroplasty and balloon kyphoplasty have shown to improve pain and functional outcome in cases with symptomatic vertebral fractures. Although restoration of the vertebral body height and kyphosis seemed to be easier with balloon kyphoplasty, it became clear that some of the correction achieved by the balloon is lost once it was deflated. Vertebral body stent was developed to eliminate this phenomenon. To our knowledge this is the first study in describing this technique in clinical settings. MATERIALS AND METHODS: Seventeen patients with 20 fractured vertebral bodies were included. All fractures were Type A1.3 or A3.1 (incomplete burst). Information about pain (visual analogue scale-VAS) and function (Oswestry disability index-ODI) and vertebral body deformity (vertebral angle-VA) was recorded in a prospective way at regular intervals. Patients were classified into osteoporotic group (7 patients) and traumatic groups (10 patients, younger than 60 years). RESULTS: There were 6 male and 11 female patients with mean age of 58.1 years (31-88 years). Mean follow up was 12 months. The preoperative pain level showed a mean VAS score of 8.9 in osteoporotic group and 9.7 in traumatic group. Postoperatively, in osteoporotic group, mean VAS was 4.8 at 6 weeks, 4.0 at 6 months and 2.5 at 12 months compared with traumatic fracture group where it was 2.7 at 6 weeks, 2.2 at 6 months and 1.6 at 12 months. Mean ODI in osteoporotic group was 41.7% (14-58%) and in traumatic group it was 20.4% (6-33%). Mean vertebral body angle prior to surgery in osteoporotic group was 9.7 whilst postoperatively it was 5.2 degrees ; so the mean correction achieved was 4.5 degrees . In traumatic group preoperative VA was 13 degrees whilst postoperatively it was 5.7 degrees ; therefore the mean correction achieved was 7.3 degrees . None of the patients lost reduction at their last follow up. CONCLUSION: Vertebral body stenting leads to satisfactory improvement in pain, function and kyphosis correction in the treatment of osteoporotic and traumatic fractures. Anterior spinal column, especially the fragmented superior endplate is nicely reconstructed by the stent provided it is inserted accurately. With addition of posterior transpedicular instrumentation, indications for this technique may be wider covering some Type B and C fractures with similar vertebral body damage. PMID- 21555125 TI - Ng YH, Gino PD, Lingaraj K, Das De S. Femoral shaft fracture in the elderly - role of prior bisphosphonate therapy. PMID- 21555126 TI - Adaptive feedback potential in dynamic stability during disturbed walking in the elderly. AB - After perturbation of the gait, feedback information may help regaining balance adequately, but it remains unknown whether adaptive feedback responses are possible after repetitive and unexpected perturbations during gait and if there are age-related differences. Prior experience may contribute to improved reactive behavior. Fourteen old (59-73 yrs) and fourteen young (22-31 yrs) males walked on a walkway which included one covered element. By exchanging this element participants either stepped on hard surface or unexpectedly on soft surface which caused a perturbation in gait. The gait protocol contained 5 unexpected soft trials to quantify the reactive adaptation. Each soft trial was followed by 4-8 hard trials to generate a wash-out effect. The dynamic stability was investigated by using the margin of stability (MoS), which was calculated as the difference between the anterior boundary of the base of support and the extrapolated position of the center of mass in the anterior-posterior direction. MoS at recovery leg touchdown were significantly lower in the unexpected soft trials compared to the baseline, indicating a less stable posture. However, MoS increased (p<0.05) in both groups within the disturbed trials, indicating feedback adaptive improvements. Young and old participants showed differences in the handling of the perturbation in the course of several trials. The magnitude of the reactive adaptation after the fifth unexpected perturbation was significantly different compared to the first unexpected perturbation (old: 49+/ 30%; young: 77+/-40%), showing a tendency (p=0.065) for higher values in the young participants. Old individuals maintain the ability to adapt to feedback controlled perturbations. However, the locomotor behavior is more conservative compared to the young ones, leading to disadvantages in the reactive adaptation during disturbed walking. PMID- 21555127 TI - Glycated collagen alters endothelial cell actin alignment and nitric oxide release in response to fluid shear stress. AB - People with diabetes suffer from early accelerated atherosclerosis, which contributes to morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Atherosclerosis is thought to initiate at sites of endothelial cell injury. Hyperglycemia, a hallmark of diabetes, leads to non enzymatic glycosylation (or glycation) of extracellular matrix proteins. Glycated collagen alters endothelial cell function and could be an important factor in atherosclerotic plaque development. This study examined the effect of collagen glycation on endothelial cell response to fluid shear stress. Porcine aortic endothelial cells were grown on native or glycated collagen and exposed to shear stress using an in vitro parallel plate system. Cells on native collagen elongated and aligned in the flow direction after 24 h of 20 dynes/cm(2) shear stress, as indicated by a 13% decrease in actin fiber angle distribution standard deviation. However, cells on glycated collagen did not align. Shear stress mediated nitric oxide release by cells on glycated collagen was half that of cells on native collagen, which correlated with decreased endothelial nitric oxide synthase (eNOS) phosphorylation. Glycated collagen likely inhibited cell shear stress response through altered cell-matrix interactions, since glycated collagen attenuated focal adhesion kinase activation with shear stress. When focal adhesion kinase was pharmacologically blocked in cells on native collagen, eNOS phosphorylation with flow was reduced in a manner similar to that of glycated collagen. These detrimental effects of glycated collagen on endothelial cell response to shear stress may be an important contributor to accelerated atherosclerosis in people with diabetes. PMID- 21555128 TI - Enantioselective open-tubular capillary electrochromatography using cyclodextrin modified gold nanoparticles as stationary phase. AB - Enantioselective open-tubular CEC (OTCEC) with thiolated beta-CD modified gold nanoparticles (CD-GNPs) as stationary phase was developed. The enantioselective OT capillary column was fabricated by electrostatic assembly of poly(diallydimethylammonium chloride) (PDDA) followed by self-adsorption of negatively charged CD-GNPs. The enantioselective capillary column has a steady EOF mobility over a wide pH range of 3.0 to 9.2 (RSD 4.8%), and is quite stable over 240 min with very good column to column reproducibility. Efficient enantioseparation of the presented method was demonstrated by analyzing three drug enantiomers. Our results show that the column exhibits good run-to-run repeatability for enantioseparations and can maintain the enantioselectivity for more than 1 month if the column was stored in CD-GNPs solution at 4 degrees C. PMID- 21555129 TI - Novel molecularly imprinted microsphere using a single chiral monomer and chirality-matching (S)-ketoprofen template. AB - We designed and synthesized a cinchonine derivative to be used as a novel chiral monomer. It was employed in a dual role of functional monomer and cross-linking monomer, displaying multi-binding sites for the template (S)-ketoprofen. Monodisperse molecularly imprinted core-shell microspheres were prepared using surface imprinting method on silica gel. The results show a substantial synergistic effect in the enantioselective recognition, confirming our initial hypothesis. Computational simulation of the monomer and template pre-arrangement strongly supports our proposed chiral recognition mechanism for the imprinted microspheres. PMID- 21555130 TI - Global and selective detection of organohalogens in environmental samples by comprehensive two-dimensional gas chromatography-tandem mass spectrometry and high-resolution time-of-flight mass spectrometry. AB - We successfully detected halogenated compounds from several kinds of environmental samples by using a comprehensive two-dimensional gas chromatograph coupled with a tandem mass spectrometer (GC*GC-MS/MS). For the global detection of organohalogens, fly ash sample extracts were directly measured without any cleanup process. The global and selective detection of halogenated compounds was achieved by neutral loss scans of chlorine, bromine and/or fluorine using an MS/MS. It was also possible to search for and identify compounds using two dimensional mass chromatograms and mass profiles obtained from measurements of the same sample with a GC*GC-high resolution time-of-flight mass spectrometer (HRTofMS) under the same conditions as those used for the GC*GC-MS/MS. In this study, novel software tools were also developed to help find target (halogenated) compounds in the data provided by a GC*GC-HRTofMS. As a result, many dioxin and polychlorinated biphenyl congeners and many other halogenated compounds were found in fly ash extract and sediment samples. By extracting the desired information, which concerned organohalogens in this study, from huge quantities of data with the GC*GC-HRTofMS, we reveal the possibility of realizing the total global detection of compounds with one GC measurement of a sample without any pre treatment. PMID- 21555131 TI - Biophysical investigation of the interfacial properties of cationic fluorocarbon/hydrocarbon hybrid surfactant: mimicking the lung surfactant protein C. AB - The interfacial behavior of the newly designed Fluorocarbon Hydrocarbon Cationic Lipid (FHCL or CH(3)(CH(2))(17)N(+)(C(2)H(5))(2)(CH(2))(3)(CF(2))(7)CF(3)I(-)) and its mixtures with a phospholipid (DPPC, Dipalmitoylphosphatidylcholine) at different mole fractions were investigated. This new molecule was synthesized to mimic the selected properties of lung surfactant, which is a natural lipid protein mixture which is known to play important roles in the process of respiration, by considering the structure/function relation of lung surfactant protein (SP-C). Each segment in the molecular structure was selected to affect the molecular level interaction at the interface whereas the keeping the overall structure as simple as possible. The surface pressure area isotherms obtained for the mixtures of DPPC/FHCL indicated that there was repulsive interaction between DPPC and FHCL molecules. Due to the molecular level interaction, specifically at mole fraction 0.3, the isotherm obtained from that mixture resembled the isotherm obtained from the DPPC monolayer in the presence of SP-C. High elasticity of the interface was one of the important parameters for the respiration process, therefore, shear and dilatational elasticities of two-component systems were determined and they were found to be similar to the case where SP-C protein is present. Fluorescence microscopy images were taken in order to investigate the monolayer in details. The FHCL was able to fluidize the DPPC monolayer even at high surface pressures effectively. In addition, the cyclic compression-expansion isotherms were obtained to understand the spreading and re-spreading ability of the pure FHCL and the mixed DPPC/FHCL monolayers. At a specific mole fraction, X(FHCL)=0.3, the mixture exhibited good hysteresis in area, compressibility, recruitment index and re-spreading ability at the interface. All these results point out that FHCL can fulfill the selected features of the lung surfactant that are attributed to the presence of SP-C protein when mixed with DPPC, even if the molecular structure of the FHCL is quite simple. PMID- 21555132 TI - General equation describing wetting of rough surfaces. AB - The problem of wetting is discussed in the framework of the variational approach. Derivation of the general equation describing the wetting of rough chemically homogenous surfaces is presented. The equation considers effects related to the line tension at the perimeter of the drop and at the details of the relief. The equation comprises as particular cases the Cassie and Wenzel equations and the equation proposed recently by Wong and Ho. PMID- 21555133 TI - Acid natural clinoptilolite: structural properties against adsorption/separation of n-paraffins. AB - The employment of an acid natural clinoptilolite (AZH-1) in the adsorption and separation of n-paraffins has been evaluated. Natural clinoptilolite, NZ, was the raw material used to prepare the sodium-exchanged clinoptilolite (AZ) starting from which the AZH-1 sample was obtained by acid treatment. The structural stability of the samples after the applied treatments was demonstrated. The nitrogen adsorption experiments indicated that the acid sample has a homogeneous porous distribution and a considerable increase in the micropore volume with respect to NZ and AZ. The employment of the inverse gas chromatography at infinite dilution (IGCID) allowed studying the adsorption and separation of n paraffin mixtures on AZH-1. It was also confirmed that the diffusion on AZH-1 took place in an unblocked structure through the A channel of ten members with minimal interactions. The IGCID results demonstrated the capacities of the acid Cuban natural zeolite in the adsorption and separation of n-paraffin mixtures. PMID- 21555134 TI - Manipulating interactions between functional colloidal particles and polyethylene surfaces using interfacial engineering. AB - The purpose of this study was to examine the interaction between lipid droplets and polyethylene surfaces, representative of those commonly used in food packaging. Lipid droplets with various surface charges were prepared by homogenizing corn oil and water in the presence of surfactants with different electrical characteristics: non-ionic (Tween 80, T80), cationic (lauric arginate, LAE), and/or anionic (sodium dodecyl sulfate, SDS). The ionic properties of polyethylene surfaces were modified by UV-treatment. Stable emulsions containing small droplets (d<200 nm) with nearly neutral (T80), cationic (T80: LAE), and anionic (T80: SDS) charges were prepared by adding different levels of the ionic surfactants to Tween 80 stabilized emulsions. Scanning electronic microscopy (SEM), confocal fluorescence microscopy, and ATR-FTIR showed that the number of droplets attached to the polyethylene surfaces depended on the droplet charge and the polyethylene surface characteristics. The greatest degree of droplet adsorption was observed for the cationic droplets to the UV-ozone treated polyethylene surfaces, which was attributed to electrostatic attraction. These results are important for understanding the behavior of encapsulated lipophilic components in food containers. PMID- 21555135 TI - The inhibition abilities of multifunctional polyelectrolytes for silica scale formation in cooling water systems: role of the nonionic functional group. AB - The abilities of multifunctional polyelectrolytes to enhance aluminum hydroxide dispersion and inhibit silica scale formation were examined in a pilot cooling water system. The following multifunctional polyelectrolytes were studied: a terpolymer of acrylic acid (AA), 2-acrylamide-2-methyl propane sulfonic acid (SA) and N-vinylpyrrolidone (NVP) (P(AA/SA/NVP)), acrylic acid homopolymer (P(AA)) and a copolymer of AA and SA (P(AA/SA)). The order of inhibition ability was P(AA/SA/NVP)>P(AA/SA)>P(AA), and was consistent with that of the dispersing ability for aluminum hydroxide. Other terpolymers incorporating different nonionic monomers were also examined and factors affecting their inhibition abilities were investigated, based on interaction energies calculated by density functional theory. Based on the correlation between scale inhibition abilities and interaction energies, we elucidated that the effective nonionic monomer of terpolymer for silica scale inhibition had low affinity for aluminum hydroxide and high affinity for H(2)O and Si(OH)(3)O(-). The affinities of nonionic monomer for aluminum hydroxide and H(2)O suggested that there was proper conformation of polyelectrolyte adsorbed for effectively dispersing aluminum hydroxide. Also, high affinity of nonionic monomer for Si(OH)(3)O(-) suggested that interacting Si(OH)(3)O(-) is an important role of inhibition of silica scale formation. PMID- 21555136 TI - Alogia and formal thought disorder: differential patterns of verbal fluency task performance. AB - BACKGROUND: There is evidence that alogia and formal thought disorder (FTD), two prominent speech symptoms in schizophrenia, are associated with different patterns of verbal fluency task deficits. Verbal fluency is thought to involve several cognitive mechanisms, including controlled retrieval, semantic memory, and context processing. METHODS: The current research examined whether alogia and FTD were associated with different patterns of verbal fluency performance and whether these patterns of verbal fluency performance would implicate deficits in controlled retrieval, semantic memory, or context processing. In the current research, 34 people with schizophrenia completed letter and category fluency tasks and detailed ratings of alogia and FTD symptoms were made from typed transcripts. RESULTS: Overall, alogia was associated with increased response latency between each word on the category fluency task, suggesting an association between alogia and poor controlled retrieval. In contrast, FTD was associated with a decreased proportion of semantically-related words on letter fluency, suggesting an association between FTD and poor context processing. CONCLUSIONS: Alogia and FTD appear to be associated with unique patterns of fluency performance, implicating separate cognitive mechanisms. PMID- 21555137 TI - Early and long-term results of reoperative total aortic root replacement with reimplantation of the coronary arteries. AB - BACKGROUND: Total root replacement with biologic valves and reimplantation of the coronaries gives good early and midterm results. There is continuing concern, however, regarding the risks and long-term results for reoperation after total replacement of the aortic root with reimplantation of the coronaries. METHODS: Between June 1981 and July 2010, a total of 84 patients underwent reoperative aortic root replacement with reimplantation of the coronaries (60 male, mean age 38 +/- 15 years). All patients had undergone first-time total aortic root replacement with homografts (82 patients) or autografts (2 patients). Indication for reoperation was structural valve deterioration in 72 patients (85%) and infective endocarditis in 12 patients (15%). Mean interval between first operation and reoperation was 11.1 +/- 4.7 years (range, 1 month-24.7 years). Median length of follow-up was 9.7 +/- 5.6 years (range, 1 month-24.4 years). RESULTS: Thirty-day mortality was 2.4% (n = 2 patients). Both patients died postoperatively of low-output syndromes with multiorgan failure. At reoperation, 74 patients received homografts (87%), 7 patients underwent a Ross procedure (9%), and 3 received stentless porcine roots (4%). One patient required pacemaker implantation (1%). Actuarial survivals were 89% +/- 4% and 81% +/- 5% at 5 and 10 years, respectively. Nine patients underwent a successful third root replacement during follow-up. Freedom from third-time aortic root operation was 97% +/- 3% at 10 years. CONCLUSIONS: Reoperative aortic root replacement can be performed safely with good short-term and midterm outcomes in a young patient cohort. PMID- 21555138 TI - Standards for relations of cardiothoracic surgical organizations with industry. PMID- 21555139 TI - Potent neuroprotection induced by remote preconditioning in a rat model of neonatal cerebral hypoxic-ischemic injury. PMID- 21555140 TI - Preparation, characterisation and application of novel composite coagulants for surface water treatment. AB - The development of the Inorganic Polymeric Flocculants (IPFs) can be regarded as significant progress in the coagulation-flocculation field. However, the IPFs may be less efficient when compared to the organic polymers (polyelectrolytes) regarding their aggregation abilities. In order to increase further their flocculation efficiency, the combination of a cationic IPF (polyaluminium chloride, PACl) and an anionic polyelectrolyte in one unique reagent is proposed in this study. During this investigation, several composite coagulants were prepared, which differ on the preparation method and polyelectrolyte content. Major typical properties of the prepared coagulants were examined, i.e. pH, turbidity, conductivity, Al species distribution. The composition, structure and morphology of the composite coagulants were studied in detail as well, with the application of FT-IR, XRD and SEM techniques. Their coagulation performance was investigated in the treatment of a model water sample (simulating surface water) and compared to the respective coagulation performance of PACl and the polyelectrolyte applied as separated reagents (common procedure). Finally, the kinetics of coagulation was studied with application of the Photometric Dispersion Analyser (PDA). From the results, it was revealed that interactions take place between the Al species and the polyelectrolyte molecules, which probably lead to the formation of new, "composite" species. The properties of the composite coagulants are significantly affected by these interactions, leading to more effective water treatment. The simplification of the overall treatment process and the cost-effectiveness are considered as the major advantages of the composite coagulants. PMID- 21555141 TI - Identification of potential nitrogenous organic precursors for C-, N-DBPs and characterization of their DBPs formation. AB - Nitrosamines are a class of emerging disinfection by-products (DBPs), which are mainly formed when water is treated by chloramination. Nitrosamines are highly carcinogenic and are hence a major concern for drinking water supplies. Although dissolved organic nitrogen (DON) compounds such as dimethylamine (DMA) have been recognized as important precursors of nitrosamines, many of them have not been identified, especially those used in consumer products. In this study, nine representative nitrogenous organic compounds with different DON characteristics and structures were selected to react with free chlorine, chlorine dioxide and monochloramine, respectively, for their DBP formation characteristics (nitrosamines, trihalomethanes (THMs) and haloacetic acids (HAAs)). It was found that in addition to DMA, benzyldimethyltetradecylamine (benzalkonium chloride, BKC) and 3-(N,N-dimethyloctyl-ammonio)propanesulfonate (3-N,N-DAPSIS) inner salt were potent precursors for carbonated DBPs (C-DBPs) and nitrogenated DBPs (N DBPs). The DBP formation potential (DBPFP) tests showed that 1 mM of BKC formed more than 2 * 10(5) ng/L of N-nitrosodimethylamine (NDMA) when treated with monochloramine and high levels of C-DBPs (2713 +/- 145 MUg/L of THMs and 356 +/- 5 MUg/L of HAAs) when treated with chlorine. 3-N,N-DAPSIS was a less potent DBP precursor: 1 mM of 3-N,N-DAPSIS generated 1155 +/- 7 ng/L of NDMA, 1351 +/- 66 MUg/L of THMs and 188 +/- 1 MUg/L of HAAs. DMA, 3-N,N-DAPSIS and BKC were examined for their DBPFPs at various pH and temperatures to determine the impact of pH and reaction temperature on DBP yields and their formation mechanisms. The results showed that DBP yields apparently increased with rising temperature. However, no consistent correlations were observed between DBPs yields and pH. Bromide shifted the DBP species into brominated DBPs, and this phenomenon was more apparent when BKC was treated with chloramine. PMID- 21555142 TI - Modelling Cryptosporidium oocysts transport in small ungauged agricultural catchments. AB - Cryptosporidium is an environmentally robust pathogen that has caused severe waterborne disease outbreaks worldwide. The main source of zoonotic Cryptosporidium parvum oocysts in human drinking water is likely to be from farm animals via catchment pathways with water as the main transport vector. The vast majority of small agricultural catchments are ungauged therefore it is difficult to use a process model to predict and understand the mechanisms and activities that regulate the risk of surface water contamination from agricultural areas. For this study, two ungauged agricultural catchments in Ireland were used to model Cryptosporidium oocyst transport using SWAT2005 on a daily basis with reference data from adjacent catchment gauging stations. The results indicated that SWAT2005 could simulate stream flow with good agreement between prediction and observation on a monthly basis (R(2) from 0.94 to 0.83 and E (efficiency) from 0.92 to 0.66), but Cryptosporidium oocyst concentration results were less reliable (R(2) from 0.20 to 0.37, P < 0.05; with poor E -0.37 to -2.57). A sensitivity analysis using independent parameter perturbation indicated that temperature was the most important parameter regulating oocyst transport in the study catchments and that the timing of manure application relative to the occurrence of water runoff event was critical. The results also showed that grazing management had little influence on predicted oocyst transport while fields fertilized with manure were the key critical source areas for microbial contaminations in the study catchments. It was concluded that the approach presented could be used to assist with understanding the epidemiology of waterborne cryptosporidiosis outbreaks and to improve catchment management for the safety of the general public health. PMID- 21555143 TI - Effects of a glyphosate-based herbicide on mate location in a wolf spider that inhabits agroecosystems. AB - Chemical communication is important to many arthropod species but the potential exists for anthropogenic chemicals to disrupt information flow. Although glyphosate-based herbicides are not acutely toxic to arthropods, little is known regarding their effects on natural chemical communication pathways. The wolf spider, Pardosamilvina, is abundant in agroecosystems where herbicides are regularly applied and uses air- and substrate-borne chemical signals extensively during mating. The aim of this study was to examine effects of a commercial formulation of a glyphosate-based herbicide on the ability of males to find females. In the field, virgin females, when hidden inside pitfall traps with herbicide, attracted fewer males than females with water. Likewise females in traps with a ring of herbicide surrounding the opening were less likely to attract males than those in traps surrounded by water. We explored the reaction of males to any airborne component of the herbicide in a laboratory two-choice olfactometer experiment. When no female pheromones were present, males were equally likely to select herbicide or water treated corridors and they all moved through the apparatus at similar speeds. When female pheromones were present, the males that selected control corridors moved more slowly than those that selected herbicide and, if we control for the initial decision time, more males selected the control corridors over the herbicide. These data suggest that glyphosate based herbicides are "info-disruptors" that alter the ability of males to detect and/or react fully to female signals. PMID- 21555144 TI - Differential expression of acid invertase genes in roots of metallicolous and non metallicolous populations of Rumex japonicus under copper stress. AB - Recent evidence indicates that during copper (Cu) stress, the roots of metallicolous plants manifest a higher activity of acid invertase enzymes, which are rate-limiting in sucrose catabolism, than non-metallicolous plants. To test whether the higher activity of acid invertases is the result of higher expression of acid invertase genes, we isolated partial cDNAs for acid invertases from two populations of Rumex japonicus (from metalliferous and non-metalliferous soils), determined their nucleotide sequences, and designed primers to measure changes in transcript levels during Cu stress. We also determined the growth of the plants' roots, Cu accumulation, and acid invertase activities. The seedlings of R. japonicus were exposed to control or 20 MUM Cu(2+) for 6d under hydroponic conditions. The transcript level and enzyme activity of acid invertases in metallicolous plants were both significantly higher than those in non metallicolous plants when treated with 20 MUM. Under Cu stress, the root length and root biomass of metallicolous plants were also significantly higher than those of non-metallicolous plants. The results suggested that under Cu stress, the expression of acid invertase genes in metallicolous plants of R. japonicus differed from those in non-metallicolous plants. Furthermore, the higher acid invertase activities of metallicolous plants under Cu stress could be due in part to elevated expression of acid invertase genes. PMID- 21555145 TI - Fish consumption reduces transfer of BDE47 from dam to murine offspring. AB - Fish and seafood are important contributions to a healthy diet, but also contain persistent organic pollutants (POPs) like polybrominated diphenylethers (PBDEs) and polychlorinated biphenyls (PCBs). Discrepancies have been found between intake and accumulated levels of POPs, where fish consumers have had similar levels of POPs to the general population. Similarly fish oil consumption has been found to reduce accumulation of POPs. This study examined the accumulation of BDE47 or PCB153 in mice fed diets with different nutritional composition, using female mice with pre-weanling pups exposed through gestation and lactation. A fish-based diet was compared to a standard casein-based rodent diet. All diets had low background levels of environmental contaminants and were spiked with BDE47 or PCB153 to levels representing a realistic (~0.004 MUmol kg bw(-1) d) or a high dietary exposure (~1.3 MUmol kg bw(-1) d). Accumulation of BDE47 or PCB153 in offspring tissues after 18d lactation reflected the maternal exposure levels. However, the pups of dams fed a fish-based diet had consistently lower BDE47 accumulation in liver, fat and stomach than pups from casein-fed dams. Similarly the pups of dams fed a high dose of PCB153 in a fish diet also accumulated less PCB153 than pups of the dams fed a casein diet, although not significant. In conclusion, the fish based diets seemed to reduce transfer of BDE47 and PCB153 from dams to pups. The study highlights that in-depth knowledge about nutritional impact on toxicokinetics is of great interest to vulnerable consumers. PMID- 21555146 TI - Significance and interspecific variability of accumulated trace metal concentrations in Antarctic benthic polychaetes. AB - Trace metals were analysed in polychaetes collected on Polarstern cruise ANT XXI/2 (2003/04) to the Weddell Sea. Pb concentrations were largely less than 1.3 mg kg(-1)DW in all samples analysed. Statistical results indicate that the accumulated Cd, Cu and Zn concentrations are related to the feeding guild to which the animals are belonging. Relatively low Cd and Cu concentrations are found in macrophagous carnivores and relatively high concentrations in microphagous detritus feeders. The relationship between Zn concentrations and the feeding guilds of polychaetes is reverse. Cd concentrations range from (median values and interquantile ranges in brackets) 2.6 (1.5-3.2) mg kg(-1)DW in the carnivorous Trypanosyllis gigantea to 133 (37-176) mg kg(-1) in the microphagous detritus feeder Lanicides bilobata; Cu concentrations from 16 (11-19) mg kg(-1) in the carnivorous Antarctinoe spicoides to 40 (23-68) mg kg(-1) in the microphagous detritus feeder Phyllocomus crocea and Zn from 89 (69-97) mg kg(-1) in the microphagous detritus feeder Isocirrus yungi to 396 (372-404) mg kg(-1) in the carnivorous Aglaophamus trissophyllus. Ni is ranging from 3.7 (1.8-6.0) mg kg(-1) in Polyeunoa laevis to 34 (20-41) mg kg(-1) in A. spicoides, but no significant differences are obvious regarding the feeding guilds. Since information on metals in Antarctic polychaetes is almost completely lacking, our results suggest further studies to clarify the role of feeding in the bioaccumulation of metals in this ecologically important taxonomic group. PMID- 21555147 TI - A prospective phase II study of topotecan (Hycamtin(r)) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. AB - OBJECTIVES: To evaluate the feasibility, toxicity and activity of neoadjuvant chemotherapy (NACT) using cisplatin and topotecan in patients affected by locally advanced cervical cancer (IB2-IIIB). METHODS: Patients with histologically confirmed FIGO stage IB2-IIIB uterine cervical cancer were treated with topotecan 0.75 mg/m(2)/day (days 1-3) followed by cisplatin 75 mg/m(2) (day 1), every 21 days for three consecutive cycles. After the last cycle of chemotherapy, within 3 or 4 weeks, patients underwent radical surgery with lymph node dissection. RESULTS: In the years 2007-2010, 46 women were enrolled into the study. Hematologic toxicity was the most relevant side effect. Thirty-eight patients (82.6%) underwent radical surgery after neoadjuvant chemotherapy (NACT) and were assessable for pathologic responses; surgery was not performed in 8 (17.4%) non responder patients or with progression disease. Objective pathological response was recorded in 34 patients (89.5%); 6 patients (15.8%) achieved a complete response (CR), 28 (73.7%) patients achieved a partial response (PR); stable disease (SD) occurred in 2 patients (5.3%) with IIA initial disease and progression disease (PD) was registered in 2 patients (5.3%) with IIIB initial disease. The cumulative 2-year progression free survival (PFS) and overall survival (OS) of the 46 enrolled patients in the study were 70% and 81%, respectively; the 2-year PFS and OS of the 38 operated patients were respectively 79% and 95%. CONCLUSIONS: The cisplatin-topotecan combination seems to be feasible and with an acceptable toxicity profile and a promising response rate for the treatment of locally advanced cervical cancer (LACC). Phase II and III studies are needed to compare this combination with other platinum-based chemotherapeutic associations. PMID- 21555148 TI - Children in the inner city of New York have high rates of food allergy and IgE sensitization to common foods. PMID- 21555149 TI - Evidence that the endothelin A receptor can enhance IgE-dependent anaphylaxis in mice. PMID- 21555150 TI - IgE to Gly m 5 and Gly m 6 is associated with severe allergic reactions to soybean in Japanese children. PMID- 21555151 TI - Enhancement of cell retention and functional benefits in myocardial infarction using human amniotic-fluid stem-cell bodies enriched with endogenous ECM. AB - Stem cell transplantation may repair the infarcted heart. Despite the encouraging preliminary results, an optimal cell type used and low retention of the transplanted cells remain to be overcome. In this study, a multiwelled methylcellulose hydrogel system was used to cultivate human amniotic-fluid stem cells (hAFSCs) to form spherically symmetric cell bodies for cellular cardiomyoplasty. The grown hAFSC bodies enriched with extracellular matrices (ECM) were xenogenically transplanted in the peri-infarct area of an immune suppressed rat, via direct intramyocardial injection. Results of bioluminescence imaging and real-time PCR revealed that hAFSC bodies could considerably enhance cell retention and engraftment in short-term and long-term observations, when compared with dissociated hAFSCs. Echocardiography and magnetic resonance imaging showed that the enhanced cell engraftment in the hAFSC-body group could significantly attenuate the progression of heart failure, improve the global function, and increase the regional wall motion. At the infarct, expressions of HGF, bFGF and VEGF were significantly up-regulated, an indication of the significantly increased vessel densities in the hearts treated with hAFSC bodies. The injected hAFSC bodies could undergo differentiation into angiogenic and cardiomyogenic lineages and contribute to functional benefits by direct regeneration. The aforementioned results demonstrate that hAFSC bodies can attenuate cell loss after intramuscular injection by providing an adequate physical size and offering an enriched ECM environment to retain the transplanted cells in the myocardium, thus improving heart function. PMID- 21555152 TI - Genetic disruption of the scaffolding protein, Kinase Suppressor of Ras 1 (KSR1), differentially regulates GM-CSF-stimulated hyperproliferation in hematopoietic progenitors expressing activating PTPN11 mutants D61Y and E76K. AB - Activating PTPN11 mutants promote hematopoietic progenitor hyperactivation of Erk and hypersensitivity to GM-CSF. We hypothesized that Kinase Suppressor of Ras 1 (KSR1) contributes to activating PTPN11-induced GM-CSF hypersensitivity. Bone marrow progenitors from WT and KSR1-/- mice expressing WT Shp2, Shp2E76K, or Shp2D61Y were evaluated functionally and biochemically. KSR1 activation and interaction with phospho-Erk was enhanced in Shp2D61Y- and ShpE76K-expressing cells. Genetic disruption of KSR1 partially normalized Shp2E76K-induced GM-CSF hypersensitivity, but failed to correct Shp2D61Y-induced GM-CSF hypersensitivity. Collectively, these studies suggest that cells expressing Shp2E76K have a greater dependence on KSR1 for GM-CSF hypersensitivity than cells expressing Shp2D61Y. PMID- 21555153 TI - Metal contamination of soil and translocation in vegetables growing under industrial wastewater irrigated agricultural field of Vadodara, Gujarat, India. AB - The present investigation was carried out to evaluate metals concentration in ten vegetable crops growing in mixed industrial effluent irrigated agricultural field near Vadodara, Gujarat, India. Differential accumulation and translocation of various metals in selected vegetables plant species was observed. A higher concentration of metals were found in order of Fe>Mn>Zn>Cd>Cu>Pb>Cr>As in soil irrigated with industrial effluent than soil irrigated with tube well water; however, the concentration of As, Cr and Pb found below detection limit in tube well water irrigated soil. Metal accumulation in root and top of vegetables varied significantly both in relations to metal concentration in the soil and the plant genotype. Among ten vegetable species studied five vegetable species, i.e. Spinach, Radish, Tomato, Chili and Cabbage growing in mixed industrial effluent irrigated agricultural field showed high accumulation and translocation of toxic metals (As, Cd, Cr, Pb and Ni) in their edible parts, thus, their cultivation are unsafe with respect to possible transfer in food chain and health hazards. However, it is suggested that vegetable crops restricting toxic metal in non edible port may be recommended for cultivation in such metal contaminated agricultural field. PMID- 21555154 TI - Post-release controls for sex offenders in the U.S. and UK. AB - In recent years, both the United States and United Kingdom have developed numerous innovations in legal efforts to protect society from sex offenders. Each country has adopted special provisions for sex offenders. In particular, governments have focused on forms of social control after release from incarceration and probation. These policy innovations for this category of offenders have been more far reaching than those for any other offender population. The two jurisdictions have adopted policies with similar goals, but the selected strategies have important differences. Generally speaking, the U.S. has favored an ever-expanding set of policies that place sex offenders into broad categories, with few opportunities that distinguish the appropriate responses for individual offenders. The UK government observed the proliferation of Megan's Laws(1) in the U.S., and deliberately chose to establish carefully controlled releases of information, primarily relying on governmental agencies to work in multi-disciplinary groups and make case-specific decisions about individual offenders. Although the UK policy leaders expressed significant concern that the public's response to knowing about identified sex offenders living in the community would result in vigilantism, to date the results have not borne out this fear. Both governments have turned to other crime control measures such as polygraphy testing, electronic monitoring, and civil protection orders as a means to prevent further sexual violence. PMID- 21555155 TI - Increased cardiac injury in NZB/W F1 mice received antibody against human parvovirus B19 VP1 unique region protein. AB - Human parvovirus B19 (B19) infection has been postulated to both myocardial injury and development of systemic lupus erythematosus (SLE). However, the influence of anti-B19-VP1u antibodies on cardiac disorders in SLE is still obscure. To elucidate the effects of anti-B19-VP1u IgG in SLE, passive transfer of PBS, normal rabbit IgG or rabbit anti-B19-VP1u IgG was injected intravenously into NZB/W F1 mice, respectively. Significant expression of IL-1beta, IL-6 and TNF-alpha were detected in NZB/W F1 mice receiving rabbit anti-B19-VP1u IgG. Markedly cardiomyocyte disarray and lymphocyte infiltration were observed in left ventricle of hearts from NZB/W F1 mice receiving rabbit anti-B19-VP1u IgG. Additionally, significant increases of matrix metalloproteinase-9 (MMP9) activity and protein expression were detected in left ventricle of hearts from NZB/W F1 mice receiving B19-VP1u IgG. Accordingly, significant increase of phosphorylated p-38 and NF-kappaB proteins were observed in left ventricle of hearts from NZB/W F1 mice receiving B19-VP1u IgG. However, no significant variation of cardiac atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), heart-type fatty acid-binding protein (h-FABP) and creatine kinase MB (CK-MB) were detected among all experimental groups. These findings firstly demonstrated the aggravated effects of anti-B19 VP1u IgG on cardiac injury by induction of inflammatory but not myocardial infarction-associated proteins through activation of phosphorylated p-38 and NF-kappaB signaling. PMID- 21555156 TI - Clinical predictors of response and remission in inpatients with depressive syndromes. AB - BACKGROUND: Most predictor analyses search for single predictors or rely on data from randomized controlled trials. We aimed at detecting a set of clinical baseline variables for prediction of response and remission in 1014 naturalistically treated inpatients with major depressive episode treated for 53.62 +/- 47.5 days. METHODS: A three-staged procedure was implemented. First, univariate tests were used for finding associations with baseline variables. Second, logistic regression and third-CART analyses were used to determine predictors of response to inpatient treatment. RESULTS: Presence of suicidality, a higher initial HAMD-21 total score, an episode length <24 months, fewer previous hospitalizations, and absence of any ICD-10F4 comorbidity predicted response in 2 different statistical models. Remission was predicted by lower HAMD 21 baseline score, episode length <24 months and fewer previous hospitalizations in both models. LIMITATION: Results were assessed by a post-hoc analysis, based on prospectively collected data. No controlled study design. CONCLUSION: Contrary to current beliefs, baseline suicidality might be associated with higher chances for response. In addition, baseline severity might impact outcome depending on which criterion (remission or response) used. PMID- 21555157 TI - Startle reactivity and prepulse inhibition in prodromal and early psychosis: effects of age, antipsychotics, tobacco and cannabis in a vulnerable population. AB - The use of biomarkers in the study of the prodrome and first episode of psychosis provides a means of not only identifying individuals at greatest risk for psychosis but also understanding neurodevelopmental abnormalities early in the course of illness. Prepulse inhibition (PPI), a marker that is deficient in schizophrenia and after developmental manipulations in animal models, was assessed in 75 early psychosis (EP), 89 at risk (AR) for psychosis and 85 comparison subjects (CS) at baseline and 6 months. Consistent with findings in chronic schizophrenia, PPI was stable with repeated assessment and EP subjects had reduced PPI but this was most evident in tobacco smokers. A significant positive PPI and age association in AR and EP samples, but not CS, demonstrated potential neurodevelopmental differences in early psychosis. Unexpected findings included the fact that medication naive EP subjects, as well as AR subjects who later developed psychosis, had greater PPI, introducing the possibility of early compensatory changes that diverge from findings in chronic patients. In addition, subjects with a history of cannabis use had greater startle reactivity while EP and AR subjects who used cannabis and were also taking an antipsychotic had greater PPI, again highlighting the potentially important cannabis/psychosis association. PMID- 21555158 TI - What factors affect life satisfaction (LS) among the oldest-old? AB - Few studies have examined the association between LS in the oldest-old and not only health-related, but also psychological and socio-economical factors. The aim of this study was to examine LS in relation to functional capacity, locus of control (LoC) health status and other factors previously known to influence LS in the oldest-old. The study population consisted of 681 individuals aged 78-98 years, drawn from the longitudinal population study "Good Aging in Skane" (GAS), part of a national survey (SNAC) who fulfilled a questionnaire. In a regression model was shown that the number of symptoms, marital status, LoC, especially internal and powerful others, depressive mood and age significantly could predict life satisfaction three years later. Specific diagnoses like stroke, dementia and cardiac disease were not related to LS. Independence in physical functioning was related to unchanged LS, stratified for age and gender during a 3-year follow-up. The clinical implications of this study are that attention should be paid to recognizing and treating factors that affect LS and are reachable for medical intervention. Relieving symptoms and paying attention to personality factors that modify LS seem to be key-factors in the care of elderly. PMID- 21555159 TI - Contextual effect of neighborhood environment on homebound elderly in a Japanese community. AB - Homebound status is associated with poorer health and disability; however, the impact of community factors on the decision to remain homebound is unclear. We applied multilevel analyses to examine the association between neighborhood environment and homebound status among Japanese community-dwelling elderly. A cross-sectional survey was conducted in February 2009 using a mailed questionnaire. A total of 4123 participants aged 20 years and over living in 72 small districts of Kashiwa, Japan, were randomly selected for the survey. Of the 1735 returned questionnaires, the 588 that were completed by individuals aged 65 years and over were used for analysis. Frequency of going outdoors was assessed and respondents going outdoors once a week or less were defined as homebound. Neighborhood environment was assessed using three subscales of the Neighborhood Environment Walkability Scale (NEWS-A) (land use mix-access, aesthetics and crime safety). Multilevel logistic regression analysis indicated that the lower score of land use mix-access at the district level was associated with the elderly being homebound after adjustment for individual demographic data, physical, psychological and social factors and district prevalence of population aged 65 years or more. This finding could contribute to devising a successful community based strategy for homebound prevention of community-dwelling elderly individuals. PMID- 21555160 TI - Red blood cell distribution width predicts new-onset anemia in heart failure patients. AB - BACKGROUND: Hematologic abnormalities such as elevated red blood cell distribution width (RDW) as well as anemia are prognostically meaningful among heart failure (HF) patients. The inter-relationship between these hematologic abnormalities in HF is unclear, however. We therefore aimed to assess whether RDW is predicting changes in hemoglobin concentrations as well as onset of anemia. METHODS: 268 consecutive non-anemic patients with acutely decompensated HF (ADHF) were enrolled at hospital discharge and RDW was measured. At 6 month follow-up, change in hemoglobin as well as new-onset anemia was studied as a function of RDW at discharge. RESULTS: RDW at discharge correlated negatively with hemoglobin values at 6 months (r=-0.220; p<0.001); a greater decrease in hemoglobin concentration occurred in those with higher values of RDW at discharge (p=0.004), independently of baseline hemoglobin concentration and other risk factors. At 6 months, 54 patients (20%) developed new-onset anemia. RDW values at discharge were significantly higher among patients who developed new-onset anemia (15.1 +/- 2.2 vs. 14.2 +/- 1.4, p=0.005). In integrated discrimination improvement analyses, the addition of RDW measurement improved the ability to predict new onset anemia (IDI 0.0531, p<0.001), beyond known risk factors as hemoglobin, renal function, age, diabetes mellitus, sex and HF symptom severity. In adjusted analyses, patients with RDW>15% (derived from receiver operating characteristic analysis) had a tripling of the risk of new-onset anemia (OR=3.1, 95% CI 1.5-5.1, p=0.002). CONCLUSION: Among non-anemic patients with ADHF, RDW measurement at the time of hospital discharge independently predicts lower hemoglobin concentrations and new-onset anemia over a 6-month follow up period. PMID- 21555161 TI - PKgraph: an R package for graphically diagnosing population pharmacokinetic models. AB - Population pharmacokinetic (PopPK) modeling has become increasing important in drug development because it handles unbalanced design, sparse data and the study of individual variation. However, the increased complexity of the model makes it more of a challenge to diagnose the fit. Graphics can play an important and unique role in PopPK model diagnostics. The software described in this paper, PKgraph, provides a graphical user interface for PopPK model diagnosis. It also provides an integrated and comprehensive platform for the analysis of pharmacokinetic data including exploratory data analysis, goodness of model fit, model validation and model comparison. Results from a variety of modeling fitting software, including NONMEM, Monolix, SAS and R, can be used. PKgraph is programmed in R, and uses the R packages lattice, ggplot2 for static graphics, and rggobi for interactive graphics. PMID- 21555162 TI - High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer. AB - BACKGROUND: Prior studies highlighted cyclin D1 as a key biomarker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This study builds on prior work by examining the roles of cyclin D1, cyclin D3, and cyclin E in mediating erlotinib sensitivity or resistance. METHODS: Expression plasmids for G1 cyclins were independently transfected into NIH 3T3 cells and effects on erlotinib sensitivity were examined. The expression profiles of G1 cyclins were compared in erlotinib-sensitive and erlotinib-resistant lung cancer cell lines. A549 and H358 cells were treated with erlotinib and changes in cyclin protein expression were assessed. Cyclin D3 immunohistochemical staining was measured in biopsy tissues obtained from patients before and after treatment with erlotinib. Erlotinib-sensitive lung cancer cells were transfected with cyclin D3 and changes in erlotinib sensitivity were examined. RESULTS: Individual transfection of cyclin D1, cyclin D3, and cyclin E expression plasmids each significantly reduced erlotinib sensitivity in NIH-3T3 cells. The erlotinib-resistant A549 cell line expressed high basal levels of cyclin D3 mRNA and protein. Comparison of tumor biopsies obtained from patients before and after treatment with erlotinib indicated an increase in the percentage of cancer cells expressing cyclin D3 following treatment with erlotinib (P=.02). Transfection of cyclin D3 into an erlotinib-sensitive lung cancer cell line inhibited erlotinib-induced signaling changes and reduced the growth-suppressive effects of erlotinib. CONCLUSIONS: High expression of cyclin D3 confers resistance to erlotinib in vitro and in vivo. Cyclin D3 immunohistochemical staining warrants investigation as a biomarker for predicting erlotinib resistance. PMID- 21555163 TI - [Stroke and paralysis of the hypoglossus in a young man]. PMID- 21555164 TI - Total synthesis of racemic and (R) and (S)-4-methoxyalkanoic acids and their antifungal activity. AB - The total synthesis of 4-methoxydecanoic acid and 4-methoxyundecanoic acid in racemic and stereoselective [(R) and (S)] forms has been accomplished. For stereoselective synthesis of the compounds (S) and (R)-BINOL complexes have been used to generate the required chiral centres. The antifungal activity of these compounds has been studied against different organisms and the results were found to be impressive. The activity of the compounds in racemic and in stereoselective forms was compared. (R)-4-Methoxydecanoic acid was found to be most potent (MIC: 0.019 mg/mL against Candida albicans MTCC 227, C. albicans MTCC 4748, Aspergillus brasiliensis (niger) MTCC 281 and Issatchenkia orientalis MTCC 3020). PMID- 21555165 TI - Preparation and characterization of polyester- and poly(ester-carbonate) paclitaxel conjugates. AB - The polyester- and poly(ester-carbonate)-paclitaxel conjugates with low molecular weight were synthesized using dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) as catalysts. Polymeric matrices were obtained by ring-opening polymerization of E-caprolactone (CL), rac-lactide (rac-LA), l lactide (LLA) and trimethylene carbonate (TMC). The macromolecular conjugates were characterized by using spectroscopic techniques, such as (1)H, (13)C NMR and FTIR. The degree of degradation of polyester- and poly(ester-carbonate) paclitaxel conjugates was tested in vitro under different conditions. The preliminary results of drug release were discussed. PMID- 21555166 TI - Synthesis and evaluation of monoamidoxime derivatives: toward new antileishmanial compounds. AB - A new series of monoamidoxime derivatives was synthesized using manganese(III) acetate by microwave irradiation. Several amidoximes (27-31, 33, 38) showed valuable in vitro activities toward Leishmania donovani promastigotes, exhibiting IC(50) values between 5.21 and 7.89 MUM. In parallel, the cytotoxicity of these compounds was evaluated on murine J774A.1 cells, revealing the corresponding selectivity index (SI). Among the 13 tested compounds, 4 monoamidoximes (27-30) exhibited an SI more than 20 times better than pentamidine. Moreover, monoamidoxime 28 (4-[5-Benzyl-3-(4-fluorophenylsulfonyl)-5-methyl-4,5 dihydrofuran-2-yl]-N'-hydroxybenzimidamide) is 40 times more selective than pentamidine, and 1.6 times more than amphotericin B, used as reference drug compounds. PMID- 21555167 TI - Using Objective Structured Clinical Examination (OSCE) in undergraduate psychiatric nursing education: is it reliable and valid? AB - While there is widespread use of OSCE in general nursing specialties, psychiatric nursing has been slow to adopt this evaluation method and it has only recently been introduced to psychiatric nursing education. AIM: The main aim of the present study is to test the first application, validity and reliability of the OSCE in undergraduate psychiatric nursing education. METHOD: OSCE was developed to assess undergraduate psychiatric nursing students' clinical skills. The students' evaluation of the OSCE process was obtained after the completion of each OSCE circuit. RESULTS: The psychiatric nursing OSCE proved to be a reliable and valid method in assessing psychiatric nursing clinical competencies. In general, the students perceived OSCE as a positive experience and stressful on the other hand. CONCLUSION: OSCE is a reliable and valid method of assessing the students' psychiatric nursing competency skills. It has been shown to have many advantages over traditional methods of assessment and has the ability to objectively assess psychiatric nursing skills. PMID- 21555168 TI - Accuracy of direct segmental multi-frequency bioimpedance analysis in the assessment of total body and segmental body composition in middle-aged adult population. AB - BACKGROUND & AIMS: Body composition measurement is a valuable tool for assessing nutritional status and physical fitness in a variety of clinical settings. Although bioimpedance analysis (BIA) can easily assess body composition, its accuracy remains unclear. We examined the accuracy of direct segmental multi frequency BIA technique (DSM-BIA) in assessing different body composition parameters, using dual energy X-ray absorptiometry (DEXA) as a reference standard. METHODS: A total of 484 middle-aged participants from the Leiden Longevity Study were recruited. Agreements between DSM-BIA and DEXA for total and segmental body composition quantification were assessed using intraclass correlation coefficients and Bland-Altman plots. RESULTS: Excellent agreements were observed between both techniques in whole body lean mass (ICC female = 0.95, ICC men = 0.96), fat mass (ICC female = 0.97, ICC male = 0.93) and percentage body fat (ICC female = 0.93, ICC male = 0.88) measurements. Similarly, Bland Altman plots revealed narrow limits of agreements with small biases noted for the whole body lean mass quantification but relatively wider limits for fat mass and percentage body fat quantifications. In segmental lean muscle mass quantification, excellent agreements between methods were demonstrated for the upper limbs (ICC female>=0.91, ICC men>=0.87) and lower limbs (ICC female>=0.83, ICC male>=0.85), with good agreements shown for the trunk measurements (ICC female = 0.73, ICC male = 0.70). CONCLUSIONS: DSM-BIA is a valid tool for the assessments of total body and segmental body composition in the general middle aged population, particularly for the quantification of body lean mass. PMID- 21555169 TI - Mean annual (222)Rn concentration in homes located in different geological regions of Poland: first approach to whole country area. AB - The paper presents the results of year-long measurements of radon ((222)Rn) concentration inside 129 buildings in Poland in relation to the geological conditions of their foundation. The authors took into account the division of the country into tectonic units, as well as the lithology of the rocks forming the bedrock of these buildings. As expected, the highest value of mean annual (222)Rn concentration (845 Bq/m(3)) was recorded in a building situated in the area of the Sudetes, while the highest geometric mean (characteristic of the expected log normal data distribution) was calculated based on measurements from buildings located within the East-European craton, in the area of Mazury-Podlasie monocline, where it reached 231 Bq/m(3). Such results reflect geological conditions - the occurrence of crystalline rocks (especially U- and Ra-enriched granites and orthogneisses) on the surface in the Sudetes, and of young post glacial sediments containing fragments of Scandinavian crystalline rocks, also enriched with U and Ra, in the area of Mazury-Podlasie monocline. However, the least expected result of the investigations was finding out that, contrary to the hitherto widespread belief, none of the major tectonic units of Poland can be excluded from the list of those containing buildings with mean annual (222)Rn concentration exceeding 200 Bq/m(3). The mean annual concentration of radon for all the buildings were much higher than the mean concentration value (49.1 Bq/m(3)) of indoor radon in Poland quoted so far. These results cast a completely new light on the necessity to perform measurements of radon concentration in residential buildings in Poland, no more with reference to small areas with outcrops of crystalline rocks (especially the Sudetes, being the Polish fragment of the European Variscan belt), but for all the major tectonic units within Poland. PMID- 21555170 TI - Vertical distributions of (99)Tc and the (99)Tc/(137)Cs activity ratio in the coastal water off Aomori, Japan. AB - Using a sector-field ICP-MS the vertical distributions of the (99)Tc concentration and (99)Tc/(137)Cs activity ratio were measured in the coastal waters off Aomori Prefecture, Japan, where a spent-nuclear-fuel reprocessing plant has begun test operation. The (99)Tc concentrations in surface water ranged from 1.8 to 2.4 mBq/m(3), no greater than the estimated background level. Relatively high (99)Tc/(137)Cs activity ratios (10-12 * 10(-4)) would be caused by the inflow of the high-(99)Tc/(137)Cs water mass from the Japan Sea. There is no observable contamination from the reprocessing plant in the investigated area. The (99)Tc concentration and the (99)Tc/(137)Cs activity ratio in water column showed gradual decreases with depth. Our results implied that (99)Tc behaves in a more conservative manner than (137)Cs in marine environments. PMID- 21555171 TI - Submucous tramadol increases the anesthetic efficacy of mepivacaine with epinephrine in inferior alveolar nerve block. AB - The purpose of this study was to evaluate the effect of submucous tramadol as adjuvant of mepivacaine with epinephrine in inferior alveolar nerve block. A double-blind, randomized, placebo-controlled, crossover clinical trial was conducted. Twenty healthy young volunteers were randomized into two treatment sequences using a series of random numbers. Sequence 1: Group A, 2% mepivacaine with 1:100,000 epinephrine plus submucous tramadol 50mg (1mL of saline) and one week later Group B, 2% mepivacaine with 1:100,000 epinephrine plus submucous placebo (1mL of saline). Sequence 2: Group B and one week later Group A. All treatments were administered 1min after that patient informed anesthesia of lower lip. We evaluated the duration of anesthesia of lower lip, anesthetic efficacy, and local and systemic adverse events. Anesthetic efficacy was better in group receiving submucous tramadol during the first 2h compared with group receiving submucous placebo (P<0.05). Submucous tramadol increased the anesthetic efficacy of mepivacaine with epinephrine of soft tissue in inferior alveolar nerve block. PMID- 21555172 TI - Assessment of reach-to-grasp trajectories toward stationary objects. AB - BACKGROUND: Patients with pronounced spasticity reveal difficulties in hand opening during the approaching grasping phase. The general description and assessment procedures of reach-to-grasp movement for rehabilitation purposes is still not established. There is a necessity to develop a universal methodology to describe the approaching phase in grasping which would allow clinical evaluation of movement pathologies. METHODS: In the paper, the evaluation of approaching trajectories assessed during grasping by healthy subjects is described. The experiment, undertaken by 7 healthy volunteers, consisted of grasping three different stationary objects positioned in various poses by a robot. 3D recordings of the hand and fingertip trajectories were performed. The kinematic trajectories of the hand and finger markers were analysed in order to evaluate the reach-to-grasp movement. FINDINGS: The results of the kinematic analysis suggest that the reach-to-grasp movement of a healthy subject can be divided into 3 dominant phases (hand acceleration, hand deceleration, and final closure of the fingers). INTERPRETATION: The presented evaluation method can provide relevant information on the modalities the hand preshapes and approaches toward the object in order to obtain a stable grasp. The potential use of the approach for rehabilitation purposes is discussed. PMID- 21555173 TI - Spatio-temporal variations of nitrogen in an agricultural watershed in eastern China: catchment export, stream attenuation and discharge. AB - Using the monthly hydrogeochemical data of ChangLe River system from 2004 to 2008, total nitrogen (TN) export load (S(n)) from nonpoint sources (NPS) to stream and in-stream attenuation load (A(L)) was estimated by the inverse and forward format of an existing in-stream nutrient transport equation, respectively. Estimated S(n) contributed 96 +/- 2% of TN entering the river system, while A(L) reduced the input TN by 23 +/- 14% in average. In-stream TN attenuation efficiency in high flow periods (10 +/- 5% in average for the entire river system) was much lower than that in low flow periods (39 +/- 17%). TN attenuation efficiency in tributaries (28 +/- 16% in average) was much higher than that in mainstream (11 +/- 8%). Hydrological conditions are important in determining the spatio-temporal distributions of NPS TN export, stream attenuation and discharge. Increasing the water residence time might be a practical method for mitigating stream TN. PMID- 21555174 TI - The use of environmental metabolomics to determine glyphosate level of exposure in rapeseed (Brassica napus L.) seedlings. AB - Metabolic profiling in plants can be used to differentiate between treatments and to search for biomarkers for exposure. A methodology for processing Ultra-High Performance Liquid Chromatography-Diode-Array-Detection data is devised. This methodology includes a scheme for selecting informative wavelengths, baseline removal, retention time alignment, selection of relevant retention times, and principal component analysis (PCA). Plant crude extracts from rapeseed seedling exposed to sublethal concentrations of glyphosate are used as a study case. Through this approach, plants exposed to concentrations down to 5 MUM could be distinguished from the controls. The compounds responsible for this differentiation were partially identified and were different from those specific for high exposure samples, which suggests that two different responses to glyphosate are elicited in rapeseed depending on the level of exposure. The PCA loadings indicate that a combination of other metabolites could be more sensitive than the response of shikimate to detect glyphosate exposure. PMID- 21555175 TI - Modeling redistribution of alpha-HCH in Chinese soil induced by environment factors. AB - This study explores long-term environmental fate of alpha-HCH in China from 1952 to 2007 using ChnGPERM (Chinese Gridded Pesticide Emission and Residue Model). The model captures well the temporal and spatial variations of alpha-HCH concentration in Chinese soils by comparing with a number of measured data across China in different periods. The results demonstrate alpha-HCH grasshopping effect in Eastern China and reveal several important features of the chemical in Northeast and Southeast China. It is found that Northeast China is a prominent sink region of alpha-HCH emitted from Chinese sources and alpha-HCH contamination in Southwest China is largely attributed to foreign sources. Southeast China is shown to be a major source contributing to alpha-HCH contamination in Northeast China, incurred by several environmental factors including temperature, soil organic carbon content, wind field and precipitation. PMID- 21555176 TI - The increasing value of education to health. AB - This paper assesses how the relationship between health and educational attainment has changed over the last three decades. We examine trends in disease prevalence and self-reported health using the US National Health Interview Survey for five chronic conditions-arthritis, diabetes, heart disease, hypertension, and lung diseases. The sample is limited to non-Hispanic Whites ages 40-64 to focus on the value of education and not changing representation of minority populations. We find that health benefits associated with additional schooling rose over time by more than ten percentage points as measured by self-reported health status. This can be attributed to both a growing disparity by education in the probability of having major chronic diseases during middle age, and better health outcomes for those with each disease. The value of education in achieving better health has increased over the last 25 years; both in protecting against onset of disease and promoting better health outcomes amongst those with a disease. Besides better access to health insurance, the more educated increasingly adapted better health behaviors, particularly not smoking and engaging in vigorous exercise, and reaped the benefits of improving medical technology. Rising health disparities by education are an important social concern which may require targeted interventions. PMID- 21555177 TI - Advanced life support versus basic life support in the pre-hospital setting: a meta-analysis. AB - BACKGROUND: The scientific evidence of a beneficial effect of ALS in pre-hospital treatment in trauma patients or patients with any acute illness is scarce. The objective of this systematic review of controlled studies was to examine whether ALS, as opposed to BLS, increases patient survival in pre-hospital treatment and if so, to identify the patient groups that gain benefit. METHODS: A systematic review of studies published in the databases Medline (PubMed), EMBASE, Cochrane Library and Scopus up to July 31st, 2010. Controlled studies comparing survival after the pre-hospital ALS treatment versus BLS treatment in trauma patients or patients with cardiac arrest were included. RESULTS: We identified 1081 studies of which 18 met our inclusion criteria. In nine of 18 studies including 16,857 trauma patients in the intervention group, ALS care did not increase survival compared to BLS treatment (pooled OR 0.892, 95% CI, 0.775-1.026). In nine of 18 studies including 7659 patients with cardiac arrest in the intervention group, ALS care increased survival compared to BLS treatment (OR 1.468, 95% CI, 1.257 1.715). Most subgroup analyses revealed no significant interactions, but data from six trials, where ALS was provided by physicians, increases the probability of survival at hospital discharge even more (OR 2.047, 95% CI 1.593-2.631). CONCLUSION: Implementation of ALS care to non-traumatic cardiac arrest patients can increase survival and further research is unlikely to change our confidence in the estimate of the effect. On the contrary, in trauma patients our meta analysis revealed that ALS care is not associated with increased survival. However, only few controlled studies of sufficient quality and strength examining survival with pre-hospital ALS treatment exist. PMID- 21555178 TI - Is laparoscopic hysterectomy feasible for uteri larger than 1000 g? AB - OBJECTIVE: To evaluate the feasibility of laparoscopic hysterectomy for uteri weighing more than 1000 g. STUDY DESIGN: A retrospective study was conducted in a tertiary center of laparoscopic surgery including 38 women submitted to hysterectomy for uteri weighing more than 1000 g. Patients submitted to open hysterectomy were compared to those submitted to laparoscopic hysterectomy. The primary statistical endpoint was the complication rate. Secondary endpoints were operating time, estimated blood loss, length of hospital stay, and conversion to laparotomy. RESULTS: The patients' mean age was 49.4 years and mean BMI was 25.2 kg/m(2). The surgical intent was laparoscopic hysterectomy in 23 patients (60.5%) and laparotomy in 15 patients (39.5%). Conversion to open surgery was required in 4 patients (17.4%) due to inaccessibility of the pelvis at the beginning of surgery (n=2), technical difficulties during surgery (n=1), and intraoperative bleeding (n=1). One patient in the laparotomy group had an intraoperative ureteral injury. Despite longer operative time (130 vs. 80 min, p=0.002), laparoscopic surgery was associated with reduced length of hospital stay (3 vs. 6 days, p<0.001). Intraoperative bleeding was evaluated by the difference of pre- and post-operative hemoglobin and was equivalent in both groups (2.2 vs. 1.6g/dL; p=0.84). There was a tendency for more postoperative complications in the laparotomic group (33.4% vs. 8.7%; p=0.05). CONCLUSION: Laparoscopic hysterectomy is feasible for selected patients with uteri weighing more than 1000 g. PMID- 21555179 TI - Abnormal methylation patterns at the IGF2/H19 imprinting control region in phenotypically normal babies conceived by assisted reproductive technologies. AB - OBJECTIVE: To evaluate epigenetic risks linked to assisted reproductive technologies (ART) by determining the methylation status of the IGF2/H19 imprinting control region (ICR) in offspring born after ART. STUDY DESIGN: A combined bisulfite restriction analysis (COBRA) and sequencing technique were used to determine the methylation status of the IGF2/H19 ICR in 61 phenotypically normal newborns conceived by ART. Thirty naturally conceived newborns were studied as controls. RESULTS: There was no significant difference in methylation between ART newborns and naturally conceived newborns (46.7 +/- 8.2% vs. 48.5 +/- 8.7%, p>0.05). Abnormal demethylation patterns of the IGF2/H19 ICR were found in three dizygotic twins conceived by intracytoplasmic sperm injection (ICSI), but all three were phenotypically normal, and their sibling twins exhibited normal methylation patterns. CONCLUSION: We hypothesize that the aberrant methylation patterns probably resulted from imprinting errors of paternal gametes or from in vitro embryo culture. Further investigation to determine whether gene expression can be regulated by other mechanisms in addition to DNA methylation would be beneficial. PMID- 21555180 TI - Desorption of cadmium from a natural Shanghai clay using citric acid industrial wastewater. AB - The sorption/desorption characteristics of heavy metals onto/from soil particle surfaces are the primary factors controlling the success of the remediation of heavy-metal contaminated soils. These characteristics are pH-dependent, chemical specific, and reversible; and can be modified by enhancement agents such as chelates and surfactants. In this study, batch experiments were conducted to evaluate the feasibility of using citric acid industrial wastewater (CAIW) to desorb cadmium from a natural clay from Shanghai, China at different soil mixture pHs. It can be observed from the results that the proportion of cadmium desorbed from the soil using synthesized CAIW is generally satisfactory, i.e., >60%, when the soil mixture pH is lower than 6. However, the proportion of desorbed cadmium decreases significantly with increase in soil mixture pH. The dominant cadmium desorption mechanism using CAIW is the complexion of cadmium with citric acid and acetic acid in CAIW. It is concluded that CAIW can be a promising enhancement agent for the remediation of cadmium-contaminated natural soils when the environmental conditions are favorable. As a result, CAIW, a waste product itself, can be put into productive use in soil remediation. PMID- 21555181 TI - Synthesis of core-shell magnetic molecularly imprinted polymers and detection of sildenafil and vardenafil in herbal dietary supplements. AB - An analytical procedure for selective extraction of sildenafil and vardenafil in herbal dietary supplements (HDSs) has been set up by using the magnetic molecularly imprinted polymers (MMIPs) as the extraction and clean-up materials, followed by high performance liquid chromatography-ultraviolet (HPLC-UV). The MMIPs were prepared by a surface molecular imprinting technique, using Fe(3)O(4) magnetite as a magnetically susceptible component, sildenafil as template molecule, 2-(trifluoromethyl) acrylic acid (TFMAA) as functional monomer, ethylene glycol dimethacrylate (EGDMA) as polymeric matrix components. The MMIPs were characterized by transmission electron microscope (TEM), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD) and vibrating sample magnetometer (VSM), respectively. The heterogeneity of the MMIPs was modeled with the Freundlich isotherm equation. The resulting MMIPs had high recognition ability and fast binding kinetics for sildenafil. The MMIPs were used as dispersive solid-phase extraction (DSPE) materials to selectively extract sildenafil and vardenafil from HDSs, the contents of sildenafil and vardenafil were found to be 8.05 and 3.86 MUg g(-1), respectively, and the average recoveries in spiked HDSs were 70.91-91.75% with a relative standard deviation (R.S.D.) below 7%. The MMIPs were successfully used to selectively enrich and determine sildenafil and vardenafil from HDSs. PMID- 21555182 TI - Regeneration of hexamminecobalt(II) catalyzed by activated carbon treated with KOH solutions. AB - The combined elimination of NO and SO(2) can be realized by hexamminecobalt(II) solution which is formed by adding soluble cobalt(II) salt into the aqueous ammonia solution. Activated carbon is used as a catalyst to regenerate hexamminecobalt(II), Co(NH(3))(6)(2+), so that NO removal efficiency can be maintained at a high level for a long time. In this study, KOH solution has been explored to modify coconut activated carbon to meliorate its catalytic performance in the reduction of hexamminecobalt(III), Co(NH(3))(6)(3+). The experiments have been performed in a batch stirred cell to investigate the effects of KOH concentration, impregnation duration, activation temperature and activation duration on the performance of activated carbon. The results show that the best KOH concentration for the improvement of activated carbon is 0.5 mol l( 1). The optimal impregnation duration is 9h. High temperature is favorable to ameliorating the catalytic performance of activated carbon. The optimum activation duration is 4h. PMID- 21555183 TI - Bioaccumulation kinetics and toxic effects of Cr, Ni and Zn on Eichhornia crassipes. AB - The aim of this work was to assess the uptake efficiencies, the uptake and bioaccumulation kinetics and the toxic effects of Cr, Ni and Zn on Eichhornia crassipes. Plants were exposed to 1 mg L(-1) of each metal and sampled during 30 days. E. crassipes removed 81%, 95% and 70% of Cr, Ni and Zn, respectively. Metal removal from water involved a fast and a slow component. Metals were accumulated fundamentally by roots. Cr was scarcely translocated to aerial parts. In these tissues, Ni showed the highest accumulation amount while Zn presented the highest accumulation rate. Metal toxicity on the biomass was different among treatments. However, biomass did not decrease in any case. All the studied metals produced chlorophyll decrease. The root cross-sectional area (CSA) and vessel number increased and the root length decreased when plants were exposed to Zn. Despite the toxic effects, E. crassipes accumulated Cr, Ni and Zn efficiently. PMID- 21555185 TI - A study of parameter setting and characterization of visible-light driven nitrogen-modified commercial TiO2 photocatalysts. AB - An optimal condition applied to the Taguchi method with an L(9) orthogonal array for preparing a visible-light driven nitrogen-modified TiO(2) (N-TiO(2)) photocatalyst by a simple hydrolysis method has been examined for material characteristics and a photodecolorization test of methyl blue (MB) under various visible light source (fluorescent and blue LED lamps) irradiations. Results of the material characterization showed that the absorption of prepared N-TiO(2) powder exhibited a significant extension into visible light regimes with an optical bandgap (Eg) of around 2.96 eV, which subsequently improved the visible light photocatalytic activity of N-TiO(2) samples. The superior photocatalytic properties, the pseudo first-order reaction rate constants (k) and photodecolorization efficiency (eta%) of a N-TiO(2) photocatalyst during the photodecolorization test of methyl blue (MB) under two different visible light irradiations were very evident compared to those for pure TiO(2). For photodecolorization of practical dyeing from the waste water from the dyeing and finishing industry, a higher photodecolorization efficiency of N-TiO(2) powder toward Direct blue-86 (DB-86) (Direct Fast Turquoise Blue GL) dye was also achieved. PMID- 21555186 TI - Ketamine hepato-toxicity in chronic pain management: another example of unexpected toxicity or a predicted result from previous clinical and pre-clinical data? PMID- 21555187 TI - Possible involvement of the endocannabinoid system in memory modulation effect of general anesthetics. AB - Amnesia is a fundamental component of a proper general anesthetic. The mechanism of anesthetic-induced amnesia remains poorly understood. Nowadays, intraoperative awareness and postoperative cognitive dysfunction are two distressing problems receiving increased attention by clinicians, patients and the general public. Extensive evidence indicates that general anesthetics cause amnesia by working on hippocampus and basolateral amygdala (BLA). Recently, evidence from studies in experimental animals has shown that either intra-hippocampus or intra-BLA injection of endogenous cannabinoid receptor 1 (CB1) drugs result in significant changes of cognitive function. In addition, several general anesthetics (i.e. propofol, etomidate and isoflurane) have been reported to interact with the endocannabinoid system. However, there are few studies about whether the CB1 receptor system is involved in anesthetic-induced amnesia. We hypothesize that the CB1 receptor activity in hippocampus and BLA might be regulated by general anesthetics. Once the involvement of the endocannabinoid system in anesthetic induced amnesia is proved, it will provide a new way to prevent and treat post traumatic stress disorder caused by intraoperative awareness and postoperative cognitive dysfunction in the future. PMID- 21555188 TI - Avocado by-products as inhibitors of color deterioration and lipid and protein oxidation in raw porcine patties subjected to chilled storage. AB - Processing of avocados generates an important amount of by-products such as peels and seeds that are rich in bioactive substances with proven radical suppressing activities. The objective of this study was to evaluate the effectiveness of peel and seed extracts from two avocado varieties-'Hass' and 'Fuerte'-as inhibitors of lipid and protein oxidation and color deterioration of raw porcine patties during chilled storage (4 degrees C/15 days). Avocado extracts significantly (p<0.05) reduced the loss of redness and the increase of lightness during storage of porcine patties. 'Fuerte' extracts were more efficient at inhibiting discoloration of chilled patties than 'Hass' extracts. Patties treated with avocado extracts had significantly lower amounts of TBA-RS than control ones throughout the storage. 'Hass' avocado extracts significantly inhibited the formation of protein carbonyls in chilled patties at day 15. The present results highlight the potential usage of extracts from avocado by-products as ingredients for the production of muscle foods with enhanced quality traits. PMID- 21555189 TI - Biodiversity and dynamics of meat fermentations: the contribution of molecular methods for a better comprehension of a complex ecosystem. AB - The ecology of fermented sausages is complex and includes different species and strains of bacteria, yeasts and molds. The developments in the field of molecular biology, allowed for new methods to become available, which could be applied to better understand dynamics and diversity of the microorganisms involved in the production of sausages. Methods, such as denaturing gradient gel electrophoresis (DGGE), employed as a culture-independent approach, allow to define the microbial dynamics during the fermentation and ripening. Such approach has highlighted that two main species of lactic acid bacteria, namely Lactobacillus sakei and Lb. curvatus, are involved in the transformation process and that they are accompanied by Staphylococcus xylosus, as representative of the coagulase negative cocci. These findings were repeatedly confirmed in different regions of the world, mainly in the Mediterranean countries where dry fermented sausages have a long tradition and history. The application of molecular methods for the identification and characterization of isolated strains from fermentations highlighted a high degree of diversity within the species mentioned above, underlining the need to better follow strain dynamics during the transformation process. While there is an important number of papers dealing with bacterial ecology by using molecular methods, studies on mycobiota of fermented sausages are just a few. This review reports on how the application of molecular methods made possible a better comprehension of the sausage fermentations, opening up new fields of research that in the near future will allow to unravel the connection between sensory properties and co-presence of multiple strains of the same species. PMID- 21555190 TI - Proteome changes in the insoluble protein fraction of bovine Longissimus dorsi muscle as a result of low-voltage electrical stimulation. AB - Changes induced by low-voltage electrical stimulation (ES; 0-95 V for 8 s; 95 V for 32 s) in the insoluble protein fraction of bovine longissimus dorsi (LD) muscle at 1 and 24h post-ES were investigated by proteomics. Protein abundance patterns from ten Norwegian Red (NRF) young bulls were compared, and significant changes due to ES were found by rotation test and partial least square (PLS) regression analyses. Five protein spots showed lower abundance in ES samples at both sampling times, and in addition, 10 proteins at 1 h post-ES and 13 proteins at 24 h post-ES changed significantly in abundance due to ES. Reduced abundance of full-length structural proteins in ES samples indicates an accelerated proteolysis due to ES. Moreover, increased abundance of small heat shock proteins indicates earlier initiation of stress responses due to ES. These findings provide a better understanding of the biochemical processes taking place as a result of ES during post mortem storage of meat. PMID- 21555191 TI - Proteomic approach for the detection of chicken mechanically recovered meat. AB - Mechanically recovered meat is cheaper than raw meat and thus has been incorporated into many meat-derived products. EU regulations exclude mechanically recovered meat from the definition of meat; as a consequence analytical procedures are needed to differentiate it from hand-deboned meat. The present pilot study has utilized a proteomic approach to find potential markers for the detection of chicken mechanically recovered meat. Intact proteins were extracted from raw meat and then analyzed with OFF-GEL electrophoresis followed by SDS-PAGE and identification of potential markers by nano-LC-MS/MS. It was shown that it is possible to extract, separate and identify key proteins from processed meat material. Potential chicken mechanically recovered meat markers--hemoglobin subunits and those similar to myosin-binding protein C were also identified. PMID- 21555192 TI - Divergent cytokine responses of macrophages to Mycobacterium avium subsp. paratuberculosis strains of Types II and III in a standardized in vitro model. AB - Based on epidemiological and clinical observations, different strains of Mycobacterium avium subsp. paratuberculosis (MAP) are suspected to significantly differ in their virulence for ruminants. In the pathogenesis of paratuberculosis, macrophages represent the principal target cell for MAP. In order to judge the ability of different MAP-genotypes to modulate macrophage responses, the cytokine responses of the monocyte cell line THP-1 were studied after challenge with three different MAP strains under standardized conditions. The bovine field isolate J1961 (major Type II) and the ovine field isolate JIII-86 (Type III) were compared with the laboratory adapted reference strain ATCC 19698 (Type II). Strains were shown by three different typing methods (IS900-RFLP-, MIRU-VNTR-, and SSR-analysis) to substantially differ in several genotypic features. Macrophage function was assessed by quantifying mRNA of the cytokines TNF-alpha, IL-1beta, and IL-10 by quantitative RT-PCR. Secreted TNF-alpha protein was measured by a cytotoxicity test, IL-1beta and IL-10 using ELISA tests. The three MAP strains of various genotypes differ in their effect on human macrophages depending on challenge dose and infection time. These differences concerned both the mRNA level and secreted protein amounts of proinflammatory cytokines TNF alpha, IL-1beta and anti-inflammatory cytokine IL-10. Type III strain produced less IL-10 and IL-1beta mRNA and protein but more TNF-alpha protein at 2h than the Type II strains. In summary, our results support the hypothesis that strain characteristics might have relevance for the host response towards MAP and, consequently, for the pathogenesis of paratuberculosis. PMID- 21555193 TI - Legumes and soy products consumption and functional disability in older women. AB - OBJECTIVES: This study was to examine the association between frequency of legumes and soy products consumption and functional disability in older Korean women. STUDY DESIGN: Cross-sectional study. Data came from the 2005 Korea National Health and Nutrition Examination Survey (KNHANES). Subjects were 562 women aged 65 years and older living in the community. MAIN OUTCOME MEASURES: Frequency of legume consumption was obtained by using food frequency questionnaire and functional disability was assessed using the instrumental activities of daily living (IADL) and ADL scales. Poisson regression analyses were conducted to examine the association of frequency of legume and soy consumption with functional disability, controlling for covariates. RESULTS: Dietary intake of legumes and soy products was associated with a significantly reduced risk of IADL disability after controlling for potential risk factors (p = 0.002 for trend). Compared with women who consumed legumes and soy products < 1 time per week, those who consumed >= 3 times per day had a reduced risk of IADL disability (prevalence ratio = 0.70; 95% confidence interval: 0.51-0.96). In contrast, legumes and soy products consumption was not significantly associated with ADL disability. CONCLUSIONS: Frequent legumes and soy products consumption was inversely associated with IADL disability in older women. Further studies are needed to clarify the protective effect of legume consumption on functional disability in older people. PMID- 21555194 TI - TITF-1 gene mutation in a case of sporadic non-progressive chorea. Response to levodopa treatment. AB - Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterized by non-progressive chorea of early onset, without other underlying progressive neurologic dysfunction. Hypothyroidism and pulmonary problems may also be associated. Recently, mutations in the thyroid transcription factor 1 gene (TITF-1), linked to chromosome 14q, have been related to this disorder. We describe the clinical phenotype and response to levodopa treatment in a 6 year old girl affected with sporadic non-progressive chorea, and a de novo TITF-1 gene mutation, in order to increase understanding of this rare and misdiagnosed disorder. PMID- 21555195 TI - Unilateral lower lung field opacities on chest radiography: a comparison of the clinical manifestations of tuberculosis and pneumonia. AB - BACKGROUND: The radiological manifestations of lower lung field (LLF) tuberculosis (LLFTB) are similar to those of LLF pneumonia (LLFP), making diagnosis challenging. The aim of this study was to determine if there are differences in the clinical manifestations of LLFTB and LLFP in patients with unilateral LLF opacities. METHODS: We performed a retrospective review of patient records to identify those with unilateral LLF opacities who were subsequently diagnosed with LLFTB or LLFP. We compared demographics, clinical manifestations, hematological data, and radiographic findings between the groups of patients. RESULTS: We identified 22 and 72 patients diagnosed with LLFTB and LLFP, respectively. Multivariate analysis revealed that age (odds ratio [OR]=1.05, 95% confidence interval [CI]=0.99-1.11, P=0.072), lack of fever>38 degrees C (OR=9.04, 95% CI=1.69-48.40, P=0.001), duration of symptoms>=7 days (OR=4.57, 95% CI=1.09-19.26, P=0.038), and the lack of air bronchograms upon radiography (OR=12.08, 95% CI=1.98-73.64, P=0.007) were significant predictors of LLFTB in patients with LLF opacities. We used these predictors to construct a mathematical model for predicting LLFTB in patients with LLF opacities. CONCLUSIONS: Our findings suggest that older age, prolonged duration of symptoms, lack of fever>38 degrees C, and the absence of air bronchograms are more common in patients with LLFTB than patients with LLFP. These findings may help clinicians differentiate between LLFTB and LLFP and thus initiate timely and appropriate treatment. PMID- 21555196 TI - The hip is a challenging joint to study. Editorial. PMID- 21555197 TI - Tolerability and diagnostic value of gadoteric acid in the general population and in patients with risk factors: results in more than 84,000 patients. AB - PURPOSE: To review the tolerability and diagnostic effectiveness of gadoteric acid under daily practice conditions in the general population and at-risk patients. MATERIALS AND METHODS: A total of 84,621 patients (45.4% men, 54.6% women, mean age 52.0 +/- 16.9 years) were studied in 129 German centers. Patients underwent contrast-enhanced magnetic resonance imaging (MRI) using gadoteric acid (Gd-DOTA, Dotarem((r)), Guerbet, Roissy CdG, France) as IV contrast medium (mean volume, 16.4 ml). 22.9% of the patients had at least one risk factor (e.g., allergies, previous allergic reaction to a contrast medium, and renal impairment). 554 patients received pretreatment before contrast medium administration (0.7%). Adverse events were documented and image quality was assessed. RESULTS: A diagnosis was possible in 99.7% of all cases. Image quality was rated good or excellent in 97.1%. Adverse events (e.g., nausea, vomiting, and urticaria) were observed in 0.34% of the examinations and were mostly rated as minor. There were 8 patients with serious adverse events. The adverse event rate was significantly higher in patients with a history of allergies (0.62%; p<0.001) and in patients with a previous allergic reaction to contrast medium (1.23%; p<0.001). There was no elevated incidence of adverse events in patients with renal impairment. CONCLUSION: Gadoteric acid is a well-tolerated MRI contrast medium in patients with and without risk factors that is associated with a low rate of adverse events and good or excellent image quality in most patients. PMID- 21555198 TI - Assessment of patient communication skills during OSCE: examining effectiveness of a training program in minimizing inter-grader variability. AB - OBJECTIVE: To assess effectiveness of a training program in reducing inter-grader variability in grading communication skills during an objective structured clinical exam (OSCE). METHODS: Global communication (GC) skills are assessed by standardized participants (SP) and faculty during each OSCE using a 6 item rubric. Despite criteria delineated in the GC rubric, inter-grader variability was observed. During 2008-2009 academic year, a training program was implemented before each OSCE to achieve more consistent interpretation and grading in GC skills. GC grades between SP and faculty for 2nd and 3rd level student OSCEs during 2008-2009 (post-training) were compared to 2007-2008 (pre-training). Data was analyzed using repeated measures ANOVA. RESULTS: 274 and 281 students participated in OSCEs during 2007-2008 and 2008-2009 academic years, respectively. Training significantly (P<.001) decreased grader variability between SPs and faculty. There was a greater mean difference between faculty vs. SP before training (faculty 14.68, SP 15.87) compared to after training (faculty 13.51, SP 13.78). Mean GC scores for both faculty and SPs also decreased significantly after training. CONCLUSION AND PRACTICE IMPLICATIONS: A training program may be necessary to reduce inter-rater variability in assessment of OSCE communication skills if it is to be truly helpful to student pharmacists learning to counsel patients. PMID- 21555199 TI - When cure is no option: how explicit and hopeful can information be given? A qualitative study in breast cancer. AB - OBJECTIVE: To investigate how oncologists can balance explicit with general and realistic with hopeful information when discussing various topics at the transition from curative to palliative care in breast cancer. METHODS: Qualitative analysis of focus groups consisting of female breast cancer survivors and healthy women. RESULTS: Perceptions of survivors and healthy women largely overlapped. Participants thought that oncologists can help patients regain a future perspective during this consultation. To achieve this, four themes seemed important: honest medical information, availability of continued support, hope has many faces, and space to choose. Moreover, participants stressed they would need time to let the message sink in before any further information was provided. CONCLUSION: Participants thought that when confronted with this type of consultation they would need - more or less explicit - medical information and information regarding support. In order to maintain hope, knowledge about (treatment) possibilities is important, but also the certainty not to be abandoned by the hospital at a later stage of the disease and the confidence to remain able to make one's own decisions. PRACTICE IMPLICATIONS: A life-limiting diagnosis may shatter patients' future perspective; however, this study provides suggestions for oncologists to create a new perspective. PMID- 21555200 TI - Multidisciplinary approach in the treatment of patients with small cell bladder carcinoma. AB - Small cell carcinoma of the urinary bladder (SCCUB) is considered to be a tumor with a neuroendocrine phenotype characterised by aggressive behaviour and poor prognosis. Small cell carcinoma of the urinary bladder comprises 0.35 to 1% of all bladder cancers and is frequently observed in combination with other histological subtypes of carcinoma. Clinical presentation is characterized by advanced stage at diagnosis and rapidly progressive disease. In daily clinical practice there is no gold standard for the management of patients affected by this disease. Treatment of patients with limited disease combines neoadjuvant platinum-based chemotherapy followed by specific local treatment of the primary tumour. Cystectomy or radiotherapy should be proposed on an individual basis. In the metastatic setting, prognosis remains poor with a potential benefit from chemotherapy containing platinum compounds. Treatment of small cell carcinoma of the urinary bladder is based on evidence obtained from case reports and retrospective analyses. Due to low disease frequency there is a lack of randomized trials to provide guidance as to optimal therapy. Thus, systemic and local approaches are extrapolated from the literature available for the treatment of small cell carcinomas at other (non-urological) sites. We provide an overview of the currently available literature with it's main focus on the treatment of either locally advanced or metastatic small cell carcinoma of the urinary bladder. PMID- 21555201 TI - Finasteride-associated cataract and intraoperative floppy-iris syndrome. AB - A 47-year-old man who had been using finasteride for male pattern alopecia for 4 years complained of progressive bilateral blurring of vision. His general health had been good, and he was not on any other long-term medication. Examination showed bilateral anterior subcapsular cataracts. Phacoemulsification and insertion of intraocular lenses were performed, and both eyes showed features of intraoperative floppy-iris syndrome (IFIS), including undulation and billowing of the iris, iris prolapse, and pupil constriction. We believe the use of finasteride can be associated with cataract formation and IFIS. Ophthalmologists and physicians prescribing finasteride should be aware of this possible association. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 21555202 TI - Cataract classification system for risk stratification in surgery. PMID- 21555203 TI - An experimental exploration of behavioral and cognitive-emotional aspects of intolerance of uncertainty in eating disorder patients. AB - OBJECTIVE: Intolerance of uncertainty (IU) is an important concept in eating disorders (ED). Cognitive, emotional, and behavioral features of IU amongst individuals with and without ED were investigated. METHOD: Participants completed the intolerance of uncertainty scale (IUS) and four versions of a data-gathering task varying in difficulty/uncertainty, and rated their Beads task experience. RESULTS: ED groups had significantly higher IUS scores than healthy controls (HC). Bulimia Nervosa (BN) participants requested more cues than HC and Anorexia Nervosa (AN) participants before making decisions. ED groups found the task more distressing than HC participants, with those with BN feeling more uncertain and less confident in their decisions, and those with AN attributing greater importance in making the correct decision. DISCUSSION: While both ED groups reported raised IUS scores only BN participants engaged in an elevated evidence requirement data gathering style. Future research might benefit from further exploration of the role of perseverative processes in BN. PMID- 21555204 TI - Septorhinoplasty with spreader grafts enhances perceived voice quality without affecting acoustic characteristics. AB - OBJECTIVE: To identify the effect of septorhinoplasty with spreader grafts on patients' perception of voice and to measure formant frequencies that may be responsible for perceived changes in voice quality. METHODS: A total of 20 patients who underwent septorhinoplasty and had spreader grafts placed during the operations were included. All subjects were tested within the week before surgery and 1-3 months postoperatively by means of perceptual assessment (Voice Handicap Index-10 [VHI-10] and self-assessment of hypo/hypernasality), acoustic analysis, and formant frequency analysis. RESULTS: The mean of VHI-10 score was decreased from 9.44+/-6.1 to 5.1+/-3.94 postoperatively (P=0.03). Fifteen patients (75%) perceived their voices to be hyponasal before surgery, but only three perceived the hyponasality to persist after surgery (P<0.001). No patient perceived the voice to be hypernasal either before or after surgery. Fifteen patients (75%) perceived their overall voice quality to be improved, whereas five patients perceived no change. None of the patients perceived their voice to be worse after surgery. There were no significant differences between pre- and postoperative acoustic analysis and formant frequency analysis (P>0.05). CONCLUSION: Septorhinoplasty with spreader grafts significantly improved patients' perception of voice; however, acoustic analysis and formant frequency analysis of nasalized vowels did not reveal any significant differences after the operation. PMID- 21555205 TI - Phonation instability flow in excised canine larynges. AB - OBJECTIVE: Disordered voices are often associated with abnormal changes in aerodynamic parameters of subglottal pressure (P(s)) and airflow. Phonation instability pressure (PIP) has been previously proposed to evaluate P(s) at the onset of chaotic phonation. We propose the concept of and measure phonation instability flow (PIF), the airflow at which phonation becomes chaotic. Phonation flow range (PFR), PIF minus phonation threshold flow (PTF), is proposed to assess the range over which normal vocal fold vibration occurs. STUDY DESIGN: Repeated measures with each ex vivo larynx serving as its own control. METHODS: Pressure and airflow were measured at phonation onset and chaos onset in seven excised canine larynges under three experimental conditions: 0% elongation with no glottal gap; 20% elongation with no glottal gap; 20% elongation with a 3-mm posterior glottal gap. Paired t tests were performed to determine if experimental measurements differed between elongations (0% and 20%) or degrees of abduction (20% elongation with and without a 3-mm glottal gap). RESULTS: Both PIF and PFR were dependent on abduction but not elongation. PIP was not significantly dependent on either condition. PIF and PFR showed greater differences for abduction than either phonation threshold pressure (PTP) or PTF. CONCLUSIONS: PIF and PFR may be useful parameters in the experimental or clinical settings, particularly when evaluating disorders characterized by a glottal gap, such as vocal fold paralysis and presbylaryngis. PMID- 21555206 TI - Different flow patterns between left and right internal thoracic artery grafts influence the evaluation of severe graft stenosis by transthoracic Doppler echocardiography. AB - OBJECTIVE: An increase in the diastolic to systolic flow velocity ratio (D/S) in the proximal left internal thoracic artery (ITA) after coronary artery bypass grafting (CABG) enables noninvasive assessment of graft patency by transthoracic Doppler echocardiography (TTDE). The increase in the D/S can be less pronounced at a site distant from the anastomosis. We postulated that proximal ITA flow patterns differ between the left and right ITAs and that the increase in D/S is less pronounced in the right than in the left proximal ITA. METHODS: Proximal ITA flow was examined by TTDE in 129 consecutive patients after CABG of the left (75) or right (69) ITA to the left coronary artery. The mean D/S of the ITAs was compared with coronary angiography. RESULTS: The D/S was lower in the group with a patent right ITA than in the group with a patent left ITA (P < .05). The D/S of both the left and right ITAs negatively correlated with angiographic stenosis (r = 0.56 or 0.67, P < .001, respectively). The regression line was significantly shifted downward in the right ITA compared with the left ITA, according to analysis of covariance (P = .01). Graft stenosis was predicted by a D/S of <0.57 and <0.28 with an accuracy of 91% and 97% in the left and right ITAs, respectively. CONCLUSION: The patency of both left and right ITA grafts to the left coronary artery can be assessed using TTDE, but different cutoff values of D/S are required to diagnose severe ITA stenosis. PMID- 21555207 TI - Quantification of coronary arterial stenoses in CTA using fuzzy distance transform. AB - Quantification of coronary arterial stenoses is useful for the diagnosis of several coronary heart diseases. Being noninvasive, economical and informative, computed tomographic angiography (CTA) has become a common modality for monitoring disease status and treatment effects. Here, we present a new method for detecting and quantifying coronary arterial stenosis in CTA using fuzzy distance transform (FDT) approach and a new coherence analysis of observed data for computing expected local diameter. FDT allows computing local depth at each image point in the presence of partial voluming and thus, eliminates the need for binarization, commonly, associated with inclusion of additional errors. In the current method, coronary arterial stenoses are detected and their severities are quantified by analyzing FDT values along the medial axis of an arterial tree obtained by its skeletonization. A new skeletal pruning algorithm has been developed toward improving the quality of medial axes and thereby, enhancing the accuracy of stenosis detection and quantification. Further, we have developed a new method to estimate "expected diameter" along a given arterial branch using a new coherence analysis of observed diameter values along the branch. The overall method is completed in the following steps--(1) fuzzy segmentation of coronary artery in CTA, (2) FDT computation of coronary arteries, (3) medial axis computation, (4) estimation of observed and expected diameters along arteries and (5) detection of stenoses and quantification of arterial blockage. The performance of this method has been quantitatively evaluated on a realistic coronary artery phantom dataset with randomly simulated stenoses and the results have been compared with a binary distance transform based and a conventional binary algorithm. The method has also been applied on a clinical CTA dataset from thirteen heart patients and the results have been compared with an expert's quantitative assessment of stenoses. Results of the phantom experiment indicate that the new method (error: 0.53%) is significantly more accurate as compared to both binary distance transform based (error 2.11%) and conventional binary (error 3.71%) methods. Also, the results of the clinical study indicate that the new FDT based method (kappa coefficient = 87.9%) is highly in agreement with the expert's assessments and, in this respect, outperforms the other two methods (kappa coefficients = 75.2% and 69.5%). PMID- 21555208 TI - Clinical isolates of New World Leishmania from cutaneous and visceral leishmaniasis patients are uniformly sensitive to tamoxifen. PMID- 21555209 TI - Surface characterization of 7S and 11S globulin powders from soy protein examined by X-ray photoelectron spectroscopy and scanning electron microscopy. AB - In this study the surface composition of 7S and 11S globulin powders from soybean proteins by aqueous buffer and reverse micelle extractions had been examined using X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). Analysis by XPS revealed that the O and N atomic percentage of 7S and 11S globulin surfaces from bis(2-ethylhexyl) sodium sulfosuccinate (AOT) reverse micelle was higher than from aqueous buffer, but the C atomic percentage was lower. The O/C ratio of the 7S globulin powder from aqueous buffer and reverse micelle was similar while significant differences were obtained in the O/C ratio of the 11S globulin powder, N/C atom ratios of the 7S and 11S globulin powders and high-resolution XPS C 1s, N 1s, O 1s spectra. Powder microstructure after reverse micelle treatment showed the presence of small pores, indicating the effect of reverse micelle on the 7S and 11S globulin structure. The obtained results indicated that the reverse micelle could affect the C, O and N components on the surface of soybean proteins. PMID- 21555210 TI - Inhibition of 5-lipoxygenase activity in mice during cuprizone-induced demyelination attenuates neuroinflammation, motor dysfunction and axonal damage. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Increased expression of 5-lipoxygenase (5-LO), a key enzyme in the biosynthesis of leukotrienes (LTs), has been reported in MS lesions and LT levels are elevated in the cerebrospinal fluid of MS patients. To determine whether pharmacological inhibition of 5-LO attenuates demyelination, MK886, a 5-LO inhibitor, was given to mice fed with cuprizone. Gene and protein expression of 5-LO were increased at the peak of cuprizone-induced demyelination. Although MK886 did not attenuate cuprizone-induced demyelination in the corpus callosum or in the cortex, it attenuated cuprizone-induced axonal damage and motor deficits and reduced microglial activation and IL-6 production. These data suggest that during cuprizone-induced demyelination, the 5-LO pathway contributes to microglial activation and neuroinflammation and to axonal damage resulting in motor dysfunction. Thus, 5-LO inhibition may be a useful therapeutic treatment in demyelinating diseases of the CNS. PMID- 21555211 TI - Lipid transfer and signaling at organelle contact sites: the tip of the iceberg. AB - Membrane contact sites (MCSs) are formed by the close apposition of membranes of two organelles. They are zones where signals and small molecules, such as lipids and calcium, are exchanged between intracellular compartments. The past few years have seen considerable progress in our understanding of how MCSs form and facilitate the exchange of lipids and signals. Here we summarize what has been learned about MCSs between the endoplamic reticulum (ER) and the plasma membrane, the ER and mitochondria, and the ER and endosomes or lysosomes. These findings suggest that we are just beginning to understand how MCSs form and function. PMID- 21555212 TI - Illegal drug use and the economic recession--what can we learn from the existing research? AB - BACKGROUND: Much research on the use of amphetamine, cocaine and heroin employs individual level data and analyses variations in drug use by factors like personal characteristics, socioeconomic factors, and the social environment. Less attention is given to how these individual responses inter-relate with key macroeconomic variables. From a drug policy perspective however, it is important to also understand the consequences for drug use and drug users of changes in the macroeconomic conditions. As the world is experiencing an economic recession one would like to know whether it will affect the number of drug users and/or consumption frequency and volume amongst established users. METHODS: There are different channels through which a recession could influence drug consumption; here the main focus is on how an economic downturn may influence drug prices and drug users' incomes. We briefly refer to relevant economic theory before reviewing the research literature. RESULTS: A fall in drug prices and income seem likely. Empirical studies confirm drug users' price responsiveness. Only a few studies have dealt with income elasticity amongst this group. CONCLUSION: As the price and the income effect may pull in opposite directions, the full effect on drug use is difficult to predict. Still, it seems likely that an economic downturn of the current magnitude could increase the use of drugs. PMID- 21555213 TI - Fundamentals of methanogenic pathways that are key to the biomethanation of complex biomass. AB - The conversion of biomass to CH4 (biomethanation) involves an anaerobic microbial food chain composed of at least three metabolic groups of which the first two decompose the complex biomass primarily to acetate, formate, and H2. The thermodynamics of these conversions are unfavorable requiring a symbiosis with the CH4-producing group (methanogens) that metabolize the decomposition products to favorable concentrations. The methanogens produce CH4 by two major pathways, conversion of the methyl group of acetate and reduction of CO2 coupled to the oxidation of formate or H2. This review covers recent advances in the fundamental understanding of both methanogenic pathways with the view of stimulating research towards improving the rate and reliability of the overall biomethanation process. PMID- 21555214 TI - Fragile X syndrome and the amygdala. AB - Fragile X syndrome (FXS) is the most commonly inherited form of mental impairment and autism. Current understanding of the molecular and cellular mechanisms underlying FXS symptoms is derived mainly from studies on the hippocampus and cortex. However, FXS is also associated with strong emotional symptoms, which are likely to involve changes in the amygdala. Unfortunately, the synaptic basis of amygdalar dysfunction in FXS remains largely unexplored. Here we describe recent findings from mouse models of FXS that have identified synaptic defects in the basolateral amygdala that are in many respects distinct from those reported earlier in the hippocampus. Long-term potentiation and surface expression of AMPA receptors are impaired. Further, presynaptic defects are seen at both excitatory and inhibitory synapses. Remarkably, some of these synaptic defects in the amygdala are also amenable to pharmacological rescue. These results also underscore the need to modify the current hippocampus-centric framework to better explain FXS-related synaptic dysfunction in the amygdala. PMID- 21555215 TI - Phase 1 trials of molecular targeted therapies: are we evaluating toxicities properly? PMID- 21555216 TI - Aqueous ionic liquid pretreatment of straw. AB - Pretreatment is the key to unlock the recalcitrance of lignocellulose for cellulosic biofuels production. Increasing attention has been drawn to ionic liquids (ILs) for pretreatment of lignocellulosic biomass, because this approach has several advantages over conventional methods. However, cost and energy intensive recycling of the solvents are major constraints preventing ILs from commercial viability. In this work, a mixture of ionic liquid 1-ethyl-3 methylimidazolium acetate and water was demonstrated to be effective for pretreatment of lignocellulosic biomass, evidenced by the removal of lignin and a reduction in cellulose crystallinity. A higher fermentable sugar yield (81%) was obtained than for pure ionic liquid pretreatment under the same conditions (67%). Aqueous ionic liquid pretreatment has the advantages of less usage and easier recycling of ILs, and reduced viscosity. PMID- 21555217 TI - Harvesting biohydrogen from cellobiose from sulfide or nitrite-containing wastewaters using Clostridium sp. R1. AB - Harvesting biohydrogen from inhibiting wastewaters is of practical interest since the toxicity of compounds in a wastewater stream commonly prevents the bioenergy content being recovered. The isolated Clostridium sp. R1 is utilized to degrade cellobiose in sulfide or nitrite-containing medium for biohydrogen production. The strain can effectively degrade cellobiose free of severe inhibitory effects at up to 200 mgl(-1) sulfide or to 5 mgl(-1) nitrite, yielding hydrogen at >2.0 mol H2 mol(-1) cellobiose. Principal metabolites of cellobiose fermentation are acetate and butyrate, with the concentration of the former increases with increasing sulfide and nitrite concentrations. The isolated strain can yield hydrogen from cellobiose in sulfide-laden wastewaters. However, the present of nitrite significantly limit the efficiency of the biohydrogen harvesting process. PMID- 21555218 TI - Temporal variations of membrane foulants in the process of using flat-sheet membrane for simultaneous thickening and digestion of waste activated sludge. AB - Membrane foulants were extracted at different operation time in simultaneous sludge thickening and digestion reactors using flat-sheet membranes. Temporal variations of foulants were analyzed by three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy, gel filtration chromatography (GFC), particle size distribution (PSD) and attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy. Results showed that during the first 4days fouling was mainly assigned to internal membrane foulants (IMFs), and afterwards external membrane foulants (EMFs) increased dramatically. EEM analysis showed that both IMFs and EMFs changed during the operation. Cluster analysis demonstrated that the characteristics of IMFs were relatively similar; however, both quantity and properties of EMFs were changed. GFC analysis showed that EMFs contained more molecules with large molecular weight compared to IMFs. PSD analysis illuminated that particle size of EMFs gradually increased and was larger than that of IMFs. ATR-FTIR analysis indicated that the foulants on membranes consisted of polysaccharides and proteins. PMID- 21555219 TI - Supercritical carbon dioxide pretreatment of corn stover and switchgrass for lignocellulosic ethanol production. AB - Supercritical CO(2) (SC-CO(2)), a green solvent suitable for a mobile lignocellulosic biomass processor, was used to pretreat corn stover and switchgrass at various temperatures and pressures. The CO(2) pressure was released as quickly as possible by opening a quick release valve during the pretreatment. The biomass was hydrolyzed after pretreatment using cellulase combined with beta-glucosidase. The hydrolysate was analyzed for the amount of glucose released. Glucose yields from corn stover samples pretreated with SC CO(2) were higher than the untreated sample's 12% glucose yield (12 g/100g dry biomass) and the highest glucose yield of 30% was achieved with SC-CO(2) pretreatment at 3500 psi and 150 degrees C for 60 min. The pretreatment method showed very limited improvement (14% vs. 12%) in glucose yield for switchgrass. X ray diffraction results indicated no change in crystallinity of the SC-CO(2) treated corn stover when compared to the untreated, while SEM images showed an increase in surface area. PMID- 21555220 TI - Design and synthesis of potent HIV-1 protease inhibitors incorporating hydroxyprolinamides as novel P2 ligands. AB - A series of new HIV-1 protease inhibitors with the hydroxyethylamine core and different hydroxyprolinamide P2 ligands were designed and synthesized. Variation of substitutions at the P2 significantly affected the enzyme inhibitory potency of the inhibitors. Compounds 2a and 2d showed excellent enzyme inhibitory activity with IC(50) values in the nanomolar range. An active site binding model for inhibitors 2a and 2d was suggested based upon the computational-docking results of the ligand with HIV-1 protease. This model offers molecular insights regarding ligand-binding site interactions of the hydroxyprolinamide-derived novel P2-ligand. PMID- 21555221 TI - Design, synthesis, and evaluation of bromo-retrochalcone derivatives as protein tyrosine phosphatase 1B inhibitors. AB - A series of bromo-retrochalcones was designed, synthesized and evaluated as PTP1B inhibitors based on licochalcone A and E. Compounds 6, 12, 13, 14, 25, 36, 37, 39, and 41 showed potent inhibitory effects against PTP1B, and compound 37, the most potent among the series, had an IC(50) value of 1.9 MUM, about two-fold better than that of the positive control, ursolic acid. PMID- 21555222 TI - Molecular hybridization of 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecane-3-ol with sigma (sigma) receptor ligands modulates off-target activity and subtype selectivity. AB - A series of N-substituted 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (sigma) receptor ligands were synthesized and evaluated for their affinity against sigma receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for sigma(1) and sigma(2) receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (4, sigma(1)K(i)=27 nM, sigma(2)K(i)=55 nM) showed reduced affinity for D(1)-D(5) dopamine receptors when compared to haloperidol itself. The compound with the greatest sigma(1) affinity in the series, benzamide 4 (sigma(1)K(i)=7.6 nM, sigma(2)K(i)=225 nM) showed a complete reversal of the subtype selectivity displayed by the highly sigma(2) selective parent benzamide, RHM-2 (3, sigma(1)K(i)=10412 nM, sigma(2)K(i)=13.3 nM). PMID- 21555223 TI - Discovery of new chromone containing sulfonamides as potent inhibitors of bovine cytosolic carbonic anhydrase. AB - Series of chromone containing sulfonamides were prepared by the reaction of (un)substituted 3-formylchromones with 3-aminobenzenesulfonamide and 4 aminobenzenesulfonamide. Bovine carbonic anhydrase (bCA) inhibitory activity of these newly synthesized compounds was determined. All compounds were active and possessed excellent bCA inhibitory activities with IC50 values ranged between 4.31 +/- 0.001 and 29.12 +/- 0.008 MUmol. Compounds derived from 6-fluoro-3 formylchromones were the most active. PMID- 21555224 TI - Quinoline-4-methyl esters as human nonpancreatic secretory phospholipase A2 inhibitors. AB - A series of novel fused heterocycle methyl esters were designed and synthesized as human nonpancreatic secretory phospholipase A2 (hnps-PLA2) competitive inhibitors. Among the 22 synthesized compounds, 17 quinoline-4-methyl esters displayed hnps-PLA2 inhibition activity in the in vitro bioassay. The IC50 value for the best compound 3o was 1.5 MUM. The structure-inhibition-activity relationships of the compounds were studied using molecular docking. PMID- 21555225 TI - Effects of CXCR1 and CXCR2 inhibition on expansion and differentiation of umbilical cord blood CD133(+) cells into megakaryocyte progenitor cells. AB - OBJECTIVE: There have been various reports on the roles of CXC receptors (CXCR) in modulation of hematopoiesis. In the present study, we investigated the effects of CXCR1 and/or CXCR2 inhibition on expansion and differentiation of umbilical cord blood (UCB) CD133(+) cells into megakaryocytic progenitors. MATERIALS AND METHODS: Purified UCB CD133(+) cells were cultured in a serum-free liquid culture either in the presence or absence of neutralizing anti-CXCR1 and/or anti-CXCR2 antibodies in combination with a conventional cytokine cocktail for up to 14days. Expression of megakaryocytic lineage markers (CD41 and CD61) and determination of ploidy level were determined by flowcytometry. In addition, colony-forming unit assay was performed using CD133(+) cultures in serum-free collagen-based medium containing the cytokine cocktail plus neutralizing CXCR1 and -R2 antibodies. Colony forming unit-megakaryocyte (CFU-MKs) and non-MKs were counted after immunocytochemistry staining on day 12. RESULTS: We show that while simultaneous inhibition of both CXCR1 and -R2 causes a significant reduction in the fold expansion of UCB CD133(+) cells, it also leads to an increase in percentages of CD61(+), CD41(+), and CFU-MK populations. CONCLUSION: CXCR1 and CXCR2 play significant roles in the suppression of megakaryopoiesis. We demonstrate that blocking of this suppressive effect by a simultaneous inhibition of both receptors can enhance the differentiation of UCB CD133(+) cells into megakayocytic progenitors. PMID- 21555226 TI - Attending to music decreases inattentional blindness. AB - This article investigates how auditory attention affects inattentional blindness (IB), a failure of conscious awareness in which an observer does not notice an unexpected event because their attention is engaged elsewhere. Previous research using the attentional blink paradigm has indicated that listening to music can reduce failures of conscious awareness. It was proposed that listening to music would decrease IB by reducing observers' frequency of task-unrelated thoughts (TUTs). Observers completed an IB task that varied both visual and auditory demands. Listening to music was associated with significantly lower IB, but only when observers actively attended to the music. Follow-up experiments suggest this was due to the distracting qualities of the audio task. The results also suggest a complex relationship between IB and TUTs: during demanding tasks, as predicted, noticers of the unexpected stimulus reported fewer TUTs than non-noticers. During less demanding tasks, however, noticers reported more TUTs than non-noticers. PMID- 21555227 TI - Comments regarding 'Venous angioplasty is safe to perform and may have benefits forin patients with multiple sclerosis. Results of a pilotcase control pilot study'. PMID- 21555228 TI - Detection of MPL exon10 mutations in 103 Chinese patients with JAK2V617F-negative myeloproliferative neoplasms. AB - JAK2V617F mutation has been reported in 90% of patients with polycythemia vera (PV) and about 50% of patients with essential thromobocythemia (ET) and primary myelofibrosis (PMF). Recently, acquired mutations in the transmembrane juxtamembrane region of MPL (MPLW515 mutations) have been reported in approximately 5% of JAK2V617F-negative PMF and about 1% of all cases of ET. MPL is the receptor for thrombopoietin that regulates the production of platelets by bone marrow. It is likely that some mutations more closely related to ET in MPL exon10 may have been missed by current assays. We inferred that there might be other mutations in MPL exon10 for MPN patients in addition to MPLW515 mutations. To investigate its mutation types and prevalence in Chinese patients with myeloproliferative neoplasms (MPN), we performed mutation detection on MPL exon10 in 103 JAK2V617F-negative MPN patients by single strand conformation polymorphism (SSCP) and allele-specific PCR (AS-PCR) combined with sequencing. As a result, one previously unrecognized MPL mutation (12-bp in-frame insertion) was identified in one patient with ET in addition to an MPLW515K mutation identified in one PMF patient. This confirms our hypothesis that BCR/ABL negative and JAK2V617F-negative MPN patients have other mutations besides W515 mutation in MPL exon10 and mutations other than single nucleotide exchange also exist. In addition, MPL mutation was associated with Chinese MPN patients. PMID- 21555229 TI - [Nursing educational intervention for the management of postoperative pain in ambulatory surgery]. AB - OBJECTIVE: Evaluate the effectiveness of educational intervention of perioperative nursing by providing graphic material for the management of postoperative pain in patients operated on for hernia in an Ambulatory Surgery Unit (ASU). METHOD: A quasi-experimental (non-randomised) study, with a control group with patients undergoing hernia between July 2006 and June 2007 and an intervention group with patients treated between July 2007 and June 2008. Both groups were given the same training on the surgical and postoperative recommendations for perioperative nursing clinics. The intervention group was reinforced with the provision of information in graphic form. The data was collected using a questionnaire at admission and phone call within 24 hours postoperative. Pain measurement was made with the visual analogue scale / verbal numerical rating scale (VAS/VNRS). RESULTS: A total 205 patients were included in the control group and 292 in the intervention group. In the bivariate analysis, the percentage of patients with VAS >3 was 23.9% for the control group and 15.1% for the intervention group. In the multivariate analysis, the variables associated with postoperative pain were: low age, female sex, mobility and walking problems, and lack of knowledge about post-discharge home-care guidelines. CONCLUSIONS: Nursing educational intervention with the provision of graphic material, suggests that it may reduce the individual's perception of postoperative pain, decrease the percentage of patients with mobility and walking problems, and improve compliance and adherence to treatment. PMID- 21555230 TI - Generalized lymphadenopathy with cystic spleen lesions: a rare presentation of tuberculosis. PMID- 21555231 TI - Water irradiation by high-frequency ultrasonic wave: effects on properties of passive film formed on stainless steel. AB - In this paper an aqueous solution was irradiated with a 1.63MHz ultrasonic wave. It is shown that if stainless steel can passivate under dynamic polarization in this medium, under static polarization, the latter does not show any repassivation behaviour with time. This is attributed to a diminution of the diffusion layer thickness that is developed at the electrode/electrolyte interface, which is associated with a production of H(2) species by sonolysis and which maintains reductive conditions at the interface. The oxide film formed under ultrasonic irradiation for 1h at a passive potential of+0.2V(SCE) shows an early stage of passivation and an increased disordered state, which implies a considerable decrease in the corrosion resistance behaviour of the sample. The polarization resistance of the stainless steel R(p) is divided by a value of 4.5 under ultrasonic conditions. PMID- 21555232 TI - Automatic endotracheal tube position confirmation system based on image classification--a preliminary assessment. AB - Endotracheal intubation is a complex medical procedure in which a ventilating tube is inserted into the human trachea. Improper positioning carries potentially fatal consequences and therefore confirmation of correct positioning is mandatory. This paper introduces a novel system for endotracheal tube position confirmation. The proposed system comprises a miniature complementary metal oxide silicon sensor (CMOS) attached to the tip of a semi rigid stylet and connected to a digital signal processor (DSP) with an integrated video acquisition component. Video signals are acquired and processed by a confirmation algorithm implemented on the processor. The confirmation approach is based on video image classification, i.e., identifying desired expected anatomical structures (upper trachea and main bifurcation of the trachea) and undesired structures (esophagus). The desired and undesired images are indicators of correct or incorrect endotracheal tube positioning. The proposed methodology is comprised of a continuous and probabilistic image representation scheme using Gaussian mixture models (GMMs), estimated using a greedy algorithm. A multi-dimensional feature space, which consists of several textural-based features, is utilized to represent the images. The performance of the proposed algorithm was evaluated using two datasets: a dataset of 1600 images extracted from 10 videos recorded during intubations on dead cows, and a dataset of 358 images extracted from 8 videos recorded during intubations performed on human subjects. Each one of the video images was classified by a medical expert into one of three categories: upper tracheal intubation, correct (carina) intubation and esophageal intubation. The results, obtained using a leave-one-case-out method, show that the system correctly classified 1530 out of 1600 (95.6%) of the cow intubations images, and 351 out of the 358 human images (98.0%). Misclassification of an image of the esophagus as carina or upper-trachea, which is potentially fatal, was extremely rare (only one case when in the animal dataset and no cases when in the human intubation dataset). The classification results of the cow intubations dataset compare favorably with a state-of-the-art classification method tested on the same dataset. PMID- 21555233 TI - Social capital and health-purely a question of context? AB - Debate still surrounds which level of analysis (individual vs. contextual) is most appropriate to investigate the effects of social capital on health. Applying multilevel ecometric analyses to British Household Panel Survey data, we estimated fixed and random effects between five individual-, household- and small area-level social capital indicators and general health. We further compared the variance in health attributable to each level using intraclass correlations. Our results demonstrate that association between social capital and health depends on indicator type and level investigated, with one quarter of total individual-level health variance found at the household level. However, individual-level social capital variables and other health determinants appear to influence contextual level variance the most. PMID- 21555234 TI - Spatial modeling of geographic inequalities in infant and child mortality across Nepal. AB - A survival regression model that allows for spatially correlated random effects is used to predict the hazard of dying among 12,714 children born between 1996 and 2006 in Nepal. The maps of fitted hazard rates show that even after accounting for individual and community-level covariates, a residual spatial pattern in infant mortality remains, with higher mortality concentrated in parts of Nepal's Far-Western and Mid-Western development regions. Results suggest a need to consider health policies and programs that reach children in spatially concentrated high-mortality areas. PMID- 21555235 TI - Dipole moment determination of 4-[N-(5,6,7,8-tetrahydroisoquinolinium-5 ylidene)methyl]-N,N-dialkylaniline iodides in solution. AB - Electronic absorption and fluorescence spectra of eight hemicyanine dyes were recorded at room temperature in several solvents of different polarity. The spectral data were analyzed using the theory of solvatochromism, based on a dielectric continuum description of the solvent and the classical Onsager cavity model. They were used to evaluate the excited state dipole moment using methods applied by McRae, Lippert, Mataga and Bakhshiev. DFT calculations were carried out to estimate the ground state dipole moment and Onsager cavity radius. The difference in the excited and ground state dipole moments (MUe-MUg) of the molecule under study is positive. It means that the excited states of the dyes are more polar than the ground state. The increase in dipole moments upon excitation is explained in terms of the nature of the excited state and its resonance structures. PMID- 21555236 TI - DFT, FT-Raman and FT-IR investigations of 5-o-tolyl-2-pentene. AB - FT-IR and Raman spectra of 5-o-tolyl-2-pentene (OTP) have been experimentally reported in the region of 4000-10 cm(-1) and 4000-100 cm(-1), respectively. The optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of cis and trans isomers of OTP (C12H16) have been theoretically examined by means of B3LYP hybrid density functional theory (DFT) method together with 6-31G(d) and 6-31++G(d,p) basis sets. Furthermore, reliable vibrational assignments have made on the basis of potential energy distribution (PED) calculated. Comparison between the experimental and theoretical results indicates that density functional B3LYP method is able to provide satisfactory results for predicting vibrational wavenumbers and trans isomer is supposed to be the most stable form of OTP molecule. PMID- 21555237 TI - Evaluating the medication process in the context of CPOE use: the significance of working around the system. AB - OBJECTIVE: To evaluate the problems experienced after implementing a computerized physician order entry (CPOE) system, their possible root causes, and the responses of providers in order to incorporate the system into daily workflow. METHODS: A qualitative study in the medication-use process after implementation of a CPOE system in an academic hospital in The Netherlands. Data included 21 interviews with clinical end-users, paper-based and system-generated documents used daily in the process, and educational materials used to train users. FINDINGS: The problems in the medication-use process included cognitive overload on physicians and nurses, unmet information needs, miscommunication of orders and ideas, problematic coordination of interrelated tasks between co-working professionals, a potentially faulty administration phase, and suboptimal monitoring of the medication plans. These problems were mainly rooted in the lack of mobile computer devices, the uneasy integration of coexisting electronic and paper-based systems, suboptimal usability of the system, and certain organizational factors with regard to procuring drugs affecting the technology use. Various types of workarounds were used to address the difficulties, including phone calls, taking multiple paper notes, issuing paper-based and verbal orders, double-checking, using other patients' procured drugs or another department's drug supply, and modifying and annotating the printed orders. CONCLUSION: This study shows how providers are actively involved in working around the interruptions in workflow by bypassing the technology or adapting the work processes. Although certain workarounds help to maintain smooth workflow and/or to ensure patient safety, others may burden providers by necessitating extra time and effort and/or endangering patient safety. It is important that workarounds having a negative nature are recognized and discussed in order to find solutions to mitigate their effects. PMID- 21555238 TI - Serum fatty acid synthase concentration is increased in patients with hepatitis viral infection and may assist in the prediction of liver steatosis. AB - BACKGROUND: Liver steatosis is frequent in patients with chronic hepatitis viral infections. Intracellular fatty acid synthase (FASN) seems to play a substantial role in its pathogenesis. FASN can also be found in circulation and is significantly increased in HIV-infected individuals, especially if they are co infected with hepatitis C virus (HCV). OBJECTIVES: To assess whether serum FASN concentration is also increased in patients with chronic hepatitis viral infections and its relationship with liver steatosis. STUDY DESIGN: Samples and associated data were obtained from stored collections in our institutions from patients with chronic infections with either hepatitis B virus (HBV, cHB, n=60), HCV (cHC, n=81) or co-infection (n=29). RESULTS: The incidence of liver steatosis was significantly (p<0.001) different among groups (23.7% in cHB, 34.2% in cHC and 69.2% in co-infected). A similar trend was observed for changes in serum ALT [in MUKat/L, 1.41 (0.08), 1.62 (0.08) and 1.95 (0.16) respectively; p=0.02] and serum FASN [in ng/mL, 9.44 (1.28), 16.38 (1.93) and 31.47 (4.26) respectively; p<0.001]. Serum FASN concentration was related to the degree of liver steatosis, and was correlated with serum ALT values when the whole group was considered (rho=0.207; p=0.007). CONCLUSIONS: Serum FASN concentration is significantly increased in patients with chronic hepatitis viral infections and correlated with the degree of liver steatosis. These findings may represent a basis for further studies searching non-invasive biomarkers with either diagnostic or prognostic value. PMID- 21555239 TI - Prolonged electrical stimulation over hip flexors increases locomotor output in human SCI. AB - OBJECTIVES: The objective of this study was to determine whether enhanced feedback from thigh afferents improves locomotor output in human spinal cord injury (SCI). METHODS: The effects of afferent feedback originating from the upper thigh muscles on locomotion was examined using electrical stimulation in 10 subjects with incomplete SCI and three neurologically intact controls during robotic-assisted treadmill walking. Electrical stimulation consisted of 20 pulses at 30 Hz, applied bilaterally to the skin of the medial thigh, approximately over the sartorius muscle. The stimulation was applied at four different phases of the gait cycle. Torque responses of hip and knee joints and electromyograms of both legs were recorded during baseline with no stimulation, stimulation, and post stimulation. RESULTS: During stimulation, enhanced hip and knee extension and flexion torque responses were observed during the stance and swing phases, respectively, for all four different stimulation conditions. Larger hip extension torque was observed when the stimulation was applied during the stance phase and the transition from stance to swing. CONCLUSIONS: Enhanced afferent feedback produced by electrical stimulation may increase the excitability of the spinal cord locomotor circuits in human SCI. SIGNIFICANCE: Results from this study emphasize the contribution of sensory information from thigh muscles, particularly the sartorius muscle afferents, to locomotor control in human SCI during treadmill walking. PMID- 21555240 TI - Velocity recovery cycles of human muscle action potentials: repeatability and variability. AB - OBJECTIVE: Velocity recovery cycles (VRCs) of human muscle action potentials have been proposed as a new technique for assessing muscle membrane function in myopathies. This study was undertaken to determine the variability and repeatability of VRC measures such as supernormality, to help guide future clinical use of the method. METHODS: To assess repeatability, VRCs with one and two conditioning stimuli were recorded from brachioradialis muscle by direct muscle stimulation in 20 normal volunteers, and the measurements repeated 1 week later. To further assess variability and dependence on electrode separation, age and sex, recordings from an additional 20 normal volunteers were added. RESULTS: There was a high intraclass correlation between repeated recordings of early supernormality, indicating excellent reliability of this VRC measure. However, relative refractory period had a smaller coefficient of repeatability in relation to the changes previously described during ischemia. We found no evidence that any of the excitability measures depended on electrode separation, conduction time or apparent velocity. There were also no significant differences between the recordings from men and women, or between the recordings from older (mean 44.9 y) and younger (26.5 y) subjects. CONCLUSIONS: VRC measures are sufficiently consistent to be suitable for comparing muscle membrane function both within subjects and between groups. Early supernormality measurements benefit most from within subject comparisons. SIGNIFICANCE: These normative data sets provide a firm basis for planning clinical studies. PMID- 21555241 TI - Nitrogen regulation of morphogenesis and protease secretion in Candida albicans. AB - In the pathogenic yeast Candida albicans, nitrogen availability regulates phenotypes that contribute to the virulence of the fungus, including filamentous growth and protease secretion. Under limiting nitrogen conditions, the ammonium permease Mep2 induces the switch from yeast to filamentous growth. Mep2 is a cytoplasmic membrane protein that mediates uptake of the preferred nitrogen source ammonium. It contains a signaling domain in its C-terminal cytoplasmic tail that induces morphogenesis in response to ammonium availability, presumably by activating the cAMP-PKA pathway and the Cph1-dependent MAP kinase pathway. MEP2 expression itself is regulated by the GATA transcription factors Gat1 and Gln3. These central regulators also control expression of the secreted aspartic protease Sap2, which is induced when proteins are the only available nitrogen source. Under these conditions, Gat1 and Gln3 upregulate the expression of STP1, which encodes a proteolytically activated transcription factor that in turn mediates the expression of SAP2 and several oligopeptide transporters required for growth on proteins. In this way, C. albicans integrates the expression of different virulence-associated phenotypes into the regulatory network controlling nitrogen metabolism. PMID- 21555242 TI - Signaling the glycoshield: maintenance of the Candida albicans cell wall. AB - In fungi, the cell wall is a scaffold, an armor and an environmental gate. Sugar polymers including protein-O- or N-linked glycosyl chains or polysaccharides such as glucan or chitin are essential components to maintain cell wall functions. We describe mechanisms in the human fungal pathogen Candida albicans, by which the integrity of glycostructures are sensed and regulated. The results stress the importance of membrane sensors and MAP kinase pathways in the maintenance of cell wall structure and function. PMID- 21555243 TI - On the way toward systems biology of Aspergillus fumigatus infection. AB - Pathogenicity of Aspergillus fumigatus is multifactorial. Thus, global studies are essential for the understanding of the infection process. Therefore, a data warehouse was established where genome sequence, transcriptome and proteome data are stored. These data are analyzed for the elucidation of virulence determinants. The data analysis workflow starts with pre-processing including imputing of missing values and normalization. Last step is the identification of differentially expressed genes/proteins as interesting candidates for further analysis, in particular for functional categorization and correlation studies. Sequence data and other prior knowledge extracted from databases are integrated to support the inference of gene regulatory networks associated with pathogenicity. This knowledge-assisted data analysis aims at establishing mathematical models with predictive strength to assist further experimental work. Recently, first steps were done to extend the integrative data analysis and computational modeling by evaluating spatio-temporal data (movies) that monitor interactions of A. fumigatus morphotypes (e.g. conidia) with host immune cells. PMID- 21555244 TI - Host-pathogen interactions and virulence-associated genes during Candida albicans oral infections. AB - Oral infections with Candida albicans are very common diseases in even only mildly immunocompromised patients. By using genome-wide microarrays, in vitro infection models and samples from patients with pseudomembranous candidiasis, several genes have been identified which encode known and unknown fungal factors associated with oral infection. The expression of selected genes has been investigated via qRT-PCR in both in vitro models and in vivo samples from patients. Several lines of evidence suggest that fungal morphology plays a key role in adhesion to and invasion into oral epithelial cells and mutants lacking regulators of hyphal formation are attenuated in their ability to invade and damage epithelial cells. Adhesion is mediated by hyphal-associated factors such as Hwp1 and the Als adhesin family. Hyphal formation facilitates epithelial invasion via two routes: active penetration and induced endocytosis. While induced endocytosis is predominantly mediated by the adhesin and invasin Als3, active penetration seems to be supported by hydrolase activity and mechanical pressure. Expression profiles reflect the morphological switch and an adaptive response to neutral pH, non-glucose carbon sources, and nitrosative stress. PMID- 21555245 TI - Smoking status and urine cadmium above levels associated with subclinical renal effects in U.S. adults without chronic kidney disease. AB - Tobacco smoke is a major source of adult exposure to cadmium (Cd). Urine Cd levels (CdU) above 1.0, 0.7, and 0.5 MUgCd/g creatinine have been associated with increased rates of microproteinuria and reduction in glomerular filtration rate. The two study objectives were to determine the prevalence and relative risk (RR) by smoking status for CdU above 1.0, 0.7, and 0.5 MUgCd/g creatinine in U.S. adults; and to describe geometric mean CdU by smoking status, age, and sex. NHANES 1999-2006 data for adults without chronic kidney disease were used to compute prevalence rates above the three CdU in current and former cigarette smokers, and non-smokers. RRs for smokers adjusted for age and sex were computed by logistic regression. Analysis of covariance was used to calculate geometric means of CdU adjusted for age, sex, smoking status, log urine creatinine, and interaction terms: age-smoking status and sex-smoking status. At selected ages, adjusted RR for exceeding each risk-associated CdU was highest for current smokers (3-13 times), followed by former smokers (2-3 times), compared to non smokers. Adjusted RR for smokers increased with age and was higher in females than males. Adjusted geometric means of CdUs increased with age, were higher in females than in males regardless of smoking status, and were higher in current smokers than former smokers, who had higher levels than non-smokers at any age. Cigarette smoking greatly increases RR of exceeding renal risk-associated CdU. Former smokers retain significant risk of exceeding these levels compared to non smokers. CdU increased with age, particularly in current smokers. PMID- 21555246 TI - Common, important, and unmet needs of cancer outpatients. AB - PURPOSE: To maximize patient well-being, health and social care should, whenever possible, address individual patient needs. The present study aims firstly, to identify prevalent, salient and unmet needs amongst cancer outpatients, and secondly, to explore socio-demographic and clinical influences on expressed need. METHODS: One-hundred and ten outpatients registered at a UK cancer treatment centre completed a self-report questionnaire measuring the presence, salience and degree to which 80 need items were met. Six broad cancer sites were represented: urology, colorectal, breast, gynaecology, haematology, and head and neck. RESULTS: The mean number of needs reported was 27. The top five needs concerned the treatment, care and health information patients receive from healthcare professionals, all of which were rated as well met. Least met needs included receiving genetic information, information about lifestyle changes, help with worries about spread or recurrence, and parking near treatment centres. Salient needs showed greater variation across the sample and were often unmet, for example the need for genetic information, and the need for information about symptoms/indicators of recurrence. Gender (female), age (younger), having an informal caregiver, and cancer site all affected aspects of need; whereas time since diagnosis and type of treatment did not. CONCLUSIONS: Acknowledging these influences on patient need could help guide patient-centred support services with potential gains to patient satisfaction and well-being. PMID- 21555247 TI - Circuits and brain rhythms in schizophrenia: a wealth of convergent targets. AB - Few common neurological illnesses trace back to single molecular disturbances. Many disparate putative causes may co-associate with a single disease state. However, uncovering functional, hierarchical networks of underlying mechanisms can provide a framework in which many primary pathologies converge on more complex, single higher level correlates of disease. This article focuses on cognitive deficits associated with schizophrenia to illustrate: a) How non invasive EEG biomarkers of cognitive function constitute such a 'higher level correlate' of underlying pathologies. b) How derangement of multiple, cell specific, molecular processes can converge on such EEG-visible, correlates of disrupted cognitive function. This approach suggests that evidence-based design of multi-target therapies may take advantage of hierarchical patterns of convergence to improve both efficacy and selectivity of disease-intervention. PMID- 21555248 TI - TIRAP polymorphisms and TB susceptibility. PMID- 21555249 TI - Predicting protein-protein interactions using graph invariants and a neural network. AB - The PDZ domain of proteins mediates a protein-protein interaction by recognizing the hydrophobic C-terminal tail of the target protein. One of the challenges put forth by the DREAM (Discussions on Reverse Engineering Assessment and Methods) 2009 Challenge consists of predicting a position weight matrix (PWM) that describes the specificity profile of five PDZ domains to their target peptides. We consider the primary structures of each of the five PDZ domains as a numerical sequence derived from graph-theoretic models of each of the individual amino acids in the protein sequence. Using available PDZ domain databases to obtain known targets, the graph-theoretic based numerical sequences are then used to train a neural network to recognize their targets. Given the challenge sequences, the target probabilities are computed and a corresponding position weight matrix is derived. In this work we present our method. The results of our method placed second in the DREAM 2009 challenge. PMID- 21555250 TI - Treatment of multiple sclerosis with anti-CD20 antibodies. AB - The recently successful targeting of B cells in patients with multiple sclerosis (MS) using monoclonal antibodies (mAbs) targeting CD20 has established that it is no longer a question of whether B cells contribute, but how they contribute, to MS disease activity. Here, the focus will be to review results that have emerged over the last few years from clinical trials of different anti-CD20 mAbs in patients with MS. We will also consider the biological basis underlying the apparent therapeutic efficacy of B cell depletion in MS. To this end, we will draw on several instructive observations made in MS patients who were treated with the anti-CD20 mAb rituximab. While the initial application of rituximab to patients with MS was based on the concept that B cell depletion may translate into decreases in potentially pathogenic CNS-autoreactive antibodies, insights from these studies have underscored the importance of non-antibody mediated functions of B cells. PMID- 21555251 TI - Persistent deja vu associated with hyperperfusion in the entorhinal cortex. AB - Deja vu is a common experience among the normal population. However, in individuals with temporal lobe epilepsy, it often occurs as a seizure manifestation. The specific cause of such deja vu is not yet known. Here, we report a case of epilepsy with persistent deja vu. The patient described the state as if he were living the same life he had lived before. Blood perfusion single-photon-emission computed tomography (SPECT) performed during the persistent deja vu showed hyperperfusion in the left medial temporal area; discontinuation of deja vu was accompanied by disappearance of the hyperperfused area on SPECT. Analysis with three-dimensional co-registration of SPECT and MRI revealed that the hyperperfused area during the persistent deja vu was in the entorhinal cortex of the left temporal lobe. According to recent theories of recognition memory, malfunction of the parahippocampal area may cause deja vu. It is also suggested that epileptic activity in the parahippocampal area, especially the entorhinal cortex, may elicit deja vu. PMID- 21555252 TI - Genetic analysis of tuberous-sclerosis genes 1 and 2 in nonlesional focal epilepsy. AB - Germline mutations of TSC1 (harmartin) and TSC2 (tuberin) are known to cause tuberous sclerosis (TSC), an autosomal dominant disorder with severe neurological and systemic manifestations. In addition, increasing data indicate aberrant patterns of allelic variants in patients with lesion-associated epilepsy, but absence of other stigmata of TSC. Animal models of TSC suggested that mutations in the TSC2 gene, even in absence of manifest neuropathological changes, induce aberrant neuronal activity. On this basis, we have carried out a mutational analysis of TSC1 and TSC2 in patients with pharmarcoresistant focal epilepsy without evidence of epileptogenic lesions on neuroradiological and histopathological examination (n=10). SSCP analysis revealed an allelic variant of TSC2 to be significantly increased (exon 41: 50.0% vs controls 14%, P=0.0132), which previously was reported to be increased in gangliogliomas and mineralized focal cortical dysplasia as well. Our data suggest allelic imbalances of TSC2 in nonlesional focal epileptic tissue. PMID- 21555253 TI - The King's Speech: should SUDEP be part of the script? PMID- 21555254 TI - Structural identification of the metabolites for strictosamide in rats bile by an ion trap-TOF mass spectrometer and mass defect filter technique. AB - We report herein, a facile metabolite identification workflow on the antimicrobial strictosamide, which is derived from accurate mass measurement by a hybrid ion trap-TOF mass spectrometer. In step 1, the parent drug and metabolites in rat bile were separated on an HPLC column followed by ion trap-TOF mass spectrometer analysis after a single oral dose of 50mg/kg strictosamide. In step 2, mass defect filter technique, which enables high-resolution mass spectrometers to be utilized for detecting drug metabolites based on well-defined mass defect ranges, was used to find metabolites in the mass spectrum. In step 3, the differences of accurate masses and their mass fragmentation pattern among the parent drug and metabolites used to assign structures for the metabolites successfully. As a result, five metabolites of strictosamide were found in rat bile, and all the metabolites were reported for the first time. PMID- 21555255 TI - High-performance liquid chromatography analysis of naturally occurring D-amino acids in sake. AB - We measured all of the D- and L-amino acids in 141 bottles of sakes using HPLC. We used two precolumn derivatization methods of amino acid enantiomer detection with o-phthalaldehyde and N-acetyl-L-cysteine, as well as (+)-1-(9 fluorenyl)ethyl chloroformate/1-aminoadamantane and one postcolumn derivatization method with o-phthalaldehyde and N-acetyl-L-cysteine. We found that the sakes contained the D-amino acids forms of Ala, Asn, Asp, Arg, Glu, Gln, His, Ile, Leu, Lys, Ser, Tyr, Val, Phe, and Pro. We were not able to detect D-Met, D-Thr D-Trp in any of the sakes analyzed. The most abundant D-Ala, D-Asp, and D-Glu ranged from 66.9 to 524.3 MUM corresponding to relative 34.4, 12.0, and 14.6% D enantiomer. The basic parameters that generally determine the taste of sake such as the sake meter value (SMV; "Nihonshudo"), acidity ("Sando"), amino acid value ("Aminosando"), alcohol content by volume, and rice species of raw material show no significant relationship to the D-amino acid content of sake. The brewing water ("Shikomimizu") and brewing process had effects on the D-amino acid content of the sakes: the D-amino acid contents of the sakes brewed with deep-sea water "Kaiyoushinosousui", "Kimoto yeast starter", "Yamahaimoto", and the long aging process "Choukijukusei" are high compared with those of other sakes analyzed. Additionally, the D-amino acid content of sakes that were brewed with the adenine auxotroph of sake yeast ("Sekishoku seishu kobo", Saccharomyces cerevisiae) without pasteurization ("Hiire") increased after storage at 25 degrees C for three months. PMID- 21555256 TI - Weight and earnings among childbearing women in Metropolitan Cebu, Philippines (1983-2002). AB - We estimated the relationship between weight status and earnings among women participating in the Cebu Longitudinal Health and Nutrition Surveys between 1983 and 2002 conducted in Cebu, Philippines. Women working for pay were selected for the analysis. We used fixed effects estimation to account for unobserved time invariant characteristics related to weight. After correcting for potential bias due to unobserved heterogeneity, our results suggest that the earnings of obese or overweight women in Cebu (Philippines) were not less than women of normal weight. The relation between earnings and weight exists only among self-employed women or women working in more than one type of activity. No discrimination was found among women working for wages or per piece rate. In contrast, among self employed and women working in more than one type of activity we found that underweight women earn less than do those with normal weight. PMID- 21555257 TI - [High prevalence of hypovitaminosis D in medical students in Gran Canaria, Canary Islands (Spain)]. AB - BACKGROUND: Vitamin D deficiency has been described in many diseases and indeed in the general population. However fewer reports have been published in young and healthy people. Vitamin D deficiency should not be found in medical students of the Canary Islands, because they have all the resources to avoid it. OBJECTIVE: To estimate the prevalence of vitamin D deficiency in a population of medical students of both gender from the University of Las Palmas de Gran Canaria. METHODS: 103 medical students of both genders from the University of Las Palmas de Gran Canaria. They completed a questionnaire and a physical examination. Vitamin D (25- hydroxycholecalciferol [25-HCC]), parathyroid hormone, biochemical markers of bone remodeling and a general biochemical study were performed. Bone mineral density was assessed by dual energy X-ray absorptiometry at the lumbar spine and the proximal femur. Quantitative ultrasounds parameters were measured at the calcaneus. RESULTS: Only 38.8% of the students of Medicine (42.1% of males and 44.9% of females) have 25-HCC values higher than 30 ng/dl as widely recommended nowadays. Vitamin D deficiency (< 20 ng/ml) is observed in 32.6% and vitamin D insufficiency (< 30 ng/ml) in 28.6% of the students of Medicine in Las Palmas de Gran Canaria. CONCLUSION: Although they have optimal conditions for having good levels of vitamin D, near two thirds of the medical students in the Canaries have low values of vitamin D. PMID- 21555258 TI - Invited commentary. PMID- 21555259 TI - Mitochondrial DNA control region variation in a Kuwaiti population sample. AB - Mitochondrial control region (16024-576) sequences were generated from 381 Kuwaiti samples. Previously, these samples were typed with the AmpFlSTR((r)) Identifiler((r)) kit (Applied Biosystems, Foster City, California). Automated high throughput lab processing combined with a redundant sequencing strategy and multiple reviews of the raw electropherograms ensure the high quality of these sequences and their utility as reference population data for Kuwait. PMID- 21555260 TI - ECTS/IBMS 2011 Scientific Programme. PMID- 21555261 TI - Clinical utility of image-guided chest wall mass biopsy: results in 28 patients. AB - The purpose of our study was to determine the clinical usefulness of percutaneous image-guided biopsy of chest wall masses. A retrospective study of 28 patients who underwent image-guided biopsy of chest wall masses from 2005 to 2007 was performed. In 19 (68%) patients, the mass was detected as part of a staging evaluation in patients with known malignancy; 9 (32%) patients had no known malignancy. Biopsy results were classified as diagnostic (malignant or benign) or non-diagnostic (atypical and insufficient). Sensitivity, specificity and negative predictive value were calculated for all patients, and the Fisher-Freeman-Halton exact test was used to determine if test characteristics varied in patients with and without a history of cancer, masses smaller and greater than 5 cm, or according to needle size. The overall diagnostic rate was 71%. Of these, there were 20 true-positives, 3 true-negatives, 5 false-negatives and no false-positive results (sensitivity 80% (20/25), specificity 100% (3/3) and negative predictive value 37.5% (3/8)). There were no differences between patients with and without cancer. Among 19 patients with known cancer, 10 had metastatic disease from their known primary. Biopsy test characteristics did not differ with respect to mass or needle size. Minor complications were seen in 7% of patients. Image-guided chest wall mass biopsy is a sensitive and specific procedure, which is clinically important in the care of patients both with and without a known primary cancer. PMID- 21555262 TI - The adnexal incidentaloma: a practical approach to management. AB - There has been explosive growth in the utilization of cross-sectional imaging studies in the evaluation of patients with known or suspected abdominal and pelvic pathology. These imaging studies have led to a veritable epidemic of incidentally detected adnexal masses in both oncology and non-oncology patient populations that in the past remained undiscovered. In this commentary we provide some guidance and practical advice for further investigation and management of the adnexal incidentaloma. PMID- 21555263 TI - A comparative study on the histological structure of the spleen in the ostrich (Struthio camelus), the kestrel (Falco tinnunculus) and the osprey (Pandion haliaetus). AB - The spleen structurally and functionally belongs to the hematopoietic organs and is also an important component of the reticuloendothelial system, which is known to play a major role in host defense. The histological structure of the spleen was investigated in the ostrich, a non-flying bird, the kestrel, a raptor, and the osprey, a fish-eating bird of prey (fish eagle). For this purpose, Mallory's modified triple stain, methyl green-pyronin and silver stain were used. Germinal centers were not present in the spleen of the osprey. In the spleen of the kestrel, penicillar arterioles and the surrounding lymphoid tissue were markedly dense. Compared to the other two birds, the red and white pulps were clearly distinguishable in the spleen of the ostrich. PMID- 21555264 TI - Energy production and redox status of rat red blood cells after reticulocytosis induced by various treatments. AB - Stimulated erythropoiesis and reticulocytosis can be induced by daily bleeding, or by phenylhydrazine (PHZ) treatment. We compared the in vivo effects of PHZ and bleeding treatment on haematological, energy and redox status parameters in red blood cells (RBC) of rats. The results showed that all followed haematological parameters were significantly lower in bleeding, compared to PHZ-treated rats. PHZ induced even 2.58-fold higher reticulocytosis as compared to bleeding treatment. Although PHZ induced higher reticulocytosis, respiration intensity and energy production was lower than in bleeding-induced reticulocytes. These alterations were the consequence of increased superoxide anion and peroxynitrite concentrations in PHZ-treated rats. Bleeding treatment resulted in increased activity of an antioxidative enzyme, superoxide dismutase. In conclusion, differences in these two experimental models for reticulocytosis may be used as tools for appropriate pharmacological testing of redox-active substances considering energy and redox processes, as well as apoptosis pathways. PMID- 21555265 TI - Changes in the amount of reduced glutathione and activity of antioxidant enzymes in chosen mouse organs influenced by zymosan and melatonin administration. AB - Reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHPx) are vital components of the antioxidative barrier in animal cells. It is suggested more often now that the effectiveness of the protection of cells against the oxidative stress caused by the inflammation process depends on the amount of GSH and the activity of SOD, CAT and GSHPx. That is why the effect of zymosan A (40 mg/kg body mass) and the combined treatment with zymosan A (at the same dose) and melatonin (50 mg/kg body mass) on the amount of GSH in the blood and the amount of GSH and activity of SOD, CAT and GSHPx in the brain, liver and kidneys of male mice was estimated. Animals (n = 108) were decapitated after 3, 6 and 24 hours since the moment of the administration of only zymosan A, and combined zymosan A and after one hour melatonin. After the injection of zymosan A it was found that the amount of GSH is significantly lower after 3 and 6 hours in the blood and studied organs. The administration of zymosan A, followed by the administration of melatonin limited the decrease in the amount of this tripeptide in the same time. Simultaneously, the decrease in the amount of GSH in the studied organs was accompanied by a similar decrease in the activity of SOD, CAT and GSHPx after the injection of only zymosan A and a limited decrease in the activity after the administration of both zymosan A and melatonin. It is suggested that a decreased content of GSH and a decrease in the activity of the studied antioxidative enzymes is caused by the oxidative stress accompanying the inflammation process. PMID- 21555266 TI - Inhibition of Smad signaling is implicated in cleft palate induced by all-trans retinoic acid. AB - The effect of all-trans retinoic acid (atRA) on palatal fusion and the underlying mechanisms were investigated using organ culture. Compared with control group, the atRA-treated group (1 MUM and 5 MUM) had more medial edge epithelium (ME) remaining within the midline epithelial seam (MES). At 10 MUM atRA, the opposing shelves were not in contact at the culture end (72 h). Cell death detection by TUNEL and laminin immunohistochemistry demonstrated that atRA (5 MUM) induced apoptosis in mesenchyme and inhibited degradation of basal lamina within MES. Notably, migration and apoptosis of ME cells and degradation of basal lamina within MES markedly represented vehicle control palatal shelves in culture. Additionally, apoptosis was not detected in mesenchyme of control palatal shelves. Immunoblotting analysis revealed that Smad2 and Smad3 were endogenously activated and expression of Smad7 was inhibited during the fusion process. In contrast, atRA treatment abrogated phosphorylation of Smad2 and Smad3 and inducible expression of Smad7 in ME. From these data, it is assumed that inhibition of Smad pathway by atRA in ME may play a critical role in abrogation of the ME cell apoptosis and degradation of the basal laminin, which might contribute to failure of palatal fusion. PMID- 21555267 TI - Enzymatic synthesis of capsaicin 4-O-beta-xylooligosaccharides by beta-xylosidase from Aspergillus sp. AB - Capsaicin 4-O-beta-xylooligosaccharides were synthesized by a biocatalytic xylosylation using Aspergillus sp. beta-xylosidase. Capsaicin was converted into three new capsaicin glycosides, i.e. capsaicin 4-O-beta-xyloside, capsaicin 4-O beta-xylobioside, and capsaicin 4-O-beta-xylotrioside in 15, 12 and 10% yield, respectively. All products were isolated from the reaction mixtures by preparative HPLC. The structures of the products were determined by NMR spectroscopic method. PMID- 21555268 TI - Determination of stress responses induced by aluminum in maize (Zea mays). AB - To assess the alternative responses to aluminum toxicity, maize (Zea mays L. cv Karadeniz yildizi) roots were exposed to different concentrations of AlCl3 (150, 300 and 450 MUM). Aluminum reduced the root elongation by 39.6% in 150 MUM, 44.1% in 300 MUM, 50.1% in 450 MUM AlCl3 after 96 h period. To correlate the root elongation with the alternative stress responses including aluminum accumulation, lipid peroxidation, mitotic abnormalities, reduction of starch content, intracellular Ca2+ accumulation, callose formation, lignin deposition and peroxidase activity, cytochemical and biochemical tests were performed. The results indicated that aluminum accumulation and lipid peroxidation were observed more densely on the root cap and the outer cortex cells. In addition to morphological deformations, cytochemical analysis displayed cellular deformations. Furthermore, mitotic abnormalities were observed such as c-mitosis, micronuclei, bi- and trinucleated cells in aluminum treated root tips. Aluminum treatment induced starch reduction, callose formation, lignin accumulation and intracellular Ca2+ increase. Moreover, the peroxidase activity increased significantly by 3, 4.4 and 7.7 times higher than in that of control after 96 h, respectively. In conclusion, aluminum is significantly stressful in maize culminating in morphological and cellular alterations. PMID- 21555269 TI - Non-TIR-NBS-LRR resistance gene analogs in apricot (Prunus armeniaca L.). AB - Genes encoding for proteins with nucleotide-binding site and leucine-rich repeat motifs (NBS-LRR) have been suggested to play a general role in plant defence mechanism. In Prunus species, many TIR (Toll / Interleukin-1 Receptor), and only very few non-TIR sequences were identified, which was explained either by the unequal distribution of TIR/non-TIR sequences in the Prunus genome or by the incapability of primers in the amplification of non-TIR RGAs. The objective of this work was to check whether a new semi-nested PCR strategy can be developed for the targeted isolation of non-TIR-NBS-LRR Resistance Gene Analog (RGA) sequences from apricot. Three primers (CUB-P-loop F, CUB-Kin2 F and CUB-HD R) were designed, from which CUB-Kin2 F and CUB-HD R were constructed to anneal selectively to the non-TIR sequences. A colony Polymerase Chain Reaction (PCR) indicated that out of the 96 clones tested 28 showed amplification using the newly developed primers, while no amplification occurred when using the formerly described primers. Half of the 28 positive clones were sequenced and they turned out to represent 11 different non-TIR RGA sequences. A phylogenetic analysis was carried out based on an alignment containing 293 Rosaceae and 21 non-Rosaceaa sequences. A significantly higher ratio (91%) of non-TIR sequences were arranged in multi-genera clades than that of (57%) the TIR groups confirming that non-TIR sequences might be of more ancient origin than TIR sequences. PMID- 21555270 TI - Physiological and anatomical adaptations induced by flooding in Cotula coronopifolia. AB - Cotula coronopifolia is a wild annual Asteraceae that grows in periodically flooded prone environments and seems highly tolerant to periodic flooding. Seedlings of about 15 cm were collected directly from the edge of Soliman sabkha (N-E Tunisia, semi-arid stage) and grown under greenhouse conditions. Two treatments were considered: drainage and flooding. After 56 days of treatment, flooded plants showed a pronounced growth increase. This performance was essentially associated with significant increment in biomass production of both shoots and roots (about 220% of the control). The appropriate response to flooding was also characterized by the ability of the species to maintain its water status under such conditions. Neither water content nor water potential showed a significant variation as compared to those of non-flooded plants. However, transpiration rate decreased slightly but significantly in flooded plants (from 0.86 to 0.64 mmol H2O m-2 s-1). Na+ and K+ concentrations were practically maintained under waterlogging conditions, except a significant increase of Na+ content in roots of flooded plants (157% of the control). These responses were concomitant with maintenance of photosynthetic rate. However, the contents of chlorophylls a and b increased to 167% and 295%, respectively. It seems that the enhancement in these photosynthetic pigments together with a significant improvement in water use efficiency (from 4.66 to 6.07 mmol CO2 mol-1 H2O) allowed to the species to compensate the decrease in photosynthetic rate. At the anatomical level, this species responded to flooding by a significant development of its root aerenchyma (+63%) and an increase in the lignification of its stem xylem tissues (+37%). Based on the presented data, the plant fitness under flooding conditions was a result of dynamic readjustment of several morphological, physiological, and anatomical adaptive traits. Flood requirement together with salt tolerance are responsible for the predominance of C. coronopifolia in a large area in its natural biotope where most plants cannot tolerate interactive effects of flooding and salinity. PMID- 21555271 TI - Antiviral effect of edaphic cyanophytes on rabies and herpes-1 viruses. AB - Five cyanophyte species (Amorphonostoc punctiforme, Gloeocapsa turgidus, Sphaeronostoc coeruleum, Stratonostoc linckia f. spongiaeforme and Synechococcus cedrorum) were isolated and identified from sandy Egyptian soils. Polysaccharides extracted from these species showed a pronounced antiviral activity against Rabies and Herpes-1 viruses represented by the absence of the characteristic cytopathic effects of these viruses. It was found that 100 MUg polysaccharide/ml induced 100% inhibition of the two viruses which, depending on the polysaccharide concentration. Both of Gloeocapsa turgidus and Synechococcus cedrorum showed higher antiviral activity against rabies virus than that against herpes-1 virus. Amorphonostoc punctiforme showed nil to weak antiviral activity against both viruses. It was suggested that polysaccharides of such species of cyanophyte react against human and animal viruses. So, it could be concluded that there is a need for further studies to explain the mode of action of these substances on the replication of different viral origins to know how one deals with cyanophyte polysaccharides as antiviral substances in the most suitable and effective manner. PMID- 21555272 TI - Characterization of stress processes of Phaffia rhodozyma stress-resistant mutant. AB - A carotenoid-less Phaffia rhodozyma mutant (MCP 325) exhibited significantly higher resistance to oxidative stressors such as menadione, H2O2 and K2Cr2O7 than its astaxanthin-producing parental strain (MCP 324). The absence of carotenoids in the mutant did not explain this phenomenon. The cause of the decreased superoxide, hydroxyl radical and glutathione contents, the increased peroxide concentration and the elevated specific activity of catalase under uninduced conditions may be a second mutation. Peroxide treatment induced specific catalase activity in the mutant but not in the parental strain. Regulation of these processes led to the result that, in spite of the mutations, the two strains exhibited the same multiplication rate and generation time. PMID- 21555273 TI - The effect of variations in sodium conductances on pacemaking in a dopaminergic retinal neuron model. AB - Dopaminergic neurons in the retina show spontaneous tetrodotoxin-sensitive pacemaking, which has been explained by a reduced Hodgkin-Huxley-type computer model. The present study used this model to investigate the effect of variations in transient and persistent sodium conductance values on pacemaking, under variable leakage conductance levels. This study indicated that transient sodium conductance plays an indispensable role in pacemaking, which occurs under conditions in which only a persistent sodium conductance is considerably reduced, thus contributing to a detailed understanding of the relationship between sodium conductance and pacemaking. PMID- 21555274 TI - Effect of photoperiod on growth and feed conversion of juvenile wild carp, Cyprinus carpio. AB - Because of the effect of photoperiod on physiological and biochemical processes in fish, this study aimed to evaluate the effect of manipulated photoperiod on growth, feed conversion and survival of wild carp, Cyprinus carpio. Fish received six photoperiod regimes (light:dark cycle) including: natural photoperiod (control), 24L:0D, 16L:8D, 12L:12D, 8L:16D and 0L:24D by the three replications. Regulated photoperiods as a 16L:8D or 12L:12D light/dark cycle significantly improved growth rate and food conversion ratio of wild carp. PMID- 21555275 TI - Manfred Anke (1931-2010). PMID- 21555277 TI - Analyzing the costs to deliver medication therapy management services. AB - OBJECTIVES: To provide pharmacy managers and consultant pharmacists with a step by-step approach for analyzing of the costs of delivering medication therapy management (MTM) services and to describe use of a free online software application for determining costs of delivering MTM. PRACTICE DESCRIPTION: The process described is applicable to community pharmacies and consultant pharmacists who provide MTM services from nonpharmacy settings. PRACTICE INNOVATION: The PharmAccount Service Cost Calculator is an Internet- based software application that uses a guided online interview to collect information needed to conduct a comprehensive cost analysis of any specialized pharmacy service. In addition to direct variable and fixed costs, the software automatically allocates indirect and overhead costs to the service and generates an itemized report that details the components of service delivery costs. RESULTS: The service cost calculator is sufficiently flexible to support the analysis of virtually any specialized pharmacy service, irrespective of whether the service is being delivered from a physical pharmacy. The software application allows users to perform sensitivity analysis to quickly determine the potential impact that alternate scenarios would have on service delivery cost. It is therefore particularly well suited to assist in the design and planning of a new pharmacy service. CONCLUSION: Good management requires that the cost implications of service delivery decisions are known and considered. Analyzing the cost of an MTM service is an important step in developing a sustainable business model. PMID- 21555278 TI - Pharmacists' guide to infant formulas for term infants. AB - OBJECTIVE: To provide pharmacists with the basic knowledge to counsel caregivers in appropriate infant formula selection and use. SUMMARY: Although the majority of infants are initially breast-fed, a transition to infant formula by the age of 6 months, either as a supplement or a replacement for human milk, is common in the United States. Manufacturers have capitalized on this growing demand for infant formulas to more closely mimic human milk by creating a variety of formulations. The mainstay of the formula market is iron-fortified cow's milk, which may have a distinct variation in carbohydrate, protein, and fat sources, depending on the manufacturer. Formulations are also available to match specific needs of the infant or family, including added rice for reflux, partially or extensively hydrolyzed for allergen sensitivity, or soy based for a vegan diet preference. CONCLUSION: With an extensive array of infant formulas available, pharmacists and caregivers can be overwhelmed when selecting an appropriate product. However, with careful questioning and a basic knowledge of the available formulas, an initial selection can be provided to caregivers. In addition to assisting in infant formula selection, pharmacists should provide information on proper preparation, handling, and storage of the product. PMID- 21555279 TI - Patient-centered medical homes: primer for pharmacists. AB - OBJECTIVE: To provide a patient-centered medical home (PCMH) primer for pharmacists, including basic background information, key terminology, and examples of success stories. DATA SOURCES: PCMH literature and resources obtained through search strategies by authors including but not limited to PubMed and Google Scholar. SUMMARY: PCMHs are a potential means of achieving cost reduction in health care and providing collaborative and comprehensive care, and they represent a promising option for achieving health care reform. Medication therapy management and collaborative drug therapy management are possible means for pharmacists to fulfill the goals of PCMHs. CONCLUSION: Pharmacists must become knowledgeable of standards of PCMH and their abilities to fulfill these standards. Advocacy at local, state, and national levels is needed to achieve recognition of the value of pharmacists in PCMHs. PMID- 21555280 TI - ISMP Medication Errrors Reporting Program. PMID- 21555281 TI - Pharmacy technician education, training, and certification: call for a single national standard and public accountability. PMID- 21555282 TI - Oh, the places they can go: response to APhA-ASHP report on concerns about accelerating expansion of pharmacy education. PMID- 21555283 TI - FDA joint collaborations: enhancing patient access to health information and the pharmacist's role. PMID- 21555284 TI - Developing collaborative relationships between pharmacists and other health professionals. PMID- 21555285 TI - APhA 2011 REMS white paper: Summary of the REMS stakeholder meeting on improving program design and implementation. AB - OBJECTIVE: To develop an improved risk evaluation and mitigation strategies (REMS) system for maximizing effective and safe patient medication use while minimizing burden on the health care delivery system. DATA SOURCES: 34 stakeholders gathered October 6-7, 2010, in Arlington, VA, for the REMS Stakeholder Meeting, convened by the American Pharmacists Association (APhA). Participants included national health care provider associations, including representatives for physicians, physician assistants, nurses, nurse practitioners, and pharmacists, as well as representatives for patient advocates, drug distributors, community pharmacists (chain and independent), drug manufacturer associations (brand, generic, and biologic organizations), and health information technology, standards, and safety organizations. Staff from the Food and Drug Administration (FDA) Center for Drug Evaluation and Research participated as observers. The meeting built on themes from the APhA's 2009 REMS white paper. SUMMARY: The current REMS environment presents many challenges for health care providers due to the growing number of REMS programs and the lack of standardization or similarities among various REMS programs. A standardized REMS process that focuses on maximizing patient safety and minimizing impacts on patient access and provider implementation could offset these challenges. A new process that includes effective provider interventions and standardized tools and systems for implementing REMS programs may improve patient care and overcome some of the communication issues providers and patients currently face. Metrics could be put in place to evaluate the effectiveness of REMS elements. By incorporating REMS program components into existing technologies and data infrastructures, achieving REMS implementation that is workflow neutral and minimizes administrative burden may be possible. An appropriate compensation model could ensure providers have adequate resources for patient care and REMS implementation. Overall, stakeholders should continue to work collaboratively with FDA and manufacturers to improve REMS program design and implementation issues. CONCLUSION: A workable REMS system will require effective patient interventions, standardized elements that limit barriers to implementation for both patients and providers, standardized yet flexible implementation strategies, use of existing technologies in practice settings, increased opportunities for provider input early in REMS design processes, improved communication strategies and awareness of program requirements, and viable provider compensation models needed to offset costs to implement and comply with REMS program requirements. PMID- 21555286 TI - Evaluation of alternative methods for radiochemical purity testing of indium-111 capromab pendetide. AB - OBJECTIVE: To evaluate alternative methods for radiochemical purity testing of indium (In)-111 capromab pendetide after the discontinuation of instant thin layer chromatography silica gel (ITLC-SG) strips. DESIGN: Descriptive experimental study. SETTING: United States in 2009. PARTICIPANTS: Not applicable. INTERVENTION: Paper chromatography using Whatman 3MM strips, paper chromatography using Whatman 31ET strips, and mini-column chromatography using silica Sep-Pak cartridges were evaluated in the radiochemical purity testing of 13 consecutive vials of In-111 capromab pendetide prepared for clinical patient imaging procedures. These methods also were evaluated by testing seven aliquots of In-111 capromab pendetide that had been spiked with 5% to 15% In-111 pentetate (diethylene triamine pentaacetic acid). MAIN OUTCOME MEASURES: Correlation coefficients, radiochemical purity values for each method compared with ITLC-SG, and procedure times. RESULTS: Correlation coefficients of 0.988, 0.996, and 0.979 were found for ITLC-SG compared with Whatman 3MM, Whatman 31ET, and silica Sep Pak, respectively. Compared with ITLC-SG, mean (+/-SD) radiochemical purity values differed by -0.8 +/- 0.8 (range -2.5 to 0.4) for Whatman 3MM, -0.8 +/- 0.6 (-2.3 to 0) for Whatman 31ET, and -0.5 +/- 1.2 (-3.6 to 0.7) for silica Sep-Pak. The approximate time required to develop the chromatography strip or elute the mini-column was 3, 14, 5, and 6 minutes for ITLC-SG, Whatman 3MM, Whatman 31ET, and silica Sep-Pak, respectively. CONCLUSION: All three methods evaluated were acceptable alternatives to ITLC-SG for radiochemical purity testing of In-111 capromab pendetide. Based on its slightly higher correlation to ITLC-SG, slightly tighter SD and range, and slightly shorter development time, Whatman 31ET is preferred in our facility. PMID- 21555287 TI - Pharmacists' self-perception of their professional role: insights into community pharmacy culture. AB - OBJECTIVE: To obtain an understanding of how community pharmacists self-describe their professional role, in order to begin understanding some of the assumptions underlying pharmacy culture. DESIGN: Cross-sectional qualitative study. SETTING: Edmonton, Canada, and surrounding area. PARTICIPANTS: 115 community pharmacists. INTERVENTION: Brief telephone interview. MAIN OUTCOMES MEASURE: Pharmacists' self description/perception of their professional role and its relation to underlying assumptions of pharmacy culture. RESULTS: 100 pharmacists provided usable responses. The majority of pharmacists practiced in a community chain setting (76%) and within the city of Edmonton (81%). The median length of time in practice was 15 years. A total of 278 separate response items were obtained. Of these responses, 45% were categorized as product focused, 29% as patient centered, and 26% as ambiguous. The first response of 52 of the 100 pharmacists was a product-focused description of their role. Overall, in either their first or second response, 57% of the pharmacists used the term "dispensing" or dispensing-related terms to describe their professional role. CONCLUSION: The results of this study seem to suggest that community pharmacists who participated viewed themselves primarily as "dispensers of medication," not patient-centered practitioners. Sustainable pharmacy practice change will be possible only if the current culture aligns with change initiatives. Our findings may suggest that pharmacists' self-perception of what they do and, perhaps by extension, the culture of pharmacy itself, could be important barriers to implementing practice change initiatives. We need to better understand the culture of pharmacy to foster meaningful practice change. PMID- 21555288 TI - Community pharmacists' use of language-access services in the United States. AB - OBJECTIVE: To examine community pharmacists' use of language-access services (LASs) in the United States. DESIGN: Cross-sectional study. SETTING: United States from January to February 2009. PARTICIPANTS: 1,000 pharmacists (500 community chain and 500 community independent pharmacists). INTERVENTION: Mailed survey. MAIN OUTCOMES MEASURE: Use, availability, and characterization of written translation and verbal interpretation LASs, along with perceived barriers for LASs. RESULTS: 296 surveys were completed, yielding an adjusted response rate of 30.0%. Computer software was used more often for translation LASs (57.4%) compared with pharmacists using on-site personnel (38.4%). Almost one-half of all pharmacies (49.8%) that possessed LAS capacity failed to notify patients of their availability. Many respondents indicated that they never used translation (40.9%) or interpretation (39.8%) in their pharmacies. The most commonly cited barrier for use of LASs by community pharmacists was potential inaccuracies in translation/interpretation (52.1%). Lack of time (25.1%) was frequently cited for failing to use LASs. CONCLUSION: Community pharmacists are not consistently or optimally using LASs in daily practice. Failure to use LASs can result in poorer outcomes for patients with limited English proficiency. Developing means to navigate work station-related barriers to LASs may yield improved patient care. Incorporation of professional continuing educational programs, automated LAS kiosks, natural language processing, and social media solutions merit exploration in addressing these challenges. PMID- 21555289 TI - Pharmacist-initiated peripheral arterial disease screening program in a community pharmacy setting. AB - OBJECTIVES: To evaluate the feasibility of implementing a pharmacist-initiated peripheral arterial disease (PAD) screening program in the community setting and to determine the ability of this screening to increase the number of patients identified with PAD. DESIGN: Prospective study. SETTING: Three locations of a large pharmacy grocery chain in the Cincinnati and Dayton, OH, area, from February 3, 2009, to May 31, 2009. PATIENTS: 39 patients 50 years or older with a diagnosis of hypertension, dyslipidemia, and/or diabetes. INTERVENTION: PAD screening, including an assessment of PAD symptoms and an ankle-brachial index (ABI) calculation using a handheld Doppler. Patients who screened positive were provided with appropriate counseling on possible treatments, medications, and lifestyle modifications and referred to their primary care physician for further evaluation. MAIN OUTCOME MEASURES: Successful implementation of program, number of patients referred to their physician for follow-up, and number of patients with ABI scores indicating PAD. RESULTS: 17 of the 39 patients screened (44%) were referred to their physician for follow-up because they had ABI scores indicating PAD, symptoms indicating PAD, or noncompressible vessels. Using ABI scores, PAD was detected in nine patients (23.1%). Pharmacists implemented the program successfully. CONCLUSION: This study successfully demonstrated the feasibility of implementing a pharmacist-initiated PAD screening program in the community setting. The implementation of this screening program included the acquisition of affordable equipment, training of pharmacists, and access to the appropriate patient population. This study also was effective in increasing the recognition of PAD in patients screened in the community setting. PMID- 21555290 TI - Conjoint analysis of patient preferences on Medicare medication therapy management. AB - OBJECTIVES: To identify attributes of medication therapy management (MTM) valued by Medicare beneficiaries and to determine patient preferences and willingness to pay for MTM attributes. DESIGN: Cross-sectional contingency valuation study. SETTING: Six senior centers in Memphis, TN, from September 2007 through August 2008. PARTICIPANTS: 355 Medicare beneficiaries. INTERVENTION: A discrete choice experiment was used, in which each study participant was asked to choose from two different hypothetical MTM services defined by seven attributes (service setting, provider type, number of drug therapy problems, provider experience in overall practice, provider experience in geriatrics, time spent, and cost of MTM service) and associated levels. MAIN OUTCOME MEASURES: Patient preferences for different attributes of MTM services and patients' estimated marginal willingness to pay for each attribute level. RESULTS: Study participants viewed cost (relative importance 32.2%) as the most important attribute of MTM, followed by service setting (24.2%), provider experience in overall practice (19.5%), and provider experience in geriatrics (16.6%). Community pharmacies (beta = 0.146, P = 0.007) were the most preferred environment for MTM services, followed by clinics, whereas telephone consultation was the least preferred environment (beta = 0.349, P < 0.001). Study participants were willing to spend as much as $31.76 (95% CI 19.84-45.27) to trade telephone MTM for clinic-based MTM. They also were willing to pay $13.31 more (3.60-23.65) for MTM service at a community pharmacy compared with clinic-based MTM. CONCLUSION: Health plans should consider developing community pharmacy-based MTM options, at least for Medicare beneficiaries without mobility limitations. PMID- 21555291 TI - Disparities in pharmacists' patient education for Hispanics using antidepressants. AB - OBJECTIVES: To assess pharmacists' provision of antidepressant information and to examine the effect of patient ethnicity and language skills on pharmacists' provision of information and patient education. DESIGN: Cross-sectional, randomized, between-subjects study. SETTING: Wisconsin, from September to November 2008. PARTICIPANTS: 540 community pharmacists. INTERVENTION: Participants were exposed to one of three vignettes describing a patient coming into the pharmacy for an initial dispensation of an antidepressant. Vignettes varied according to patient ethnicity (white or Hispanic) and language spoken (English or Spanish). MAIN OUTCOME MEASURES: Respondents' information and education messages given to patients about antidepressants and whether Hispanic patient ethnicity and English language ability reduced pharmacists' communication about antidepressants. RESULTS: A majority of participants would provide information regarding the medication's name (93.3%) and dosage schedule (92.8%). Many pharmacists also reported that they would tell the patient to take the medication on a daily basis (92.6%) and that it takes 2 to 4 weeks for the medication to have a noticeable effect (87.8%). Multivariate models showed that pharmacists would provide significantly less information (beta = -0.24 [95% CI 0.31 to -0.17]) and education messages (-0.17 [-0.24 to -0.09]) to Spanish speaking patients. CONCLUSION: These findings suggest that Spanish-speaking patients may face disparities in the level of care received from community pharmacists. Interventions should be available to enhance pharmacists' communication with Spanish-speaking patients in an effort to facilitate safe and effective medication use. PMID- 21555292 TI - Texas pharmacists' knowledge of reporting serious adverse drug events to the Food and Drug Administration. AB - OBJECTIVES: To assess Texas pharmacists' knowledge of adverse drug event (ADE) reporting to the Food and Drug Administration (FDA) and to determine demographic and practice characteristics associated with this knowledge. DESIGN: Cross sectional descriptive study. SETTING: Austin, TX, in June and July 2009. PARTICIPANTS: 377 pharmacists practicing in hospital and community settings. INTERVENTION: Survey instrument mailed to participants. MAIN OUTCOME MEASURES: Scores on an eight-item test were used to assess pharmacists' knowledge about ADE reporting to FDA. Pharmacists' demographic and practice characteristics, as well as past reporting, were also measured. RESULTS: 1,500 surveys were mailed and 377 usable responses were obtained (26.4% response rate). Most (67.9%) pharmacists had never reported ADEs to FDA. A majority of pharmacists (65.7%) reported having inadequate knowledge about ADE reporting. Pharmacists had low knowledge scores on ADE reporting, and the pass rate for all items ranged from 56.7% to 96.0%. Pharmacists' age (r = -0.106, P = 0.042) and years of experience (-0.134, P = 0.010) were negatively correlated with knowledge levels, whereas hours worked by pharmacists was positively correlated with knowledge levels (0.130, P = 0.012). Mean knowledge levels differed by practice setting, job title, and area/setting of primary place of employment (P < 0.001). CONCLUSION: Texas pharmacists have knowledge gaps concerning ADE reporting to FDA. Pharmacists need more education, awareness, and training on ADE reporting, especially regarding reportable ADEs, how to report, and what constitutes a good report. PMID- 21555293 TI - Patient interpretations of prescription order quantitative statements. AB - OBJECTIVES: To characterize the variability in patient understanding and interpretation of quantitative statements from prescription orders and to evaluate the influence of sociodemographic characteristics on how patients interpret quantitative statements. METHODS: Participants were recruited in both a clinic and pharmacy setting in Kentucky. Patients were given a survey that asked for general background information and two questions pertaining to their experience with topical products. Then, patients were read a scenario and asked to use a provided tube of cream and squeeze out what they considered a small amount. RESULTS: 100 eligible patients participated in the study, with the majority having previous counseling on the use of topical products. The mean (+/ SD) cream weight representing a small amount was 0.36 +/- 0.50 g. Regression analysis demonstrated a significant nonlinear relationship for two of the patient characteristics, age and body mass index (BMI), with the greatest effect in the middle of age and BMI distributions (at approximately age 50 years and BMI 30 kg/m2). No evidence indicated that gender, race, education, or previous experience with or education about topical products had any effect on cream weight perception. CONCLUSION: Patients demonstrated tremendous variability in the interpretation of a small amount of topical product cream. Further research should be conducted to determine whether policy changes are warranted to require more specific prescription order instructions in the outpatient setting. PMID- 21555294 TI - Accuracy of automated community pharmacy-based blood pressure devices. AB - OBJECTIVES: To estimate accuracy and reliability of pharmacy-based fixed-location automated blood pressure devices (ABPDs) and to test the hypothesis that an ABPD is less accurate with more variable results than a home blood pressure device (HBPD). METHODS: Randomized study comparing 99 ABPDs with an Omron Digital HBPD in Indiana pharmacies. Each site was visited by one of five study investigators. A questionnaire was used to collect information about ABPDs. To test the ABPD against the HBPD, investigators measured their own blood pressure with each device three times in random order. RESULTS: No significant differences were observed between HBPD and ABPD diastolic readings, whereas a statistically significant difference between HBPD and ABPD systolic readings was found. ABPD measurements are as reliable as HBPD measurements when comparing single measurements from each, but reliability differs with more than one reading. CONCLUSION: Compared with a valid HBPD, the ABPD produces inaccurate systolic blood pressure values but similar reliability. Regular blood pressure measurement by health professionals remains optimal for managing hypertensive individuals. PMID- 21555295 TI - Exploring stages of pharmacist-physician collaboration using the model of collaborative working relationship. AB - OBJECTIVE: To compare factors affecting pharmacist-physician collaboration across three groups of study participants with increasing collaboration using the model of collaborative working relationship (CWR). METHODS: A random sample of 750 Iowa pharmacists were surveyed. The measures for CWR constructs used 5- and 7-point scales. Descriptive statistics of exchange characteristics such as relationship initiation, trustworthiness, and role specification were calculated for each tertile group. A one-way analysis of variance (ANOVA) and post hoc ANOVAs were used to compare exchange characteristics across groups. In addition, for each tertile group, a linear regression was conducted in which collaborative care was regressed over relationship initiation, trustworthiness, role specification, professional interaction, practice setting, and physician specialty. RESULTS: The usable survey response rate was 33% (n = 239). Exchange characteristics increased from the first tertile group to the third tertile group. The regression model of CWR explained variation in collaborative care for each tertile group (range 23 76%). Trustworthiness and role specification were key factors affecting collaborative care. Role specification had a strong effect on collaborative care for the first tertile group. Internal medicine as a physician specialty was a significant predictor for collaborative care for the third tertile group. CONCLUSION: The impact of predictors on collaborative care differed across three groups according to the tertiles of collaborative care. These findings support a multistage model of CWR. In addition, future studies of CWR can add other predictors for collaborative care. PMID- 21555296 TI - Assessment tool for pharmacy drug-drug interaction software. AB - OBJECTIVES: To assess the performance of pharmacy clinical decision support (CDS) systems for drug-drug interaction (DDI) detection and to identify approaches for improving the ability to recognize important DDIs. PRACTICE DESCRIPTION: Pharmacists rely on CDS systems to assist in the identification of DDIs, and research suggests that these systems perform suboptimally. The software evaluation tool described here may be used in all pharmacy settings that use electronic decision support to detect potential DDIs, including large and small community chain pharmacies, community independent pharmacies, hospital pharmacies, and governmental facility pharmacies. PRACTICE INNOVATION: A tool is provided to determine the ability of pharmacy CDS systems to identify established DDIs. It can be adapted to evaluate potential DDIs that reflect local practice patterns and patient safety priorities. Beyond assessing software performance, going through the evaluation processes creates the opportunity to evaluate inadequacies in policies, procedures, workflow, and training of all pharmacy staff relating to pharmacy information systems and DDIs. CONCLUSION: The DDI evaluation tool can be used to assess pharmacy information systems' ability to recognize relevant DDIs. Suggestions for improvement include determining whether the software allows for customization, creating standard policies for handling specific interactions, and ensuring that drug knowledge database updates occur frequently. PMID- 21555297 TI - Pay-for-performance model of medication therapy management in pharmacy practice. AB - OBJECTIVE: To use an existing pharmacist-run medication therapy management (MTM)/lifestyle medicine program to propose a new model of reimbursement for pharmacists that is based on pay for performance (P4P) rather than product-based dispensing or fee for service. DATA SOURCES: Specific patient outcomes were collected during a 1-year period from an existing pharmacist-run MTM/lifestyle medicine program as the basis to propose this new model of reimbursement. DATA SYNTHESIS: The proposed model outlines a P4P model of reimbursement for pharmacists that includes both traditional MTM services and patient-centered lifestyle medicine programming. The model uses an all-or-none bundled approach for reimbursement in which the pharmacist is reimbursed at a higher rate if patients achieve all six proposed outcome criteria at 1 year. Pharmacists could earn as much a 43% more income with this model compared with traditional MTM services. This model is an incentive for payers because it is based on patient outcomes and preestablished return on investment models. CONCLUSION: Pharmacist should begin to explore ways they can participate in a high-performance health care system by moving to a P4P model of reimbursement rather than fee-for-service or product-based dispensing reimbursement models. P4P models of reimbursement could be beneficial to the patient, the payer, and the pharmacist. PMID- 21555298 TI - JAPhA centennial. APhA publications: the Bulletin and the Year Book. PMID- 21555299 TI - Vaccine update. Adult travel immunizations: update for pharmacists. PMID- 21555300 TI - New drugs. Azilsartan medoxomil, belimumab, and lurasidone hydrochloride. PMID- 21555301 TI - Science snippets. Medicare Part D out-of-pocket costs, net present value of a PhD, and health literacy and self-care. PMID- 21555302 TI - A case of lupus vulgaris with rare localization diagnosed 30 years after onset. AB - Cutaneous tuberculosis (tuberculosis cutis) is one of the extrapulmonary forms of tuberculosis, which may affect the skin only or co-exist with tuberculosis of other organs, particularly the lungs. We describe a case of lupus vulgaris in a 72-year-old male patient with a single lesion localized on his lower extremity, developing for 30 years before correct diagnosis and previously treated with topical steroids. Bacillus infection in other organs was not detected. Diagnosis of tuberculosis was made based on personal history, clinical picture, hypersensitivity to tuberculin, histopathology and polymerase chain reaction. A multidrug therapy with rifampicin, isoniazid and pyrazinamide resulted in regression of the lesion. The common lack of knowledge about the clinical picture of cutaneous tuberculosis causes its late diagnosis and treatment. PMID- 21555303 TI - The effect of combined tocolysis on in vitro uterine contractility in preterm labour. AB - PURPOSE: Animal models have confirmed high efficiency of combined tocolytic treatment in preterm labour. In humans, the recommended doses of tocolytic drugs prolong pregnancy in threatened preterm labour. The aim of the study was to evaluate the inhibitory effect of dual combinations of atosiban, nifedipine and celecoxib on human myometrial strips contractility on the in vitro model of preterm labour. MATERIAL/METHODS: Two groups of patients who delivered by cesarean section were involved in the study: 36 patients who delivered preterm between the 24(th) and 34(th) week of pregnancy and 40 patients who delivered at term. Myometrial samples were obtained from the lower uterine segment during cesarean sections. Contractile activity was recorded with digital software for each drug combination: atosiban/nifedipine; atosiban/celecoxib, nifedipine/celecoxib. Tocolytic efficiency of the drug combinations was assessed using IC(50) parameter - a molar drug concentration inhibiting 50% of contractility. RESULTS: The atosiban/nifedipine combination has shown additive tocolytic effect on myometrial strips contractility in preterm and term patients. The other combinations: atosiban/celecoxib and nifedipine/celecoxib presented only antagonistic effects in both studied groups. CONCLUSIONS: The effect of the combined therapy on human myometrial contractility presented in the study could be a base for further in vivo clinical trials. PMID- 21555304 TI - Immunohistochemical assessment of PRL-3 (PTP4A3) expression in tumor buds, invasion front, central region of tumor and metastases of colorectal cancer. AB - PURPOSE: The aim of the study was to evaluate immunohistochemical expression of PRL-3 protein tumor buds, invasion front, central region of tumor and metastases of colorectal cancer. MATERIAL/METHODS: The PRL-3 expression was analyzed in 103 colorectal carcinoma patients, using the immunohistochemical method with a monoclonal antibody 3B6 anti-PRL-3 (Attogen Biomedical Research, USA). RESULTS: Positive reaction for PRL-3 was observed in 36.9% of cases in the central region of tumor, in 64.3% in the invasion front, and in as many as 81.4% in buds (present in 70/103 cases), in 100% in metastases to local lymph nodes, in 100% in metastases to the liver and in 97.1% in metastases to the lungs. The findings indicate that cancer cells obtain this protein already in the early stages of metastasizing. PRL-3 is present not only in metastases to local lymph nodes but also to distant organs. It is likely that PRL-3 protein takes part in the initiation of metastasizing of cancer cells. Also the presence of lymph and blood vessel invasion was found only to correlate with increased percentage of patients with strong PRL-3 expression in tumor buds (p=0.046). CONCLUSION: Our results may suggests the participation of PRL-3 protein as a marker of the presence of colorectal cancer metastasis to the lymph nodes and distant metastases, which is independent of parameters such as gender and age of the patients, tumor location, histological type and grade of histological malignancy and stage of tumor. PMID- 21555305 TI - Changes in plasma level of heat shock protein 27 after acute coronary syndrome. AB - We assessed the association between serum heat shock protein 27 (Hsp 27)concentrations in patients with acute coronary syndrome (ACS) and compared them with healthy participants. Patients with ACS (n = 75) were recruited and their biochemical parameters were compared with 75 healthy participants. Heat shock protein 27 concentrations were measured from blood samples taken on admission and 12 hours after the onset of chest pain. In the patient group, Hsp 27 concentrations (31.62 [20.12-38.51] ng/mL) in the first blood samples were significantly (P < .001) higher than in control samples (20.12 [16.67-28.17] ng/mL). In patients, serum Hsp-27 levels on admission were significantly (P < .001) higher than for the samples collected 12 hours after the onset of chest pain (25.87 [15.52-31.62]); the latter did not differ significantly from samples of healthy controls. In conclusion, serum Hsp-27 concentrations are elevated in the early hours following ACS, but fall to levels near to those in healthy individuals after about 12 hours from the onset of chest pain. PMID- 21555306 TI - Soluble Fas and Fas ligand in pregnancy: influence of hypertension. AB - The pathophysiology of pregnancy-induced hypertension and preeclampsia may involve abnormalities in placentation and the Fas/Fas ligand system. Hypothesizing abnormal plasma Fas and Fas ligand in pregnancy-induced hypertension, we recruited 20 hypertensive pregnant women at mean week 15 and 29 at week 30: 18 were studied at both time points. Control groups were 20 normotensive pregnant women at week 20, 29 women at week 27, and 50 nonpregnant women. sFas and sFas ligand (sFasL) were measured by enzyme-linked immunosorbent assay (ELISA). The hypertensive women had lower sFasL at both stages of their pregnancy (P < .05). There were no differences in sFas. In 18 hypertensive pregnant women, sFasL fell from week 15 to week 29 (P < .03). We conclude that sFas and sFasL is unchanged in normal pregnancy. Hypertension in pregnancy is characterized by low sFasL, and levels fall from weeks 15 to 29. This may reflect differences in placentation in the differing physiological and pathological states. PMID- 21555307 TI - Some aspects of preventing coronary heart disease. AB - Coronary heart disease (CHD) is the leading cause of mortality in the industrialized world and that might also soon be the case in other parts of the world. There are several easily measured and potentially modifiable risk factors that account for a substantial proportion of the risk of CHD. The effect of risk factors interventions appears to be consistent in both genders, across different geographic regions, and by all ethnic groups, suggesting that approaches to prevention can be based on similar principles worldwide. Optimal target levels for serum cholesterol and blood pressure are not yet clear. Future risk CHD reduction will mainly be achieved by improved primary prevention. PMID- 21555308 TI - Relationship between white blood cell count and in-hospital outcomes in acute coronary syndrome patients from the Middle East. AB - We evaluated the relationship between admission white blood cell (WBC) count and in-hospital outcomes in acute coronary syndrome (ACS) patients from the Middle East. Data were analyzed from 7806 consecutive patients with ACS who were divided into 4 groups (G) according to their WBC count (* 10(9)/L; G1: < 6.00; G2: 6.00 9.99; G3: 10.00-11.99; G4: >= 12.00). After significant covariate adjustment, those in G4 were 68% more likely to have cardiogenic shock than those in G1 (95% confidence interval [CI]: 1.05-2.68; P = .030) and G2 (odds ratio [OR], 2.02; 95% CI: 1.51-2.71; P < .001). Those in G4 were 2.02 times (95% CI: 1.11-3.67; P = .021) and 65% (95% CI: 1.17-2.32; P = .004) more likely to die in hospital than those in G1 and G2, respectively. Admission WBC count is an independent risk factor for in-hospital cardiogenic shock and mortality, in Middle Eastern patients with ACS. Novel therapeutic agents targeting WBCs in patients with ACS may improve outcomes. PMID- 21555309 TI - High-sensitivity C-reactive protein is a predictor of in-hospital cardiac events in acute myocardial infarction independently of GRACE risk score. AB - High-sensitivity CRP (hsCRP) is being increasingly used as a marker for cardiac risk assessment and as a prognostic tool in acute coronary syndrome. We analyzed the relation between hsCRP values at admission and in-hospital outcomes in 98 consecutive patients with acute myocardial infarction (AMI) undergoing catheterization. Patients with cardiac events had more advanced Killip class, more proportion of depressed left ventricular ejection fraction (LVEF), higher Global Registry of Acute Coronary Events (GRACE) risk score, and higher hsCRP levels. High-sensitivity CRP and GRACE risk score showed a significant positive correlation (r = .320, P = .002). In multivariate analysis, hsCRP resulted as a predictor of worse in-hospital outcomes independently of GRACE risk score (OR 1.122, CI95%:1.005-1.252, P = .040). The hsCRP value showing the maximum likelihood ratio for predicting cardiac events was 1.45 mg/dL. High levels of hsCRP were also associated with development of contrast-induced nephropathy but not with bleeding events. PMID- 21555310 TI - Impact of diabetes and smoking epidemic in the Middle East on the presentation with acute coronary syndrome in very young patients. AB - We describe the baseline characteristics, management, and outcomes of acute coronary syndrome (ACS) in patients of age <= 40 in the Gulf region of the Middle East. We studied 8176 hospitalized patients (<= 40 years) with ACS. Ten percent (805) of the recruited patients were <= 40 years. The mean age was 37 years and 89% were males. The prevalence of smoking and diabetes in the young patients was high (58% and 21%, respectively). The most common ACS was ST elevation myocardial infarction. Younger patients were more aggressively treated with more frequent use of glycoprotein inhibitors, thrombolytics, and primary percutaneous coronary intervention. They had less in-hospital heart failure, left ventricular dysfunction, shock, stroke, and low rate of in-hospital mortality (1%). Measures to combat the rising prevalence of diabetes and smoking are needed. PMID- 21555311 TI - Prevalence of metabolic syndrome according to different definitions in a hypertensive population. AB - AIMS: The metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD) and diabetes mellitus (DM). Several definitions of MetS have been proposed. The aim of the present study was to estimate and compare the prevalence of MetS according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), American Heart Association-National Heart Lung and Blood Institute (AHA-NHLBI), International Diabetes Federation (IDF) and the more recent Joint Interim Statement (JIS) definitions in patients attending a hypertension clinic. METHODS: The records of patients referred to the hypertension clinic at the University Hospital (Heraklion, Crete) from January 2001 to June 2009 were screened retrospectively. A total 384 patients (146 men) were included in the study. RESULTS: The prevalence of MetS according to the IDF and JIS definitions was significantly higher compared with that of the NCEP ATP III in both genders (IDF: P = .009 and P = .002, JIS: P = .002 and P = 0.001 for men and women, respectively); this was the case for the AHA-NHLBI definition only among women (P = .03). All MetS components differed significantly (P from < .0001 to .02) between patients with and without MetS for all definitions. CONCLUSIONS: The prevalence of MetS varies considerably depending on the definition used in a hypertensive population in a Mediterranean country. These differences will influence risk assessment. PMID- 21555312 TI - Incremental value of arterial stiffness over traditional risk factors in predicting subclinical cardiovascular remodeling in patients with moderate chronic renal failure. AB - Cardiovascular remodeling in chronic kidney disease (CKD) is responsible for the high mortality found in this condition. A total of 89 consecutive outpatients with stage III CKD and 52 patients with stage II CKD with similar degree of traditional atherosclerotic risk factors underwent routine echocardiographic and carotid Doppler examination, evaluating vascular and cardiac remodeling (intima media thickness [IMT] and left ventricular mass index [LVMi]), and its relation with arterial stiffness, determined in the same examination, using an echo tracking technique. Also the absolute values of LVMi and IMT were statistically similar between the 2 groups, their determinants were completely different, only in stage III the markers of renal impairment and arterial stiffness being independent predictors of cardiac and vascular modifications. We concluded that macroanatomical measurements do not fully describe cardiovascular remodeling in this setting. Arterial stiffness echo-tracking derived could add valuable information, being an easy-to-perform parameter during a routine examination. PMID- 21555313 TI - General or local anesthesia for carotid endarterectomy--the "real-world" experience. AB - Perioperative complications from carotid endarterectomy (CEA) are the main drawbacks of the procedure. The aim of this study was to assess the complication rates in patients undergoing CEA under general anesthesia (GA) or regional anesthesia (local anesthesia [LA]) at our institution. Patients undergoing CEA at our regional vascular unit between 2000 and 2004 were included. Data were collated retrospectively from a prospective database. Follow-up was up to 62 months. In all, 383 endarterectomies were performed, 260 of which were under LA. Outcome measures included 30-day death (2.1%), stroke (1.8%), and combined stroke and death (2.8%). A 30-day incidence of stroke, death, and combined stroke and death was lower in the LA group. Incidence of myocardial infarction and transient ischemic attacks, and annual mortality were higher in the LA group. No significant difference was found between the 2 groups. In a unit where CEA is preferentially performed under LA, anesthesia technique failed to significantly influence outcome. PMID- 21555314 TI - The 1-year clinical impact of rotational aspiration atherectomy of infrainguinal lesions. AB - The present study was carried out to provide information about outcome of the Jetstream atherectomy device for treatment of infrainguinal arteries. From February 2006 to February 2007, 172 patients with Rutherford class 1 to 5 lower limb ischemia were enrolled at 9 study sites. The endpoints were evaluation of quality of life according to the walking impairment questionnaire (WIQ) besides technical parameters. In the total study cohort, the WIQ scale maintained improved up to 12-month follow-up. Furthermore, target lesion revascularization rate was 26% (42/162), ankle-brachial index (ABI) increased from 0.59 +/- 0.21 at baseline to 0.82 +/- 0.27 (P < 0.05), and mean Rutherford class dropped from 3.0 +/- 0.9 at baseline to 1.5 +/- 1.3 at 1 year (P < .05). The results of this prospective, multicenter, clinical study demonstrate that the Jetstream atherectomy device is a potential treatment alternative for the endovascular management to improve clinical outcome in patients with peripheral arterial occlusive disease. PMID- 21555315 TI - Osborn waves. PMID- 21555316 TI - Have You Been HIT? AB - This review is specifically designed to aid the vascular surgeon in the management of heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia is a rare complication of heparin administration, which poses significant morbidity and mortality. Its onset is usually 5 to 10 days after the heparin administration and should be suspected if platelet counts drop by at least 50%. Confirmation is given by the presence of HIT antibodies on an enzyme linked immunosorbent assay (ELISA) or in functional platelet activation assays. The major complication is thrombosis and surprisingly bleeding is rare. Heparin must be stopped immediately if there is a clinical suspicion of HIT and alternative anticoagulation must be started. Anticoagulation is required for at least 2 to 3 months to prevent recurrence of thrombosis. Oral anticoagulation with warfarin should not be initiated until the platelet count has been recovered and there should be an overlap of at least 5 days between starting warfarin and stopping the alternative anticoagulant. PMID- 21555317 TI - Understanding whole systems change in health care: the case of nurse practitioners in Canada. AB - Nurse practitioners (NPs) were introduced into the Canadian health system almost half a century ago. Despite early evidence of their effectiveness, it took decades to establish a substantial critical mass of NPs. Using the NP as a case study exemplar, we adopted a whole system change perspective to understand what else besides evidence was needed to ensure the success of desirable health systems innovations. We identified elements of whole systems change to analyze literature on the NP movement in terms of leverages, blockages, and system dynamics. Results suggest that evidence was only one of many factors shaping the uptake of NP services as part of larger, ongoing, adaptive whole systems change. The changes required to integrate the NP role within the health system reflect a socio-ecological perspective that may be used to understand sustainable health systems innovation and improvement. PMID- 21555319 TI - PREDIMED trial: Mediterranean diet may reduce the risk of type 2 diabetes. PMID- 21555320 TI - Oral misoprostol reduces the risk of postpartum haemorrhage in home births assisted by trained traditional birth attendants in Pakistan. PMID- 21555321 TI - Efficacy of implementation intentions intervention on prevention of smoking among adolescents. PMID- 21555322 TI - Taking aspirin daily for at least 4 years reduces long-term risk of cancer death. PMID- 21555324 TI - Fluid status monitoring with a wireless network to reduce cardiovascular-related hospitalizations and mortality in heart failure: rationale and design of the OptiLink HF Study (Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink). AB - AIMS: The Optimization of Heart Failure Management using OptiVol Fluid Status Monitoring and CareLink (OptiLink HF) study is designed to investigate whether OptiVol fluid status monitoring with an automatically generated wireless CareAlert notification via the CareLink Network can reduce all-cause death and cardiovascular hospitalizations in an HF population, compared with standard clinical assessment. Methods Patients with newly implanted or replacement cardioverter-defibrillator devices with or without cardiac resynchronization therapy, who have chronic HF in New York Heart Association class II or III and a left ventricular ejection fraction <=35% will be eligible to participate. Following device implantation, patients are randomized to either OptiVol fluid status monitoring through CareAlert notification or regular care (OptiLink 'on' vs. 'off'). The primary endpoint is a composite of all-cause death or cardiovascular hospitalization. It is estimated that 1000 patients will be required to demonstrate superiority of the intervention group to reduce the primary outcome by 30% with 80% power. CONCLUSION: The OptiLink HF study is designed to investigate whether early detection of congestion reduces mortality and cardiovascular hospitalization in patients with chronic HF. The study is expected to close recruitment in September 2012 and to report first results in May 2014. PMID- 21555325 TI - Impact of different descriptions of the Kellgren and Lawrence classification criteria on the diagnosis of knee osteoarthritis. AB - OBJECTIVES: Although the Kellgren and Lawrence (K&L) criteria for defining radiological osteoarthritis are widely used in epidemiological and clinical studies, the authors previously documented the existence of five different versions of these criteria. This study identifies the impact of the use of alternative versions of the K&L criteria and evaluates which description has the highest association with knee complaints. METHODS: Two readers scored most radiographs of the knees of participants of the Rotterdam Study with the original K&L description (90%). In addition, each alternative description was used in a random part (20%) of the radiographs. The authors calculated reproducibility of all descriptions, and compared sensitivity and specificity of the alternative descriptions for three cut-off points with the original description as reference standard (K&L>=1, K&L>=2 and K&L>=3). The authors calculated kappa statistics to compare agreement between the original and alternative descriptions, and evaluated the association with knee complaints. RESULTS: The dataset comprises radiographs of knees of 3071 people. For cut-off K&L>=1 all four alternatives classified more people as having osteoarthritis than the original description; kappa was low, and sensitivity and specificity were moderate to good. For cut offs K&L>=2 and K&L>=3 there was little difference in the number of cases and kappa, sensitivity and specificity were good to perfect. The original description and alternative 3 showed the strongest association with knee complaints. CONCLUSIONS: The different descriptions of the K&L criteria have impact on the classification of osteoarthritis in the lowest grade (K&L>=1). All descriptions have strengths and weaknesses. It depends on the purpose which is the best description. PMID- 21555327 TI - Reproducibility in research. AB - Progress in biomedical research depends in part on being able to build on the findings of other researchers - and thereby on being able to apply others' methods to your own research. However, most of us have struggled to understand how to repeat or adapt another researcher's study because of minimal or missing details in the Methods section of a published paper. In expensive and complex experiments involving animal models, clear descriptions of the methods are particularly important. In this and the accompanying Editorial in this issue, we discuss how crucial the Methods section is to the integrity and utility of a biomedical research paper, and encourage researchers working with animal models to follow the recently released ARRIVE guidelines when preparing their studies for publication. PMID- 21555328 TI - Improving the reporting of animal research: when will we ARRIVE? PMID- 21555329 TI - Translating science in more ways than one: an interview with Frances Balkwill. PMID- 21555330 TI - Behavioural phenotyping of knockout mice for the sigma-1 (sigma1) chaperone protein revealed gender-related anxiety, depressive-like and memory alterations. AB - The sigma-1 (sigma1) protein regulates calcium homeostasis and acts as an endoplasmic reticulum chaperone. It can be activated by ligands which impact memory, depression, anxiety or addiction processes. We here characterized the behavioural phenotype of knockout (KO) mice for the sigma1 protein. Two-month old male sigma1-/- mice showed signs of anxiety in the open-field, passive avoidance or elevated plus-maze test, but other activity or memory responses were unchanged. Female sigma1-/- mice showed deficits in spontaneous alternation or water-maze learning. Twelve-month old sigma1+/- female mice showed deficits in alternation and sigma1-/- mice in avoidance escape latency. Two- and 14-month old female sigma1-/- mice showed decreased plasma 17beta-estradiol levels. Treatment with 17beta-estradiol (0.1, 0.2 mg/kg i.p.) reversed the spatial memory deficits in young and aged mice. Male sigma1 KO mice showed enhanced response in the forced swimming test. Igmesine, a sigma1 agonist, failed to decrease immobility in sigma1 KO mice. Fluoxetine and sertraline were more efficient in sigma1 KO mice, an effect likely related to their sigma1 antagonist activity. Imipramine, desipramine and amitriptyline were equally active. sigma1 protein invalidation therefore affected stress or anxiety response but not memory in males. Changes in steroid tonus in female animals led, however, to memory impairments that increased with age. PMID- 21555331 TI - Preliminary evidence of anxiolytic effects of the CRF(1) receptor antagonist R317573 in the 7.5% CO(2) proof-of-concept experimental model of human anxiety. AB - We have validated the use of prolonged inhalation of 7.5% carbon dioxide (CO(2)) as a human model of anxiety and have shown that drugs from two prototypical classes of anxiolytics, benzodiazepines and a serotonin reuptake inhibitor, attenuate CO(2)-induced symptoms (Bailey et al., 2007a). Preclinical evidence suggests that drugs acting at the corticotropin-releasing factor (CRF) system may be useful for the treatment of depression, anxiety, and other stress-related disorders (Valdez, 2006), hence we have now examined the effects of a CRF(1) receptor antagonist in the 7.5% CO(2) model. In a randomized double-blind, placebo-controlled, study in 32 healthy participants we examined the effects of 7 days of treatment with the CRF(1) receptor antagonist, R317573, at a dose that shows a favourable safety profile and is comparable with those effective in preclinical models (40 mg). On day 8, eight of the placebo-treated group received lorazepam (LZP) 2 mg as a positive control. All participants underwent 20 min inhalation of 7.5% CO(2)-enriched air. Subjective reports of peak gas effects were assessed using visual analogue scales and questionnaires. The mean age of participants was 26 years, and 13 were male. The peak effects of CO(2) were expressed as a difference from baseline scores obtained while breathing air alone. Compared with placebo (PLAC), both drug groups showed a decrease in all subjective symptoms, total score on the panic symptom inventory (CRF 11 [2.6], PLAC 16.4 [3.1], LZP 2.9 [3.0]) and a generalized anxiety disorder symptom scale (CRF 2.2 [1.5], PLAC 8.2 [2.2], LZP 1.1 [1.5]). We have shown that a drug that acts to inhibit the CRF(1) receptor shows efficacy in the 7.5% CO(2) model of anxiety in healthy participants. PMID- 21555332 TI - Anxiolytic-like effect of oxytocin in the simulated public speaking test. AB - Oxytocin (OT) is known to be involved in anxiety, as well as cardiovascular and hormonal regulation. The objective of this study was to assess the acute effect of intranasally administered OT on subjective states, as well as cardiovascular and endocrine parameters, in healthy volunteers (n = 14) performing a simulated public speaking test. OT or placebo was administered intranasally 50 min before the test. Assessments were made across time during the experimental session: (1) baseline (-30 min); (2) pre-test (-15 min); (3) anticipation of the speech (50 min); (4) during the speech (1:03 h), post-test time 1 (1:26 h), and post-test time 2 (1:46 h). Subjective states were evaluated by self-assessment scales. Cortisol serum and plasma adrenocorticotropic hormone (ACTH) were measured. Additionally, heart rate, blood pressure, skin conductance, and the number of spontaneous fluctuations in skin conductance were measured. Compared with placebo, OT reduced the Visual Analogue Mood Scale (VAMS) anxiety index during the pre-test phase only, while increasing sedation at the pre-test, anticipation, and speech phases. OT also lowered the skin conductance level at the pre-test, anticipation, speech, and post-test 2 phases. Other parameters evaluated were not significantly affected by OT. The present results show that OT reduces anticipatory anxiety, but does not affect public speaking fear, suggesting that this hormone has anxiolytic properties. PMID- 21555333 TI - Effects of acute alcohol intoxication on automated processing: evidence from the double-step paradigm. AB - Reflexive and voluntary levels of processing have been studied extensively with respect to possible impairments due to alcohol intoxication. This study examined alcohol effects at the 'automated' level of processing essential to many complex visual processing tasks (e.g., reading, visual search) that involve ongoing modifications or reprogramming of well-practiced routines. Data from 30 participants (16 male) were collected in two counterbalanced sessions (alcohol vs. no-alcohol control; mean breath alcohol concentration = 68 mg/dL vs. 0 mg/dL). Eye movements were recorded during a double-step task where 75% of trials involved two target stimuli in rapid succession (inter-stimulus interval [ISI]=40, 70, or 100 ms) so that they could elicit two distinct saccades or eye movements (double steps). On 25% of trials a single target appeared. Results indicated that saccade latencies were longer under alcohol. In addition, the proportion of single-step responses and the mean saccade amplitude (length) of primary saccades decreased significantly with increasing ISI. The key novel finding, however, was that the reprogramming time needed to cancel the first saccade and adjust saccade amplitude was extended significantly by alcohol. The additional time made available by prolonged latencies due to alcohol was not utilized by the saccade programming system to decrease the number of two-step responses. These results represent the first demonstration of specific alcohol induced programming deficits at the automated level of oculomotor processing. PMID- 21555334 TI - Adiponectin and cardiovascular risk profile in patients with type 2 diabetes mellitus: parameters associated with adiponectin complex distribution. AB - AIMS: Plasma levels of the adipokine adiponectin are accepted as excellent correlates to metabolic health. Here, we aim to characterise associations between circulating plasma adiponectin complexes and baseline parameters in a population of patients with type 2 diabetes mellitus (DM) with increased risk of cardiovascular disease. METHODS: We measured levels of high molecular weight (HMW), low molecular weight (LMW) and trimeric adiponectin. RESULTS: The study population comprised 53 subjects, mean age 57 years, 36% non-white and 44% women, with an average body mass index (BMI) of 34 and duration of DM of 8.5 years. There was an established history of cardiovascular disease in 36% of the patients. BMI was inversely associated with the proportion of HMW adiponectin compared with LMW and trimeric adiponectin. Longer duration of DM correlated with an increased proportion of trimeric adiponectin. CONCLUSIONS: Patients with elevated BMI, longer history of diabetes and cardiovascular disease have lower levels of the higher order adiponectin complex. In addition, we have measured for the first time levels of trimeric adiponectin in a diabetic population using high resolution fast protein liquid chromatography (FPLC) analysis and identified trimeric adiponectin as a promising new biomarker for cardiovascular disease with a stronger correlative relationship to cardiovascular disease than HMW adiponectin. PMID- 21555335 TI - Reliability of immunolabelling in the determination of Huntington's disease neuropathy. PMID- 21555336 TI - Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography. AB - We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of abeta-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score>=18) underwent a conventional clinical evaluation followed by 11C dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical abeta-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer's disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer's disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer's disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ~35% of subjects (Cohen's kappa=0.39). Discordant classifications were least frequent in clinical consensus Alzheimer's disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia. PMID- 21555337 TI - The incorporation of lysine into the peroxidase peptide reactivity assay for skin sensitization assessments. AB - To establish further a practical quantitative in chemico reactivity assay for screening contact allergens, lysine peptide was incorporated into a liquid chromatography and tandem mass spectrometry-based assay for reactivity assessments of hapten and pre-/pro-hapten chemical sensitizers. Loss of peptide was determined following 24 h coincubation with test chemical using a concentration-response study design. A total of 70 chemicals were tested in discrete reactions with cysteine or lysine peptide, in the presence and absence of horseradish peroxidase-hydrogen peroxide oxidation system. An empirically derived prediction model for discriminating sensitizers from nonsensitizers resulted in an accuracy of 83% for 26 haptens, 19 pre-/pro-haptens, and 25 nonsensitizers. Four sensitizers were shown to selectively react with lysine including two strong/extreme and two weak sensitizers. In addition, seven sensitizers were identified as having higher reactivity toward lysine compared with cysteine. The majority of sensitizing chemicals (27/45) were reactive toward both cysteine and lysine peptides. An estimate of the relative reactivity potency was determined based on the concentration of test chemical that depletes peptide at or above a threshold positive value. Here, we report the use of EC15 as one example to illustrate the use of the model for screening the skin sensitization potential of novel chemicals. Results from this initial assessment highlight the utility of lysine for assessing a chemical's potential to elicit sensitization reactions or induce hypersensitivity. This approach has the potential to qualitatively and quantitatively evaluate an important mechanism in contact allergy for hazard and quantitative risk assessments without animal testing. PMID- 21555338 TI - Mechanism of pyrethroid pesticide-induced apoptosis: role of calpain and the ER stress pathway. AB - Exposure to the pyrethroid pesticide deltamethrin has been demonstrated to cause apoptosis both in vitro and in vivo. However, the molecular pathways leading to deltamethrin-induced apoptosis have not been established. To identify these pathways, SK-N-AS neuroblastoma cells were exposed to deltamethrin (100 nM-5 MUM) for 24-48 h. Deltamethrin produced a time- and dose-dependent increase (21-300%) in DNA fragmentation, an indicator of apoptosis. Data demonstrate that the initiation of DNA fragmentation resulted from interaction of deltamethrin with Na+ channels and consequent calcium influx, as tetrodotoxin and the intracellular Ca2+ chelator BAPTA-AM completely prevented apoptosis. DNA fragmentation was accompanied by increased caspase-9 and -3 activities and was abolished by specific caspase-9 and -3 inhibitors. However, deltamethrin did not increase cytosolic cytochrome c levels, indicating that the mitochondrial pathway was likely not involved. Additional studies demonstrated that deltamethrin exposure activated caspase-12 activity and that pharmacological inhibition and siRNA knockdown of calpain prevented deltamethrin-induced DNA fragmentation, thus indicating a role for the endoplasmic reticulum (ER) stress pathway. This was confirmed by the observation that inhibition of eIF2alpha abolished deltamethrin induced DNA fragmentation. Together, these data demonstrate that deltamethrin causes apoptosis through its interaction with Na+ channels, leading to calcium overload and activation of the ER stress pathway. Because ER stress and the subsequent unfolded protein response have been observed in a number of neurodegenerative diseases, these data provide mechanistic information by which high-level exposure to pyrethroids may contribute to neurodegeneration. PMID- 21555339 TI - Effectiveness of cognitive behavioural therapy in primary health care: a review. AB - BACKGROUND: Depression and anxiety are highly prevalent disorders causing substantial impairment in daily life. Cognitive behavioural therapy (CBT) delivered face-to-face or as self-help has shown to be an effective treatment for these disorders. Such treatments may be suitable for delivery in primary health care. AIM: The aim of the article was to review research on the effectiveness of CBT for depression and anxiety disorders delivered in primary care by primary care therapists. METHODS: A literature search of quantitative studies of the effectiveness of CBT delivered in primary care was conducted on multiple electronic databases. A total of 17 studies were included in the review. RESULTS: Eight studies of supported Internet- or computer-based CBT, six of which were randomized controlled trials (RCTs), indicate that this treatment is effective for mild to moderate depression and anxiety. Five studies suggest that this treatment may be more effective than usual care for mild to moderate but not for more severe symptoms. Results of four RCTs of brief therapies using written self help material suggest that while such interventions are effective, no particular approach outperformed any other, including usual care. Five RCTs of CBT delivered face-to-face show that this treatment can be effective when delivered by therapists highly educated in the mental health field. However, many primary care therapists may find such interventions too time consuming. CONCLUSIONS: CBT delivered in primary care, especially including computer- or Internet-based self help programs, is potentially more effective than usual care and could be delivered effectively by primary care therapists. PMID- 21555340 TI - Presentation, antibiotic management and associated outcome in Polish adults presenting with acute cough/LRTI. AB - OBJECTIVE: In-depth knowledge of existing practice is required to inform interventions aimed at antibiotic prescribing quality improvement. We set out to describe the presentation, antimicrobial management and associated outcome of adults presenting in general practice with acute cough/lower respiratory tract infection (LRTI) in Poland. METHODS: Observational study of 301 adults with acute cough/LRTI. Clinicians completed a case report form (CRF) describing presentation, history and management and patients completed a symptom diary for up to 28 days after consultation. RESULTS: Two hundred and twenty-one patients (with CRF and symptom diary completed) were analysed. The median duration of feeling unwell before presentation was 4 days. Clinicians recorded an average of eight symptoms for patients at presentation. Apart from cough, patients most commonly reported feeling generally unwell (91.9%), limitation of normal activities (80.5%), coryza (80.1%) and phlegm production (76.0%). Auscultation abnormalities were present in 55.0%. Overall, medicines were prescribed for 95.0%; 72.4% were prescribed antibiotics [mostly macrolides/lincosamides (38.8%) and amoxicillin/co-amoxiclav (36.3%)) with 11.3% advised to take antibiotics only if still necessary after a specified delay. Mucolytics were prescribed for 61.1%. Antibiotic prescription was strongly associated with a diagnosis of LRTI and the presence of auscultation abnormalities. The median duration of cough after presentation was 8 days. CONCLUSIONS: Antibiotics continue to be frequently prescribed for acute cough/LRTI in Poland, and the decision to prescribe was strongly associated with clinicians' findings of abnormalities on auscultation and diagnosis of LRTI. Delayed prescribing was infrequent. Mucolytics were commonly prescribed despite evidence of no effect. PMID- 21555341 TI - Patients' hopes and expectations of a specialist chronic fatigue syndrome/ME service: a qualitative study. AB - BACKGROUND: The 2007 National Institute for Health and Clinical Excellence guidelines on Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) recommend early management of the condition. Investment by the Department of Health has expanded the number of specialist U.K. CFS/ME services but there has been little research on what patients hope or expect from referral. METHODS: A qualitative study exploring hopes and expectations of patients newly referred to a CFS/ME Service in the South of England. Interviews with 20 patients were analysed using the constant comparative method. RESULTS: Participants hoped referral to a specialist service would clarify diagnosis, give guidance and support, assist in understanding the complexity of the illness and provide hope for the future. While many participants valued the support of their GP, all viewed referral as offering a level of specialist expertise beyond that available in primary care. Many participants expressed high levels of uncertainty about the nature of CFS/ME. While participants hoped that the service would be able to provide information and guidance, many expressed the view that more information earlier in their illness would make the waiting period less stressful and make it possible for them to do more to help themselves. CONCLUSIONS: GP referral to a specialist service appeared to be highly valued by the participants in this study. The levels of uncertainty expressed by many patients about the nature of CFS/ME raises the issue of the role of information on CFS/ME during the early stages of the illness and suggests a need for more reassurance and positive advice during the waiting period. PMID- 21555342 TI - Biochemical analysis of human POLG2 variants associated with mitochondrial disease. AB - Defects in mitochondrial DNA (mtDNA) maintenance comprise an expanding repertoire of polymorphic diseases caused, in part, by mutations in the genes encoding the p140 mtDNA polymerase (POLG), its p55 accessory subunit (POLG2) or the mtDNA helicase (C10orf2). In an exploration of nuclear genes for mtDNA maintenance linked to mitochondrial disease, eight heterozygous mutations (six novel) in POLG2 were identified in one control and eight patients with POLG-related mitochondrial disease that lacked POLG mutations. Of these eight mutations, we biochemically characterized seven variants [c.307G>A (G103S); c.457C>G (L153V); c.614C>G (P205R); c.1105A>G (R369G); c.1158T>G (D386E); c.1268C>A (S423Y); c.1423_1424delTT (L475DfsX2)] that were previously uncharacterized along with the wild-type protein and the G451E pathogenic variant. These seven mutations encode amino acid substitutions that map throughout the protein, including the p55 dimer interface and the C-terminal domain that interacts with the catalytic subunit. Recombinant proteins harboring these alterations were assessed for stimulation of processive DNA synthesis, binding to the p140 catalytic subunit, binding to dsDNA and self-dimerization. Whereas the G103S, L153V, D386E and S423Y proteins displayed wild-type behavior, the P205R and R369G p55 variants had reduced stimulation of processivity and decreased affinity for the catalytic subunit. Additionally, the L475DfsX2 variant, which possesses a C-terminal truncation, was unable to bind the p140 catalytic subunit, unable to bind dsDNA and formed aberrant oligomeric complexes. Our biochemical analysis helps explain the pathogenesis of POLG2 mutations in mitochondrial disease and emphasizes the need to quantitatively characterize the biochemical consequences of newly discovered mutations before classifying them as pathogenic. PMID- 21555343 TI - Subcellular effects of myocyte-specific androgen receptor overexpression in mice. AB - Although androgen receptor (AR) within myocytes is thought to mediate many of the effects of testosterone and other androgens on skeletal muscle, little is known about the functions of AR within these cells. We, therefore, studied the ultrastructure of skeletal muscle of HSA-AR transgenic (Tg) mice that overexpress AR selectively in myocytes and exhibit neuromuscular atrophy. We examined male HSA-AR mice from two different founding lines: L78 (lower copy number and less severe phenotype) and L141 (higher copy number and more severe phenotype) and compared these to wild-type (Wt) brothers. We also examined testosterone-treated female mice from these two lines and compared them both to their Wt sisters and to vehicle-treated controls. Ultrastructural examination of extensor digitorum longus sections using transmission electron microscopy revealed remarkably disorganized myofibrils in male Tg and testosterone-treated female Tg mice. Quantification of ultrastructural pathology indicated reduced myofibril width, hypertrophic and hyperplastic intermyofibrillar mitochondria, and pronounced glycogen accumulation in HSA-AR males of both lines. Reduced myofibrillar width and increases in mitochondrial number, size, and volume density were also observed in testosterone-treated HSA-AR females, although glycogen accumulation was not observed. Structural abnormalities in mitochondria were also associated with increases in electron transport chain activity and systemic resting metabolic rate, indicative of hypermetabolism. We find that overexpression of AR in myocytes of HSA-AR mice results in alterations in myofibrils, mitochondria, and glycogen. Alterations in myofibrils and mitochondria appear to result from acute actions of testosterone, whereas those on glycogen do not. Pathology of myofibrils and/or mitochondria may, therefore, mediate in part the neuromuscular atrophy observed in HSA-AR mice. PMID- 21555344 TI - Matrix metalloproteinases: keys to healthier blood vessels in diabetes? AB - In this issue of Journal of Endocrinology, Schuyler et al. show that intimal lesions in atherosclerosis-prone diabetic apoE(-/-) mice are reduced by insulin treatment. An increase of metalloproteinase-9 expression was observed in untreated diabetic apoE(-/-) mice; this was absent in insulin-treated mice. The study suggests that hindering of tissue-remodeling metalloproteinases may account for the beneficial effects of proper metabolic control in patients with diabetes. This clinically relevant finding prompts further exploration. PMID- 21555345 TI - eNOS activation and NO function: pregnancy adaptive programming of capacitative entry responses alters nitric oxide (NO) output in vascular endothelium--new insights into eNOS regulation through adaptive cell signaling. AB - In pregnancy, vascular nitric oxide (NO) production is increased in the systemic and more so in the uterine vasculature, thereby supporting maximal perfusion of the uterus. This high level of functionality is matched in the umbilical vein, and in corresponding disease states such as pre-eclampsia, reduced vascular responses are seen in both uterine artery and umbilical vein. In any endothelial cell, NO actually produced by endothelial NO synthase (eNOS) is determined by the maximum capacity of the cell (eNOS expression levels), eNOS phosphorylation state, and the intracellular [Ca(2+)](i) concentration in response to circulating hormones or physical forces. Herein, we discuss how pregnancy-specific reprogramming of NO output is determined as much by pregnancy adaptation of [Ca(2+)](i) signaling responses as it is by eNOS expression and phosphorylation. By examining the changes in [Ca(2+)](i) signaling responses from human hand vein endothelial cells, uterine artery endothelial cells, and human umbilical vein endothelial cells in (where appropriate) nonpregnant, normal pregnant, and pathological pregnant (pre-eclamptic) state, it is clear that pregnancy adaptation of NO output occurs at the level of sustained phase 'capacitative entry' [Ca(2+)](i) response, and the adapted response is lacking in pre-eclamptic pregnancies. Moreover, gap junction function is an essential permissive regulator of the capacitative response and impairment of NO output results from any inhibitor of gap junction function, or capacitative entry using TRPC channels. Identifying these [Ca(2+)](i) signaling mechanisms underlying normal pregnancy adaptation of NO output not only provides novel targets for future treatment of diseases of pregnancy but may also apply to other common forms of hypertension. PMID- 21555346 TI - Efficacy of contrast-enhanced US and magnetic microbubbles targeted to vascular cell adhesion molecule-1 for molecular imaging of atherosclerosis. AB - PURPOSE: To evaluate whether microbubbles targeted to vascular cell adhesion molecule-1 (VCAM-1) (CD106) coupled with a magnetic guidance system could improve the efficacy of contrast-enhanced molecular ultrasonography (US) of atherosclerosis in the aorta. MATERIALS AND METHODS: The animal research committee at Southern Medical University approved all experiments. Adherence of magnetic VCAM-1-targeted microbubbles, control inactive magnetic microbubbles, and nonmagnetic VCAM-1-targeted microbubbles to VCAM-1-Fc was determined in vitro by using a flow chamber at variable shear stress (1-24 dyne/cm(2)) under magnetic field guidance. Attachment of microbubbles under magnetic field guidance was determined in vivo with fluorescent microscopy and contrast-enhanced US of the abdominal aorta in wild-type (C57BL/6) or apolipoprotein E (APOE)-deficient mice on a regular or hypercholesterolemic diet. General factorial analysis of variance was used to compare the targeted effect of the microbubbles among different animal groups to identify significant differences. RESULTS: Attachment was noted for magnetic and nonmagnetic microbubbles but not for inactive magnetic microbubbles; firm attachment at high shear stress (16-20 dyne/cm(2)) was achieved only with magnetic microbubbles. Fluorescence intensity and video intensity were significantly higher in magnetic microbubbles with magnetic field guidance than in inactive magnetic microbubbles and nonmagnetic microbubbles (P < .05). Video intensity from retained magnetic microbubbles in APOE-deficient mice was significantly greater than that in wild-type mice (mean video intensity for APOE-deficient mice: 28.25 [interquartile range, or IQR, 26.55-29.20] with a hypercholesterolemic diet and 16.10 [IQR, 14.15-18.75] with a regular diet; mean video intensity for wild-type mice: 9.55 [IQR, 8.85-10.5] with a hypercholesterolemic diet and 2.90 [IQR, 1.25-3.85] with a regular diet; P < .001). CONCLUSION: Use of a magnetic targeted microbubble system results in greater attachment to endothelial VCAM-1 in atherosclerotic aortas in conditions of high shear stress and improved detection of early inflammatory changes of atherosclerosis. PMID- 21555347 TI - FDG PET/CT early dynamic blood flow and late standardized uptake value determination in hepatocellular carcinoma. AB - PURPOSE: To prospectively determine whether fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) early dynamic blood flow estimates could be used to discriminate hepatocellular carcinoma (HCC) from background liver and to characterize HCC in patients with and those without angioinvasion; and to evaluate the association between blood flow measures at FDG PET/CT with metabolism in HCCs. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this prospective study. Twenty-one consecutive patients (mean age, 65 years) with 30 established HCCs (mean size, 5.5 cm; seven lesions in five patients with angioinvasion) underwent a blood flow study with an FDG dynamic scan divided into 18 sequences of 5 seconds each and a standard PET/CT scan. On the dynamic study, three independent operators obtained volumes of interest (VOIs) for which three blood flow estimates were calculated (hepatic perfusion index [HPI], time to peak [TTP], and peak intensity [PI]). On the late study, a VOI was placed on the fused scan for each HCC, and maximum standardized uptake value (SUV(max)) was obtained. By using a mixed-effects model analysis, comparison of blood flow estimates between HCC with and that without angioinvasion and background liver was performed. The association between blood flow estimates and SUV(max) was also assessed. RESULTS: HPI and TTP showed better performance than did SUV(max) for discriminating HCC and background liver (areas under receiver operating characteristic curve: 0.96, 0.95, and 0.83, respectively; P < .05). HPI was higher in HCC in patients with angioinvasion (0.91 +/- 0.15 [standard deviation]) than in those without angioinvasion (0.80 +/- 0.18; P = .03). There was no difference in SUV(max) between HCC in patients with and those without angioinvasion (7.8 +/- 2.9 vs 6.3 +/- 3.4; P = .85). No clear association was found between HPI, PI, or TTP and SUV(max) (P = .49, .77, and .91, respectively). CONCLUSION: Early dynamic blood flow FDG PET/CT may be used to help discriminate and characterize HCC tumors. PMID- 21555348 TI - Lead versus bismuth-antimony shield for fetal dose reduction at different gestational ages at CT pulmonary angiography. AB - PURPOSE: To compare the effective fetal dose reduction at different stages of gestation during maternal computed tomographic (CT) pulmonary angiography by using traditional lead apron and bismuth-antimony shields combined with limited z axis and tube current. MATERIALS AND METHODS: Phantom with gravid prosthesis, 0.5 mm lead, and two grades of bismuth-antimony shield was used. Thermoluminescent dosimeters (TLDs) measured radiation in the first- to third-trimester uterus. Fetal dose was determined for each gestation by using 100 kVp to the costophrenic angles (CPAs) with and without shielding for a total of 12 scans. Eight third trimester scans were used to compare shields using 120 kVp to CPAs versus those using 100 kVp to the diaphragm. RESULTS: Average fetal dose increased with gestation with use of 100 kVp to CPAs, from 0.11 mGy in first trimester to 0.50 mGy in third trimester. Average third-trimester unshielded fetal dose was reduced from 0.82 mGy by using 120 kVp to CPAs to 0.17 mGy (79%, P < .001) by using 100 kVp to the diaphragm. Lead apron reduced dose more than either of the bismuth antimony shields (72%-79% vs 57%-81%) with use of 100 kVp to CPAs. Shields reduced the dose by 73% (lead), 62% (90% attenuation bismuth-antimony), and 72% (95% attenuation bismuth-antimony) (P < .01) at 120 kVp to CPAs. No significant difference between shields was demonstrated with 100 kVp to the diaphragm (P < .01). Maternal dose was 8.13 mSv at 120 kVp to CPAs, 4.90 mSv at 100 kVp to CPAs, and 4.02 mSv at 100 kVp to the diaphragm. CONCLUSION: Reducing voltage and limiting z-axis is more effective than shields at reducing fetal dose. Shielding improves reduction with no significant difference between lead and bismuth antimony shields when conservative scanning parameters are observed. PMID- 21555349 TI - Diagnosis of renal angiomyolipoma with hounsfield unit thresholds: effect of size of region of interest and nephrographic phase imaging. AB - PURPOSE: To retrospectively determine the optimal Hounsfield unit threshold and region of interest (ROI) size required to accurately diagnose renal angiomyolipoma (AML) and differentiate it from renal cell carcinoma (RCC). MATERIALS AND METHODS: This retrospective study was institutional review board approved and HIPAA compliant, and the requirement for written informed patient consent was waived. The radiologic reports on 4502 dual-phase abdominal computed tomography (CT) examinations (nonenhanced and nephrographic phases, 5-mm collimation, 120-140 kVp, variable milliampere-second settings) performed in 2872 patients from June 2002 through October 2007 were reviewed. Solid-component masses reported as suspicious for RCC or AML were correlated with histologic and/or follow-up imaging findings. ROIs of three different sizes-tiny (8-13 mm(2)), small (19-24 mm(2)), and medium (30-35 mm(2))-were drawn in the lowest attenuation focus on images obtained during both phases. The test characteristics (sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate) of multiple attenuation thresholds at each combination of ROI size and contrast enhancement phase were calculated, and receiver operating characteristic (ROC) curves were derived. Areas under the ROC curve were calculated. RESULTS: There were 217 RCCs and 65 AMLs. With an attenuation threshold of -10 HU or lower at nonenhanced CT, RCC would be misdiagnosed as AML in 11 (5.1%) cases, one (0.5%) case, and one (0.5%) case with use of the tiny, small, and medium ROIs, respectively. With use of the tiny, small, and medium ROIs, misdiagnosis rates would be 2.3%, 0.5%, and 0.5%, respectively, at a threshold of -15 HU or lower and 1.8%, 0%, and 0%, respectively, at a threshold of -20 HU or lower. Areas under the ROC curve for the nonenhanced phase images (range, 0.874-0.889) were superior to those for the nephrographic phase images (range, 0.790-0.826). CONCLUSION: Nonenhanced CT images were superior to nephrographic phase CT images for the diagnosis of AML. An attenuation threshold of -10 HU or lower with an ROI of at least 19-24 mm(2) is optimal for the diagnosis of AML. This threshold is not accurate with use of smaller (8-13-mm(2)) ROIs. PMID- 21555350 TI - Posterior interatrial muscular connection between the coronary sinus and left atrium: anatomic and functional study of the coronary sinus with multidetector CT. AB - PURPOSE: To demonstrate coronary sinus-left atrium connections and evaluate coronary sinus function and anatomy in detail by using multidetector computed tomography (CT). MATERIALS AND METHODS: In this institutional review board approved retrospective study, the authors evaluated coronary CT angiograms obtained in 65 patients with normal sinus rhythm (normal group) and seven with atrial fibrillation at CT (atrial fibrillation group). Coronary sinus-right atrium muscle continuity was indirectly evaluated by measuring the length of the coronary sinus contraction during atrial systole. The length, number, and extent of coronary sinus-left atrium connections were recorded. The accuracy of CT was validated by comparing microscopic images of autopsied hearts with corresponding CT images. Comparisons were performed by using Student t tests for continuous variables. P <= .05 was considered indicative of a statistically significant difference. RESULTS: In the normal group, coronary sinus contraction was seen in 60 of the 65 patients (92%, mean length +/- standard deviation, 25.7 mm +/- 8.0). The coronary sinus narrowed 26% from middiastole to atrial systole (P < .0001). Coronary sinus-left atrium muscle connections were seen in 58 of the 65 patients (89%). A single connection was seen in 43 of the 65 patients (66%), with a mean length of 21.0 mm +/- 14.0 within 12.0 mm +/- 11.0 of the coronary sinus ostium. In 10 of the 43 patients (26%) with single connections, the connection extended to the coronary sinus ostium. In 10 of the 65 patients (15%), the entire coronary sinus was attached to the left atrial wall. Fifteen patients (23%) had two connections; distal connections measured 9 mm +/- 2.4 in length within 2.2 mm +/- 3.8 of the coronary sinus ostium, and proximal connections measured 15.4 mm +/- 10.0 in length within 24.0 mm +/- 8.0 of the coronary sinus ostium. In seven patients (11%), no coronary sinus-left atrium connection was seen; however, all showed a coronary sinus constriction during atrial systole, indicating that coronary sinus-right atrium muscle continuity is likely the primary cause for coronary sinus contractions. In the atrial fibrillation group, no coronary sinus contraction was seen. All images in the atrial fibrillation group showed a coronary sinus-left atrium connection, which was single in five patients and double in two. The area of the coronary sinus during diastole was larger in the atrial fibrillation group than in the normal group (114 mm(2) +/- 37 vs 77 mm(2) +/- 40, respectively; P = .02). CONCLUSION: CT can provide excellent information about coronary sinus function and coronary sinus-left atrium muscle connections. PMID- 21555351 TI - Distal ureteral calculi: US follow-up. AB - PURPOSE: To assess accuracy of ultrasonographic (US) follow-up of distal ureteral calculi by using computed tomography (CT) and conventional radiography (kidneys, ureters, and bladder) as reference standards. MATERIALS AND METHODS: The study was approved by the Regional Ethics Committee, and written informed consent was obtained. One hundred fifty-eight patients with CT-diagnosed symptomatic ureteral calculi, for whom follow-up imaging was ordered, were enrolled from February 2006 to December 2008. Six were excluded, having not met study entry criteria, with 121 men (mean age, 49 years; range, 20-91 years) and 31 women (mean age, 44 years; range, 34-77 years) completing the protocol with adequate reference standard imaging. Targeted transabdominal US occurred coincidently with follow-up CT (n = 92) or radiography (n = 60), with US evaluation prospectively compared considering sensitivity and specificity. Statistical analysis was performed with a chi(2) test, t test, or paired t test, as appropriate. RESULTS: Results of nine US examinations were nondiagnostic because of inadequate ureteral visualization, and among these, two cases showed residual distal calculi. Of the remaining 143 patients, 33 had residual distal calculi, all visualized with US. There was a single false-positive study, giving sensitivity, including nondiagnostic US examinations, of 94.3% (95% confidence interval [CI]: 80.8%, 99.3%) and specificity of 99.1% (95% CI: 95.3%, 100%). All calculi appeared hyperechoic with posterior acoustic shadowing. Additional diagnostic features included presence of a hypoechoic rim and Doppler twinkle artifact. Mean stone length was 7.2 mm +/- 2.6 (standard deviation) (range, 4-18 mm). Mean ureteral length visualized was 36.4 mm (range, 12-77 mm), with calculi positioned at a mean of 13.1 mm +/- 11.2 (range, 0-40 mm) from the ureterovesical junction (UVJ). Nondiagnostic results were more likely with bladder volume of 110 mL or less (eight [16%] of 50 vs one [1%] of 102, P = .0009). CONCLUSION: Ureteral calculi within 35 mm of the UVJ can be accurately followed-up by using transabdominal US, which substantially reduces patient radiation burden. PMID- 21555352 TI - Dynamic microbubble contrast-enhanced US to measure tumor response to targeted therapy: a proposed clinical protocol with results from renal cell carcinoma patients receiving antiangiogenic therapy. AB - PURPOSE: To develop and implement an evidence-based protocol for characterizing vascular response of renal cell carcinoma (RCC) to targeted therapy by using dynamic contrast material-enhanced (DCE) ultrasonography (US). MATERIALS AND METHODS: The study was approved by the institutional research ethics board; written informed consent was obtained from all patients. Seventeen patients (four women; median age, 58 years; range, 42-72 years; 13 men, median age, 62 years; range, 45-81 years) with metastatic RCC were examined by using DCE US before and after 2 weeks of treatment with sunitinib (May 2007 to October 2009). Two contrast agent techniques--bolus injection and disruption-replenishment infusion of microbubbles--were compared. Changes in tumor blood velocity and fractional blood volume were measured with both methods, together with reproducibility and effect of compensation for respiratory motion. Tumor changes were assessed with computed tomography, by using the best response with the Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free survival (PFS). Follow-up RECIST measurements were performed at 6-week intervals until progressive disease was detected. RESULTS: In response to treatment, median tumor fractional blood volume measured with the disruption-replenishment infusion method decreased by 73.2% (interquartile range, 46%-87%) (P < .002), with repeated-measure reproducibility of 9%-15%. Significant decreases were also seen with the bolus method, but with poor correlation of changes in bolus peak (r = 0.46, P = .066) and area under the curve (r = 0.47, P = .058), compared with infusion measurements. Changes in DCE US parameters over 2 weeks did not correlate with PFS and could not be used to predict long-term assessment of best response by using RECIST. Follow-up times ranged 28-501 days; the median was 164 days. CONCLUSION: DCE US provides reproducible and sensitive assessment of vascular changes in response to antiangiogenic therapy. The disruption-replenishment infusion protocol is a flexible method suitable for many tumor types, but further studies are needed to assess whether this protocol may be predictive of patient outcome. PMID- 21555353 TI - Differentiating neoplastic from nonneoplastic processes in the anterior extradural space. AB - PURPOSE: To compare neoplastic and nonneoplastic disease in the anterior extradural space (AES) with regard to the contour of the disease and the tethering of the central septum, as seen on axial magnetic resonance (MR) images. MATERIALS AND METHODS: In this institutional review board-approved HIPAA compliant study, the data of patients who had AES disease determined at MR imaging and underwent diagnostic biopsy were studied. Two blinded observers reviewed the MR images and assigned the patients to one of two groups on the basis of the contour of AES disease: those with a centrally convex disease contour posteriorly and those whose disease contour was tethered in the midline to the posterior aspect of the vertebral body. Biopsy results served as the standard of reference. The two-tailed Fisher exact test, the Breslow-Day test, and kappa statistics were used to compare groups. The sensitivity, specificity, and accuracy of the midline tethered contour of AES disease for the detection of neoplasm were calculated. RESULTS: The data of 32 patients (16 men, 16 women; mean age, 68 years) were studied. Seventeen patients had malignant epidural disease. Fifteen patients had nonneoplastic epidural disease: Six patients had hematomas, and nine had abscesses. A greater proportion of AES neoplasms (13 [76%] and 14 [82%] of 17 lesions for observers 1 and 2, respectively) than nonneoplastic AES lesions (four [27%] and three [20%] of 15 lesions for observers 1 and 2, respectively) demonstrated midline tethering of the central septum. For observers 1 and 2, a unilobed or bilobed appearance of AES disease had sensitivities of 76% (13 of 17 lesions) and 82% (14 of 17 lesions), respectively; specificities of 73% (11 of 15 lesions) and 80% (12 of 15 lesions), respectively; and accuracies of 75% (24 of 32 lesions) and 81% (26 of 32 lesions), respectively, for the detection of neoplasm. The mean kappa value for interobserver variability was 0.62 (95% confidence interval: 0.35, 0.90). CONCLUSION: AES disease preserving the midline tethering of the central septum is more common with neoplastic disease than with infections or hematomas. PMID- 21555354 TI - Athetotic and spastic cerebral palsy: anatomic characterization based on diffusion-tensor imaging. AB - PURPOSE: To evaluate the anatomy of deep gray and white matter structures in children with athetotic cerebral palsy (CP) and those with spastic CP by using diffusion-tensor (DT) imaging and to investigate whether these types of CP have unique anatomic correlates that can support their diagnosis and prognosis. MATERIALS AND METHODS: This study was approved by the institutional review board of each participating institution, and written informed consent was obtained from the parents of each patient. DT imaging was used to retrospectively evaluate 19 children with clinically diagnosed athetotic CP (mean age, 3.4 years +/- 3.3 [standard deviation]), 26 children with spastic CP (mean age, 3.3 years +/- 3.2), and 31 healthy control subjects (mean age, 3.2 years +/- 3.0). Fractional anisotropy (FA) and mean diffusivity (MD) were measured with a region of interest (ROI) method. The ROIs were drawn on bilateral deep gray and white matter structures, including projection fibers, association fibers, and commissural fibers. Statistical analysis was performed by using the Kruskal-Wallis test with Bonferroni correction. P < .05 indicated a significant difference. RESULTS: FA values in the athetotic CP group were significantly lower than those in the control and spastic CP groups for multiple structures, including deep gray and white matter (P < .05 and P = .0001, respectively); these differences were also associated with increasing MD (P < .05 and P < .001, respectively). On the other hand, in the spastic CP group, the significantly decreased FA values, compared with those of the normal group, were limited to several white matter structures (P < .05 and P = .0001). CONCLUSION: In children with athetotic CP, the extent of change on DT images due to early brain damage tends to be more diffuse, including multiple brain structures, compared with the changes in children with spastic CP. PMID- 21555355 TI - Temperature dependence of internal friction in enzyme reactions. AB - Our aim was to elucidate the physical background of internal friction of enzyme reactions by investigating the temperature dependence of internal viscosity. By rapid transient kinetic methods, we directly measured the rate constant of trypsin 4 activation, which is an interdomain conformational rearrangement, as a function of temperature and solvent viscosity. We found that the apparent internal viscosity shows an Arrhenius-like temperature dependence, which can be characterized by the activation energy of internal friction. Glycine and alanine mutations were introduced at a single position of the hinge of the interdomain region to evaluate how the flexibility of the hinge affects internal friction. We found that the apparent activation energies of the conformational change and the internal friction are interconvertible parameters depending on the protein flexibility. The more flexible a protein was, the greater proportion of the total activation energy of the reaction was observed as the apparent activation energy of internal friction. Based on the coupling of the internal and external movements of the protein during its conformational change, we constructed a model that quantitatively relates activation energy, internal friction, and protein flexibility. PMID- 21555356 TI - Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake. AB - Prion diseases are infectious neurodegenerative disorders associated with the misfolded prion protein (PrP(Sc)), which appears to be the sole component of the infectious agent (termed prion). To produce disease, prions have to be absorbed into the body and reach sufficient quantities in the brain. Very little is known about the biological mechanisms controlling the initial fate of prions. Here, we studied the systemic pharmacokinetics and biodistribution of PrP(Sc) in vivo. After an intravenous injection of highly purified radiolabeled or native unlabeled PrP(Sc), the protein was eliminated rapidly from the serum (half-life of 3.24 h), mostly through tissue uptake. The quantity of intact PrP(Sc) reaching the brain was ~ 0.2% of the injected dose per gram of brain tissue (ID/g). The highest levels were found in liver (~ 20% ID/g), spleen (~ 13% ID/g), and kidney (~ 7.4% ID/g). Cell surface PrP(C) does not appear to play a role in PrP(Sc) pharmacokinetics, since the infectious protein distributed similarly in wild-type and PrP-null mice. To measure tissue uptake kinetics and biodistribution accurately, vascular space in tissues was measured with radioactively labeled albumin coinjected with radioactively labeled PrP(Sc). Our results provide a fundamental pharmacokinetic characterization of PrP(Sc) in vivo, which may be relevant to estimate tissue risks and mechanisms of prion neuroinvasion and to identify novel therapeutic strategies. PMID- 21555357 TI - Notice of Concern. AB - The editors of The FASEB Journal have been informed by Bente Klarlund Pedersen, MD, DMSc, Professor of Integrative Medicine, Director of Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC Rigshospitalet at the University of Copenhagen Faculty of Health Sciences, Copenhagen, Denmark, of an ongoing investigation into the validity of the data contained in an article published in The FASEB Journal in 2003, which is part of a larger investigation involving other articles appearing in other journals. We await a final report from the investigating institution to learn the outcome of this investigation. The article is: Penkowa, M., Keller, C., Keller, P., Jauffred, S., and Pedersen, B. K. (2003) Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise. PMID- 21555358 TI - Serotonin-enhanced hyperactivation of hamster sperm. AB - The effects of serotonin on reproductive function were examined using hamster spermatozoa. When serotonin at concentrations from 1 fmol/l to 1 MUmol/l was added to modified Tyrode's albumin lactate pyruvate (mTALP) medium, hyperactivation was significantly enhanced. Agonists and antagonists of 5 hydroxytryptamine hydrochloride (5-HT) receptors (5-HT(2) and 5-HT(4) receptors) were added to the medium. Both 5-HT(2) and 5-HT(4) receptor agonists significantly enhanced hyperactivation, although the effect was greater than the former. However, both 5-HT(2) and 5-HT(4) receptor antagonists significantly suppressed serotonin-enhanced hyperactivation, with the former suppressing stimulation by a lower concentration of serotonin than the latter. These results indicate that serotonin enhances hyperactivation via 5-HT(2) and/or 5-HT(4) receptors in a dose-dependent manner. PMID- 21555359 TI - Nuclear-cytoplasmic incompatibility and inefficient development of pig-mouse cytoplasmic hybrid embryos. AB - Inter-species somatic cell nuclear transfer (iSCNT) embryos usually fail to develop to the blastocyst stage and beyond due to incomplete reprogramming of donor cell. We evaluated whether using a karyoplast that would require less extensive reprogramming such as an embryonic blastomere or the meiotic spindle from metaphase II oocytes would provide additional insight into the development of iSCNT embryos. Our results showed that karyoplasts of embryonic or oocyte origin are no different from somatic cells; all iSCNT embryos, irrespective of karyoplast origin, were arrested during early development. We hypothesized that nuclear-cytoplasmic incompatibility could be another reason for failure of embryonic development from iSCNT. We used pig-mouse cytoplasmic hybrids as a model to address nuclear-cytoplasmic incompatibility in iSCNT embryos. Fertilized murine zygotes were reconstructed by fusing with porcine cytoplasts of varying cytoplasmic volumes (1/10 (small) and 1/5 (large) total volume of mouse zygote). The presence of pig cytoplasm significantly reduced the development of mouse zygotes to the blastocyst stage compared with control embryos at 120 h post-human chorionic gondotropin (41 vs 6 vs 94%, P<0.05; 1/10, 1/5, control respectively). While mitochondrial DNA copy numbers remained relatively unchanged, expression of several important genes namely Tfam, Polg, Polg2, Mfn2, Slc2a3 (Glut3), Slc2a1 (Glut1), Bcl2, Hspb1, Pou5f1 (Oct4), Nanog, Cdx2, Gata3, Tcfap2c, mt-Cox1 and mt Cox2 was significantly reduced in cytoplasmic hybrids compared with control embryos. These results demonstrate that the presence of even a small amount of porcine cytoplasm is detrimental to murine embryo development and suggest that a range of factors are likely to contribute to the failure of inter-species nuclear transfer embryos. PMID- 21555360 TI - A role for lipoxin A4 as an anti-inflammatory mediator in the human endometrium. AB - Lipoxin A(4) is a lipid mediator that elicits anti-inflammatory and pro resolution actions via its receptor, formyl peptide receptor 2 (FPR2/ALX). In this study, we aimed to investigate the expression and potential role of lipoxin A(4) and FPR2/ALX in the regulation of inflammation associated with cyclical remodeling of the human endometrium across the menstrual cycle and during early pregnancy. Using quantitative RT-PCR analysis, we found that FPR2/ALX expression is upregulated during the menstrual phase of the cycle and in decidua tissue from the first trimester of pregnancy. We localized the site of expression of FPR2/ALX in menstrual phase endometrium and first-trimester decidua tissue to glandular epithelial cells and cells within the stromal compartment, including cells lining the blood vessels and immune cells. Measurement of serum lipoxin A(4) by ELISA revealed no difference in its levels across the menstrual cycle but an elevation in early pregnancy (P<0.001). We found that lipoxin A(4) was regulated by human chorionic gonadotrophin (hCG) during early pregnancy, because treatment of human decidua tissue with hCG increased lipoxin A(4) release (P<0.01). Finally, we have shown that lipoxin A(4) can suppress phorbol myristate acetate-induced expression of the inflammatory cytokines interleukin 6 and 8 in human endometrium and decidua tissue. These results demonstrate for the first time that lipoxin A(4) and its receptor FPR2/ALX can regulate inflammatory events in the human endometrium and decidua of early pregnancy. PMID- 21555361 TI - Anthracycline-induced cardiomyopathy in siblings with early breast cancer. PMID- 21555362 TI - VEGF gene polymorphisms may be associated with an increased risk of fluorouracil induced diarrhea. PMID- 21555363 TI - Cost-utility and expected value of perfect information related to trabectedin in the treatment of metastatic soft-tissue sarcoma: the publicly funded comments explored. PMID- 21555364 TI - Zebrafish mRNA sequencing deciphers novelties in transcriptome dynamics during maternal to zygotic transition. AB - Maternally deposited mRNAs direct early development before the initiation of zygotic transcription during mid-blastula transition (MBT). To study mechanisms regulating this developmental event in zebrafish, we applied mRNA deep sequencing technology and generated comprehensive information and valuable resources on transcriptome dynamics during early embryonic (egg to early gastrulation) stages. Genome-wide transcriptome analysis documented at least 8000 maternal genes and identified the earliest cohort of zygotic transcripts. We determined expression levels of maternal and zygotic transcripts with the highest resolution possible using mRNA-seq and clustered them based on their expression pattern. We unravel delayed polyadenylation in a large cohort of maternal transcripts prior to the MBT for the first time in zebrafish. Blocking polyadenylation of these transcripts confirms their role in regulating development from the MBT onward. Our study also identified a large number of novel transcribed regions in annotated and unannotated regions of the genome, which will facilitate reannotation of the zebrafish genome. We also identified splice variants with an estimated frequency of 50%-60%. Taken together, our data constitute a useful genomic information and valuable transcriptome resource for gene discovery and for understanding the mechanisms of early embryogenesis in zebrafish. PMID- 21555365 TI - Genome-wide detection of chromosomal rearrangements, indels, and mutations in circular chromosomes by short read sequencing. AB - Whole-genome sequencing (WGS) with new short-read sequencing technologies has recently been applied for genome-wide identification of mutations. Genomic rearrangements have, however, often remained undetected by WGS, and additional analyses are required for their detection. Here, we have applied a combination of WGS and genome copy number analysis, for the identification of mutations that suppress the growth deficiency imposed by excessive initiations from the Escherichia coli origin of replication, oriC. The E. coli chromosome, like the majority of bacterial chromosomes, is circular, and DNA replication is initiated by assembling two replication complexes at the origin, oriC. These complexes then replicate the chromosome bidirectionally toward the terminus, ter. In a population of growing cells, this results in a copy number gradient, so that origin-proximal sequences are more frequent than origin-distal sequences. Major rearrangements in the chromosome are, therefore, readily identified by changes in copy number, i.e., certain sequences become over- or under-represented. Of the eight mutations analyzed in detail here, six were found to affect a single gene only, one was a large chromosomal inversion, and one was a large chromosomal duplication. The latter two mutations could not be detected solely by WGS, validating the present approach for identification of genomic rearrangements. We further suggest the use of copy number analysis in combination with WGS for validation of newly assembled bacterial chromosomes. PMID- 21555366 TI - Akt2 regulates all Akt isoforms and promotes resistance to hypoxia through induction of miR-21 upon oxygen deprivation. AB - The growth and survival of tumor cells in an unfavorable hypoxic environment depend upon their adaptability. Here, we show that both normal and tumor cells expressing the protein kinase Akt2 are more resistant to hypoxia than cells expressing Akt1 or Akt3. This is due to the differential regulation of microRNA (miR) 21, which is upregulated by hypoxia only in Akt2-expressing cells. By upregulating miR-21 upon oxygen deprivation, Akt2 downregulates PTEN and activates all three Akt isoforms. miR-21 also targets PDCD4 and Sprouty 1 (Spry1), and the combined downregulation of these proteins with PTEN is sufficient to confer resistance to hypoxia. Furthermore, the miR-21 induction by Akt2 during hypoxia depends upon the binding of NF-kappaB, cAMP responsive element-binding protein (CREB), and CBP/p300 to the miR-21 promoter, in addition to the regional acetylation of histone H3K9, all of which are under the control of Akt2. Analysis of the Akt2/miR-21 pathway in hypoxic MMTV-PyMT-induced mouse mammary adenocarcinomas and human ovarian carcinomas confirmed the activity of the pathway in vivo. Taken together, this study identifies a novel Akt2-dependent pathway that is activated by hypoxia and promotes tumor resistance via induction of miR-21. PMID- 21555367 TI - Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. AB - The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor kappaB (NFkappaB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression. PMID- 21555368 TI - Blocking EphB1 receptor forward signaling in spinal cord relieves bone cancer pain and rescues analgesic effect of morphine treatment in rodents. AB - Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we report that EphB1 receptor forward signaling in the spinal cord is critical to the development of bone cancer pain and morphine tolerance in treating bone cancer pain. Tibia bone cavity tumor cell implantation (TCI) produces bone cancer-related thermal hyperalgesia, mechanical allodynia, spontaneous and movement-evoked pain behaviors, and bone destruction. Production and persistence of these pain behaviors are well correlated with TCI-induced upregulation of EphB1 receptor and its ligand ephrinB2 in the dorsal horn and primary sensory neurons. Spinal administration of an EphB1 receptor blocking reagent EphB2-Fc prevents and reverses bone cancer pain behaviors and the associated induction of c-Fos and activation of astrocytes and microglial cells, NR1 and NR2B receptors, Src within the N-methyl-D-aspartate receptor complex, and the subsequent Ca(2+)-dependent signals. The exogenous ligand ephrinB2-Fc upregulates level of phosphorylation of NR1 and NR2B receptors depending on the activation of EphB1 receptor. Spinal administration of EphB2-Fc and ephrinB2-Fc induces downregulation of EphB1 and ephrinB2, respectively, accompanied with increased activity of matrix metalloproteinase (MMP)-2/9. Blocking MMP-2 or MMP-9 reverses EphB1-Fc treatment induced downregulation of EphB1 receptor. In addition, spinal blocking or targeted mutation of EphB1 receptor reverses morphine tolerance in treating bone cancer pain in rats and defensive pain in mice. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest a potential target for treating bone cancer pain and improving analgesic effect of morphine clinically. PMID- 21555369 TI - Nuclear ErbB2 enhances translation and cell growth by activating transcription of ribosomal RNA genes. AB - Aberrant regulation of rRNA synthesis and translation control can facilitate tumorigenesis. The ErbB2 growth factor receptor is overexpressed in many human tumors and has been detected in the nucleus, but the role of nuclear ErbB2 is obscure. In this study, we defined a novel function of nuclear ErbB2 in enhancing rRNA gene transcription by RNA polymerase-I (RNA Pol I). Nuclear ErbB2 physically associates with beta-actin and RNA Pol I, coinciding with active RNA Pol I transcription sites in nucleoli. RNA interference-mediated knockdown of ErbB2 reduced pre-rRNA and protein synthesis. In contrast, wild-type ErbB2 augmented pre-rRNA level, protein production, and cell size/cell growth, but not by an ErbB2 mutant that is defective in nuclear translocation. Chromatin immunoprecipitation assays revealed that ErbB2 enhances binding of RNA Pol I to rDNA. In addition, ErbB2 associated with rDNA, RNA Pol I, and beta-actin, suggesting how it could stimulate rRNA production, protein synthesis, and increased cell size and cell growth. Finally, ErbB2-potentiated RNA Pol I transcription could be stimulated by ligand and was not substantially repressed by inhibition of PI3-K and MEK/ERK (extracellular signal regulated kinase), the main ErbB2 effector signaling pathways. Together, our findings indicate that nuclear ErbB2 functions as a regulator of rRNA synthesis and cellular translation, which may contribute to tumor development and progression. PMID- 21555370 TI - MET-independent lung cancer cells evading EGFR kinase inhibitors are therapeutically susceptible to BH3 mimetic agents. AB - Targeted therapies for cancer are inherently limited by the inevitable recurrence of resistant disease after initial responses. To define early molecular changes within residual tumor cells that persist after treatment, we analyzed drug sensitive lung adenocarcinoma cell lines exposed to reversible or irreversible epidermal growth factor receptor (EGFR) inhibitors, alone or in combination with MET-kinase inhibitors, to characterize the adaptive response that engenders drug resistance. Tumor cells displaying early resistance exhibited dependence on MET independent activation of BCL-2/BCL-XL survival signaling. Further, such cells displayed a quiescence-like state associated with greatly retarded cell proliferation and cytoskeletal functions that were readily reversed after withdrawal of targeted inhibitors. Findings were validated in a xenograft model, showing BCL-2 induction and p-STAT3[Y705] activation within the residual tumor cells surviving the initial antitumor response to targeted therapies. Disrupting the mitochondrial BCL-2/BCL-XL antiapoptotic machinery in early survivor cells using BCL-2 Homology Domain 3 (BH3) mimetic agents such as ABT-737, or by dual RNAi-mediated knockdown of BCL-2/BCL-XL, was sufficient to eradicate the early resistant lung-tumor-cells evading targeted inhibitors. Similarly, in a xenograft model the preemptive cotreatment of lung tumor cells with an EGFR inhibitor and a BH3 mimetic eradicated early TKI-resistant evaders and ultimately achieved a more durable response with prolonged remission. Our findings prompt prospective clinical investigations using BH3-mimetics combined with targeted receptor kinase inhibitors to optimize and improve clinical outcomes in lung-cancer treatment. PMID- 21555371 TI - TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. AB - Breast cancer recurrence is believed to be caused by a subpopulation of cancer cells that possess the stem cell attribute of treatment resistance. Recently, we and others have reported the generation of breast cancer stem cells (BCSC) by epithelial-mesenchymal transition (EMT), although the physiologic process by which these cells may arise in vivo remains unclear. We show here that exposure of tumor cells to TGFbeta and TNFalpha induces EMT and, more importantly, generates cells with a stable BCSC phenotype which is shown by increased self renewing capacity, greatly increased tumorigenicity, and increased resistance to oxaliplatin, etoposide, and paclitaxel. Furthermore, gene expression analyses found that the TGFbeta/TNFalpha-derived BCSCs showed downregulated expression of genes encoding claudin 3, 4, and 7 and the luminal marker, cytokeratin 18. These changes indicate a shift to the claudin-low molecular subtype, a recently identified breast cancer subtype characterized by the expression of mesenchymal and stem cell-associated markers and correlated with a poor prognosis. Taken together, the data show that cytokine exposure can be used to generate stable BCSCs ex vivo, and suggest that these cells may provide a valuable tool in the identification of stem cell-directed biomarkers and therapies in breast cancer. PMID- 21555372 TI - Correlation of somatic mutation and expression identifies genes important in human glioblastoma progression and survival. AB - Cooperative dysregulation of gene sequence and expression may contribute to cancer formation and progression. The Cancer Genome Atlas (TCGA) Network recently catalogued gene sequence and expression data for a collection of glioblastoma multiforme (GBM) tumors. We developed an automated, model-free method to rapidly and exhaustively examine the correlation among somatic mutation and gene expression and interrogated 149 GBM tumor samples from the TCGA. The method identified 41 genes whose mutation status is highly correlated with drastic changes in the expression (z-score +/- 2.0), across tumor samples, of other genes. Some of the 41 genes have been previously implicated in GBM pathogenesis (e.g., NF1, TP53, RB1, and IDH1) and others, while implicated in cancer, had not previously been highlighted in studies using TCGA data (e.g., SYNE1, KLF6, FGFR4, and EPHB4). The method also predicted that known oncogenes and tumor suppressors participate in GBM via drastic over- and underexpression, respectively. In addition, the method identified a known synthetic lethal interaction between TP53 and PLK1, other potential synthetic lethal interactions with TP53, and correlations between IDH1 mutation status and the overexpression of known GBM survival genes. PMID- 21555373 TI - The Akt inhibitor ISC-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model. AB - PURPOSE: Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy; however, Akt1 inactivates Par-4. Previously we showed that Par-4 overexpressing colon cancer cells responded more readily to 5-fluorouracil (5-FU) than their wild-type counterparts. In this study we investigated (i) the effects of the Akt inhibitor, phenylbutyl isoselenocyanate (ISC-4), on tumor growth in nude mice and (ii) bystander effect of Par-4-overexpressing cells on wild-type tumor growth. EXPERIMENTAL DESIGN: Mice (n = 80) were injected with wild-type HT29 human colon cancer cells in the right flank. Forty of the mice were also injected in the left flank with HT29 cells engineered to overexpress Par-4. The mice were treated with 5-FU, ISC-4, a combination, or vehicle. RESULTS: ISC-4 reduced tumor growth, with or without 5-FU. When Par-4-overexpressing tumors were present, wild-type tumors grew more slowly compared to when no Par-4 overexpressing tumors were present. The level of Par-4 protein as well as the Par 4 binding protein, GRP78, was increased in wild-type cells growing in the same mouse as Par-4-overexpressing tumors compared with wild-type tumors growing without Par-4-overexpressing tumors. CONCLUSIONS: Par-4-overexpressing tumors exhibited a bystander effect on wild-type tumors growing distally in the same mouse. This suggests that gene therapy need not achieve total penetration to have a positive effect on tumor treatment. Inhibition of Akt with ISC-4 inhibited tumor growth and had a greater effect on cells overexpressing Par-4. The data indicate ISC-4 alone or in combination with Par-4 can greatly reduce tumor growth. PMID- 21555374 TI - SWOG Cooperative Group biorepository resource: access for scientific research studies. AB - SWOG (formerly the Southwest Oncology Group), a National Cancer Institute supported cooperative group, conducts multi-institutional, multidisciplinary clinical trials for adult patients with cancer, covering a wide range of solid tumors and hematologic cancers. The group has amassed a large set of biospecimens, collected from patients in numerous studies over many years and linked to clinical data. SWOG is now actively promoting the use of this unique scientific resource by making it available to a much wider group of researchers. This biospecimen resource offers material for research on disease mechanisms, genomic changes associated with cancer progression, markers of response and resistance to therapies, diagnosis or detection of recurrence, and more. By collecting, storing, and distributing the specimens, SWOG provides the framework for translational scientists to complete the feedback loop from "bedside to bench." This article provides an overview of the group's biospecimen resources and guidelines for gaining access to them. PMID- 21555375 TI - Characterization of bone metastases from rapid autopsies of prostate cancer patients. AB - PURPOSE: Bone is the most common metastatic site for prostate cancer, and osseous metastases are the leading cause of morbidity from this disease. Recent autopsy studies prove that 100% of men who die of prostate cancer have bone involvement. Understanding the biology of prostate cancer and its evolution to an incurable androgen-independent phenotype requires an understanding of the genetic and cellular alterations that lead to the seeding and proliferation of tumor foci in bone, as well as the microenvironment in which these metastases arise. No intensive studies, however, have been conducted on osseous metastatic tissues from patients with metastatic prostate cancer due to lack of access to such tissues for profiling and other research. EXPERIMENTAL DESIGN: We show, for the first time, a reproducible methodology to obtain high quality clinical tumor tissues metastatic to the bone. This technique allowed the procurement of viable metastatic tumor tissue from involved bones in 13 recent autopsies conducted at the University of Michigan and analyzed the gene expression of these tissues using real-time PCR and microarrays. RESULTS: We present here the discovery of nonossified bone metastases from multiple patients with advanced prostate cancer and their subsequent characterization and comparison to nonosseous metastases from the same patients. CONCLUSION: This represents a versatile and practical approach that may be employed to characterize the steps in metastasis and the phenotypic characteristics of osseous metastasis of prostate cancer and to profile RNA, DNA, and cDNA from tumor samples metastatic to the bone. PMID- 21555376 TI - Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells. AB - Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and the release of a transcriptionally active Notch1 intracellular domain (NICD). Chromatin immunoprecipitation analysis shows that NICD gets recruited to the survivin promoter at the CSL (CBF1/RBP-Jk, Su(H), Lag-1) binding site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of epidermal growth factor receptor (EGFR) is involved in leptin mediated Notch1 and survivin upregulation, demonstrating a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3 methylglutaryl-coenzyme-A-reductase inhibitors, such as lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic strategy. This conclusion is supported by in vivo data showing the overexpression of leptin and survivin in epithelial cells of high-grade ductal carcinomas in situ and in high-grade invasive carcinomas. PMID- 21555377 TI - Evaluation of LMI1195, a novel 18F-labeled cardiac neuronal PET imaging agent, in cells and animal models. AB - BACKGROUND: Heart failure has been associated with impaired cardiac sympathetic neuronal function. Cardiac imaging with radiolabeled agents that are substrates for the neuronal norepinephrine transporter (NET) has demonstrated the potential to identify individuals at risk of cardiac events. N-[3-Bromo-4-(3-[18F]fluoro propoxy)-benzyl]-guanidine (LMI1195) is a newly developed 18F-labeled NET substrate designed to allow cardiac neuronal imaging with the high sensitivity, resolution, and quantification afforded by positron emission tomography (PET). METHODS AND RESULTS: LMI1195 was evaluated in comparison with norepinephrine (NE) in vitro and 123I-meta-iodobenzylguanidine (MIBG) in vivo. The affinity (Ki) of LMI1195 for NET was 5.16 +/- 2.83 MUmol/L, similar to that of NE (3.36 +/- 2.77 MUmol/L) in a cell membrane-binding assay. Similarly, LMI1195 uptake kinetics examined in a human neuroblastoma cell line had Km and Vmax values of 1.44 +/- 0.76 MUmol/L and 6.05 +/- 3.09 pmol/million cells per minute, comparable to NE (2.01 +/- 0.85 MUmol/L and 6.23 +/- 1.52 pmol/million cells per minute). In rats, LMI1195 heart uptake at 15 and 60 minutes after intravenous administration was 2.36 +/- 0.38% and 2.16 +/- 0.38% injected dose per gram of tissue (%ID/g), similar to 123I-MIBG (2.14 +/- 0.30 and 2.19 +/- 0.27%ID/g). However, the heart to liver and lung uptake ratios were significantly higher for LMI1195 than for 123I-MIBG. In rabbits, desipramine (1 mg/kg), a selective NET inhibitor, blocked LMI1195 heart uptake by 82%, which was more effective than 123I-MIBG (53%), at 1 hour after dosing. Sympathetic denervation with 6-hydroxydopamine, a neurotoxin, resulted in a marked (79%) decrease in LMI1195 heart uptake. Cardiac PET imaging with LMI1195 in rats, rabbits, and nonhuman primates revealed clear myocardium with low radioactivity levels in the blood, lung, and liver. Imaging in rabbits pretreated with desipramine showed reduced heart radioactivity levels in a dose dependent manner. Additionally, imaging in sympathetically denervated rabbits resulted in low cardiac image intensity with LMI1195 but normal perfusion images with flurpiridaz F 18, a PET myocardial perfusion imaging agent. In nonhuman primates pretreated with desipramine (0.5 mg/kg), imaging with LMI1195 showed a 66% decrease in myocardial uptake. In a rat model of heart failure, the LMI1195 cardiac uptake decreased as heart failure progressed. CONCLUSIONS: LMI1195 is a novel (18)F imaging agent retained in the heart through the NET and allowing evaluation of the cardiac sympathetic neuronal function by PET imaging. PMID- 21555378 TI - The need for new mechanisms to ensure research integrity. PMID- 21555379 TI - Federal government tightens live-in caregiver regulations. PMID- 21555380 TI - Lower growth rate for drug spending. PMID- 21555381 TI - European reforms urged to reduce differential drug costs between nations. PMID- 21555382 TI - Battle renewed over value of fluoridation. PMID- 21555383 TI - Tobacco, alcohol and illicit drug use among Aboriginal youth living off-reserve: results from the Youth Smoking Survey. AB - BACKGROUND: Despite the high prevalence of smoking among Aboriginal youth, there is a paucity of research related to tobacco use and other risk behaviours among Aboriginal youth living off-reserve in Canada. We used data from the national Youth Smoking Survey to characterize non-traditional tobacco use, exposure to second-hand smoke, and alcohol and drug use among Aboriginal youth living off reserve. We examined whether these youth were at increased health risk compared with non-Aboriginal youth. METHODS: We examined cigarette smoking behaviour, use of other tobacco products, use of alcohol and other drugs, and exposure to second hand smoke among 2620 Aboriginal youth living off-reserve and 26,223 non Aboriginal youth in grades 9 to 12 who participated in the 2008/09 Youth Smoking Survey. RESULTS: The prevalence of current smoking among the Aboriginal youth was more than double that among non-Aboriginal youth (24.9% v. 10.4%). Aboriginal youth also had a higher prevalence of regular exposure to second-hand smoke at home (37.3% v. 19.7%) and in cars (51.0% v. 30.3%). Aboriginal youth were more likely than non-Aboriginal youth to be current smokers, to be regularly exposed to second-hand smoke, to have tried marijuana and other illicit drugs, and to engage in binge drinking. They were less likely than non-Aboriginal youth to have tried to quit smoking. INTERPRETATION: Current national estimates of smoking, and alcohol and illicit drug use among youth underestimate the prevalence of these behaviours among Aboriginal youth living off-reserve. Our findings highlight the need for culturally appropriate prevention and cessation policies and programs for this at-risk population. PMID- 21555384 TI - Sparse promises and meager medical representation. PMID- 21555385 TI - Scurvy in a man with schizophrenia. PMID- 21555386 TI - Hypertriglyceridemic-waist phenotype and glucose intolerance among Canadian Inuit: the International Polar Year Inuit Health Survey for Adults 2007-2008. AB - BACKGROUND: Inuit have not experienced an epidemic in type 2 diabetes mellitus, and it has been speculated that they may be protected from obesity's metabolic consequences. We conducted a population-based screening for diabetes among Inuit in the Canadian Arctic and evaluated the association of visceral adiposity with diabetes. METHODS: A total of 36 communities participated in the International Polar Year Inuit Health Survey. Of the 2796 Inuit households approached, 1901 (68%) participated, with 2595 participants. Households were randomly selected, and adult residents were invited to participate. Assessments included anthropometry and fasting plasma lipids and glucose, and, because of survey logistics, only 32% of participants underwent a 75 g oral glucose tolerance test. We calculated weighted prevalence estimates of metabolic risk factors for all participants. RESULTS: Participants' mean age was 43.3 years; 35% were obese, 43.8% had an at-risk waist, and 25% had an elevated triglyceride level. Diabetes was identified in 12.2% of participants aged 50 years and older and in 1.9% of those younger than 50 years. A hypertriglyceridemic-waist phenotype was a strong predictor of diabetes (odds ratio [OR] 8.6, 95% confidence interval [CI] 2.1 34.6) in analyses adjusted for age, sex, region, family history of diabetes, education and use of lipid-lowering medications. INTERPRETATION: Metabolic risk factors were prevalent among Inuit. Our results suggest that Inuit are not protected from the metabolic consequences of obesity, and that their rate of diabetes prevalence is now comparable to that observed in the general Canadian population. Assessment of waist circumference and fasting triglyceride levels could represent an efficient means for identifying Inuit at high risk for diabetes. PMID- 21555388 TI - Scurvy in the developed world. PMID- 21555390 TI - Toll-like receptor 4 engagement contributes to expression of NKG2D ligands by renal tubular epithelial cells. AB - BACKGROUND: Engagement of Toll-like receptor (TLR) 4 on intrinsic kidney cells is critical for the full development of renal ischaemia-reperfusion injury (IRI). Effects of TLR signalling in renal parenchymal cells include the production of cytokines, chemokines and other soluble mediators which contribute to local inflammation and leucocyte accumulation. Whether engagement of TLR4 on kidney cells results in additional pro-inflammatory modifications of the renal microenvironment remains to be determined. METHODS: Renal IRI was induced by clamping of the renal pedicles, and expression of NKG2D ligands in mice deficient in TLR4 or its adaptor molecule MyD88, or else pretreated with blocking antibodies against the endogenous TLR4 ligand HMGB1, was compared to that in wild type mice. Cultures of isolated renal tubular epithelial cells (TECs) from WT, TLR4(-/-) and MyD88(-/-) mice were stimulated with the TLR4 ligand lipopolysaccharide (LPS), or mineral oil occlusion was used to simulate IRI in vitro, prior to determination of NKG2D ligand expression. Chimeric mice lacking TLR4 in either the bone marrow derived or the parenchymal compartment were also subjected to IRI. RESULTS: In this study, we demonstrate a substantial increase in the expression of the NKG2D ligands retinoic acid early inducible-1 (RAE-1), murine ULBP-like transcript 1 (MULT-1) and histocompatibility-60 (H-60) in mouse kidneys during renal IRI. Expression of NKG2D ligands was attenuated in mice deficient in either TLR4 or the adaptor molecule MyD88. Antibody blockade of HMGB1 reduced NKG2D ligand expression by a comparable extent to TLR4 deficiency and did not result in further reduction of NKG2D ligand expression in TLR4(-/-) mice. Isolated TECs from normal mice but not those with defects in the TLR4-MyD88 signalling pathway expressed RAE-1 and MULT-1 upon exposure to LPS and after being subjected to in vitro conditions resembling ischaemia-reperfusion. TLR4 competence in the parenchymal but not the bone marrow-derived compartment was required for RAE-1 up-regulation in mouse kidneys after ischaemia, while TLR4 signalling in both compartments contributed to the intrarenal expression of MULT 1 during IRI. CONCLUSION: Expression of the NKG2D ligands RAE-1 and MULT-1 on kidney cells in response to TLR4 engagement by HMGB1 represents another mechanism by which TLR4 signalling may participate in the pathogenesis of renal IRI. PMID- 21555391 TI - Renal stress in vivo in real-time--visualised by the NGAL reporter mouse. PMID- 21555392 TI - Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement. AB - KDIGO (Kidney Disease: Improving Global Outcomes) is an international independent body aiming to 'improve the care and outcomes of kidney disease patients worldwide, through the development and implementation of clinical practice guidelines'. Recently, the KDIGO work group has produced comprehensive clinical practice guidelines for the care of kidney transplant recipients (KTRs). The guideline makes recommendations for immunosuppression, graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy and other complications that are common in KTRs, including haematological and bone disorders. Because most guidelines were 'soft' rather than 'strong', and because global guidelines need to be adapted and implemented into the regional context where they are used, the European Renal Best Practice (ERBP) Advisory Board appointed a work group of transplant nephrologists and surgeons to review the newest KDIGO guideline and comment on its relevance and applicability for European KTRs. In this article, we concentrate only on those guidelines which we considered worth amending or adapting. All guidelines not mentioned are fully endorsed. PMID- 21555393 TI - Effect of post-dilutional on-line haemodiafiltration on serum calcium, phosphate and parathyroid hormone concentrations in uraemic patients. AB - BACKGROUND: Strict control of serum calcium and phosphate concentrations is paramount to prevent secondary hyperparathyroidism in haemodialysis (HD) patients. Standard intermittent low-flux HD (Lf-HD) is not sufficient to reach this goal. The aim of this study was to evaluate the effect of on-line haemodiafiltration (Ol-HDF) on serum calcium (sCa), phosphate (sPO4) and parathyroid hormone (PTHint) concentrations. METHODS: Of the 220 patients screened, 65 met the inclusion criteria for the study; 30 of whom agreed to participate in the study (Study group), the others were considered as the control group (Controls). Protocol for Study the group consisted of 6 months conventional Lf-HD (Period 1) and 6 months of post-dilutional Ol-HDF (Period 2). Controls continued their usual Lf-HD and were followed for 12 months. The main variables evaluated at the start and at the end of each period were sCa, sPO(4) and PTHint. RESULTS: The switchover from Lf-HD to Ol-HDF resulted in a significant reduction of sPO4 (from 5.1 +/- 1.0 to 4.0 +/- 0.7; P < 0.0001) and PTHint concentrations (from 307 +/- 167 to 194 +/- 98; P < 0.0001), no significant changes were found in both sCa concentrations (from 9.1 +/- 0.7 to 8.9 +/- 0.6) and phosphate binder dose. Kt/Vurea increased significantly, and beta(2) microglobulin concentrations decreased significantly. In the Controls, no significant variations of the same variables were observed over time, except for a significant increase in sevelamer intake. CONCLUSION: This study supports the idea that Ol-HDF could be better than Lf-HD in controlling mineral metabolism in HD patients. PMID- 21555394 TI - Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy. AB - BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end stage renal disease (ESRD). METHODS: Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive. RESULTS: Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 +/- 338 versus 94 +/- 101 MUg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 MUg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88. CONCLUSION: In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts. PMID- 21555395 TI - A left/right asymmetric neuronal differentiation program is controlled by the Caenorhabditis elegans lsy-27 zinc-finger transcription factor. AB - Functional diversification across the left/right axis is a common feature of many nervous systems. The genetic programs that control left/right asymmetric neuron function and gene expression in the nervous system are, however, poorly understood. We describe here the molecular characterization of two phenotypically similar mutant Caenorhabditis elegans strains in which left/right asymmetric gene expression programs of two gustatory neurons, called ASEL and ASER, are disrupted such that the differentiation program of the ASER neuron is derepressed in the ASEL neuron. We show that in one mutant strain the LIM homeobox gene lim-6 is defective whereas in another strain a novel member of a nematode-specific, fast evolving family of C2H2 zinc-finger transcription factors, lsy-27, is mutated, as revealed by whole-genome sequencing. lsy-27 is broadly and exclusively expressed in the embryo and acts during the initiation, but not during the maintenance phase of ASE asymmetry control to assist in the initiation of lim-6 expression. PMID- 21555396 TI - Functions of yeast Hsp40 chaperone Sis1p dispensable for prion propagation but important for prion curing and protection from prion toxicity. AB - Replication of amyloid-based yeast prions [PSI(+)], [URE3], and [PIN(+)] depends on the protein disaggregation machinery that includes Hsp104, Hsp70, and Hsp40 molecular chaperones. Yet, overexpressing Hsp104 cures cells of [PSI(+)] prions. An Hsp70 mutant (Ssa1-21p) antagonizes propagation of [PSI(+)] in a manner resembling elevated Hsp104. The major cytosolic Hsp40 Sis1p is the only Hsp40 required for replication of these prions, but its role in [PSI(+)] curing is unknown. Here we find that all nonessential functional regions of Sis1p are dispensable for [PSI(+)] propagation, suggesting that other Hsp40's might provide Hsp40 functions required for [PSI(+)] replication. Conversely, several Sis1p functions were important for promoting antiprion effects of both Ssa1-21p and Hsp104, which implies a link between the antiprion effects of these chaperones and suggests that Sis1p is a specific Hsp40 important for [PSI(+)] curing. These contrasting findings suggest that the functions of Hsp104 that are important for propagation and elimination of [PSI(+)] are either distinct or specified by different Hsp40's. This work also uncovered a growth inhibition caused by [PSI(+)] when certain functions of Sis1p were absent, suggesting that Sis1p protects cells from cytotoxicity caused by [PSI(+)] prions. PMID- 21555397 TI - Immune response of chicken gut to natural colonization by gut microflora and to Salmonella enterica serovar enteritidis infection. AB - In commercial poultry production, there is a lack of natural flora providers since chickens are hatched in the clean environment of a hatchery. Events occurring soon after hatching are therefore of particular importance, and that is why we were interested in the development of the gut microbial community, the immune response to natural microbial colonization, and the response to Salmonella enterica serovar Enteritidis infection as a function of chicken age. The complexity of chicken gut microbiota gradually increased from day 1 to day 19 of life and consisted of Proteobacteria and Firmicutes. For the first 3 days of life, chicken cecum was protected by increased expression of chicken beta defensins (i.e., gallinacins 1, 2, 4, and 6), expression of which dropped from day 4 of life. On the other hand, a transient increase in interleukin-8 (IL-8) and IL-17 expression could be observed in chicken cecum on day 4 of life, indicating physiological inflammation and maturation of the gut immune system. In agreement, the response of chickens infected with S. Enteritidis on days 1, 4, and 16 of life shifted from Th1 (characterized mainly by induction of gamma interferon [IFN-gamma] and inducible nitric oxide synthase [iNOS]), observed in younger chickens, to Th17, observed in 16-day-old chickens (characterized mainly by IL-17 induction). Active modification of chicken gut microbiota in the future may accelerate or potentiate the maturation of the gut immune system and increase its resistance to infection with different pathogens. PMID- 21555398 TI - Prevalence and significance of plasmid maintenance functions in the virulence plasmids of pathogenic bacteria. AB - Virulence functions of pathogenic bacteria are often encoded on large extrachromosomal plasmids. These plasmids are maintained at low copy number to reduce the metabolic burden on their host. Low-copy-number plasmids risk loss during cell division. This is countered by plasmid-encoded systems that ensure that each cell receives at least one plasmid copy. Plasmid replication and recombination can produce plasmid multimers that hinder plasmid segregation. These are removed by multimer resolution systems. Equitable distribution of the resulting monomers to daughter cells is ensured by plasmid partition systems that actively segregate plasmid copies to daughter cells in a process akin to mitosis in higher organisms. Any plasmid-free cells that still arise due to occasional failures of replication, multimer resolution, or partition are eliminated by plasmid-encoded postsegregational killing systems. Here we argue that all of these three systems are essential for the stable maintenance of large low-copy number plasmids. Thus, they should be found on all large virulence plasmids. Where available, well-annotated sequences of virulence plasmids confirm this. Indeed, virulence plasmids often appear to contain more than one example conforming to each of the three system classes. Since these systems are essential for virulence, they can be regarded as ubiquitous virulence factors. As such, they should be informative in the search for new antibacterial agents and drug targets. PMID- 21555399 TI - Vibrio cholerae requires the type VI secretion system virulence factor VasX to kill Dictyostelium discoideum. AB - The type VI secretion system (T6SS) is recognized as an important virulence mechanism in several Gram-negative pathogens. In Vibrio cholerae, the causative agent of the diarrheal disease cholera, a minimum of three gene clusters--one main cluster and two auxiliary clusters--are required to form a functional T6SS apparatus capable of conferring virulence toward eukaryotic and prokaryotic hosts. Despite an increasing understanding of the components that make up the T6SS apparatus, little is known about the regulation of these genes and the gene products delivered by this nanomachine. VasH is an important regulator of the V. cholerae T6SS. Here, we present evidence that VasH regulates the production of a newly identified protein, VasX, which in turn requires a functional T6SS for secretion. Deletion of vasX does not affect export or enzymatic function of the structural T6SS proteins Hcp and VgrG-1, suggesting that VasX is dispensable for the assembly of the physical translocon complex. VasX localizes to the bacterial membrane and interacts with membrane lipids. We present VasX as a novel virulence factor of the T6SS, as a V. cholerae mutant lacking vasX exhibits a phenotype of attenuated virulence toward Dictyostelium discoideum. PMID- 21555400 TI - Burkholderia pseudomallei-induced expression of a negative regulator, sterile alpha and Armadillo motif-containing protein, in mouse macrophages: a possible mechanism for suppression of the MyD88-independent pathway. AB - Burkholderia pseudomallei, a causative agent of melioidosis, is a Gram-negative facultative intracellular bacterium that can survive and multiply in macrophages. Previously, we demonstrated that B. pseudomallei failed to activate gene expression downstream of the MyD88-independent pathway, particularly the expression of beta interferon (IFN-beta) and inducible nitric oxide synthase (iNOS), leading to the inability of macrophages to kill this bacterium. In the present report, we extended our study to show that B. pseudomallei was able to activate sterile-alpha and Armadillo motif (SARM)-containing protein, a known negative regulator of the MyD88-independent pathway. Both live B. pseudomallei and heat-killed B. pseudomallei were able to upregulate SARM expression in a time dependent manner in mouse macrophage cell line RAW 264.7. The expression of SARM required bacterial internalization, as it could be inhibited by cytochalasin D. In addition, the intracellular survival of B. pseudomallei was suppressed in SARM deficient macrophages. Increased expression of IFN-beta and iNOS and degradation of IkappaBalpha correlated with enhanced macrophage killing capability. These results demonstrated that B. pseudomallei modulated macrophage defense mechanisms by upregulating SARM, thus leading to the suppression of IFN-beta and iNOS needed for bacterial elimination. PMID- 21555401 TI - Protective role of Akt2 in Salmonella enterica serovar typhimurium-induced gastroenterocolitis. AB - The Salmonella effector protein SopB has previously been shown to induce activation of Akt and protect epithelial cells from apoptosis in vitro. To characterize the role of Akt2 in host defense against Salmonella enterica serovar Typhimurium infection, wild-type (WT) mice and mice lacking Akt2 (Akt2 knockout [KO] mice) were infected using a Salmonella acute gastroenteritis model. Infected Akt2 KO mice showed a more pronounced morbidity and mortality associated with higher bacterial loads in the intestines and elevated levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), and MCP-1, in the colons at 1 day postinfection compared to those shown in WT mice. Histopathological assessment and immunohistochemical analysis of cecal sections at 1 day postinfection revealed more severe inflammation and higher levels of neutrophil infiltration in the ceca of Akt2 KO mice. Flow cytometry analysis further confirmed an increase in the recruitment of Gr-1(+) CD11b(+) neutrophils and F4/80(+) CD11b(+) macrophages in the intestines of infected Akt2 KO mice. Additionally, enhanced levels of annexin V(+) and terminal transferase dUTP nick end labeling-positive (TUNEL(+)) apoptotic cells in the intestines of infected Akt2 KO mice were also observed, indicating that Akt2 plays an essential role in protection against apoptosis. Finally, the differences in bacterial loads and cecal inflammation in WT and Akt2 KO mice infected with WT Salmonella were abolished when these mice were infected with the sopB deletion mutant, indicating that SopB may play a role in protecting the mice from Salmonella infection through the activation of Akt2. These data demonstrate a definitive phenotypic abnormality in the innate response in mice lacking Akt2, underscoring the important protective role of Akt2 in Salmonella infection. PMID- 21555402 TI - Anaerobiosis-induced loss of cytotoxicity is due to inactivation of quorum sensing in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, an opportunistic pathogen of clinical importance, causes chronic airway infections in patients with cystic fibrosis (CF). Current literature suggests that pockets with reduced oxygen tension exist in the CF airway mucus. However, virulence features of this opportunistic pathogen under such conditions are largely unknown. Cell-free supernatant of the standard laboratory P. aeruginosa strain PAO1 obtained from anaerobic culture, but not aerobic culture, failed to kill A549 human airway epithelial cells. Further investigation revealed that this reduced cytotoxicity upon anaerobiosis was due to the suppressed secretion of elastase, a virulence factor controlled by P. aeruginosa quorum sensing (QS). Both a lacZ-reporter fusion assay and quantitative real-time PCR (RT-PCR) analysis demonstrated that transcription of the elastase-encoding lasB gene was substantially decreased during anaerobic growth compared with aerobic growth. Moreover, transcription of other genes controlled by the LasI/R QS system, such as rhlR, vqsR, mvfR, and rsaL, was also repressed under the same anaerobic growth conditions. Importantly, synthesis of 3 oxo-C(12)-HSL (PAI-1), an autoinducer molecule that mediates induction of the LasI/R QS system, was >22-fold decreased during anaerobic growth while C(4)-HSL (PAI-2), which mediates RhlI/R QS, was nondetectable under the same growth conditions. Transcription of the lasB gene was restored by exogenous supplementation with autoinducers, with PAI-2 more effective than PAI-1 or Pseudomonas quinolone signal (PQS) at restoring transcription of the lasB gene. Together, these results suggest that anaerobiosis deprives P. aeruginosa of the ability to regulate its virulence via QS and this misregulation attenuates the pathogenic potential of this important pathogen. PMID- 21555403 TI - TREM-1 amplifies corneal inflammation after Pseudomonas aeruginosa infection by modulating Toll-like receptor signaling and Th1/Th2-type immune responses. AB - As a novel family of cell surface receptors, triggering receptors expressed on myeloid cells (TREMs) play an important role in inflammatory responses. However, the role of TREMs in the ocular immune system remains unknown. In this study, we examined the expression and function of TREM-1 in Pseudomonas aeruginosa keratitis, one of the most common sight-threatening ocular diseases. TREM-1 was significantly increased in human corneas after P. aeruginosa infection. Consistent with TREM-1 expression at the human ocular surface, TREM-1 levels (mRNA and protein) were also elevated in the infected corneas of C57BL/6 (B6) mice at 1, 3, and 5 days postinfection. To determine whether TREM-1 dictates the outcome of P. aeruginosa keratitis in susceptible mice, TREM-1 signaling in B6 mice was blocked with a soluble mTREM-1/Fc fusion protein. The results indicated that blockade of TREM-1 reduced the severity of corneal disease, polymorphonuclear neutrophil infiltration, Th1/proinflammatory cytokine expression and Toll-like receptor (TLR) activation but enhanced the production of Th2 cytokines, murine beta-defensin 2 (mBD2), single Ig interleukin-1R-related molecule (SIGIRR), and ST2. Furthermore, we also used agonistic anti-mTREM-1 antibody to activate TREM-1 signaling in B6 mice and found that TREM-1 activation resulted in worsened disease and earlier corneal perforation in infected B6 mouse corneas and elevated production of proinflammatory cytokines and TLR signaling molecules but reduced expression of mBD2, SIGIRR, and ST2. To the best of our knowledge, this study provides the first evidence that TREM-1 functions as an inflammatory amplifier in P. aeruginosa keratitis by modulating TLR signaling and Th1/Th2 responses. PMID- 21555404 TI - Early prediction of proarrhythmic cardiotoxicity in the drug development process. PMID- 21555405 TI - Neuronal activity-regulated gene transcription in synapse development and cognitive function. AB - Activity-dependent plasticity of vertebrate neurons allows the brain to respond to its environment. During brain development, both spontaneous and sensory-driven neural activity are essential for instructively guiding the process of synapse development. These effects of neuronal activity are transduced in part through the concerted regulation of a set of activity-dependent transcription factors that coordinate a program of gene expression required for the formation and maturation of synapses. Here we review the cellular signaling networks that regulate the activity of transcription factors during brain development and discuss the functional roles of specific activity-regulated transcription factors in specific stages of synapse formation, refinement, and maturation. Interestingly, a number of neurodevelopmental disorders have been linked to abnormalities in activity-regulated transcriptional pathways, indicating that these signaling networks are critical for cognitive development and function. PMID- 21555407 TI - Nuclear transfer to eggs and oocytes. AB - We review experiments in which somatic cell nuclei are transplanted singly to enucleated eggs (metaphase II) in amphibia and mammals and as multiple nuclei to the germinal vesicle of amphibian oocytes (prophase I). These experiments have shown the totipotency of some somatic cell nuclei, as well as switches in cell type and changes in gene expression. Abnormalities of nuclear transplant embryo development increase greatly as nuclei are taken from progressively more differentiated donor cells. The molecular changes that accompany the reprogramming of transplanted nuclei help to indicate the mechanisms used by eggs and oocytes to reprogram gene expression. We discuss the importance of chromosomal protein exchange, of transcription factor supply, and of chromatin access in reprogramming. PMID- 21555408 TI - Unique aspects of transcription regulation in male germ cells. AB - Spermatogenesis is a complex and ordered differentiation process in which the spermatogonial stem cell population gives rise to primary spermatocytes that undergo two successive meiotic divisions followed by a major biochemical and structural reorganization of the haploid cells to generate mature elongate spermatids. The transcriptional regulatory programs that orchestrate this process have been intensively studied in model organisms such as Drosophila melanogaster and mouse. Genetic and biochemical approaches have identified the factors involved and revealed mechanisms of action that are unique to male germ cells. In a well-studied example, cofactors and pathways distinct from those used in somatic tissues mediate the action of CREM in male germ cells. But perhaps the most striking feature concerns the paralogs of somatically expressed transcription factors and of components of the general transcription machinery that act in distinct regulatory mechanisms in both Drosophila and murine spermatogenesis. PMID- 21555409 TI - A collaborative approach to understanding EPS: the European perspective. PMID- 21555406 TI - Glycosphingolipid functions. AB - The combination of carbohydrate and lipid generates unusual molecules in which the two distinctive halves of the glycoconjugate influence the function of each other. Membrane glycolipids can act as primary receptors for carbohydrate binding proteins to mediate transmembrane signaling despite restriction to the outer bilayer leaflet. The extensive heterogeneity of the lipid moiety plays a significant, but still largely unknown, role in glycosphingolipid function. Potential interplay between glycolipids and their fatty acid isoforms, together with their preferential interaction with cholesterol, generates a complex mechanism for the regulation of their function in cellular physiology. PMID- 21555410 TI - Permeability of peritoneal and glomerular capillaries: what are the differences according to pore theory? AB - Pore and fiber-matrix theory can both be used to model the peritoneal and glomerular filtration barriers in an attempt to shed light on their differing structure-function relationships. The glomerular filtration barrier (GFB) is structurally more specialized, morphologically complex, and also highly dynamic; but paradoxically, because of its uniformity, it conforms more closely to the predictions of pore theory than does the peritoneum, and it in fact resembles a more simple synthetic membrane. Compared with the peritoneal capillary wall, the GFB has no transcellular "third" pores (aquaporins), and it is far less leaky and more size-selective to proteins, mainly as a result of having far fewer "large" pores. It does have charge-selective properties, although these are considered much less important in excluding albumin than was once thought, and it is also able to select polymers according to their shape and flexibility. Even this property might reflect the relative uniformity of the GFB, which has a high diffusion area and short diffusion distances, compared with the peritoneal barrier, which behaves more like a gel filtration column. Furthermore, the length of the diffusion path across the peritoneal membrane is much greater for small solutes, given the relatively high ultrafiltration coefficient for that membrane compared with the GFB--a situation that reflects both the tortuosity of the interendothelial clefts and the distribution of peritoneal capillaries within the interstitium. These comparisons reveal the peritoneal barrier as a relatively complex structure to model; and yet this model may be more representative of the general microcirculation, and thus shed light on systemic endothelial function in renal failure. PMID- 21555411 TI - Exploring the association between icodextrin and encapsulating peritoneal sclerosis. PMID- 21555412 TI - Is encapsulating peritoneal sclerosis rare in North America? PMID- 21555413 TI - New strategy for encapsulating peritoneal sclerosis from the perspective of hormone receptor expression in peritoneal tissue. PMID- 21555414 TI - Can detection of changes in the motion of abdominal contents using "cine" MRI help in the management of encapsulating peritoneal sclerosis? PMID- 21555415 TI - Incidence of encapsulating peritoneal sclerosis: a single-center experience with long-term peritoneal dialysis in the United States. AB - Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis (PD). The reported incidence varies between 0.5% and 4.4% and increases with length of time on PD. Very few data are available on the epidemiology of EPS in the United States. The aim of the present study was assess the incidence of EPS in a single center in New Haven, Connecticut. In a retrospective analysis of all patients maintained on PD for 5 or more years, clinical symptoms were documented, abdominal computed tomography (CT) findings were reviewed, and surgical and pathology findings were noted. Patients were tracked whether they remained on PD, transferred to hemodialysis (HD), underwent transplantation, or died. Among the 76 patients that met the inclusion criteria (mean dialysis duration: 81.5 +/- 22 months), 14 (18%) developed clinical symptoms (persisting for 3 or more months) suggestive of EPS. Abdominal CT imaging was done in 38 patients; 25 had radiologic features consistent with EPS. At laparotomy, 6 of 7 patients had gross findings consistent with EPS. Eleven patients met the 2000 criteria of the International Society for Peritoneal Dialysis for a diagnosis of EPS; they had clinical features, plus either radiologic or histopathologic confirmation. In 3 patients with clinical symptoms, the radiologic or surgical findings did not support a diagnosis of EPS. Of the 11 patients meeting the EPS criteria, 1 remains on PD and is doing well, 2 were transferred to HD and are doing well, 2 died as a result of EPS complications, and 6 died of other causes. The present study suggests that, in patients maintained on PD for 5 or more years at our center, the incidence of EPS is 14%. Those findings suggest that EPS may be underrecognized in the United States and that a high index of suspicion is warranted in patients maintained on PD for 5 or more years. PMID- 21555416 TI - Impact of dialysis modality on the incidence of 2009 pandemic H1N1 influenza in end-stage renal disease patients. PMID- 21555417 TI - Early partial re-implantation of Tenckhoff catheters to treat intractable exit site or tunnel infection. PMID- 21555418 TI - PD catheter insertion using a double-lumen hemodialysis catheter: an alternative to the peel-away sheath method. PMID- 21555419 TI - Resolution of eosinophilic peritonitis with oral prednisolone in a child receiving peritoneal dialysis. PMID- 21555420 TI - Adult peritoneal dialysis patient with Tenckhoff and percutaneous endoscopic gastrostomy catheters. PMID- 21555421 TI - Imaging of the lesser sac by magnetic resonance peritoneography. PMID- 21555422 TI - Concerns regarding the ISPD guidelines/recommendations for peritonitis due to mycobacteria. PMID- 21555425 TI - Simultaneous peritoneal dialysis-associated peritonitis and bacteremia due to ceftriaxone-resistant Campylobacter fetus. PMID- 21555426 TI - Successful treatment of Mycobacterium gordonae exit-site and tunnel infection by partial catheter reimplantation of the Tenckhoff catheter. PMID- 21555427 TI - Major urologic complication of laparoscopic peritoneal dialysis catheter placement for failed pediatric kidney transplant. PMID- 21555428 TI - Intraluminal stone in a PD catheter--a rare complication. PMID- 21555429 TI - Recurrent exit-site infection due to Staphylococcus lugdunensis--a virulent coagulase-negative Staphylococcus. PMID- 21555430 TI - Implications of new ESC/EACTS guidelines on myocardial revascularization for patients with multivessel coronary artery disease. PMID- 21555431 TI - eComment: Talc pleurodesis by flexi-rigid thoracoscope under local anaesthesia: visual talc slurry? PMID- 21555432 TI - eComment: Talc pleurodesis using rigid thoracoscope. PMID- 21555433 TI - eComment: Early and late atrial fibrillation recurrence after the Cox maze procedure. PMID- 21555434 TI - eComment: Re: The early recurrence is a predictor of late failure in surgical ablation of atrial fibrillation. PMID- 21555435 TI - eComment: Optic nerve blood flow measurements during on-pump heart surgery. PMID- 21555436 TI - eComment: Extracorporeal circulation and ocular/neurological status during heart surgery. PMID- 21555437 TI - eComment: Debridement for empyema: an alternative to decortication but in whom and when? PMID- 21555438 TI - eComment: Stage IIIA-N2 non-small cell lung cancer: could a new scoring system improve the management of heterogeneous disease? PMID- 21555439 TI - eComment: The crucial role of multimodality management of stage IV thymoma. PMID- 21555440 TI - eComment: Octogenarians: do we have to consider new age specific parameters in our practice? PMID- 21555441 TI - eComment: Mortality, morbidity and late survival in lung resection for non-small cell lung cancer in the elderly population. PMID- 21555442 TI - eComment: No change in B-type natriuretic peptide levels assessed in the intermediate postoperative period in patients with severe mitral regurgitation after mitral valve surgery. PMID- 21555443 TI - eComment: To pump or not to pump in lung transplantation--question solved? PMID- 21555444 TI - eComment: What is the best way to diagnose and stage malignant pleural mesothelioma? PMID- 21555445 TI - eComment: Two- or three-dimensional echocardiography: an important diagnostic and prognostic tool in patients with large central pulmonary embolism. PMID- 21555446 TI - eComment: Three-dimensional transesophageal echocardiography: diagnosing intraoperative pulmonary artery thrombus. PMID- 21555447 TI - eComment: Diagnostic pathway in anterior mediastinal mass. PMID- 21555448 TI - eComment: Minimally-invasive technique for benign mediastinal masses. PMID- 21555449 TI - The new social learning: connect better for better health. PMID- 21555452 TI - A hypoxia-induced positive feedback loop promotes hypoxia-inducible factor 1alpha stability through miR-210 suppression of glycerol-3-phosphate dehydrogenase 1 like. AB - Oxygen-dependent regulation of the transcription factor HIF-1alpha relies on a family of prolyl hydroxylases (PHDs) that hydroxylate hypoxia-inducible factor 1alpha (HIF-1alpha) protein at two prolines during normal oxygen conditions, resulting in degradation by the proteasome. During low-oxygen conditions, these prolines are no longer hydroxylated and HIF-1alpha degradation is blocked. Hypoxia-induced miRNA-210 (miR-210) is a direct transcriptional target of HIF 1alpha, but its complete role and targets during hypoxia are not well understood. Here, we identify the enzyme glycerol-3-phosphate dehydrogenase 1-like (GPD1L) as a novel regulator of HIF-1alpha stability and a direct target of miR-210. Expression of miR-210 results in stabilization of HIF-1alpha due to decreased levels of GPD1L resulting in an increase in HIF-1alpha target genes. Altering GPD1L levels by overexpression or knockdown results in a decrease or increase in HIF-1alpha stability, respectively. GPD1L-mediated decreases in HIF-1alpha stability can be reversed by pharmacological inhibition of the proteasome or PHD activity. When rescued from degradation by proteasome inhibition, elevated amounts of GPD1L cause hyperhydroxylation of HIF-1alpha, suggesting increases in PHD activity. Importantly, expression of GPD1L attenuates the hypoxic response, preventing complete HIF-1alpha induction. We propose a model in which hypoxia induced miR-210 represses GPD1L, contributing to suppression of PHD activity, and increases of HIF-1alpha protein levels. PMID- 21555453 TI - Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3. AB - Recent data demonstrate that small synthetic compounds specifically targeting bromodomain proteins can modulate the expression of cancer-related or inflammatory genes. Although these studies have focused on the ability of bromodomains to recognize acetylated histones, it is increasingly becoming clear that histone-like modifications exist on other important proteins, such as transcription factors. However, our understanding of the molecular mechanisms through which these modifications modulate protein function is far from complete. The transcription factor GATA1 can be acetylated at lysine residues adjacent to the zinc finger domains, and this acetylation is essential for the normal chromatin occupancy of GATA1. We have recently identified the bromodomain containing protein Brd3 as a cofactor that interacts with acetylated GATA1 and shown that this interaction is essential for the targeting of GATA1 to chromatin. Here we describe the structural basis for this interaction. Our data reveal for the first time the molecular details of an interaction between a transcription factor bearing multiple acetylation modifications and its cognate recognition module. We also show that this interaction can be inhibited by an acetyllysine mimic, highlighting the importance of further increasing the specificity of compounds that target bromodomain and extraterminal (BET) bromodomains in order to fully realize their therapeutic potential. PMID- 21555454 TI - The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. AB - Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb. PMID- 21555455 TI - Recommendations of the European Association of Echocardiography: how to use echo Doppler in clinical trials: different modalities for different purposes. AB - The European Association of Echocardiography (EAE) has developed the present recommendations to assist clinical researchers in the design, implementation, and conduction of echocardiographic protocols for clinical trials and to guarantee their quality. Clinical trials should be designed and conducted based on the knowledge of the pathophysiology of the clinical condition studied, the technical characteristics of the echo-Doppler modalities, and the variability of the tested parameters. These procedures are important to choose the most reliable and reproducible techniques and parameters. Quality assurance must be guaranteed by adequate training of peripheral site operators to obtain optimal echo-Doppler data and by using a core laboratory for accurate and reproducible data analysis. PMID- 21555456 TI - Valvuloarterial impedance in aortic stenosis: look at the load, but do not forget the flow. PMID- 21555457 TI - Valvuloarterial impedance does not improve risk stratification in low-ejection fraction, low-gradient aortic stenosis: results from a multicentre study. AB - OBJECTIVES: In a multicentre series of patients with low-ejection fraction/low gradient aortic stenosis (LEF/LGAS), we evaluated the prognostic impact of valvuloarterial impedance (Zva). BACKGROUND: Zva in AS, a measure of global afterload taking into account systemic arterial compliance, has been proposed for risk stratification in paradoxical LGAS. We hypothesized that Zva could help risk stratification in LEF/LGAS. METHODS AND RESULTS: We retrospectively calculated Zva (5.6 +/- 1.7 mmHg/mL/m(2)) of 184 consecutive patients (mean age: 71 +/- 10 years) with severe symptomatic LEF/LGAS (valve area <=1 cm2;, EF <=40%, mean transaortic pressure gradient <=40 mmHg) included between 1995 and 2005 in a multicentre registry. Zva was higher in patients with LVEF at rest <=20% (6.6 +/- 2.3 vs. 5.5 +/- 1.6; P = 0.05) and correlated negatively with LVEF at rest (R = 0.25; P = 0.001). Zva was lower in patients without contractile reserve (CR) on dobutamine stress echocardiography (DSE) compared with patients with true severe AS (5.3 +/- 1.3 vs. 5.8 +/- 1.8 mmHg/mL/m(2); P = 0.048). Zva and the variation in stroke volume during DSE were positively correlated (P = 0.0001) but Zva did not allow distinction between true and pseudo-severe AS (5.8 +/- 1.8 vs. 5.3 +/- 1.8 mm Hg/mL/m(2); P = 0.30). In the total population, Zva was not predictive of long-term mortality. In the 128 patients who underwent aortic valve replacement, Zva was not predictive of operative death and of long-term mortality. CONCLUSIONS: Increased Zva is related to low LVEF and more frequent CR on DSE in LEF/LGAS. However, Zva did not allow an accurate distinction between true and pseudo-severe AS and failed to predict operative and long-term mortality after aortic valve replacement, in LEF/LGAS. PMID- 21555458 TI - Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. AB - Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division. PMID- 21555459 TI - Asymmetric properties of the Chlamydomonas reinhardtii cytoskeleton direct rhodopsin photoreceptor localization. AB - The eyespot of the unicellular green alga Chlamydomonas reinhardtii is a photoreceptive organelle required for phototaxis. Relative to the anterior flagella, the eyespot is asymmetrically positioned adjacent to the daughter four membered rootlet (D4), a unique bundle of acetylated microtubules extending from the daughter basal body toward the posterior of the cell. Here, we detail the relationship between the rhodopsin eyespot photoreceptor Channelrhodopsin 1 (ChR1) and acetylated microtubules. In wild-type cells, ChR1 was observed in an equatorial patch adjacent to D4 near the end of the acetylated microtubules and along the D4 rootlet. In cells with cytoskeletal protein mutations, supernumerary ChR1 patches remained adjacent to acetylated microtubules. In mlt1 (multieyed) mutant cells, supernumerary photoreceptor patches were not restricted to the D4 rootlet, and more anterior eyespots correlated with shorter acetylated microtubule rootlets. The data suggest a model in which photoreceptor localization is dependent on microtubule-based trafficking selective for the D4 rootlet, which is perturbed in mlt1 mutant cells. PMID- 21555460 TI - Titin visualization in real time reveals an unexpected level of mobility within and between sarcomeres. AB - The giant muscle protein titin is an essential structural component of the sarcomere. It forms a continuous periodic backbone along the myofiber that provides resistance to mechanical strain. Thus, the titin filament has been regarded as a blueprint for sarcomere assembly and a prerequisite for stability. Here, a novel titin-eGFP knockin mouse provided evidence that sarcomeric titin is more dynamic than previously suggested. To study the mobility of titin in embryonic and neonatal cardiomyocytes, we used fluorescence recovery after photobleaching and investigated the contribution of protein synthesis, contractility, and calcium load to titin motility. Overall, the kinetics of lateral and longitudinal movement of titin-eGFP were similar. Whereas protein synthesis and developmental stage did not alter titin dynamics, there was a strong, inhibitory effect of calcium on titin mobility. Our results suggest a model in which the largely unrestricted movement of titin within and between sarcomeres primarily depends on calcium, suggesting that fortification of the titin filament system is activity dependent. PMID- 21555461 TI - Dual-mode of insulin action controls GLUT4 vesicle exocytosis. AB - Insulin stimulates translocation of GLUT4 storage vesicles (GSVs) to the surface of adipocytes, but precisely where insulin acts is controversial. Here we quantify the size, dynamics, and frequency of single vesicle exocytosis in 3T3-L1 adipocytes. We use a new GSV reporter, VAMP2-pHluorin, and bypass insulin signaling by disrupting the GLUT4-retention protein TUG. Remarkably, in unstimulated TUG-depleted cells, the exocytic rate is similar to that in insulin stimulated control cells. In TUG-depleted cells, insulin triggers a transient, twofold burst of exocytosis. Surprisingly, insulin promotes fusion pore expansion, blocked by acute perturbation of phospholipase D, which reflects both properties intrinsic to the mobilized vesicles and a novel regulatory site at the fusion pore itself. Prolonged stimulation causes cargo to switch from approximately 60 nm GSVs to larger exocytic vesicles characteristic of endosomes. Our results support a model whereby insulin promotes exocytic flux primarily by releasing an intracellular brake, but also by accelerating plasma membrane fusion and switching vesicle traffic between two distinct circuits. PMID- 21555462 TI - NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway. AB - The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling. PMID- 21555463 TI - Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. AB - To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P(2) receptor in the cells neighboring a dying cell, as S1P(2) knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells. PMID- 21555464 TI - Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. AB - Dendritic arborization is a critical neuronal differentiation process. Here, we demonstrate that syndecan-2 (Sdc2), a synaptic heparan sulfate proteoglycan that triggers dendritic filopodia and spine formation, regulates dendritic arborization in cultured hippocampal neurons. This process is controlled by sterile alpha and TIR motif-containing 1 protein (Sarm1), a negative regulator of Toll-like receptor 3 (TLR3) in innate immunity signaling. We show that Sarm1 interacts with and receives signal from Sdc2 and controls dendritic arborization through the MKK4-JNK pathway. In Sarm1 knockdown mice, dendritic arbors of neurons were less complex than those of wild-type littermates. In addition to acting downstream of Sdc2, Sarm1 is expressed earlier than Sdc2, which suggests that it has multiple roles in neuronal morphogenesis. Specifically, it is required for proper initiation and elongation of dendrites, axonal outgrowth, and neuronal polarization. These functions likely involve Sarm1-mediated regulation of microtubule stability, as Sarm1 influenced tubulin acetylation. This study thus reveals the molecular mechanism underlying the action of Sarm1 in neuronal morphogenesis. PMID- 21555465 TI - Embarking on a new course: environmental health coverage. PMID- 21555466 TI - Japan's nuclear crisis renews debate over environment, health, and global energy use. PMID- 21555467 TI - From endocrine disruptors to nanomaterials: advancing our understanding of environmental health to protect public health. AB - Environmental health science is the study of the impact of the environment on human health. This paper introduces basic topics in environmental health, including clean air, clean water, and healthful food, as well as a range of current issues and controversies in environmental health. Conceptual shifts in modern toxicology have changed the field. There is a new understanding of the effects of exposure to chemicals at low doses, and in combination, and the impact on human growth and development. Other emerging topics include the role of epigenetics, or changes in genes and gene expression that can be brought about by chemical exposure; environmental justice; and potential effects of engineered nanomaterials and climate change. We review the important implications for public health policy and recommend a broad environmental health research strategy aimed at protecting and improving human health. PMID- 21555468 TI - Why behavioral and environmental interventions are needed to improve health at lower cost. AB - We used a dynamic simulation model of the US health system to test three proposed strategies to reduce deaths and improve the cost-effectiveness of interventions: expanding health insurance coverage, delivering better preventive and chronic care, and protecting health by enabling healthier behavior and improving environmental conditions. We found that each alone could save lives and provide good economic value, but they are likely to be more effective in combination. Although coverage and care save lives quickly, they tend to increase costs. The impact of protection grows more gradually, but it is a critical ingredient over time for lowering both the number of deaths and reducing costs. Only protection slows the growth in the prevalence of disease and injury and thereby alleviates rather than exacerbates demand on limited primary care capacity. When added to a simulated scenario with coverage and care, protection could save 90 percent more lives and reduce costs by 30 percent in year 10; by year 25, that same investment in protection could save about 140 percent more lives and reduce costs by 62 percent. PMID- 21555469 TI - Discovering how environmental exposures alter genes could lead to new treatments for chronic illnesses. AB - Emerging research demonstrates that diet, pollution, and other environmental triggers can alter both the function and expression of human genes and lead to a heightened disease risk. These environment-gene interactions can cause so-called epigenetic changes in gene expression-patterns of which genes are switched "on" or "off"-that may account for the rising mortality from chronic diseases in industrialized nations. In this paper, we call for a new transdisciplinary approach to public health that would examine how environmental exposures, both physical and social, influence gene expression and a person's susceptibility to chronic disease. This initiative could lead to new ways to prevent and treat such illnesses. PMID- 21555471 TI - Understanding the cumulative impacts of inequalities in environmental health: implications for policy. AB - Racial or ethnic minority groups and low-income communities have poorer health outcomes than others. They are more frequently exposed to multiple environmental hazards and social stressors, including poverty, poor housing quality, and social inequality. Researchers are grappling with how best to characterize the cumulative effects of these hazards and stressors in order to help regulators and decision makers craft more-effective policies to address health and environmental disparities. In this article we synthesize the existing scientific evidence regarding the cumulative health implications of higher rates of exposure to environmental hazards, along with individual biological susceptibility and social vulnerability. We conclude that current environmental policy, which is focused narrowly on pollutants and their sources, should be broadened to take into account the cumulative impact of exposures and vulnerabilities encountered by people who live in neighborhoods consisting largely of racial or ethnic minorities or people of low socioeconomic status. PMID- 21555472 TI - Reproductive health and the industrialized food system: a point of intervention for health policy. AB - What food is produced, and how, can have a critical impact on human nutrition and the environment, which in turn are key drivers of healthy human reproduction and development. The US food production system yields a large volume of food that is relatively low in cost for consumers but is often high in calories and low in nutritional value. In this article we examine the evidence that intensive use of pesticides, chemical fertilizers, hormones, antibiotics, and fossil fuel in food production, as well as chemicals in food packaging, are potentially harmful to human reproductive and developmental health. We conclude that policies to advance a healthy food system are necessary to prevent adverse reproductive health effects and avoid associated health costs among current and future generations. These policies include changes to the Farm Bill and the Toxic Substances Control Act, and greater involvement by the health care sector in supporting and sourcing food from urban agriculture programs, farmers' markets, and local food outlets, as well as increasing understanding by clinicians of the links between reproductive health and industrialized food production. PMID- 21555473 TI - Why the toxic substances control act needs an overhaul, and how to strengthen oversight of chemicals in the interim. AB - The Toxic Substances Control Act gives the Environmental Protection Agency (EPA) the authority to regulate industrial chemicals not covered by other statutes. Today there are more than 83,000 such chemicals. However, the law is widely perceived as weak and outdated, and various stakeholders have called for its reform, citing the EPA's inability to regulate the use of asbestos, among other substances. We analyze the flaws in the act and suggest ways in which the EPA might better position itself to manage chemical risks and protect the public's health. In addition to the new tools and technologies it is adopting, the agency needs new allies-both inside and outside the government-in its efforts to identify and control hazardous chemicals. PMID- 21555474 TI - Lessons learned from flame retardant use and regulation could enhance future control of potentially hazardous chemicals. AB - Flame retardant chemicals, used in many furniture and electronic products to slow combustion, are an example of science and policy problems related to chemical usage. Drawing on a literature review and interviews with stakeholders, we argue that early warnings of the health hazards some flame retardants pose were not heeded as their use expanded to different products. Continued use of flame retardants coincides with their increased presence in people and adverse human health effects. We recommend policy changes applicable to oversight of chemicals in general: examining classes of chemicals rather than individual ones, assessing alternative methods and materials, product labeling, and stronger regulation. PMID- 21555475 TI - Protecting food safety: more needs to be done to keep pace with scientific advances and the changing food supply. AB - Foodborne illness and the health risks from chemicals in food are a concern. However, food safety statutes largely unchanged for more than forty years are failing to keep pace with scientific advances and the changing food supply. The FDA Food Safety Modernization Act, enacted in January 2011, is intended to help reduce foodborne illness by establishing new prevention measures for food regulated by the Food and Drug Administration. Additional funding is needed so that the agency has enough resources to help realize the law's potential. Furthermore, key food safety issues untouched by the 2011 statute, including restrictions on antibiotic use in animal agriculture, laws governing meat and poultry safety, and requirements governing the use of chemicals in food, should be reviewed and updated as necessary-using up-to-date science-to tighten the focus on preventing disease. PMID- 21555476 TI - Climate change and health risks: assessing and responding to them through 'adaptive management'. AB - Climate change and associated changing weather patterns, including severe weather events, are expected to increase the prevalence of a wide range of health risks. Yet there is uncertainty about the timing, location, and severity of these changes. Adaptive management, a structured process of decision making in the face of imperfect information, is an approach that can help the public health field effectively anticipate, plan for, and respond to the health risks of climate change. In this article I describe adaptive management and how it could increase the effectiveness of local and national strategies, policies, and programs to manage climate-sensitive health outcomes. PMID- 21555477 TI - An evidence-based medicine methodology to bridge the gap between clinical and environmental health sciences. AB - Physicians and other clinicians could help educate patients about hazardous environmental exposures, especially to substances that could affect their reproductive health. But the relevant scientific evidence is voluminous, of variable quality, and largely unfamiliar to health professionals caring for people of childbearing age. To bridge this gap between clinical and environmental health, we created a methodology to help evaluate the quality of evidence and to support evidence-based decision making by clinicians and patients. The methodology can also support professional societies, health care organizations, government agencies, and others in developing prevention-oriented guidelines for use in clinical and policy settings. PMID- 21555478 TI - Use of electronic health records can improve the health care industry's environmental footprint. AB - Electronic health records have the potential to improve the environmental footprint of the health care industry. We estimate that Kaiser Permanente's electronic health record system, which covers 8.7 million beneficiaries, eliminated 1,000 tons of paper records and 68 tons of x-ray film, and that it has lowered gasoline consumption among patients who otherwise would have made trips to the doctor by at least three million gallons per year. However, the use of personal computers resulted in higher energy consumption and generated an additional 250 tons of waste. We conclude that electronic health records have a positive net effect on the environment, and that our model for evaluating their impact can be used to determine whether their use can improve communities' health. PMID- 21555479 TI - Health impact assessments are needed in decision making about environmental and land-use policy. AB - The importance to public health of environmental decisions-including those about land use, transportation, power generation, agriculture, and environmental regulation-is increasingly well documented. Yet many decision makers in fields not traditionally focused on health continue to pay little if any attention to the important health effects of their work. This article examines the emerging practice of health impact assessment and offers real-world examples of its effective implementation, including studying the impact of nearby highways-a major source of air pollution-on proposed new housing for seniors. The article argues that officials at the federal, state, and local levels should consult health experts and consider using health impact assessments when their decisions on such issues as urban planning, land use, and environmental regulation have the potential to directly affect the conditions in which people live and work. PMID- 21555480 TI - The need for better public health decisions on chemicals released into our environment. AB - Protecting the health of the public-particularly the most vulnerable groups, such as children-requires rethinking current approaches to reducing environmental risks. We review the evolving understanding of the relationship between exposure to chemicals in the environment and disease, as well as the current state of managing those chemicals. We present recommendations to improve current approaches, including changing the burden of proof so that chemicals are not presumed safe in the absence of scientific data. We also propose modernizing approaches to assessing health risks. PMID- 21555481 TI - Coding complexity: US Health Care gets ready for the coming Of ICD-10. PMID- 21555483 TI - Toxic tale: an 'enviro' learns why we need tighter controls on home pesticide use. AB - She had her house sprayed for fleas and then suffered a severe autoimmune reaction to the chemicals. Now she argues for tighter controls. PMID- 21555482 TI - Fewer hospitalizations result when primary care is highly integrated into a continuing care retirement community. AB - Meeting the medical and social needs of elderly people is likely to be costly, disruptive, and at odds with personal preferences if efforts to do so are not well coordinated. We compared two different models of primary care in four different continuing care retirement communities. In the first model, used in one community, the physicians and two part-time nurse practitioners delivered clinical care only at that site, covered all settings within it, and provided all after-hours coverage. In the second model, used in three communities, on-site primary care physician hours were limited; the same physicians also had independent practices outside the retirement community; and after-hours calls were covered by all members of the practices, including physicians who did not practice on site. We found that residents in the first model had two to three times fewer hospitalizations and emergency department visits. Only 5 percent of those who died did so in a hospital, compared to 15 percent at the other sites and 27 percent nationally. These findings provide insight into what is possible when medical care is highly integrated into a residential retirement setting. PMID- 21555484 TI - Philanthropy at the intersection of health and the environment. AB - Scores of foundations are supporting efforts to improve the environmental conditions that affect health outcomes. Environmental health philanthropy has grown from a few foundations in 1999 to more than 100 today, and to annual investments of at least $70 million. This dynamic area of philanthropy is assisting disaster-stricken communities in the Gulf Coast, supporting a national movement to reform chemicals policy, defending clean air and water standards, and underwriting environmental justice work in low-income communities and communities of color. We argue that these investments are yielding sizable returns, but more funding opportunities exist to deepen understanding of hazards, clean up communities, reform policies, and embed environmental health in new economic development. PMID- 21555485 TI - Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. AB - Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological alpha galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-gamma production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor-driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12-induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections. PMID- 21555486 TI - miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. AB - Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ~22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation. PMID- 21555487 TI - Physician assistant and nurse practitioner utilization in academic medical centers. AB - The purpose of this study was to collect information on the utilization of physician assistants (PAs) and nurse practitioners (NPs) in academic health centers. Data were gathered from a national sample of University HealthSystem Consortium member academic medical centers (AMCs). PAs and NPs have been integrated into most services of respondent AMCs, where they are positively rated for the value they bring to these organizations. The primary reason cited by most AMCs for employing PAs and NPs was Accreditation Council for Graduate Medical Education resident duty hour restrictions (26.9%). Secondary reasons for employing PAs and NPs include increasing patient throughput (88%), increasing patient access (77%), improving patient safety/quality (77%), reducing length of stay (73%), and improving continuity of care (73%). However, 69% of AMCs report they have not successfully documented the financial impact of PA/NP practice or outcomes associated with individual PA or NP care. PMID- 21555488 TI - The evolution of the ACMQ's Student and Resident Initiative. PMID- 21555490 TI - Outcomes for children hospitalized with abusive versus noninflicted abdominal trauma. AB - BACKGROUND: Abusive abdominal trauma (AAT) is the second leading cause of child abuse mortality. Previous outcome studies have been limited to data from trauma centers. OBJECTIVES: The goals of this study were (1) to examine mortality, length of hospitalization, and hospital charges among a national sample of children hospitalized for AAT; and (2) to compare these outcomes with children with noninflicted abdominal trauma. METHODS: Hospitalization data for children aged 0 to 9 years were obtained from the 2003 and 2006 Kids' Inpatient Database. Cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification and external cause of injury codes. Multivariable regression analyses were used to compare outcomes of children with AAT versus those with noninflicted injury. RESULTS: Children with AAT were younger, and more often insured by Medicaid. Among children surviving to discharge, those with AAT had longer hospitalizations (adjusted mean [95% confidence interval (CI)] length of stay: 7.9 (6.6-9.3) vs 6.4 (6.1-6.7) days, P < .01) and higher charges (adjusted mean [95% CI] costs: $24 343 [$20 952-$28 567] vs $19 341 [$18 770-$20 131]; P < .01). Among children aged 1 to 9 years, those with AAT had higher mortality (adjusted rate [95% CI]: 9.2% [5.0%-16.1%] vs 2.7% [2.2%-3.2%], P < .01). There was no significant difference in mortality for children aged younger than 1 year. CONCLUSIONS: Children hospitalized for AAT generally had poorer short-term outcomes compared with children with noninflicted abdominal trauma. Studies to explain these differences are needed. In addition, efforts to prevent these injuries and to assist families at risk should be supported. PMID- 21555491 TI - Long-term impact of poor birth condition on social and economic outcomes in early adulthood. AB - OBJECTIVE: The goal of this study was to investigate the association of poor birth condition with long-term social and economic outcomes at 25 to 31 years of age. METHODS: This was a population-based cohort study using data derived from linkage of routinely collected Swedish data. All term infants born in Sweden between 1973 and 1979 identified from the Swedish birth registry (n = 651 615) were included in the study. Infants were categorized into 3 groups: (1) infants with a normal (>7) Apgar score at 1 or 5 minutes of age without encephalopathy; (2) infants with a low (<7) Apgar score at 1 and 5 minutes of age without encephalopathy; and (3) infants with a low (<7) Apgar score at 1 and 5 minutes with evidence of encephalopathy. The main outcome measures were achievement of a university education and participant's income in early adulthood. RESULTS: Infants with low Apgar scores who did not develop encephalopathy were less likely to have attended university (odds ratio [OR]: 1.14 [95% confidence interval (CI): 1.05-1.23]) and were more likely to have no income from work (OR: 1.19 [95% CI: 1.07-1.32]) than those born in good condition. Infants who developed encephalopathy also had greater risks of these adverse outcomes (not attended university, OR: 1.94 [95% CI: 1.13-3.33]); no income from work, OR: 3.08 [95% CI: 1.89-5.01]). CONCLUSIONS: Infants born in poor condition had worse measures of social performance than their peers, and this association was not restricted to those infants who developed obvious neurologic symptoms in the neonatal period. However, even in infants with likely encephalopathy, more than half obtained employment and one third attended university. PMID- 21555492 TI - Self-embedding behavior: a new primary care challenge. AB - OBJECTIVE: The goal of this study was to define self-embedding behavior (SEB), develop a clinical profile of adolescents who engage in SEB, and emphasize the importance of rapid, targeted, and effective identification and intervention. METHODS: As part of a retrospective study with a database evaluating 600 patients percutaneously treated for soft-tissue foreign body removal, adolescents were identified with self-embedded soft-tissue foreign bodies. We describe patients' gender, age, and psychiatric diagnoses; SEB age of onset, frequency, and self reported reasons; and the number, type, location of, and removal technique for objects. RESULTS: Eleven patients (9 females) who engaged in SEB were identified. Ten of the 11 patients were members of a group home or psychiatric facility at the time they engaged in SEB. All patients had previous and multiple psychiatric diagnoses. SEB mean age-of-onset was 16 years, and mean number of SEB episodes per patient was 1.9. The most common self-reported purpose for SEB was suicidal ideation (6 of 8 [75%]) versus nonsuicidal ideation (2 of 8 [25%]), with 3 cases lacking this documentation. The mean number of objects embedded in a single episode was 2.4, usually composed of metal and embedded in the arm. Seventy-six foreign bodies were percutaneously removed (using ultrasound or fluoroscopic guidance), including metal, glass, wood, plastic, graphite, and crayon. CONCLUSIONS: SEB is an extreme form of self-injury requiring aggressive and timely interdisciplinary assessment and treatment. An understanding of SEB allows medical professionals to pursue rapid, targeted, and effective intervention to interrupt the cycle of self-harm and institute appropriate long-term therapy. PMID- 21555493 TI - Epidemiology of 15-Day Readmissions to a Children's Hospital. AB - OBJECTIVE: To describe the population of pediatric patients readmitted to a children's hospital within 15 days of discharge. PATIENTS AND METHODS: Medical records were reviewed to identify characteristics of patients and their hospitalizations for all children hospitalized during calendar years 2007-2008 who were readmitted up to and including 15 days after a previous discharge. RESULTS: Of 30 188 total hospital admissions during the study period, 2546 (8.4%) were followed by a readmission within 15 days of discharge. The age groups with the greatest number of readmissions were infants (aged 31-364 days, 20.8% of readmissions) and patients aged >10 years (31.3% of readmissions). Most readmitted patients (78.0%) had an underlying chronic illness, and patients with malignancies were most likely to be readmitted, followed by newborns and patients with neurologic conditions. Patients with malignancies also experienced the greatest number of readmissions per patient (4.1). Most patients who were readmitted had only 1 readmission (71.5%), but the small subset of patients with 3 or more readmissions accounted for 43.7% of all 15-day readmissions. Disease recurrence and natural course of the original diagnosis were the most common reasons for readmission (44.9%), followed by planned readmissions (20.6%) and readmissions for a new, unrelated illness (7.7%). CONCLUSIONS: This report is the first description of the epidemiology of all 15-day pediatric readmissions at a children's hospital. The results of this study serve as a basis for additional analysis to determine the extent to which readmissions in the pediatric population may or may not be preventable. PMID- 21555494 TI - Preventing medication overdoses in young children: an opportunity for harm elimination. PMID- 21555495 TI - Pediatric palliative care patients: a prospective multicenter cohort study. AB - OBJECTIVE: To describe demographic and clinical characteristics and outcomes of patients who received hospital-based pediatric palliative care (PPC) consultations. DESIGN, SETTING, AND PATIENTS: Prospective observational cohort study of all patients served by 6 hospital-based PPC teams in the United States and Canada from January to March 2008. RESULTS: There were 515 new (35.7%) or established (64.3%) patients who received care from the 6 programs during the 3 month enrollment interval. Of these, 54.0% were male, and 69.5% were identified as white and 8.1% as Hispanic. Patient age ranged from less than one month (4.7%) to 19 years or older (15.5%). Of the patients, 60.4% lived with both parents, and 72.6% had siblings. The predominant primary clinical conditions were genetic/congenital (40.8%), neuromuscular (39.2%), cancer (19.8%), respiratory (12.8%), and gastrointestinal (10.7%). Most patients had chronic use of some form of medical technology, with gastrostomy tubes (48.5%) being the most common. At the time of consultation, 47.2% of the patients had cognitive impairment; 30.9% of the cohort experienced pain. Patients were receiving many medications (mean: 9.1). During the 12-month follow-up, 30.3% of the cohort died; the median time from consult to death was 107 days. Patients who died within 30 days of cohort entry were more likely to be infants and have cancer or cardiovascular conditions. CONCLUSIONS: PPC teams currently serve a diverse cohort of children and young adults with life-threatening conditions. In contrast to the reported experience of adult-oriented palliative care teams, most PPC patients are alive for more than a year after initiating PPC. PMID- 21555496 TI - Linezolid-associated peripheral and optic neuropathy in children. AB - OBJECTIVE: Peripheral neuropathy (PN) and optic neuropathy (ON) associated with linezolid use are described in the adult literature; however limited information is available in pediatrics. The purpose of this communication is to summarize pediatric cases of linezolid-associated neuropathy and to increase awareness of these neurologic side effects so that clinicians can most appropriately balance the benefits and risks of linezolid in the pediatric population. METHODS: A search of the FDA Adverse Events Reporting System was performed for all pediatric cases of neuropathy from April 2000-2009. AERS includes both inpatient and outpatient data. Inpatient utilization patterns for linezolid were also assessed from January 2000 to December 2008. RESULTS: Eight pediatric cases of linezolid associated neuropathy were identified. Treatment duration ranged from 4 weeks to 1 year. Five patients had PN alone, one had only ON and two had both. Symptoms of PN included pain, numbness, weakness, and paresthesias. Symptoms of ON included decreased visual acuity and color vision. Three children had other adverse events associated with linezolid including acidosis, anemia, and leukopenia. Outcomes were reported in 5 cases. Resolution of symptoms occurred between 2 weeks and 6 months after discontinuation of linezolid. Utilization data showed that during the study period, overall inpatient utilization of linezolid had increased. CONCLUSIONS: While linezolid may be used to treat serious infections often needing extended courses of therapy, potential safety concerns should be kept in mind. In the circumstance of prolonged use of linezolid in children, it is likely that more cases of neuropathy may occur. PMID- 21555497 TI - Abnormal high-density lipoproteins in overweight adolescents with atherogenic dyslipidemia. AB - OBJECTIVE: This study aimed to evaluate high-density lipoprotein functionality and the cardiovascular risk factor profile in the overweight pediatric population. We hypothesized that overweight adolescents with low high-density lipoprotein cholesterol and elevated triglyceride plasma levels have metabolic abnormalities and dysfunctional high-density lipoprotein particles, similar to those reported in adults. PATIENTS AND METHODS: Overweight adolescents with (group 1 [n = 21]) and without (group 2 [n = 36]) atherogenic dyslipidemia (high density lipoprotein cholesterol: <= 40 mg/dL and triglycerides: >= 150 mg/dL) and normal-weight normolipidemic subjects, as a reference (group 3 [n = 36]), were included. The cardiovascular risk factor profile (lipids, lipoproteins, high sensitivity C-reactive protein, and insulin), high-density lipoprotein subclass distribution, composition, and cholesterol efflux capacity were studied. RESULTS: Group 1 adolescents showed abnormalities in high-density lipoprotein subclass distribution and high-density lipoprotein chemical composition, as well as a significantly lower capacity to promote cholesterol efflux (14.8 +/- 2.8, 16.5 +/ 3.8, 20.4 +/- 3.5, for groups 1, 2 and 3, respectively). High-density lipoprotein(2a) (R(2) = 0.212, beta = 0.472, P < .0001) and the Tanner score (R(2) = 0.054, beta = -0.253, P = .02) were the independent predictors of cholesterol efflux. Group 1 also showed a higher degree of cardiovascular abnormalities (an adverse lipoprotein profile, greater insulin resistance and systemic inflammation; and lower low-density lipoprotein size) than group 2, even after BMI and Tanner score adjustment. CONCLUSIONS: This study suggests that atherogenic dyslipidemia identifies overweight adolescents with quantitative, qualitative, and functional high-density lipoprotein abnormalities. Atherogenic dyslipidemia seems to be a marker of an increased risk for developing cardiovascular disease and indicates that those adolescents should be a target of aggressive prevention programs and lipid management guidelines. PMID- 21555498 TI - The effect of observation on cranial computed tomography utilization for children after blunt head trauma. AB - OBJECTIVE: Children with minor blunt head trauma often are observed in the emergency department before a decision is made regarding computed tomography use. We studied the impact of this clinical strategy on computed tomography use and outcomes. METHODS: We performed a subanalysis of a prospective multicenter observational study of children with minor blunt head trauma. Clinicians completed case report forms indicating whether the child was observed before making a decision regarding computed tomography. We defined clinically important traumatic brain injury as an intracranial injury resulting in death, neurosurgical intervention, intubation for longer than 24 hours, or hospital admission for 2 nights or longer. To compare computed tomography rates between children observed and those not observed before a decision was made regarding computed tomography use, we used a generalized estimating equation model to control for hospital clustering and patient characteristics. RESULTS: Of 42 412 children enrolled in the study, clinicians noted if the patient was observed before making a decision on computed tomography in 40 113 (95%). Of these, 5433 (14%) children were observed. The computed tomography use rate was lower in those observed than in those not observed (31.1% vs 35.0%; difference: -3.9% [95% confidence interval: -5.3 to -2.6]), but the rate of clinically important traumatic brain injury was similar (0.75% vs 0.87%; difference: -0.1% [95% confidence interval: -0.4 to 0.1]). After adjustment for hospital and patient characteristics, the difference in the computed tomography use rate remained significant (adjusted odds ratio for obtaining a computed tomography in the observed group: 0.53 [95% confidence interval: 0.43-0.66]). CONCLUSIONS: Clinical observation was associated with reduced computed tomography use among children with minor blunt head trauma and may be an effective strategy to reduce computed tomography use. PMID- 21555499 TI - Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI. OBJECTIVE: To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI. DESIGN: A prospective birth cohort study was performed in healthy term neonates. Concentrations of 25-hydroxyvitamin D (25 OHD) in cord blood plasma were related to RSV LRTI in the first year of life, defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen. RESULTS: The study population included 156 neonates. Eighteen (12%) developed RSV LRTI. The mean plasma 25-OHD concentration was 82 nmol/L. Overall, 27% of neonates had 25-OHD concentrations < 50 nmol/L, 27% had 50-74 nmol/L and only 46% had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy. Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not (65 nmol/L versus 84 nmol/L, P = .009). Neonates born with 25-OHD concentrations <50 nmol/L had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations >= 75 nmol/L. CONCLUSIONS: Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life. Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy. PMID- 21555500 TI - Preterm birth and inhaled corticosteroid use in 6- to 19-year-olds: a Swedish national cohort study. AB - OBJECTIVE: Preterm birth is associated with respiratory morbidity later in life, including asthma. Previous studies have mainly focused on asthma in early childhood in children born extremely preterm. In this study, we examined the risk of asthma in a national cohort of schoolchildren grouped according to degree of immaturity expressed as completed gestational weeks at birth. METHODS: This was a register study in a Swedish national cohort of 1 100 826 children 6 to 19 years old. Retrieval of at least 1 prescription of inhaled corticosteroids (ICS) during 2006 was used as the main indicator for asthma. Logistic regression was used to test hypotheses, with adjustment for multiple socioeconomic and perinatal indicators. RESULTS: Degree of immaturity, expressed as completed gestational weeks at birth, had an inverse dose-response relationship with ICS use. Compared with children born between 39 and 41 weeks' gestation, the odds ratio for ICS use increased with the degree of prematurity, from 1.10 (95% confidence interval: 1.08-1.13) for children born in weeks 37 to 38, to 2.28 (95% confidence interval: 1.96-2.64) for children born in weeks 23 to 28, after adjustment for confounders. The increase in ICS use with decreasing gestational age at delivery was similar in boys and girls, and declined with older age. CONCLUSION: Preterm birth increased the risk of ICS use in these 6- to 19-year-olds by degree of immaturity, from extremely preterm to early term birth. PMID- 21555501 TI - Clonidine extended-release tablets as add-on therapy to psychostimulants in children and adolescents with ADHD. AB - OBJECTIVE: To assess the efficacy and safety of clonidine hydrochloride extended release tablets (CLON-XR) combined with stimulants (ie, methylphenidate or amphetamine) for attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS: In this phase 3, double-blind, placebo-controlled trial, children and adolescents with hyperactive- or combined-subtype ADHD who had an inadequate response to their stable stimulant regimen were randomized to receive CLON-XR or placebo in combination with their baseline stimulant medication. Predefined efficacy measures evaluated change from baseline to week 5. Safety was assessed by spontaneously reported adverse events, vital signs, electrocardiogram recordings, and clinical laboratory values. Improvement from baseline for all efficacy measures was evaluated using analysis of covariance. RESULTS: Of 198 patients randomized, 102 received CLON-XR plus stimulant and 96 received placebo plus stimulant. At week 5, greater improvement from baseline in ADHD Rating Scale IV (ADHD-RS-IV) total score (95% confidence interval: -7.83 to -1.13; P = .009), ADHD-RS-IV hyperactivity and inattention subscale scores (P = .014 and P = .017, respectively), Conners' Parent Rating Scale scores (P < .062), Clinical Global Impression of Severity (P = .021), Clinical Global Impression of Improvement (P = .006), and Parent Global Assessment (P = .001) was observed in the CLON-XR plus stimulant group versus the placebo plus stimulant group. Adverse events and changes in vital signs in the CLON-XR group were generally mild. CONCLUSIONS: The results of this study suggest that CLON-XR in combination with stimulants is useful in reducing ADHD in children and adolescents with partial response to stimulants. PMID- 21555502 TI - National ambulatory antibiotic prescribing patterns for pediatric urinary tract infection, 1998-2007. AB - OBJECTIVE: The goal of this study was to investigate patterns of ambulatory antibiotic use and to identify factors associated with broad-spectrum antibiotic prescribing for pediatric urinary tract infections (UTIs). METHODS: We examined antibiotics prescribed for UTIs for children aged younger than 18 years from 1998 to 2007 using the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. Amoxicillin-clavulanate, quinolones, macrolides, and second- and third-generation cephalosporins were classified as broad-spectrum antibiotics. We evaluated trends in broad-spectrum antibiotic prescribing patterns and performed multivariable logistic regression to identify factors associated with broad-spectrum antibiotic use. RESULTS: Antibiotics were prescribed for 70% of pediatric UTI visits. Trimethoprim-sulfamethoxazole was the most commonly prescribed antibiotic (49% of visits). Broad-spectrum antibiotics were prescribed one third of the time. There was no increase in overall use of broad-spectrum antibiotics (P = .67); however, third-generation cephalosporin use doubled from 12% to 25% (P = .02). Children younger than 2 years old (odds ratio: 6.4 [95% confidence interval: 2.2-18.7, compared with children 13-17 years old]), females (odds ratio: 3.6 [95% confidence interval: 1.6-8.5]), and temperature >= 100.4 degrees F (odds ratio: 2.9 [95% confidence interval: 1.0-8.6]) were independent predictors of broad-spectrum antibiotic prescribing. Race, physician specialty, region, and insurance status were not associated with antibiotic selection. CONCLUSIONS: Ambulatory care physicians commonly prescribe broad spectrum antibiotics for the treatment of pediatric UTIs, especially for febrile infants in whom complicated infections are more likely. The doubling in use of third-generation cephalosporins suggests that opportunities exist to promote more judicious antibiotic prescribing because most pediatric UTIs are susceptible to narrower alternatives. PMID- 21555503 TI - Stereotype threat undermines academic learning. AB - Two experiments tested whether stereotype threat can undermine the acquisition of academic knowledge and thus harm performance even in nonthreatening settings. In Experiment 1, Black and White students studied rare words in either nonthreatening or threatening conditions. One to two weeks later, participants recalled word definitions, half in a nonthreatening "warm-up" and half in a threatening "test." Replicating past research, Black students performed worse on the test than on the warm-up. But importantly, Black students who had studied in the threatening rather than nonthreatening environment performed worse even on the warm-up. White students were unaffected. In Experiment 2, a value affirmation eliminated the learning-threat effect and provided evidence of psychological process. The results suggest that stereotype threat causes a form of "double jeopardy" whereby threat can undermine both learning and performance. The discussion addresses implications for the interpretation of group differences and for understanding how brief threat-reducing interventions can produce long lasting benefits. PMID- 21555504 TI - Does climate undermine subjective well-being? A 58-nation study. AB - The authors test predictions from climato-economic theories of culture that climate and wealth interact in their influence on psychological processes. Demanding climates (defined as colder than temperate and hotter than temperate climates) create potential threats for humans. If these demands can be met by available economic resources, individuals experience challenging opportunities for self-expression and personal growth and consequently will report lowest levels of ill-being. If threatening climatic demands cannot be met by resources, resulting levels of reported ill-being will be highest. These predictions are confirmed in nation-level means of health complaints, burnout, anxiety, and depression across 58 societies. Climate, wealth, and their interaction together account for 35% of the variation in overall subjective ill-being, even when controlling for known predictors of subjective well-being. Further investigations of the process suggest that cultural individualism does not mediate these effects, but subjective well-being may function as a mediator of the impact of ecological variables on ill-being. PMID- 21555505 TI - Early start of dialysis: a critical review. AB - In the US, patients who initiate dialysis "early" (at Modification of Diet in Renal Disease estimated GFR [eGFR]> 10 ml/min per 1.73 m(2)) account for over 50 percent of new dialysis starts. This trend to an early start is based on conventional wisdoms regarding benefits of dialytic clearance, that albumin levels are nutritional markers, and early dialytic therapy is justified to improve nutrition especially in diabetics and that waiting until low levels of eGFR (i.e., <6 ml/min per 1.73 m(2)) may be dangerous. In order to justify early dialysis treatment, the therapy must provide a morbidity, mortality, or quality of life benefit. The current review examines whether early dialysis initiation provides any of these benefits and whether the conventional wisdoms that have promoted this early dialysis trend are valid. Utilizing this information and the results of recent large observational studies and the randomized controlled Initiating Dialysis Early and Late (IDEAL) study, we suggest that dialysis initiation is justified at GFR levels of 5-9 ml/min/1.73 m(2), if accompanied by uremia symptoms or fluid management issues. PMID- 21555506 TI - The imidazoacridinone antitumor drug, C-1311, is metabolized by flavin monooxygenases but not by cytochrome P450s. AB - 5-Diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) is an antitumor agent that is also active against autoimmune diseases. The intention of the present studies was to elucidate the role of selected liver enzymes in metabolism of C-1311 and the less active 8-methyl derivative, 5-diethylaminoethylamino-8 methoxyimidazoacridinone (C-1330). Compounds were incubated with rat liver microsomal fraction, with a set of 16 human liver protein samples, and with human recombinant isoenzymes of cytochrome P450, flavin monooxygenases (FMO), and UDP glucuronosyltransferase (UGT). Our results showed that C-1311 and C-1330 were metabolized with human liver microsomal enzymes but not with any tested human recombinant cytochromes P450 (P450s). Two of these, CYP1A2 and CYP3A4, were inhibited by both compounds. In addition, results of C-1311 elimination from hepatic reductase-null mice, in which liver NADPH-P450 oxidoreductase has been deleted indicated that liver P450s were slightly engaged in drug transformation. In contrast, both compounds were good substrates for human recombinant FMO1 and FMO3 but not for FMO5. The product of FMO metabolism, P(FMO), which is identified as an N-oxide derivative, was identical to P3(R) of liver microsomes. P3(R) was observed even in the presence of the P450 inhibitor, 1-aminobenzotriazole, and it disappeared after heating. Therefore, FMO enzymes could be responsible for microsomal metabolism to P3(R) = P(FMO). Glucuronidation on the 8-hydroxyl group of C-1311 was observed with liver microsomes supported by UDP-glucuronic acid and with recombinant UGT1A1, but it was not the case with UGT2B7. Summing up, we showed that, whereas liver P450 isoenzymes were involved in the metabolism of C 1311 to a limited extent, FMO plays a significant role in the microsomal transformations of this compound, which is also a specific substrate of UGT1A1. PMID- 21555507 TI - Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug metabolizing enzymes in human hepatocyte culture. AB - The cytokine-mediated suppression of hepatic drug-metabolizing enzymes by inflammatory disease and the relief of this suppression by successful disease treatment have recently become an issue in the development of drug interaction labels for new biological products. This study examined the effects of the inflammatory cytokine interleukin-6 (IL-6) on drug-metabolizing enzymes in human hepatocyte culture and the abrogation of these effects by a monoclonal antibody directed against IL-6. Treatment of human hepatocytes with IL-6 (n = 9 donors) revealed pan-suppression of mRNA of 10 major cytochrome P450 isoenzymes, but with EC(50) values that differed by isoenzyme. Some EC(50) values were above the range of clinically relevant serum concentrations of IL-6. Marker activities for CYP1A2 and CYP3A4 enzyme were similarly suppressed by IL-6 in both freshly isolated and cryopreserved hepatocytes. IL-6 suppressed induction of CYP1A2 enzyme activity by omeprazole and CYP3A4 enzyme activity by rifampicin but only at supraphysiological concentrations of IL-6. Glycosylated and nonglycosylated IL-6 did not significantly differ in their ability to suppress CYP1A2 and CYP3A4 enzyme activity. A monoclonal antibody directed against IL-6 abolished or partially blocked IL-6-mediated suppression of CYP1A2 and CYP3A4 enzyme activity, respectively. These data indicate that experimentation with IL-6 and anti-IL-6 monoclonal antibodies in human hepatocyte primary culture can quantitatively measure cytochrome P450 suppression and desuppression and determine EC(50) values for IL-6 against individual cytochrome P450 isoenzymes. However, the complex biology of inflammatory disease may not allow for quantitative in vitro-in vivo extrapolation of these simple in vitro data. PMID- 21555508 TI - Augmentation of a rotator cuff suture repair using rhPDGF-BB and a type I bovine collagen matrix in an ovine model. AB - BACKGROUND: Rotator cuff tears are a common source of shoulder pain. High rates (20%-94%) of structural failure of the repair have been attributed to multiple factors, including poor repair tissue quality and tendon-to-bone integration. Biologic augmentation using growth factors has potential to promote tendon-to bone integration, improving the function and long-term success of the repair. One such growth factor is platelet-derived growth factor-BB (PDGF-BB), which has been shown to improve healing in tendon and bone repair models. HYPOTHESIS: Recombinant human PDGF-BB (rhPDGF-BB) combined with a highly porous type I bovine collagen matrix will improve the biomechanical function and morphologic appearance of the repair in a dose-dependent manner, relative to a suture-only control, after 12 weeks in an acute ovine model of rotator cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: An interpositional graft consisting of rhPDGF-BB and a type I collagen matrix was implanted in an ovine model of rotator cuff repair. Biomechanical and histologic analyses were performed to determine the functional and anatomic characteristics of the repair after 12 weeks. RESULTS: A significant increase in the ultimate load to failure was observed in repairs treated with 75 ug (1490.5 +/- 224.5 N, P = .029) or 150 ug (1486.6 +/- 229.0 N, P = .029) of rhPDGF-BB, relative to suture-only controls (910.4 +/- 156.1 N) and the 500-ug rhPDGF-BB group (677.8 +/- 105.9 N). The 75-ug and 150-ug rhPDGF-BB groups also exhibited increased tendon-to-bone interdigitation histologically. No differences in inflammation or cellularity were observed among treatments. CONCLUSION: This study demonstrated that an interpositional graft consisting of rhPDGF-BB (75 or 150 ug) and a type I collagen matrix was able to improve the biomechanical strength and anatomic appearance in an ovine model of rotator cuff repair compared to a suture-only control and the 500-ug rhPDGF-BB group. CLINICAL RELEVANCE: Recombinant human PDGF-BB combined with a type I collagen matrix has potential to be used to augment surgical repair of rotator cuff tears, thereby improving clinical success. PMID- 21555509 TI - Quantitative analysis of the medial ulnar collateral ligament ulnar footprint and its relationship to the ulnar sublime tubercle. AB - BACKGROUND: The medial ulnar collateral ligament is the major soft tissue restraint to valgus displacement of the elbow. Currently, little has been published regarding the medial ulnar collateral ligament's ulnar footprint. HYPOTHESIS: The medial ulnar collateral ligament has a long attachment onto the ulna and the anatomy of the footprint is consistent. STUDY DESIGN: Descriptive laboratory study. METHODS: The authors studied the morphologic characteristics of the ulnar footprint of the medial ulnar collateral ligament in 10 fresh-frozen cadaveric specimens, 100 osseous specimens, and with 3-dimensional computed tomography in an additional 10 osseous specimens. They measured the length of the anterior band's ulnar attachment and the entire ligament length. They also measured the length of the osseous ridge, which extends distally from the sublime tubercle in both osseous specimens and on computed tomography. RESULTS: The mean length of the medial ulnar collateral ligament was 53.9 mm and the mean length of the ulnar soft tissue footprint was 29.2 mm. The authors identified an osseous ridge that extended distally from the sublime tubercle to just medial to the ulnar insertion of the brachialis muscle tendon. This osseous ridge was present in all osseous and fresh-frozen cadaveric specimens. The mean length of this osseous ridge was 24.5 mm. CONCLUSION: The medial ulnar collateral ligament has a long attachment along the proximal ulna. The ligament attaches to a previously undescribed ridge of bone located on the medial aspect of the proximal ulna, the medial ulnar collateral ligament ridge. This ridge is present in all skeletal specimens. CLINICAL RELEVANCE: Injuries to the medial ulnar collateral ligament are common. Published success rates after reconstruction of the medial ulnar collateral ligament are highly variable. The present study illustrates how current reconstruction techniques fail to fully restore the true anatomy of the native ligament. Further studies are needed to investigate this issue. PMID- 21555510 TI - Hormonal regulation of galectin 3 in trophoblasts and its effects on endometrium. AB - Previous studies had shown important functions of galectin 3 (Gal-3) in endometrium during embryo implantation, in regulation of endometrial cell proliferation and adhesion by interacting with integrin beta3. In this study, we investigated hormonal regulation of Gal-3 in trophoblasts and its extracellular effects on endometrium. We used BeWo and RL95-2 cells as a model of trophoblastic and endometrial epithelial cells, respectively, to create an in vivo model of embryo implantation. Our results indicated that 17beta-estradiol (E2), progesterone (P4), and human chorionic gonadotropin (hCG) induced the expression of Gal-3 and promoted its secretion from BeWo cells. The exogenous Gal-3 inhibited cell proliferation and induced apoptosis of endometrial cells (RL95-2 cells) through activation of integrin beta1. We further validated the proapoptotic effect of Gal-3 secreted by trophoblastic cell on endometrial cells by culturing RL95-2 cells with Bewo cells and measuring the apoptotic rate. Our analysis provides new insight into the critical roles of Gal-3 in embryo implantation. PMID- 21555511 TI - Na+ channel Scn1b gene regulates dorsal root ganglion nociceptor excitability in vivo. AB - Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na(+) current (I(Na)) mediated by voltage-gated Na(+) channels (VGSCs). In nociceptive DRG neurons, VGSC beta2 subunits, encoded by Scn2b, selectively regulate TTX-S alpha subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by beta1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S I(Na) inactivation, reduced persistent TTX-R I(Na), a prolonged rate of recovery of TTX R I(Na) from inactivation, and reduced cell surface expression of Na(v)1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K(+) current (I(to)) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both I(Na) and I(K). PMID- 21555512 TI - Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension. AB - We have observed that, in renal proximal tubular cells, cardiotonic steroids such as ouabain in vitro signal through Na/K-ATPase, which results in inhibition of transepithelial (22)Na(+) transport by redistributing Na/K-ATPase and NHE3. In the present study, we investigate the role of Na/K-ATPase signaling in renal sodium excretion and blood pressure regulation in vivo. In Sprague-Dawley rats, high salt diet activated c-Src and induced redistribution of Na/K-ATPase and NHE3 in renal proximal tubules. In Dahl salt sensitive (S) and resistant (R) rats given high dietary salt, we found different effects on blood pressure but, more interestingly, different effects on renal salt handling. These differences could be explained by different signaling through the proximal tubular Na/K-ATPase. Specifically, in Dahl R rats, high salt diet significantly stimulated phosphorylation of c-Src and ERK1/2, reduced Na/K-ATPase activity and NHE3 activity, and caused redistribution of Na/K-ATPase and NHE3. In contrast, these adaptations were either much less effective or not seen in the Dahl S rats. We also studied the primary culture of renal proximal tubule isolated from Dahl S and R rats fed a low salt diet. In this system, ouabain induced Na/K-ATPase/c-Src signaling and redistribution of Na/K-ATPase and NHE3 in the Dahl R rats, but not in the Dahl S rats. Our data suggested that impairment of Na/K-ATPase signaling and consequent regulation of Na/K-ATPase and NHE3 in renal proximal tubule may contribute to salt-induced hypertension in the Dahl S rat. PMID- 21555513 TI - Detailed structural and quantitative analysis reveals the spatial organization of the cell walls of in vivo grown Mycobacterium leprae and in vitro grown Mycobacterium tuberculosis. AB - The cell wall of mycobacteria consists of an outer membrane, analogous to that of gram-negative bacteria, attached to the peptidoglycan (PG) via a connecting polysaccharide arabinogalactan (AG). Although the primary structure of these components is fairly well deciphered, issues such as the coverage of the PG layer by covalently attached mycolates in the outer membrane and the spatial details of the mycolic acid attachment to the arabinan have remained unknown. It is also not understood how these components work together to lead to the classical acid-fast staining of mycobacteria. Because the majority of Mycobacterium tuberculosis bacteria in established experimental animal infections are acid-fast negative, clearly cell wall changes are occurring. To address both the spatial properties of mycobacterial cell walls and to begin to study the differences between bacteria grown in animals and cultures, the cell walls of Mycobacterium leprae grown in armadillos was characterized and compared with that of M. tuberculosis grown in culture. Most fundamentally, it was determined that the cell wall of M. leprae contained significantly more mycolic acids attached to PG than that of in vitro grown M. tuberculosis (mycolate:PG ratios of 21:10 versus 16:10, respectively). In keeping with this difference, more arabinogalactan (AG) molecules, linking the mycolic acids to PG, were found. Differences in the structures of the AG were also found; the AG of M. leprae is smaller than that of M. tuberculosis, although the same basic structural motifs are retained. PMID- 21555514 TI - Cyclin K inhibits HIV-1 gene expression and replication by interfering with cyclin-dependent kinase 9 (CDK9)-cyclin T1 interaction in Nef-dependent manner. AB - Human immunodeficiency virus-1 (HIV-1) exploits a number of host cellular factors for successful survival and propagation. The viral protein Nef plays an important role in HIV-1 pathogenesis by interacting with various cellular proteins. In the present work, we identified Cyclin K (CycK) as a novel Nef-interacting protein, and for the first time, we showed that CycK inhibits HIV-1 gene expression and replication in a Nef-dependent manner. The positive elongation factor b complex comprising cyclin-dependent kinase 9 (CDK9) and Cyclin T1 is a critical cellular complex required for viral gene expression and replication. Enhanced expression of CycK in the presence of Nef induced CycK-CDK9 binding, which prevented CDK9 Cyclin T1 complex formation and nuclear translocation of CDK9, resulting in inhibition of HIV-1 long terminal repeat-driven gene expression. Furthermore, this effect of CycK was not observed with Nef-deleted virus, indicating the importance of Nef in this phenomenon. Finally, silencing of CycK in HIV-1 infected cells resulted in increased translocation of CDK9 into the nucleus, leading to increased viral gene expression and replication. These data also suggest that endogenous CycK might act as an inhibitory factor for HIV-1 gene expression and replication in T-cells. Thus, our results clearly demonstrate that CycK utilizes HIV-1 Nef protein to displace CycT1 from the positive elongation factor b complex, resulting in inhibition of HIV-1 gene expression and replication. PMID- 21555515 TI - Identification of a binding motif in the S5 helix that confers cholesterol sensitivity to the TRPV1 ion channel. AB - The TRPV1 ion channel serves as an integrator of noxious stimuli with its activation linked to pain and neurogenic inflammation. Cholesterol, a major component of cell membranes, modifies the function of several types of ion channels. Here, using measurements of capsaicin-activated currents in excised patches from TRPV1-expressing HEK cells, we show that enrichment with cholesterol, but not its diastereoisomer epicholesterol, markedly decreased wild type rat TRPV1 currents. Substitutions in the S5 helix, rTRPV1-R579D, and rTRPV1 F582Q, decreased this cholesterol response and rTRPV1-L585I was insensitive to cholesterol addition. Two human TRPV1 variants, with different amino acids at position 585, had different responses to cholesterol with hTRPV1-Ile(585) being insensitive to this molecule. However, hTRPV1-I585L was inhibited by cholesterol addition similar to rTRPV1 with the same S5 sequence. In the absence of capsaicin, cholesterol enrichment also inhibited TRPV1 currents induced by elevated temperature and voltage. These data suggest that there is a cholesterol binding site in TRPV1 and that the functions of TRPV1 depend on the genetic variant and membrane cholesterol content. PMID- 21555516 TI - Assembly of the human origin recognition complex occurs through independent nuclear localization of its components. AB - Initiation of eukaryotic genome duplication begins when a six-subunit origin recognition complex (ORC) binds to DNA. However, the mechanism by which this occurs in vivo and the roles played by individual subunits appear to differ significantly among organisms. Previous studies identified a soluble human ORC(2 5) complex in the nucleus, an ORC(1-5) complex bound to chromatin, and an Orc6 protein that binds weakly, if at all, to other ORC subunits. Here we show that stable ORC(1-6) complexes also can be purified from human cell extracts and that Orc6 and Orc1 each contain a single nuclear localization signal that is essential for nuclear localization but not for ORC assembly. The Orc6 nuclear localization signal, which is essential for Orc6 function, is facilitated by phosphorylation at its cyclin-dependent kinase consensus site and by association with Kpna6/1, nuclear transport proteins that did not co-purify with other ORC subunits. These and other results support a model in which Orc6, Orc1, and ORC(2-5) are transported independently to the nucleus where they can either assemble into ORC(1-6) or function individually. PMID- 21555517 TI - SIGLEC12, a human-specific segregating (pseudo)gene, encodes a signaling molecule expressed in prostate carcinomas. AB - The primate SIGLEC12 gene encodes one of the CD33-related Siglec family of signaling molecules in immune cells. We had previously reported that this gene harbors a human-specific missense mutation of the codon for an Arg residue required for sialic acid recognition. Here we show that this R122C mutation of the Siglec-XII protein is fixed in the human population, i.e. it occurred prior to the origin of modern humans. Additional mutations have since completely inactivated the SIGLEC12 gene in some but not all humans. The most common inactivating mutation with a global allele frequency of 58% is a single nucleotide frameshift that markedly shortens the open reading frame. Unlike other CD33-related Siglecs that are primarily found on immune cells, we found that Siglec-XII protein is expressed not only on some macrophages but also on various epithelial cell surfaces in humans and chimpanzees. We also found expression on certain human prostate epithelial carcinomas and carcinoma cell lines. This expression correlates with the presence of the nonframeshifted, intact SIGLEC12 allele. Although SIGLEC12 allele status did not predict prostate carcinoma incidence, restoration of expression in a prostate carcinoma cell line homozygous for the frameshift mutation induced altered regulation of several genes associated with carcinoma progression. These stably transfected Siglec-XII expressing prostate cancer cells also showed enhanced growth in nude mice. Finally, monoclonal antibodies against the protein were internalized by Siglec XII-expressing prostate carcinoma cells, allowing targeting of a toxin to such cells. Polymorphic expression of Siglec-XII in humans thus has implications for prostate cancer biology and therapeutics. PMID- 21555519 TI - Identification of interactions in the E1E2 heterodimer of hepatitis C virus important for cell entry. AB - Several conserved domains critical for E1E2 assembly and hepatitis C virus entry have been identified in E1 and E2 envelope glycoproteins. However, the role of less conserved domains involved in cross-talk between either glycoprotein must be defined to fully understand how E1E2 undergoes conformational changes during cell entry. To characterize such domains and to identify their functional partners, we analyzed a set of intergenotypic E1E2 heterodimers derived from E1 and E2 of different genotypes. The infectivity of virions indicated that Con1 E1 did not form functional heterodimers when associated with E2 from H77. Biochemical analyses demonstrated that the reduced infectivity was not related to alteration of conformation and incorporation of Con1 E1/H77 E2 heterodimers but rather to cell entry defects. Thus, we generated chimeric E1E2 glycoproteins by exchanging different domains of each protein in order to restore functional heterodimers. We found that both the ectodomain and transmembrane domain of E1 influenced infectivity. Site-directed mutagenesis highlighted the role of amino acids 359, 373, and 375 in transmembrane domain in entry. In addition, we identified one domain involved in entry within the N-terminal part of E1, and we isolated a motif at position 219 that is critical for H77 function. Interestingly, using additional chimeric E1E2 complexes harboring substitutions in this motif, we found that the transmembrane domain of E1 acts as a partner of this motif. Therefore, we characterized domains of E1 and E2 that have co-evolved inside a given genotype to optimize their interactions and allow efficient entry. PMID- 21555518 TI - The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle. AB - The regulation of gene expression in response to environmental signals and metabolic imbalances is a key step in maintaining cellular homeostasis. BTB and CNC homology 1 (BACH1) is a heme-binding transcription factor repressing the transcription from a subset of MAF recognition elements at low intracellular heme levels. Upon heme binding, BACH1 is released from the MAF recognition elements, resulting in increased expression of antioxidant response genes. To systematically address the gene regulatory networks involving BACH1, we combined chromatin immunoprecipitation sequencing analysis of BACH1 target genes in HEK 293 cells with knockdown of BACH1 using three independent types of small interfering RNAs followed by transcriptome profiling using microarrays. The 59 BACH1 target genes identified by chromatin immunoprecipitation sequencing were found highly enriched in genes showing expression changes after BACH1 knockdown, demonstrating the impact of BACH1 repression on transcription. In addition to known and new BACH1 targets involved in heme degradation (HMOX1, FTL, FTH1, ME1, and SLC48A1) and redox regulation (GCLC, GCLM, and SLC7A11), we also discovered BACH1 target genes affecting cell cycle and apoptosis pathways (ITPR2, CALM1, SQSTM1, TFE3, EWSR1, CDK6, BCL2L11, and MAFG) as well as subcellular transport processes (CLSTN1, PSAP, MAPT, and vault RNA). The newly identified impact of BACH1 on genes involved in neurodegenerative processes and proliferation provides an interesting basis for future dissection of BACH1-mediated gene repression in neurodegeneration and virus-induced cancerogenesis. PMID- 21555520 TI - Biophysical analysis of influenza A virus RNA promoter at physiological temperatures. AB - Each segment of the influenza A virus (IAV) genome contains conserved sequences at the 5'- and 3'-terminal ends, which form the promoter region necessary for polymerase binding and initiation of RNA synthesis. Although several models of interaction have been proposed it remains unclear if these two short, partially complementary, and highly conserved sequences can form a stable RNA duplex at physiological temperatures. First, our time-resolved FRET analysis revealed that a 14-mer 3'-RNA and a 15-mer 5'-RNA associate in solution, even at 42 degrees C. We also found that a nonfunctional RNA promoter containing the 3'-G3U mutation, as well as a promoter containing the compensatory 3'-G3U/C8A mutations, was able to form a duplex as efficiently as wild type. Second, UV melting analysis demonstrated that the wild-type and mutant RNA duplexes have similar stabilities in solution. We also observed an increase in thermostability for a looped promoter structure. The absence of differences in the stability and binding kinetics between wild type and a nonfunctional sequence suggests that the IAV promoter can be functionally inactivated without losing the capability to form a stable RNA duplex. Finally, using uridine specific chemical probing combined with mass spectrometry, we confirmed that the 5' and 3' sequences form a duplex which protects both RNAs from chemical modification, consistent with the previously published panhandle structure. These data support that these short, conserved promoter sequences form a stable complex at physiological temperatures, and this complex likely is important for polymerase recognition and viral replication. PMID- 21555521 TI - Phosphorylation of caspase-7 by p21-activated protein kinase (PAK) 2 inhibits chemotherapeutic drug-induced apoptosis of breast cancer cell lines. AB - p21-activated kinase (PAK) 2, a member of the PAK family of serine/threonine protein kinases, plays an important role in physiological processes such as motility, survival, mitosis, and apoptosis. However, the role of PAK2 in resistance to chemotherapy is unclear. Here we report that PAK2 is highly expressed in human breast cancer cell lines and human breast invasive carcinoma tissue compared with a human non-tumorigenic mammary epithelial cell line and adjacent normal breast tissue, respectively. Interestingly, we found that PAK2 can bind with caspase-7 and phosphorylate caspase-7 at the Ser-30, Thr-173, and Ser-239 sites. Functionally, the phosphorylation of caspase-7 decreases its activity, thereby inhibiting cellular apoptosis. Our data indicate that highly expressed PAK2 mediates chemotherapeutic resistance in human breast invasive ductal carcinoma by negatively regulating caspase-7 activity. PMID- 21555522 TI - When categories collide: accumulation of information about multiple categories in rapid scene perception. AB - Experiments have shown that people can rapidly determine if categories such as "animal" or "beach" are present in scenes that are presented for only a few milliseconds. Typically, observers in these experiments report on one prespecified category. For the first time, we show that observers can rapidly extract information about multiple categories. Moreover, we demonstrate task dependent interactions between accumulating information about different categories in a scene. This interaction can be constructive or destructive, depending on whether the presence of one category can be taken as evidence for or against the presence of the other. PMID- 21555523 TI - Automation can lead to confounds in text analysis: Back, Kufner, and Egloff (2010) and the not-so-angry Americans. PMID- 21555524 TI - Integration without awareness: expanding the limits of unconscious processing. AB - Human conscious awareness is commonly seen as the climax of evolution. However, what function-if any-it serves in human behavior is still debated. One of the leading suggestions is that the cardinal function of conscious awareness is to integrate numerous inputs-including the multitude of features and objects in a complex scene-across different levels of analysis into a unified, coherent, and meaningful perceptual experience. Here we demonstrate, however, that integration of objects with their background scenes can be achieved without awareness of either. We used a binocular rivalry technique known as continuous flash suppression to induce perceptual suppression in a group of human observers. Complex scenes that included incongruent objects escaped perceptual suppression faster than normal scenes did. We conclude that visual awareness is not needed for object-background integration or for processing the likelihood of an object to appear within a given semantic context, but may be needed for dealing with novel situations. PMID- 21555525 TI - Cerebral Hirano-like bodies in an alpaca (Vicugna pacos): histologic and ultrastructural characterization. AB - A 14-year-old female alpaca (Vicugna pacos) was presented with a 1-week history of lethargy and anorexia and a 2-day history of recumbency, trembling, and hypothermia. There were no significant gross findings on postmortem examination. Hematoxylin and eosin-stained sections of brain demonstrated the presence of intracytoplasmic crystalline eosinophilic rod-shaped inclusions, mainly in the hippocampal pyramidal cells. Immunohistochemical staining for synuclein, tau protein, ubiquitin, and smooth muscle actin was negative. All inclusions were positive with phosphotungstic acid hematoxylin. Ultrastructurally, the inclusions were multilamellar and filamentous with longitudinal herringbone pattern and cross-sectional latticelike structure. The combination of hematoxylin and eosin appearance, special stains, immunostaining, and ultrastructural findings was consistent with Hirano-like bodies. The Hirano-like bodies were highly unlikely to be the cause of the neurologic signs experienced by this alpaca. To the authors' knowledge, this is the first report of spontaneous cerebral Hirano-like bodies in an alpaca. PMID- 21555529 TI - Lung neutrophils facilitate activation of naive antigen-specific CD4+ T cells during Mycobacterium tuberculosis infection. AB - Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously published observations that 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis-infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naive M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role of neutrophils in DC migration, we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results revealed a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that makes DCs more effective initiators of naive CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis. PMID- 21555530 TI - Nitric oxide modulates TGF-beta-directive signals to suppress Foxp3+ regulatory T cell differentiation and potentiate Th1 development. AB - TGF-beta can induce Foxp3(+) inducible regulatory T cells (Treg) and also synergize with IL-6 and IL-4 to induce Th17 and Th9 cells. We now report that NO modulates TGF-beta activity away from Treg but toward the Th1 lineage. NO potentiated Th1 differentiation in the presence of TGF-beta in both IL-12 independent and -dependent fashions by augmenting IFN-gamma-activated STAT-1 and T-bet. Differentiation into Treg, Th1, and Th17 lineages could be modulated by NO competing with other cofactors, such as IL-6 and retinoic acid. NO antagonized IL 6 to block TGF-beta-directed Th17 differentiation, and together with IL-6, NO suppressed Treg development induced by TGF-beta and retinoic acid. Furthermore, we show that physiologically produced NO from TNF and inducible NO synthase producing dendritic cells can contribute to Th1 development predominating over Treg development through a synergistic activity induced when these cells cocluster with conventional dendritic cells presenting Ag to naive Th cells. This illustrates that NO is another cofactor allowing TGF-beta to participate in development of multiple Th lineages and suggests a new mechanism by which NO, which is associated with protection against intracellular pathogens, might maintain effective Th1 immunity. PMID- 21555531 TI - Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. AB - Programmed death ligand 1 (PDL1, or B7-H1) is expressed constitutively or is induced by IFN-gamma on the cell surface of most human cancer cells and acts as a "molecular shield" by protecting tumor cells from T cell-mediated destruction. Using seven cell lines representing four histologically distinct solid tumors (lung adenocarcinoma, mammary carcinoma, cutaneous melanoma, and uveal melanoma), we demonstrate that transfection of human tumor cells with the gene encoding the costimulatory molecule CD80 prevents PDL1-mediated immune suppression by tumor cells and restores T cell activation. Mechanistically, CD80 mediates its effects through its extracellular domain, which blocks the cell surface expression of PDL1 but does not prevent intracellular expression of PDL1 protein. These studies demonstrate a new role for CD80 in facilitating antitumor immunity and suggest new therapeutic avenues for preventing tumor cell PDL1-induced immune suppression. PMID- 21555532 TI - Murine guanylate cyclase C regulates colonic injury and inflammation. AB - Guanylate cyclase C (GUCY2C or GC-C) and its ligands, guanylin (GUCA2A or Gn) and uroguanylin (GUCA2B or Ugn), are expressed in intestinal epithelial cells and regulate ion secretion, intestinal barrier function, and epithelial monolayer homeostasis via cGMP-dependent signaling pathways. The aim of this study was to determine whether GC-C and its ligands direct the course of intestinal inflammation. In this article, we show that dextran sodium sulfate (DSS)-induced clinical disease and histological damage to the colonic mucosa were significantly less severe in GC-C(-/-) mice and moderately reduced in Gn(-/-) animals. Relative to wild-type controls, GC-C(-/-) and Gn(-/-) mice had reduced apoptosis and increased proliferation of intestinal epithelial cells during DSS colitis. Basal and DSS-induced production of resistin-like molecule beta (RELMbeta) was substantially diminished in GC-C(-/-) mice. RELMbeta is thought to stimulate cytokine production in macrophages in this disease model and, consistent with this, TNF-alpha and IFN-gamma production was minimal in GC-C(-/-) animals. RELMbeta and cytokine levels were similar to wild-type in Gn(-/-) mice, however. Colonic instillation of recombinant RELMbeta by enema into GC-C(-/-) mice restores sensitivity to DSS-mediated mucosal injury. These findings demonstrate a novel role for GC-C signaling in facilitating mucosal wounding and inflammation, and further suggest that this may be mediated, in part, through control of RELMbeta production. PMID- 21555533 TI - Antigen delivery to plasmacytoid dendritic cells via BST2 induces protective T cell-mediated immunity. AB - Plasmacytoid dendritic cells (PDCs) are capable of presenting Ags to T cells in a tolerogenic or immunogenic manner depending on the formulation of the Ag and the mode of stimulation. It has not been investigated whether effective adaptive immune responses useful for vaccination can be induced by Ab-mediated Ag targeting to PDCs in vivo. In this study, we show that Ag delivered to murine PDCs via bone marrow stromal cell Ag 2 (BST2)/CD317 in combination with TLR agonists as adjuvants is specifically presented by PDCs in vivo and elicits strong cellular and humoral immune responses. These include IFN-gamma production by CD4(+) T cells and high Ab titers with a broad range of IgG isotypes. In addition, BST2-mediated Ag delivery in the presence of polyinosinic-polycytidylic acid as adjuvant induces cytotoxic T lymphocytes that are functional in vivo. A single immunization with Ag-fused anti-BST2 Ab together with polyinosinic polycytidylic acid as adjuvant is sufficient to trigger protective immunity against subsequent viral infection and tumor growth. We conclude that despite the potential tolerogenic properties of PDCs, Ag targeting to PDCs in combination with TLR agonists as adjuvants is an effective vaccination strategy. PMID- 21555534 TI - CD56brightCD16+ NK cells: a functional intermediate stage of NK cell differentiation. AB - Human NK cells comprise two main subsets, CD56(bright) and CD56(dim) cells, which differ in function, phenotype, and tissue localization. To further dissect the differentiation from CD56(bright) to CD56(dim) cells, we performed ex vivo and in vitro experiments demonstrating that the CD56(bright)CD16(+) cells are an intermediate stage of NK cell maturation. We observed that the maximal frequency of the CD56(bright)CD16(+) subset among NK cells, following unrelated cord blood transplantation, occurs later than this of the CD56(bright)CD16(-) subset. We next performed an extensive phenotypic and functional analysis of CD56(bright)CD16(+) cells in healthy donors, which displayed a phenotypic intermediary profile between CD56(bright)CD16(-) and CD56(dim)CD16(+) NK cells. We also demonstrated that CD56(bright)CD16(+) NK cells were fully able to kill target cells, both by Ab-dependent cell cytotoxicity (ADCC) and direct lysis, as compared with CD56(bright)CD16(-) cells. Importantly, in vitro differentiation experiments revealed that autologous T cells specifically encourage the differentiation from CD56(bright)CD16(-) to CD56(bright)CD16(+) cells. Finally, further investigations performed in elderly patients clearly showed that both CD56(bright)CD16(+) and CD56(dim)CD16(+) mature subsets were substantially increased in older individuals, whereas the CD56(bright)CD16(-) precursor subset was decreased. Altogether, these data provide evidence that the CD56(bright)CD16(+) NK cell subset is a functional intermediate between the CD56(bright) and CD56(dim) cells and is generated in the presence of autologous T CD3(+) cells. PMID- 21555535 TI - Inhibiting CXCR3-dependent CD8+ T cell trafficking enhances tolerance induction in a mouse model of lung rejection. AB - Lung transplantation remains the only effective therapy for patients with end stage pulmonary diseases. Unfortunately, acute rejection of the lung remains a frequent complication and is an important cause of morbidity and mortality. The induction of transplant tolerance is thought to be dependent, in part, on the balance between allograft effector mechanisms mediated by effector T lymphocytes (Teff), and regulatory mechanisms mediated by FOXP3(+) regulatory T cells (Treg). In this study, we explored an approach to tip the balance in favor of regulatory mechanisms by modulating chemokine activity. We demonstrate in an adoptive transfer model of lung rejection that CXCR3-deficient CD8(+) Teff have impaired migration into the lungs compared with wild-type Teff, which results in a dramatic reduction in fatal pulmonary inflammation. The lungs of surviving mice contained tolerized CXCR3-deficient Teff, as well as a large increase in Treg. We confirmed that Treg were needed for tolerance and that their ability to induce tolerance was dependent on their numbers in the lung relative to the numbers of Teff. These data suggest that transplantation tolerance can be achieved by reducing the recruitment of some, but not necessarily all, CD8(+) Teff into the target organ and suggest a novel approach to achieve transplant tolerance. PMID- 21555536 TI - Transcriptional activation of the Pirb gene in B cells by PU.1 and Runx3. AB - Cells in the immune system are regulated positively or negatively by sets of receptor pairs that conduct balanced, activating, or inhibitory intracellular signaling. One such receptor pair termed paired Ig-like receptor (PIR) is composed of the inhibitory PIR-B and its activating isoform, PIR-A. Upon binding to their shared ligand, MHC class I molecules, these receptors control the threshold for immune cell activation. Gene-targeting studies on PIR-B in mice revealed the importance of the inhibition mediated by the PIR-B-MHC interaction in the immune system. Recent studies also revealed the significance of the interaction of PIR-B with neurite outgrowth inhibitors, including Nogo in the CNS. The coordinated regulation by PIR-B and PIR-A is considered to be primarily dependent on their expression balance in cells. However, the mechanism underlying transcriptional control of the genes for PIR-B and PIR-A (Pirb and Pira, respectively) remains to be clarified. In this study, we identified the major cis acting promoter segment for Pirb and Pira in B cells as the -212 to -117 region upstream from the translation initiation codon. PU.1 and Runx3 were found to bind to this Pirb promoter. Truncation of the PU.1-binding motif significantly reduced the promoter activity, whereas the influence of elimination of the Runx3 site was marginal in B lymphoma BCL1-B20 cells. Unexpectedly, PU.1, but not Runx3, knockdown reduced the levels of both the Pirb and Pira transcripts. We conclude that the major promoter of Pirb, and probably Pira as well, is activated dominantly by PU.1 and marginally by Runx3 in B cells. PMID- 21555537 TI - Large TCR diversity of virus-specific CD8 T cells provides the mechanistic basis for massive TCR renewal after antigen exposure. AB - Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR beta-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV 1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (<= 80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (<= 9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re exposure. PMID- 21555538 TI - Pathology Harmony; a pragmatic and scientific approach to unfounded variation in the clinical laboratory. PMID- 21555539 TI - How low can we go: high-sensitivity troponin T in patients presenting with chest pain. PMID- 21555540 TI - Resource and outcome in paediatric diabetes services. AB - The availability of resource (staffing and services) in all 21 paediatric diabetes services in Yorkshire and Humber Strategic Health Authority, UK was surveyed and this information was combined with demographic and clinical data on 2683 children and young people with diabetes (aged 0-23 years) to assess whether level of resource was associated with glycaemic control (mean HbA1c %). Multilevel modelling and graphical techniques were used to analyse the relationship between resource and outcome for paediatric diabetes services. No services achieved all resource recommendations based on National Institute for Health and Clinical Excellence guidelines, but there was no direct association between level of resource and glycaemic control after controlling for deprivation, age and duration of diabetes. Transitional care, nurse caseload and access to specialist services are not adequately resourced but variation in outcome between services is not accounted for by level of resource. PMID- 21555541 TI - Concerted electron-proton transfer in the optical excitation of hydrogen-bonded dyes. AB - The simultaneous, concerted transfer of electrons and protons--electron-proton transfer (EPT)--is an important mechanism utilized in chemistry and biology to avoid high energy intermediates. There are many examples of thermally activated EPT in ground-state reactions and in excited states following photoexcitation and thermal relaxation. Here we report application of ultrafast excitation with absorption and Raman monitoring to detect a photochemically driven EPT process (photo-EPT). In this process, both electrons and protons are transferred during the absorption of a photon. Photo-EPT is induced by intramolecular charge transfer (ICT) excitation of hydrogen-bonded-base adducts with either a coumarin dye or 4-nitro-4'-biphenylphenol. Femtosecond transient absorption spectral measurements following ICT excitation reveal the appearance of two spectroscopically distinct states having different dynamical signatures. One of these states corresponds to a conventional ICT excited state in which the transferring H(+) is initially associated with the proton donor. Proton transfer to the base (B) then occurs on the picosecond time scale. The other state is an ICT-EPT photoproduct. Upon excitation it forms initially in the nuclear configuration of the ground state by application of the Franck-Condon principle. However, due to the change in electronic configuration induced by the transition, excitation is accompanied by proton transfer with the protonated base formed with a highly elongated (+)H ? B bond. Coherent Raman spectroscopy confirms the presence of a vibrational mode corresponding to the protonated base in the optically prepared state. PMID- 21555542 TI - Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha) sulfotyrosines through a two-site mechanism involving exosite I. AB - The involvement of exosite I in alpha-thrombin (FIIa) binding to platelet glycoprotein Ibalpha (GPIbalpha), which could influence interactions with other substrates, remains undefined. To address the problem, we generated the GPIbalpha amino terminal domain (GPIbalpha-N) fully sulfated on three tyrosine residues and solved the structure of its complex with FIIa. We found that sulfotyrosine (Tys) 278 enhances the interaction mainly by establishing contacts with exosite I. We then evaluated how substituting tyrosine with phenylalanine, which cannot be sulfated, affects FIIa binding to soluble or surface-immobilized GPIbalpha-N. Mutating Tyr(276), which mostly contacts exosite II residues, markedly reduced FIIa interaction with both soluble and immobilized GPIbalpha-N; mutating Tyr(278) or Tyr(279), which mostly contact exosite I residues, reduced FIIa complexing in solution by 0-20% but affinity for immobilized GPIbalpha-N 2 to 6-fold, respectively. Moreover, three exosite I ligands--aptamer HD1, hirugen, and lepirudin--did not interfere with soluble FIIa complexing to GPIbalpha-N, excluding that their binding caused allosteric effects influencing the interaction; nonetheless, all impaired FIIa binding to immobilized GPIbalpha-N and platelet GPIb nearly as much as aptamer HD22 and heparin, both exosite II ligands. Bound HD1 and hirugen alter Trp(148) orientation in a loop near exosite I preventing contacts with the sulfate oxygen atoms of Tys(279). These results support a mechanism in which binding occurs when the two exosites of one FIIa molecule independently interact with two immobilized GPIbalpha molecules. Through exosite engagement, GPIbalpha may influence FIIa-dependent processes relevant to hemostasis and thrombosis. PMID- 21555543 TI - Solute diffusion is hindered in the mitochondrial matrix. AB - Intracellular chemical reactions generally constitute reaction-diffusion systems located inside nanostructured compartments like the cytosol, nucleus, endoplasmic reticulum, Golgi, and mitochondrion. Understanding the properties of such systems requires quantitative information about solute diffusion. Here we present a novel approach that allows determination of the solvent-dependent solute diffusion constant (D(solvent)) inside cell compartments with an experimentally quantifiable nanostructure. In essence, our method consists of the matching of synthetic fluorescence recovery after photobleaching (FRAP) curves, generated by a mathematical model with a realistic nanostructure, and experimental FRAP data. As a proof of principle, we assessed D(solvent) of a monomeric fluorescent protein (AcGFP1) and its tandem fusion (AcGFP1(2)) in the mitochondrial matrix of HEK293 cells. Our results demonstrate that diffusion of both proteins is substantially slowed by barriers in the mitochondrial matrix (cristae), suggesting that cells can control the dynamics of biochemical reactions in this compartment by modifying its nanostructure. PMID- 21555544 TI - Peptide secondary structure modulates single-walled carbon nanotube fluorescence as a chaperone sensor for nitroaromatics. AB - A class of peptides from the bombolitin family, not previously identified for nitroaromatic recognition, allows near-infrared fluorescent single-walled carbon nanotubes to transduce specific changes in their conformation. In response to the binding of specific nitroaromatic species, such peptide-nanotube complexes form a virtual "chaperone sensor," which reports modulation of the peptide secondary structure via changes in single-walled carbon nanotubes, near-infrared photoluminescence. A split-channel microscope constructed to image quantized spectral wavelength shifts in real time, in response to nitroaromatic adsorption, results in the first single-nanotube imaging of solvatochromic events. The described indirect detection mechanism, as well as an additional exciton quenching-based optical nitroaromatic detection method, illustrate that functionalization of the carbon nanotube surface can result in completely unique sites for recognition, resolvable at the single-molecule level. PMID- 21555545 TI - Solar composition from the Genesis Discovery Mission. AB - Science results from the Genesis Mission illustrate the major advantages of sample return missions. (i) Important results not otherwise obtainable except by analysis in terrestrial laboratories: the isotopic compositions of O, N, and noble gases differ in the Sun from other inner solar system objects. The N isotopic composition is the same as that of Jupiter. Genesis has resolved discrepancies in the noble gas data from solar wind implanted in lunar soils. (ii) The most advanced analytical instruments have been applied to Genesis samples, including some developed specifically for the mission. (iii) The N isotope result has been replicated with four different instruments. PMID- 21555546 TI - Lipid cubic phase as a membrane mimetic for integral membrane protein enzymes. AB - The lipidic cubic mesophase has been used to crystallize important membrane proteins for high-resolution structure determination. To date, however, no integral membrane enzymes have yielded to this method, the in meso. For a crystal structure to be meaningful the target protein must be functional. Using the in meso method with a membrane enzyme requires that the protein is active in the mesophase that grows crystals. Because the cubic phase is sticky and viscous and is bicontinuous topologically, quantitatively assessing enzyme activity in meso is a challenge. Here, we describe a procedure for characterizing the catalytic properties of the integral membrane enzyme, diacylglycerol kinase, reconstituted into the bilayer of the lipidic cubic phase. The kinase activity of this elusive crystallographic target was monitored spectrophotometrically using a coupled assay in a high-throughput, 96-well plate format. In meso, the enzyme exhibits classic Michaelis-Menten kinetics and works with a range of lipid substrates. The fact that the enzyme and its lipid substrate and product remain confined to the porous mesophase while its water-soluble substrate and product are free to partition into the aqueous bathing solution suggests a general and convenient approach for characterizing membrane enzymes that function with lipids in a membrane-like environment. The distinctive rheology of the cubic phase means that a procedural step to physically separate substrate from product is not needed. Because of its open, bicontinuous nature, the cubic phase offers the added benefit that the protein is accessible for assay from both sides of the membrane. PMID- 21555547 TI - Methane contamination of drinking water accompanying gas-well drilling and hydraulic fracturing. AB - Directional drilling and hydraulic-fracturing technologies are dramatically increasing natural-gas extraction. In aquifers overlying the Marcellus and Utica shale formations of northeastern Pennsylvania and upstate New York, we document systematic evidence for methane contamination of drinking water associated with shale-gas extraction. In active gas-extraction areas (one or more gas wells within 1 km), average and maximum methane concentrations in drinking-water wells increased with proximity to the nearest gas well and were 19.2 and 64 mg CH(4) L( 1) (n = 26), a potential explosion hazard; in contrast, dissolved methane samples in neighboring nonextraction sites (no gas wells within 1 km) within similar geologic formations and hydrogeologic regimes averaged only 1.1 mg L(-1) (P < 0.05; n = 34). Average delta(13)C-CH(4) values of dissolved methane in shallow groundwater were significantly less negative for active than for nonactive sites (-37 +/- 70/00 and -54 +/- 110/00, respectively; P < 0.0001). These delta(13)C CH(4) data, coupled with the ratios of methane-to-higher-chain hydrocarbons, and delta(2)H-CH(4) values, are consistent with deeper thermogenic methane sources such as the Marcellus and Utica shales at the active sites and matched gas geochemistry from gas wells nearby. In contrast, lower-concentration samples from shallow groundwater at nonactive sites had isotopic signatures reflecting a more biogenic or mixed biogenic/thermogenic methane source. We found no evidence for contamination of drinking-water samples with deep saline brines or fracturing fluids. We conclude that greater stewardship, data, and-possibly-regulation are needed to ensure the sustainable future of shale-gas extraction and to improve public confidence in its use. PMID- 21555548 TI - A 2,300-year-long annually resolved record of the South American summer monsoon from the Peruvian Andes. AB - Decadal and centennial mean state changes in South American summer monsoon (SASM) precipitation during the last 2,300 years are detailed using an annually resolved authigenic calcite record of precipitation delta(18)O from a varved lake in the Central Peruvian Andes. This unique sediment record shows that delta(18)O peaked during the Medieval Climate Anomaly (MCA) from A.D. 900 to 1100, providing evidence that the SASM weakened considerably during this period. Minimum delta(18)O values occurred during the Little Ice Age (LIA) between A.D. 1400 and 1820, reflecting a prolonged intensification of the SASM that was regionally synchronous. After the LIA, delta(18)O increased rapidly, particularly during the current warm period (CWP; A.D. 1900 to present), indicating a return to reduced SASM precipitation that was more abrupt and sustained than the onset of the MCA. Diminished SASM precipitation during the MCA and CWP tracks reconstructed Northern Hemisphere and North Atlantic warming and a northward displacement of the Intertropical Convergence Zone (ITCZ) over the Atlantic, and likely the Pacific. Intensified SASM precipitation during the LIA follows reconstructed Northern Hemisphere and North Atlantic cooling, El Nino-like warming in the Pacific, and a southward displacement of the ITCZ over both oceans. These results suggest that SASM mean state changes are sensitive to ITCZ variability as mediated by Western Hemisphere tropical sea surface temperatures, particularly in the Atlantic. Continued Northern Hemisphere and North Atlantic warming may therefore help perpetuate the recent reductions in SASM precipitation that characterize the last 100 years, which would negatively impact Andean water resources. PMID- 21555549 TI - Versatile RNA-sensing transcriptional regulators for engineering genetic networks. AB - The widespread natural ability of RNA to sense small molecules and regulate genes has become an important tool for synthetic biology in applications as diverse as environmental sensing and metabolic engineering. Previous work in RNA synthetic biology has engineered RNA mechanisms that independently regulate multiple targets and integrate regulatory signals. However, intracellular regulatory networks built with these systems have required proteins to propagate regulatory signals. In this work, we remove this requirement and expand the RNA synthetic biology toolkit by engineering three unique features of the plasmid pT181 antisense-RNA-mediated transcription attenuation mechanism. First, because the antisense RNA mechanism relies on RNA-RNA interactions, we show how the specificity of the natural system can be engineered to create variants that independently regulate multiple targets in the same cell. Second, because the pT181 mechanism controls transcription, we show how independently acting variants can be configured in tandem to integrate regulatory signals and perform genetic logic. Finally, because both the input and output of the attenuator is RNA, we show how these variants can be configured to directly propagate RNA regulatory signals by constructing an RNA-meditated transcriptional cascade. The combination of these three features within a single RNA-based regulatory mechanism has the potential to simplify the design and construction of genetic networks by directly propagating signals as RNA molecules. PMID- 21555550 TI - Synthesis and characterization of a nanocrystalline diamond aerogel. AB - Aerogel materials have myriad scientific and technological applications due to their large intrinsic surface areas and ultralow densities. However, creating a nanodiamond aerogel matrix has remained an outstanding and intriguing challenge. Here we report the high-pressure, high-temperature synthesis of a diamond aerogel from an amorphous carbon aerogel precursor using a laser-heated diamond anvil cell. Neon is used as a chemically inert, near-hydrostatic pressure medium that prevents collapse of the aerogel under pressure by conformally filling the aerogel's void volume. Electron and X-ray spectromicroscopy confirm the aerogel morphology and composition of the nanodiamond matrix. Time-resolved photoluminescence measurements of recovered material reveal the formation of both nitrogen- and silicon- vacancy point-defects, suggesting a broad range of applications for this nanocrystalline diamond aerogel. PMID- 21555551 TI - Intra- and intermolecular translocation of the bi-domain transcription factor Oct1 characterized by liquid crystal and paramagnetic NMR. AB - The intra- and intermolecular translocation processes whereby the bi-domain transcription factor Oct1 searches for its specific DNA target site have been investigated by residual dipolar coupling (RDC) and paramagnetic relaxation enhancement (PRE) measurements. The RDC data show that the orientation of the POU(S) and POU(HD) domains of Oct1 relative to the long axis of the DNA is the same for specific and nonspecific complexes with DNA. In the context of the specific Oct1-DNA complex, sparsely-populated, spectroscopically "invisible" states reveal their footprints on the PRE profiles observed for the specific complex. Analysis of the PRE data indicates that the POU(HD) domain searches the DNA primarily by rotation-coupled sliding (intramolecular translocation), while the POU(S) domain functions as an antenna to promote intersegment transfer via intermolecular translocation. The latter involves the formation of a bridged intermediate in which the POU(HD) domain is located on the first DNA molecule and the POU(S) domain on the second. The formation of the bridge intermediate promotes the completion of intermolecular translocation of Oct1 via a first order process involving dissociation and association of the POU(HD) domain from one DNA molecule to another. Thus cross-talk between the POU(S) and POU(HD) domains, each fulfilling different and complementary components of the search process ensures efficient sampling of DNA, thereby facilitating the location of specific Oct1 target sites. PMID- 21555552 TI - Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. AB - Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3(R102G)), factor B (fB(R32Q)), and factor H (fH(V62I)) are associated with age related macular degeneration (AMD) and other pathologies. Our published work showed that fB(R32Q) influences C3 convertase formation, whereas fH(V62I) affects factor I cofactor activity. Here we show how C3(R102G) (C3S/F) influences AP activity. In hemolysis assays, C3(102G) activated AP more efficiently (EC(50) C3(102G): 157 nM; C3(102R): 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b(102R) (K(D) C3b(102R): 1.0 MUM; C3b(102G): 1.4 MUM; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b(102G), favoring AP amplification. Combining disease "risk" variants (C3(102G), fB(32R), and fH(62V)) in add-back assays yielded sixfold higher hemolytic activity compared with "protective" variants (C3(102R), fB(32Q), and fH(62I); P < 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease. PMID- 21555553 TI - Representation and redistribution in federations. AB - Many of the world's most populous democracies are political unions composed of states or provinces that are unequally represented in the national legislature. Scattered empirical studies, most of them focusing on the United States, have discovered that overrepresented states appear to receive larger shares of the national budget. Although this relationship is typically attributed to bargaining advantages associated with greater legislative representation, an important threat to empirical identification stems from the fact that the representation scheme was chosen by the provinces. Thus, it is possible that representation and fiscal transfers are both determined by other characteristics of the provinces in a specific country. To obtain an improved estimate of the relationship between representation and redistribution, we collect and analyze provincial-level data from nine federations over several decades, taking advantage of the historical process through which federations formed and expanded. Controlling for a variety of country- and province-level factors and using a variety of estimation techniques, we show that overrepresented provinces in political unions around the world are rather dramatically favored in the distribution of resources. PMID- 21555555 TI - Crossmodal reorganization in the early deaf switches sensory, but not behavioral roles of auditory cortex. AB - It is well known that early disruption of sensory input from one modality can induce crossmodal reorganization of a deprived cortical area, resulting in compensatory abilities in the remaining senses. Compensatory effects, however, occur in selected cortical regions and it is not known whether such compensatory phenomena have any relation to the original function of the reorganized area. In the cortex of hearing cats, the auditory field of the anterior ectosylvian sulcus (FAES) is largely responsive to acoustic stimulation and its unilateral deactivation results in profound contralateral acoustic orienting deficits. Given these functional and behavioral roles, the FAES was studied in early-deafened cats to examine its crossmodal sensory properties as well as to assess the behavioral role of that reorganization. Recordings in the FAES of early-deafened adults revealed robust responses to visual stimulation as well as receptive fields that collectively represented the contralateral visual field. A second group of early-deafened cats was trained to localize visual targets in a perimetry array. In these animals, cooling loops were surgically placed on the FAES to reversibly deactivate the region, which resulted in substantial contralateral visual orienting deficits. These results demonstrate that crossmodal plasticity can substitute one sensory modality for another while maintaining the functional repertoire of the reorganized region. PMID- 21555554 TI - Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. AB - Defective homologous recombination (HR) DNA repair imposed by BRCA1 or BRCA2 deficiency sensitizes cells to poly (ADP-ribose) polymerase (PARP)-1 inhibition and is currently exploited in clinical treatment of HR-deficient tumors. Here we show that mild hyperthermia (41-42.5 degrees C) induces degradation of BRCA2 and inhibits HR. We demonstrate that hyperthermia can be used to sensitize innately HR-proficient tumor cells to PARP-1 inhibitors and that this effect can be enhanced by heat shock protein inhibition. Our results, obtained from cell lines and in vivo tumor models, enable the design of unique therapeutic strategies involving localized on-demand induction of HR deficiency, an approach that we term induced synthetic lethality. PMID- 21555556 TI - Measuring the evolutionary rate of protein-protein interaction. AB - Despite our extensive knowledge about the rate of protein sequence evolution for thousands of genes in hundreds of species, the corresponding rate of protein function evolution is virtually unknown, especially at the genomic scale. This lack of knowledge is primarily because of the huge diversity in protein function and the consequent difficulty in gauging and comparing rates of protein function evolution. Nevertheless, most proteins function through interacting with other proteins, and protein-protein interaction (PPI) can be tested by standard assays. Thus, the rate of protein function evolution may be measured by the rate of PPI evolution. Here, we experimentally examine 87 potential interactions between Kluyveromyces waltii proteins, whose one to one orthologs in the related budding yeast Saccharomyces cerevisiae have been reported to interact. Combining our results with available data from other eukaryotes, we estimate that the evolutionary rate of protein interaction is (2.6 +/- 1.6) * 10(-10) per PPI per year, which is three orders of magnitude lower than the rate of protein sequence evolution measured by the number of amino acid substitutions per protein per year. The extremely slow evolution of protein molecular function may account for the remarkable conservation of life at molecular and cellular levels and allow for studying the mechanistic basis of human disease in much simpler organisms. PMID- 21555557 TI - RAS-converting enzyme 1-mediated endoproteolysis is required for trafficking of rod phosphodiesterase 6 to photoreceptor outer segments. AB - Prenylation is the posttranslational modification of a carboxyl-terminal cysteine residue of proteins that terminate with a CAAX motif. Following prenylation, the last three amino acids are cleaved off by the endoprotease, RAS-converting enzyme 1 (RCE1), and the prenylcysteine residue is methylated. Although it is clear that prenylation increases membrane affinity of CAAX proteins, less is known about the importance of the postprenylation processing steps. RCE1 function has been studied in a variety of tissues but not in neuronal cells. To approach this issue, we generated mice lacking Rce1 in the retina. Retinal development proceeded normally in the absence of Rce1, but photoreceptor cells failed to respond to light and subsequently degenerated in a rapid fashion. In contrast, the inner nuclear and ganglion cell layers were unaffected. We found that the multimeric rod phosphodiesterase 6 (PDE6), a prenylated protein and RCE1 substrate, was unable to be transported to the outer segments in Rce1-deficient photoreceptor cells. PDE6 present in the inner segment of Rce1-deficient photoreceptor cells was assembled and functional. Synthesis and transport of transducin, and rhodopsin kinase 1 (GRK1), also prenylated substrates of RCE1, was unaffected by Rce1 deficiency. We conclude that RCE1 is essential for the intracellular trafficking of PDE6 and survival of photoreceptor cells. PMID- 21555558 TI - Mitochondrial DNA polymerase editing mutation, PolgD257A, reduces the diabetic phenotype of Akita male mice by suppressing appetite. AB - Diabetes and the development of its complications have been associated with mitochondrial DNA (mtDNA) dysfunction, but causal relationships remain undetermined. With the objective of testing whether increased mtDNA mutations exacerbate the diabetic phenotype, we have compared mice heterozygous for the Akita diabetogenic mutation (Akita) with mice homozygous for the D257A mutation in mitochondrial DNA polymerase gamma (Polg) or with mice having both mutations (Polg-Akita). The Polg-D257A protein is defective in proofreading and increases mtDNA mutations. At 3 mo of age, the Polg-Akita and Akita male mice were equally hyperglycemic. Unexpectedly, as the Polg-Akita males aged to 9 mo, their diabetic symptoms decreased. Thus, their hyperglycemia, hyperphagia and urine output declined significantly. The decrease in their food intake was accompanied by increased plasma leptin and decreased plasma ghrelin, while hypothalamic expression of the orexic gene, neuropeptide Y, was lower and expression of the anorexic gene, proopiomelanocortin, was higher. Testis function progressively worsened with age in the double mutants, and plasma testosterone levels in 9-mo old Polg-Akita males were significantly reduced compared with Akita males. The hyperglycemia and hyperphagia returned in aged Polg-Akita males after testosterone administration. Hyperglycemia-associated distal tubular damage in the kidney also returned, and Polg-D257A-associated proximal tubular damage was enhanced. The mild diabetes of female Akita mice was not affected by the Polg D257A mutation. We conclude that reduced diabetic symptoms of aging Polg-Akita males results from appetite suppression triggered by decreased testosterone associated with damage to the Leydig cells of the testis. PMID- 21555559 TI - F-box protein MAX2 has dual roles in karrikin and strigolactone signaling in Arabidopsis thaliana. AB - Smoke is an important abiotic cue for plant regeneration in postfire landscapes. Karrikins are a class of compounds discovered in smoke that promote seed germination and influence early development of many plants by an unknown mechanism. A genetic screen for karrikin-insensitive mutants in Arabidopsis thaliana revealed that karrikin signaling requires the F-box protein MAX2, which also mediates responses to the structurally-related strigolactone family of phytohormones. Karrikins and the synthetic strigolactone GR24 trigger similar effects on seed germination, seedling photomorphogenesis, and expression of a small set of genes during these developmental stages. Karrikins also repress MAX4 and IAA1 transcripts, which show negative feedback regulation by strigolactone. We demonstrate that all of these common responses are abolished in max2 mutants. Unlike strigolactones, however, karrikins do not inhibit shoot branching in Arabidopsis or pea, indicating that plants can distinguish between these signals. These results suggest that a MAX2-dependent signal transduction mechanism was adapted to mediate responses to two chemical cues with distinct roles in plant ecology and development. PMID- 21555560 TI - Gammadelta intraepithelial lymphocytes are essential mediators of host-microbial homeostasis at the intestinal mucosal surface. AB - The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. Here we show that gammadelta intraepithelial lymphocytes (gammadelta IEL) of the small intestine produce innate antimicrobial factors in response to resident bacterial "pathobionts" that penetrate the intestinal epithelium. gammadelta IEL activation was dependent on epithelial cell-intrinsic MyD88, suggesting that epithelial cells supply microbe-dependent cues to gammadelta IEL. Finally, gammadelta T cells protect against invasion of intestinal tissues by resident bacteria specifically during the first few hours after bacterial encounter, indicating that gammadelta IEL occupy a unique temporal niche among intestinal immune defenses. Thus, gammadelta IEL detect the presence of invading bacteria through cross-talk with neighboring epithelial cells and are an essential component of the hierarchy of immune defenses that maintain homeostasis with the intestinal microbiota. PMID- 21555561 TI - Functional agonism of insect odorant receptor ion channels. AB - In insects, odor cues are discriminated through a divergent family of odorant receptors (ORs). A functional OR complex consists of both a conventional odorant binding OR and a nonconventional coreceptor (Orco) that is highly conserved across insect taxa. Recent reports have characterized insect ORs as ion channels, but the precise mechanism of signaling remains unclear. We report the identification and characterization of an Orco family agonist, VUAA1, using the Anopheles gambiae coreceptor (AgOrco) and other orthologues. These studies reveal that the Orco family can form functional ion channels in the absence of an odor binding OR, and in addition, demonstrate a first-in-class agonist to further research in insect OR signaling. In light of the extraordinary conservation and widespread expression of the Orco family, VUAA1 represents a powerful new family of compounds that can be used to disrupt the destructive behaviors of nuisance insects, agricultural pests, and disease vectors alike. PMID- 21555562 TI - Herpesviral replication compartments move and coalesce at nuclear speckles to enhance export of viral late mRNA. AB - The role of the intranuclear movement of chromatin in gene expression is not well understood. Herpes simplex virus forms replication compartments (RCs) in infected cell nuclei as sites of viral DNA replication and late gene transcription. These structures develop from small compartments that grow in size, move, and coalesce. Quantitative analysis of RC trajectories, derived from 4D images, shows that most RCs move by directed motion. Directed movement is impaired in the presence of actin and myosin inhibitors as well as a transcription inhibitor. In addition, RCs coalesce at and reorganize nuclear speckles. Lastly, distinct effects of actin and myosin inhibitors on viral gene expression suggest that RC movement is not required for transcription, but rather, movement results in the bridging of transcriptionally active RCs with nuclear speckles to form structures that enhance export of viral late mRNAs. PMID- 21555563 TI - Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases. AB - The mechanisms by which enteric commensal microbiota influence maturation and repair of the epithelial barrier are relatively unknown. Epithelial restitution requires active cell migration, a process dependent on dynamic turnover of focal cell-matrix adhesions (FAs). Here, we demonstrate that natural, commensal bacteria stimulate generation of reactive oxygen species (ROS) in intestinal epithelia. Bacteria-mediated ROS generation induces oxidation of target cysteines in the redox-sensitive tyrosine phosphatases, LMW-PTP and SHP-2, which in turn results in increased phosphorylation of focal adhesion kinase (FAK), a key protein regulating the turnover of FAs. Accordingly, phosphorylation of FAK substrate proteins, focal adhesion formation, and cell migration are all significantly enhanced by bacterial contact in both in vitro and in vivo models of wound closure. These results suggest that commensal bacteria regulate cell migration via induced generation of ROS in epithelial cells. PMID- 21555564 TI - Cacao use and the San Lorenzo Olmec. AB - Mesoamerican peoples had a long history of cacao use--spanning more than 34 centuries--as confirmed by previous identification of cacao residues on archaeological pottery from Paso de la Amada on the Pacific Coast and the Olmec site of El Manati on the Gulf Coast. Until now, comparable evidence from San Lorenzo, the premier Olmec capital, was lacking. The present study of theobromine residues confirms the continuous presence and use of cacao products at San Lorenzo between 1800 and 1000 BCE, and documents assorted vessels forms used in its preparation and consumption. One elite context reveals cacao use as part of a mortuary ritual for sacrificial victims, an event that occurred during the height of San Lorenzo's power. PMID- 21555565 TI - Tracking brain states under general anesthesia by using global coherence analysis. AB - Time and frequency domain analyses of scalp EEG recordings are widely used to track changes in brain states under general anesthesia. Although these analyses have suggested that different spatial patterns are associated with changes in the state of general anesthesia, the extent to which these patterns are spatially coordinated has not been systematically characterized. Global coherence, the ratio of the largest eigenvalue to the sum of the eigenvalues of the cross spectral matrix at a given frequency and time, has been used to analyze the spatiotemporal dynamics of multivariate time-series. Using 64-lead EEG recorded from human subjects receiving computer-controlled infusions of the anesthetic propofol, we used surface Laplacian referencing combined with spectral and global coherence analyses to track the spatiotemporal dynamics of the brain's anesthetic state. During unconsciousness the spectrograms in the frontal leads showed increasing alpha (8-12 Hz) and delta power (0-4 Hz) and in the occipital leads delta power greater than alpha power. The global coherence detected strong coordinated alpha activity in the occipital leads in the awake state that shifted to the frontal leads during unconsciousness. It revealed a lack of coordinated delta activity during both the awake and unconscious states. Although strong frontal power during general anesthesia-induced unconsciousness--termed anteriorization--is well known, its possible association with strong alpha range global coherence suggests highly coordinated spatial activity. Our findings suggest that combined spectral and global coherence analyses may offer a new approach to tracking brain states under general anesthesia. PMID- 21555566 TI - Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer. AB - Prostasomes are microvesicles (mean diameter, 150 nm) that are produced and secreted by normal and malignant prostate acinar cells. It has been hypothesized that invasive growth of malignant prostate cells may cause these microvesicles, normally released into seminal fluid, to appear in interstitial space and therewith into peripheral circulation. The suitability of prostasomes as blood biomarkers in patients with prostate cancer was tested by using an expanded variant of the proximity ligation assay (PLA). We developed an extremely sensitive and specific assay (4PLA) for detection of complex target structures such as microvesicles in which the target is first captured via an immobilized antibody and subsequently detected by using four other antibodies with attached DNA strands. The requirement for coincident binding by five antibodies to generate an amplifiable reporter results in both increased specificity and sensitivity. The assay successfully detected significantly elevated levels of prostasomes in blood samples from patients with prostate cancer before radical prostatectomy, compared with controls and men with benign biopsy results. The medians for prostasome levels in blood plasma of patients with prostate cancer were 2.5 to sevenfold higher compared with control samples in two independent studies, and the assay also distinguished patients with high and medium prostatectomy Gleason scores (8/9 and 7, respectively) from those with low score (<= 6), thus reflecting disease aggressiveness. This approach that enables detection of prostasomes in peripheral blood may be useful for early diagnosis and assessment of prognosis in organ-confined prostate cancer. PMID- 21555567 TI - Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. AB - Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K ras(G12D) allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras-driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras mediated malignancies. PMID- 21555568 TI - Quantitative descriptions of generalized arousal, an elementary function of the vertebrate brain. AB - We review a concept of the most primitive, fundamental function of the vertebrate CNS, generalized arousal (GA). Three independent lines of evidence indicate the existence of GA: statistical, genetic, and mechanistic. Here we ask, is this concept amenable to quantitative analysis? Answering in the affirmative, four quantitative approaches have proven useful: (i) factor analysis, (ii) information theory, (iii) deterministic chaos, and (iv) application of a Gaussian equation. It strikes us that, to date, not just one but at least four different quantitative approaches seem necessary for describing different aspects of scientific work on GA. PMID- 21555569 TI - B cells within germinal centers migrate preferentially from dark to light zone. AB - One of the main questions in the field of imaging immune cell migration in living tissues is whether cells fulfill their functionality via random or nonrandom migration processes. For some applications, this issue has remained controversial even after publication of various imaging studies. A prime example is B-cell migration in germinal centers (GCs) where somatic hypermutation and clonal selection of B cells are thought to occur within morphologically distinct regions termed dark zone (DZ) and light zone (LZ). Here, we reanalyze a previously published dataset on GC B-cell migration, applying a sensitive analysis technique to detect directed migration and using a procedure to correct for a number of artifacts that frequently occur in time-lapse imaging experiments. Although B cells roughly perform a persistent random walk, we present evidence that they have a small preference (of on average about 0.2-0.3 MUm min(-1)) to migrate from DZ to LZ, which is consistent with classical views of the GC reaction. This preference is most pronounced among a large subset of almost half of the B-cell population migrating along relatively straight tracks. Using a computational model to generate long-lasting B-cell tracks based on the experimental motility data (including the small directional preference), we predict a time course to travel from DZ to LZ of a few hours. This is consistent with experimental observations, and we show that at the observed cellular motility such a time course cannot be explained without the small preferential migration from DZ to LZ. PMID- 21555570 TI - Revised age of late Neanderthal occupation and the end of the Middle Paleolithic in the northern Caucasus. AB - Advances in direct radiocarbon dating of Neanderthal and anatomically modern human (AMH) fossils and the development of archaeostratigraphic chronologies now allow refined regional models for Neanderthal-AMH coexistence. In addition, they allow us to explore the issue of late Neanderthal survival in regions of Western Eurasia located within early routes of AMH expansion such as the Caucasus. Here we report the direct radiocarbon ((14)C) dating of a late Neanderthal specimen from a Late Middle Paleolithic (LMP) layer in Mezmaiskaya Cave, northern Caucasus. Additionally, we provide a more accurate chronology for the timing of Neanderthal extinction in the region through a robust series of 16 ultrafiltered bone collagen radiocarbon dates from LMP layers and using Bayesian modeling to produce a boundary probability distribution function corresponding to the end of the LMP at Mezmaiskaya. The direct date of the fossil (39,700 +/- 1,100 (14)C BP) is in good agreement with the probability distribution function, indicating at a high level of probability that Neanderthals did not survive at Mezmaiskaya Cave after 39 ka cal BP ("calendrical" age in kiloannum before present, based on IntCal09 calibration curve). This challenges previous claims for late Neanderthal survival in the northern Caucasus. We see striking and largely synchronous chronometric similarities between the Bayesian age modeling for the end of the LMP at Mezmaiskaya and chronometric data from Ortvale Klde for the end of the LMP in the southern Caucasus. Our results confirm the lack of reliably dated Neanderthal fossils younger than ~ 40 ka cal BP in any other region of Western Eurasia, including the Caucasus. PMID- 21555571 TI - Active transport, substrate specificity, and methylation of Hg(II) in anaerobic bacteria. AB - The formation of methylmercury (MeHg), which is biomagnified in aquatic food chains and poses a risk to human health, is effected by some iron- and sulfate reducing bacteria (FeRB and SRB) in anaerobic environments. However, very little is known regarding the mechanism of uptake of inorganic Hg by these organisms, in part because of the inherent difficulty in measuring the intracellular Hg concentration. By using the FeRB Geobacter sulfurreducens and the SRB Desulfovibrio desulfuricans ND132 as model organisms, we demonstrate that Hg(II) uptake occurs by active transport. We also establish that Hg(II) uptake by G. sulfurreducens is highly dependent on the characteristics of the thiols that bind Hg(II) in the external medium, with some thiols promoting uptake and methylation and others inhibiting both. The Hg(II) uptake system of D. desulfuricans has a higher affinity than that of G. sulfurreducens and promotes Hg methylation in the presence of stronger complexing thiols. We observed a tight coupling between Hg methylation and MeHg export from the cell, suggesting that these two processes may serve to avoid the build up and toxicity of cellular Hg. Our results bring up the question of whether cellular Hg uptake is specific for Hg(II) or accidental, occurring via some essential metal importer. Our data also point at Hg(II) complexation by thiols as an important factor controlling Hg methylation in anaerobic environments. PMID- 21555572 TI - Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. AB - Tumor cells require a constant supply of macromolecular precursors, and interrupting this supply has been proposed as a therapeutic strategy in cancer. Precursors for lipids, nucleic acids, and proteins are generated in the tricarboxylic acid (TCA) cycle and removed from the mitochondria to participate in biosynthetic reactions. Refilling the pool of precursor molecules (anaplerosis) is therefore crucial to maintain cell growth. Many tumor cells use glutamine to feed anaplerosis. Here we studied how "glutamine-addicted" cells react to interruptions of glutamine metabolism. Silencing of glutaminase (GLS), which catalyzes the first step in glutamine-dependent anaplerosis, suppressed but did not eliminate the growth of glioblastoma cells in culture and in vivo. Profiling metabolic fluxes in GLS-suppressed cells revealed induction of a compensatory anaplerotic mechanism catalyzed by pyruvate carboxylase (PC), allowing the cells to use glucose-derived pyruvate rather than glutamine for anaplerosis. Although PC was dispensable when glutamine was available, forcing cells to adapt to low-glutamine conditions rendered them absolutely dependent on PC for growth. Furthermore, in other cell lines, measuring PC activity in nutrient-replete conditions predicted dependence on specific anaplerotic enzymes. Cells with high PC activity were resistant to GLS silencing and did not require glutamine for survival or growth, but displayed suppressed growth when PC was silenced. Thus, PC-mediated, glucose-dependent anaplerosis allows cells to achieve glutamine independence. Induction of PC during chronic suppression of glutamine metabolism may prove to be a mechanism of resistance to therapies targeting glutaminolysis. PMID- 21555573 TI - Optogenetic-guided cortical plasticity after nerve injury. AB - Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable to changes in neuronal activity occurring in somatosensory cortices both contralateral and ipsilateral to the injury. Recent studies suggest that distorted functional response observed in deprived primary somatosensory cortex (S1) may be the result of an increase in inhibitory interneuron activity and is mediated by the transcallosal pathway. The goal of this study was to develop a strategy to manipulate and control the transcallosal activity to facilitate appropriate plasticity by guiding the cortical reorganization in a rat model of sensory deprivation. Since transcallosal fibers originate mainly from excitatory pyramidal neurons somata situated in laminae III and V, the excitatory neurons in rat S1 were engineered to express halorhodopsin, a light-sensitive chloride pump that triggers neuronal hyperpolarization. Results from electrophysiology, optical imaging, and functional MRI measurements are concordant with that within the deprived S1, activity in response to intact forepaw electrical stimulation was significantly increased by concurrent illumination of halorhodopsin over the healthy S1. Optogenetic manipulations effectively decreased the adverse inhibition of deprived cortex and revealed the major contribution of the transcallosal projections, showing interhemispheric neuroplasticity and thus, setting a foundation to develop improved rehabilitation strategies to restore cortical functions. PMID- 21555574 TI - N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice. AB - N-acetylserotonin (NAS), the immediate precursor of melatonin, the pineal gland indole, is regulated in a circadian rhythm. NAS swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. Here we show that NAS regulates an early event of neurogenesis by increasing neuronal progenitor cell (NPC) proliferation. Subchronic and chronic NAS administration induces NPC proliferation in adult mice. Chronic NAS treatment triggers TrkB receptor activation and its downstream signaling in NPCs. Blockade of TrkB abolishes NAS-elicited neurogenesis in TrkBF616A knockin mice, suggesting that TrkB activation is essential for the effect of NAS-induced NPC proliferation. Moreover, NAS induces NPC proliferation in both active and sleeping phases of the mice. Strikingly, NAS significantly enhances NPC proliferation in sleep-deprived mice. Thus, our finding demonstrates a unique function of NAS in promoting robust NPC proliferation, which may contribute to hippocampal plasticity during sleeping period. PMID- 21555575 TI - Tissue-specific roles of Axin2 in the inhibition and activation of Wnt signaling in the mouse embryo. AB - Axin proteins are key negative regulators of the canonical Wnt signal transduction pathway. Although Axin2 null mice are viable, we identified an unusual ENU-induced recessive allele of Axin2, canp, that causes midgestation lethality in homozygotes. We show that the Axin2(canp) mutation is a V26D substitution in an invariant N-terminal sequence motif and that the Axin2(canp) protein is more stable than wild type. As predicted for an increased level of a negative regulator, the Axin2(canp) mutation leads to decreased Wnt signaling in most tissues, and this can account for most of the morphological phenotypes of Axin2(canp) mutants. In contrast, there is a paradoxical increase in canonical Wnt activity in the late primitive streak of all Axin2(canp) mutant embryos that is associated with the formation of an ectopic tail in some mutants. Treatment of wild-type embryos with an inhibitor of Tankyrase that stabilizes Axin proteins also causes inhibition of Wnt signaling in anterior regions of the embryo and a gain of Wnt signaling in the primitive streak. The results indicate that although increased stability of Axin2 leads to a loss of canonical Wnt signaling in most tissues, stabilized Axin2 enhances Wnt pathway activity in a specific progenitor population in the late primitive streak. PMID- 21555576 TI - Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis. AB - Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat(-)(/-), a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat(-)(/-) cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65(-)(/-) and Lrat(-)(/-) LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lrat(-)(/-) retina and transfected cells. Replacing rhodopsin with S opsin in Lrat(-)(/-) rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA. PMID- 21555577 TI - CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input. AB - Rapid induction of CD8(+) cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4(+) T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naive precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4(+) T cells in early phases of the immune response. We show that CD4(+) T cells help optimal CTL expansion by facilitating entry of naive polyclonal CD8(+) T cells into the draining lymph node (dLN) early after infection or immunization. CD4(+) T cells also facilitate input of naive B cells into reactive LNs. Such "help" involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen- and CD40-dependent manner, CD4(+) T cells activate dendritic cells to support naive lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4(+) T-cell help, whereby they increase the input of naive lymphocytes to the relevant LN for efficient screening of cognate CD8(+) T cells. PMID- 21555578 TI - Neuroprotection mediated through estrogen receptor-alpha in astrocytes. AB - Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-alpha (ERalpha) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERalpha ligand-mediated neuroprotective effects in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERalpha ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERalpha from astrocytes, whereas conditional deletion of ERalpha from neurons had no significant effect. These findings show that signaling through ERalpha in astrocytes, but not through ERalpha in neurons, is essential for the beneficial effects of ERalpha ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders. PMID- 21555579 TI - Variation in individual walking behavior creates the impression of a Levy flight. AB - Many animal paths have an intricate statistical pattern that manifests itself as a power law-like tail in the distribution of movement lengths. Such distributions occur if individuals move according to a Levy flight (a mode of dispersal in which the distance moved follows a power law), or if there is variation between individuals such that some individuals move much farther than others. Distinguishing between these two mechanisms requires large quantities of data, which are not available for most species studied. Here, we analyze paths of black bean aphids (Aphis fabae Scopoli) and show that individual animals move in a predominantly diffusive manner, but that, because of variation at population level, they collectively appear to display superdiffusive characteristics, often interpreted as being characteristic for a Levy flight. PMID- 21555580 TI - Functional relevance of the histone gammaH2Ax in the response to DNA damaging agents. AB - The phosphorylation of H2Ax on its S139 site, gammaH2Ax, is important during DNA double-strand repair and is considered necessary for assembly of repair complexes, but its functional role after other kinds of DNA damage is less clear. We have measured the survival of isogenic mouse cell lines with the H2Ax gene knocked out, and replaced with wild-type or mutant (S139A) H2Ax genes, exposed to a range of agents with varied mechanisms of DNA damage. Knockout and mutant cells were sensitive to gamma-rays, etoposide, temozolamide, and endogenously generated reactive oxygen species, each of which can include double-strand breaks among their spectra of DNA lesions. The absence or mutation of H2Ax had no influence on sensitivity to cisplatin or mitomycin C. Although UV light induced the highest levels of gammaH2Ax, mutation of S139 had no influence on UV sensitivity or the UV DNA damage response. Complete loss of H2Ax reduced the survival of cells exposed to UV light and reduced pChk1 induction, suggesting that sites other than S139 may impact the ATR-pChk1 pathway. The relative intensity of gammaH2Ax measured in Western blots in wild-type cells did not correlate with the functional importance of gammaH2Ax. The use of gammaH2Ax as a general biomarker of DNA damage is therefore potentially misleading because it is not an unambiguous indicator of double-strand breaks, and a significant fraction of DNA repair, especially involving nucleotide excision or crosslink repair, can occur without functional involvement of gammaH2Ax. PMID- 21555581 TI - Age-related memory deficits linked to circuit-specific disruptions in the hippocampus. AB - Converging data from rodents and humans have demonstrated an age-related decline in pattern separation abilities (the ability to discriminate among similar experiences). Several studies have proposed the dentate and CA3 subfields of the hippocampus as the potential locus of this change. Specifically, these studies identified rigidity in place cell remapping in similar environments in the CA3. We used high-resolution fMRI to examine activity profiles in the dentate gyrus and CA3 in young and older adults as stimulus similarity was incrementally varied. We report evidence for "representational rigidity" in older adults' dentate/CA3 that is linked to behavioral discrimination deficits. Using ultrahigh resolution diffusion imaging, we quantified both the integrity of the perforant path as well as dentate/CA3 dendritic changes and found that both were correlated with dentate/CA3 functional rigidity. These results highlight structural and functional alterations in the hippocampal network that predict age-related changes in memory function and present potential targets for intervention. PMID- 21555582 TI - Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop. AB - Ca(2+)-activated Cl(-) channels (CaCCs) are exceptionally well adapted to subserve diverse physiological roles, from epithelial fluid transport to sensory transduction, because their gating is cooperatively controlled by the interplay between ionotropic and metabotropic signals. A molecular understanding of the dual regulation of CaCCs by voltage and Ca(2+) has recently become possible with the discovery that Ano1 (TMEM16a) is an essential subunit of CaCCs. Ano1 can be gated by Ca(2+) or by voltage in the absence of Ca(2+), but Ca(2+)- and voltage dependent gating are very closely coupled. Here we identify a region in the first intracellular loop that is crucial for both Ca(2+) and voltage sensing. Deleting (448)EAVK in the first intracellular loop dramatically decreases apparent Ca(2+) affinity. In contrast, mutating the adjacent amino acids (444)EEEE abolishes intrinsic voltage dependence without altering the apparent Ca(2+)affinity. Voltage-dependent gating of Ano1 measured in the presence of intracellular Ca(2+) was facilitated by anions with high permeability or by an increase in [Cl(-)](e). Our data show that the transition between closed and open states is governed by Ca(2+) in a voltage-dependent manner and suggest that anions allosterically modulate Ca(2+)-binding affinity. This mechanism provides a unified explanation of CaCC channel gating by voltage and ligand that has long been enigmatic. PMID- 21555583 TI - Anuran radiations and the evolution of tadpole morphospace. AB - Anurans (frogs and toads) are unique among land vertebrates in possessing a free living larval stage that, parallel to adult frogs, diversified into an impressive range of ecomorphs. The tempo and mode at which tadpole morphology evolved through anuran history as well as its relationship to lineage diversification remain elusive. We used a molecular phylogenetic framework to examine patterns of morphological evolution in tadpoles in light of observed episodes of accelerated lineage diversification. Our reconstructions show that the expansion of tadpole morphospace during the basal anuran radiation in the Triassic/Early Jurassic was unparalleled by the basal neobatrachian radiation in the Late Jurassic/Early Cretaceous or any subsequent radiation in the Late Cretaceous/Early Tertiary. Comparative analyses of radiation episodes indicate that the slowdown of morphospace expansion was caused not only by a drop in evolutionary rate after the basal anuran radiation but also by an overall increase in homoplasy in the characters that did evolve during later radiations. The overlapping sets of evolving characters among more recent radiations may have enhanced tadpole diversity by creating unique combinations of homoplastic traits, but the lack of innovative character changes prevented the exploration of fundamental regions in morphospace. These complex patterns transcend the four traditionally recognized tadpole morphotypes and apply to most tissue types and body parts. PMID- 21555584 TI - Synchrotron-aided reconstruction of the conodont feeding apparatus and implications for the mouth of the first vertebrates. AB - The origin of jaws remains largely an enigma that is best addressed by studying fossil and living jawless vertebrates. Conodonts were eel-shaped jawless animals, whose vertebrate affinity is still disputed. The geometrical analysis of exceptional three-dimensionally preserved clusters of oro-pharyngeal elements of the Early Triassic Novispathodus, imaged using propagation phase-contrast X-ray synchrotron microtomography, suggests the presence of a pulley-shaped lingual cartilage similar to that of extant cyclostomes within the feeding apparatus of euconodonts ("true" conodonts). This would lend strong support to their interpretation as vertebrates and demonstrates that the presence of such cartilage is a plesiomorphic condition of crown vertebrates. PMID- 21555585 TI - Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. AB - As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic beta-cells, we generated beta-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from beta-cells. Ablation of XBP1 markedly decreased the number of insulin granules in beta-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in beta-cells but also caused constitutive hyperactivation of its upstream activator, IRE1alpha, which could degrade a subset of mRNAs encoding proinsulin processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1alpha caused beta-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1alpha has dual and opposing roles in beta-cells, and that a precisely regulated feedback circuit involving IRE1alpha and its product XBP1s is required to achieve optimal insulin secretion and glucose control. PMID- 21555586 TI - Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells. AB - Embryonic stem cells (ESCs) have an unlimited proliferative capacity and extensive differentiation capability. They are an alternative source for regenerative therapies with a potential role in the treatment of several human diseases. The clinical use of ESCs, however, has significant ethical and biological obstacles related to their derivation from embryos and potential for immunological rejection, respectively. These disadvantages can be circumvented by the alternative use of induced pluripotent stem cells (iPSCs), which are generated from an individual's (autologous) somatic cells by exogenous expression of defined transcription factors and have biological characteristics similar to ESCs. In recent years, patient-specific iPSCs have been generated to study disease mechanisms and develop iPSC-based therapies. The development of iPSC based therapies for skin diseases requires successful differentiation of iPSCs into cellular components of the skin, including epidermal keratinocytes. Here, we succeeded in generating iPSCs not only from normal human fibroblasts but also from fibroblasts isolated from the skin of two patients with recessive dystrophic epidermolysis bullosa. Moreover, we differentiated both of these iPSCs into keratinocytes with high efficiency, and generated 3D skin equivalents using iPSC derived keratinocytes, suggesting that they were fully functional. Our studies indicate that autologous iPSCs have the potential to provide a source of cells for regenerative therapies for specific skin diseases. PMID- 21555587 TI - TGF-beta signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells. AB - Oncogene-induced senescence (OIS), the proliferative arrest engaged in response to persistent oncogene activation, serves as an important tumor-suppressive barrier. We show here that finite lifespan human mammary epithelial cells (HMEC) undergo a p16/RB- and p53-independent OIS in response to oncogenic RAS that requires TGF-beta signaling. Suppression of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor, use of a TGF-beta type I receptor inhibitor, or ectopic expression of MYC permitted continued proliferation upon RAS expression. Surprisingly, unlike fibroblasts, shRNA-mediated knockdown of ATM or CHK2 was unable to prevent RAS-mediated OIS, arguing that the DNA damage response is not required for OIS in HMEC. Abrogation of TGF-beta signaling not only allowed HMEC lacking p53 to tolerate oncogenic RAS but also conferred the capacity for anchorage-independent growth. Thus, the OIS engaged after dysregulated RAS expression provides an early barrier to malignant progression and is mediated by TGF-beta receptor activation in HMEC. Understanding the mechanisms that initiate and maintain OIS in epithelial cells may provide a foundation for future therapies aimed at reengaging this proliferative barrier as a cancer therapy. PMID- 21555588 TI - Genomic insights into the physiology and ecology of the marine filamentous cyanobacterium Lyngbya majuscula. AB - Filamentous cyanobacteria of the genus Lyngbya are important contributors to coral reef ecosystems, occasionally forming dominant cover and impacting the health of many other co-occurring organisms. Moreover, they are extraordinarily rich sources of bioactive secondary metabolites, with 35% of all reported cyanobacterial natural products deriving from this single pantropical genus. However, the true natural product potential and life strategies of Lyngbya strains are poorly understood because of phylogenetic ambiguity, lack of genomic information, and their close associations with heterotrophic bacteria and other cyanobacteria. To gauge the natural product potential of Lyngbya and gain insights into potential microbial interactions, we sequenced the genome of Lyngbya majuscula 3L, a Caribbean strain that produces the tubulin polymerization inhibitor curacin A and the molluscicide barbamide, using a combination of Sanger and 454 sequencing approaches. Whereas ~ 293,000 nucleotides of the draft genome are putatively dedicated to secondary metabolism, this is far too few to encode a large suite of Lyngbya metabolites, suggesting Lyngbya metabolites are strain specific and may be useful in species delineation. Our analysis revealed a complex gene regulatory network, including a large number of sigma factors and other regulatory proteins, indicating an enhanced ability for environmental adaptation or microbial associations. Although Lyngbya species are reported to fix nitrogen, nitrogenase genes were not found in the genome or by PCR of genomic DNA. Subsequent growth experiments confirmed that L. majuscula 3L is unable to fix atmospheric nitrogen. These unanticipated life history characteristics challenge current views of the genus Lyngbya. PMID- 21555589 TI - Bidirectional autoregulatory mechanism of metastasis-associated protein 1 alternative reading frame pathway in oncogenesis. AB - Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and histone deacetylation complex, is widely up-regulated in human cancers and correlates with tumor metastasis, its regulatory mechanism and related signaling pathways remain unknown. Here, we report a previously unrecognized bidirectional autoregulatory loop between MTA1 and tumor suppressor alternative reading frame (ARF). MTA1 transactivates ARF transcription by recruiting the transcription factor c-Jun onto the ARF promoter in a p53 independent manner. ARF, in turn, negatively regulates MTA1 expression independently of p53 and c-Myc. In this context, ARF interacts with transcription factor specificity protein 1 (SP1) and promotes its proteasomal degradation by enhancing its interaction with proteasome subunit regulatory particle ATPase 6, thereby abrogating the ability of SP1 to stimulate MTA1 transcription. ARF also physically associates with MTA1 and affects its protein stability. Thus, MTA1 mediated activation of ARF and ARF-mediated functional inhibition of MTA1 represent a p53-independent bidirectional autoregulatory mechanism in which these two opposites act in concert to regulate cell homeostasis and oncogenesis, depending on the cellular context and the environment. PMID- 21555590 TI - Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small vessel disease. AB - The most common monogenic cause of small-vessel disease leading to ischemic stroke and vascular dementia is the neurodegenerative syndrome cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is associated with mutations in the Notch 3 receptor. CADASIL pathology is characterized by vascular smooth muscle cell degeneration and accumulation of diagnostic granular osmiophilic material (GOM) in vessels. The functional nature of the Notch 3 mutations causing CADASIL and their mechanistic connection to small-vessel disease and GOM accumulation remain enigmatic. To gain insight into how Notch 3 function is linked to CADASIL pathophysiology, we studied two phenotypically distinct mutations, C455R and R1031C, respectively associated with early and late onset of stroke, by using hemodynamic analyses in transgenic mouse models, receptor activity assays in cell culture, and proteomic examination of postmortem human tissue. We demonstrate that the C455R and R1031C mutations define different hypomorphic activity states of Notch 3, a property linked to ischemic stroke susceptibility in mouse models we generated. Importantly, these mice develop osmiophilic deposits and other age-dependent phenotypes that parallel remarkably the human condition. Proteomic analysis of human brain vessels, carrying the same CADASIL mutations, identified clusterin and collagen 18 alpha1/endostatin as GOM components. Our findings link loss of Notch signaling with ischemic cerebral small-vessel disease, a prevalent human condition. We determine that CADASIL pathophysiology is associated with hypomorphic Notch 3 function in vascular smooth muscle cells and implicate the accumulation of clusterin and collagen 18 alpha1/endostatin in brain vessel pathology. PMID- 21555591 TI - Control of mTORC1 signaling by the Opitz syndrome protein MID1. AB - Mutations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of diverse ventral midline structures. The MID1 protein has been shown to function as an E3 ligase targeting the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitin-mediated degradation. However, the molecular pathways downstream of the MID1/PP2A axis that are dysregulated in OS and that translate dysfunctional MID1 and elevated levels of PP2A-C into the OS phenotype are poorly understood. Here, we show that perturbations in MID1/PP2A affect mTORC1 signaling. Increased PP2A levels, resulting from proteasome inhibition or depletion of MID1, lead to disruption of the mTOR/Raptor complex and down-regulated mTORC1 signaling. Congruously, cells derived from OS patients that carry MID1 mutations exhibit decreased mTORC1 formation, S6K1 phosphorylation, cell size, and cap-dependent translation, all of which is rescued by expression of wild-type MID1 or an activated mTOR allele. Our findings define mTORC1 signaling as a downstream pathway regulated by the MID1/PP2A axis, suggesting that mTORC1 plays a key role in OS pathogenesis. PMID- 21555592 TI - Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity. AB - Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1), is required for mda-7/IL-24-mediated apoptosis of prostate carcinomas. Here we demonstrate that pharmacological inhibition of Mcl-1 expression with the unique Apogossypol derivative BI-97C1, also called Sabutoclax, is sufficient to sensitize prostate tumors to mda-7/IL-24-induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not sensitize mda-7/IL-24-mediated cytotoxicity. A combination regimen of tropism-modified adenovirus delivered mda-7/IL-24 (Ad.5/3 mda-7) and BI-97C1 enhances cytotoxicity in human PC cells, including those resistant to mda-7/IL-24 or BI-97C1 alone. The combination regimen causes autophagy that facilitates NOXA- and Bim-induced and Bak/Bax-mediated mitochondrial apoptosis. Treatment with Ad.5/3-mda-7 and BI-97C1 significantly inhibits the growth of human PC xenografts in nude mice and spontaneously induced PC in Hi-myc transgenic mice. Tumor growth inhibition correlated with increased TUNEL staining and decreased Ki-67 expression in both PC xenografts and prostates of Hi-myc mice. These findings demonstrate that pharmacological inhibition of Mcl 1 with the Apogossypol derivative, BI-97C1, sensitizes human PCs to mda-7/IL-24 mediated cytotoxicity, thus potentially augmenting the therapeutic benefit of this combinatorial approach toward PC. PMID- 21555593 TI - Retinoic acid receptor signaling regulates choroid fissure closure through independent mechanisms in the ventral optic cup and periocular mesenchyme. AB - Retinoic acid receptor (RAR) signaling is required for morphogenesis of the ventral optic cup and closure of the choroid fissure, but the mechanisms by which this pathway regulates ventral eye development remain controversial and poorly understood. Although previous studies have implicated neural crest-derived periocular mesenchyme (POM) as the critical target of RA action in the eye, we show here that RAR signaling regulates choroid fissure closure in zebrafish by acting on both the ventral optic cup and the POM. We describe RAR-dependent regulation of eight genes in the neuroepithelial cells of the ventral retina and optic stalk and of six genes in the POM and show that these ventral retina/optic stalk and POM genes function independently of each other. Consequently, RAR signaling regulates ventral eye development through two independent, nonredundant mechanisms in different ocular tissues. Furthermore, the identification of two cohorts of genes implicated in ventral eye morphogenesis may help to elucidate the genetic basis of ocular coloboma in humans. PMID- 21555594 TI - Object decoding with attention in inferior temporal cortex. AB - Recognizing objects in cluttered scenes requires attentional mechanisms to filter out distracting information. Previous studies have found several physiological correlates of attention in visual cortex, including larger responses for attended objects. However, it has been unclear whether these attention-related changes have a large impact on information about objects at the neural population level. To address this question, we trained monkeys to covertly deploy their visual attention from a central fixation point to one of three objects displayed in the periphery, and we decoded information about the identity and position of the objects from populations of ~ 200 neurons from the inferior temporal cortex using a pattern classifier. The results show that before attention was deployed, information about the identity and position of each object was greatly reduced relative to when these objects were shown in isolation. However, when a monkey attended to an object, the pattern of neural activity, represented as a vector with dimensionality equal to the size of the neural population, was restored toward the vector representing the isolated object. Despite this nearly exclusive representation of the attended object, an increase in the salience of nonattended objects caused "bottom-up" mechanisms to override these "top-down" attentional enhancements. The method described here can be used to assess which attention related physiological changes are directly related to object recognition, and should be helpful in assessing the role of additional physiological changes in the future. PMID- 21555595 TI - Invasive pneumococcal disease. PMID- 21555597 TI - Descemet-stripping automated endothelial keratoplasty for congenital hereditary endothelial dystrophy. AB - OBJECTIVE: To describe the results of Descemet-stripping automated endothelial keratoplasty (DSAEK) for congenital hereditary endothelial dystrophy (CHED). METHODS: The medical records of all patients with CHED who underwent DSAEK at our institution were reviewed. A standard DSAEK was performed in all cases with the exception of the Descemet membrane not being removed in patients younger than 12 months. A thorough ophthalmic examination was performed preoperatively and at each postoperative visit in all patients. RESULTS: Fifteen eyes of 8 patients with phakic eyes (4 male and 4 female) were included. The mean age was 9 years (range, 6 months to 30 years). The average follow-up was 15.9 months (range, 3 to 48 months). There were 4 cases of graft detachment, all of which were managed by rebubbling. All corneas were clear within 1 week after surgery. Two of the three infants (6 eyes) could fix and follow preoperatively, while all 3 could do so as early as 1 week following surgery on the second eye. In older patients (9 eyes), preoperative best-corrected visual acuity was 20/200 or less in 6 eyes. Postoperatively, 8 eyes achieved a best-corrected visual acuity of 20/40 or better. Endothelial cell loss (= 7 eyes) averaged 30.0% (range, 8.3% to 43.0%). CONCLUSIONS: DSAEK performed in eyes with CHED allows rapid restoration of corneal clarity while minimizing intraoperative and postoperative complications. Our data suggest performing surgery at an earlier age, thus providing opportunity for improved visual development and potentially avoiding amblyopia. PMID- 21555598 TI - Prognostic indicators and outcome measures for surgical removal of symptomatic nonadvanced cataract. AB - OBJECTIVES: To report changes in perceived visual functioning after surgery for symptomatic cataract with preoperative corrected distance visual acuity [CDVA] of 0.4 logMAR or better (Snellen equivalent, 20/50) and to investigate the relationship between any observed changes and preoperative physical characteristics and psychophysical consequences of the lens opacity and any changes in psychophysical findings after the procedure. METHODS: Eighty-five patients with cataract completed a validated questionnaire concerning functional vision satisfaction and a series of visual performance assessments before and 2 months after cataract surgery. The lens optical density and Lens Opacities Classification System III score of the cataract were recorded. Correlations between changes in the Rasch-analyzed questionnaire score and changes in visual performance after cataract surgery, as well as preoperative psychophysical measures, lens optical density, and Lens Opacities Classification System III score, were determined. RESULTS: The mean (SD) questionnaire score improved from 2.15 (0.36) to 1.54 (0.41) (P < .001). The preoperative questionnaire score (r = 0.44), preoperative mesopic glare disability [GD] (at 1.5 cycles per degree [cpd] [r = 0.34] and 3.0 cpd [r = 0.27]), and preoperative photopic GD (at 1.5 cpd [r = 0.24] and 3.0 cpd [r = 0.30]) showed statistically significant correlations with perceived improvements in visual functioning after surgery (P < .05). Changes in perceived visual functioning correlated significantly with changes in mesopic GD (at 1.5 cpd [r = -0.43] and 3.0 cpd [r = -0.28]; P < .05) and photopic GD (at 1.5 cpd [r = -0.24] and 3.0 cpd [r = -0.39]; P < .05). Neither preoperative CDVA nor change in CDVA after surgery correlated significantly with perceived improvement in visual functioning after the procedure (P > .05 for both). CONCLUSION: Psychophysical tests alternative to CDVA better represent improvements in self reported visual functioning following removal of symptomatic nonadvanced cataract. PMID- 21555599 TI - Quantifying discordance between structure and function measurements in the clinical assessment of glaucoma. AB - OBJECTIVE: To evaluate a new method of quantifying and visualizing discordance between structural and functional measurements in glaucomatous eyes by predicting the visual field (VF) from retinal nerve fiber layer thickness (RNFLT) using a bayesian radial basis function. METHODS: Five GDx VCC RNFLT scans and 5 Humphrey 24-2 Swedish Interactive Thresholding Algorithm VF tests were performed for 50 glaucomatous eyes from 50 patients. A best-available estimate (BAE) of the true VF was calculated as the pointwise median of these 5 replications. This BAE VF was compared with every RNFLT-predicted VF from the bayesian radial basis function and every measured VF. Predictability of VFs from RNFLT was established from previous data. A structure-function pattern discordance map and a structure function discordance index (scores of 0-1) were established from the predictability limits for each structure-function measurement pair to quantify and visualize the discordance between the structure-predicted and measured VFs. RESULTS: The mean absolute difference between the structure-predicted and BAE VFs was 3.9 dB. The mean absolute difference between measured and BAE VFs was 2.6 dB. The mean (SD) structure-function discordance index score was 0.34 (0.11). Ninety seven (39%) of the structure-predicted VFs showed significant discordance (structure-function discordance index score >0.3) from measured VFs. CONCLUSIONS: On average, the bayesian radial basis function predicts the BAE VF from RNFLT slightly less well than a measured VF from the 5 VFs composing the BAE VF. The pattern discordance map highlights locations with structure-function discordance, with the structure-function discordance index providing a summary index. These tools may help clinicians trust the mutually confirmatory structure-function measurements with good concordance or identify unreliable ones with poor concordance. PMID- 21555600 TI - Baseline factors related to endothelial cell loss following penetrating keratoplasty. AB - OBJECTIVE: To identify baseline (donor, recipient, and operative) factors that affect endothelial cell loss following penetrating keratoplasty for a moderate risk condition (principally Fuchs dystrophy or pseudophakic or aphakic corneal edema). METHODS: In a subset (n = 567) of Cornea Donor Study participants, preoperative and postoperative endothelial cell densities (ECDs) were determined by a central reading center. Multivariate regression analyses were performed to examine which baseline factors correlated with ECD over time. RESULTS: Larger grafts (P < .001), younger donor age (P < .001), and female donor (P = .004) were significantly associated with higher ECD during follow-up. Median endothelial cell loss at 5 years was 68% for grafts larger than 8.0 to 9.0 mm in diameter, 75% for grafts 7.0 mm to smaller than 8.0 mm in diameter, and 74% for grafts 8.0 mm in diameter. Grafts from female donors experienced a 67% cell loss compared with a 72% cell loss among grafts from male donors. Method of tissue retrieval, donor cause of death, history of diabetes, and time from death to preservation or to surgery were not significantly associated with changes in ECD over time. CONCLUSIONS: Following penetrating keratoplasty for endothelial dysfunction conditions, larger donor graft size, younger donor age, and female donor were associated with higher ECD over 5 years. These data warrant exploring the possibility that similar associations may exist following endothelial keratoplasty. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006411. PMID- 21555601 TI - Risk factors and preventive interventions for Alzheimer disease: state of the science. AB - BACKGROUND: Numerous studies have investigated risk factors for Alzheimer disease (AD). However, at a recent National Institutes of Health State-of-the-Science Conference, an independent panel found insufficient evidence to support the association of any modifiable factor with risk of cognitive decline or AD. OBJECTIVE: To present key findings for selected factors and AD risk that led the panel to their conclusion. DATA SOURCES: An evidence report was commissioned by the Agency for Healthcare Research and Quality. It included English-language publications in MEDLINE and the Cochrane Database of Systematic Reviews from 1984 through October 27, 2009. Expert presentations and public discussions were considered. STUDY SELECTION: Study inclusion criteria for the evidence report were participants aged 50 years and older from general populations in developed countries; minimum sample sizes of 300 for cohort studies and 50 for randomized controlled trials; at least 2 years between exposure and outcome assessment; and use of well-accepted diagnostic criteria for AD. DATA EXTRACTION: Included studies were evaluated for eligibility and data were abstracted. Quality of overall evidence for each factor was summarized as low, moderate, or high. DATA SYNTHESIS: Diabetes mellitus, hyperlipidemia in midlife, and current tobacco use were associated with increased risk of AD, and Mediterranean-type diet, folic acid intake, low or moderate alcohol intake, cognitive activities, and physical activity were associated with decreased risk. The quality of evidence was low for all of these associations. CONCLUSION: Currently, insufficient evidence exists to draw firm conclusions on the association of any modifiable factors with risk of AD. PMID- 21555602 TI - Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. AB - OBJECTIVE: To determine if a significant proportion of patients with myoclonic astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. DESIGN: Genetic analysis. SETTING: Ambulatory and hospitalized care. PATIENTS: Eighty four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. MAIN OUTCOME MEASURE: Any SLC2A1 mutations. RESULTS: Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. CONCLUSIONS: Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder. PMID- 21555603 TI - Comparison of analytical platforms for cerebrospinal fluid measures of beta amyloid 1-42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. AB - BACKGROUND: Cerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of antemortem diagnosis. OBJECTIVE: To test whether CSF biomarker assays differ in their ability to identify true markers of underlying AD pathology (eg, amyloid plaques and/or neurofibrillary tangles) in living individuals. DESIGN: We compared the performances of the 2 most commonly used platforms, INNOTEST enzyme-linked immunosorbent assay and INNO-BIA AlzBio3, for measurement of CSF beta-amyloid (Abeta) and tau proteins to identify the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Abeta1-42, total tau, and phosphorylated tau 181 (p-tau(181)) using the 2 assay platforms were compared with brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent Pittsburgh compound B. SETTING: The Knight Alzheimer's Disease Research Center at Washington University in St Louis, Missouri. SUBJECTS: Research volunteers who were cognitively normal or had mild to moderate AD dementia. RESULTS: The 2 assay platforms yielded different (approximately 2- to 6 fold) absolute values for the various analytes, but relative values were highly correlated. The CSF Abeta1-42 correlated inversely and tau and p-tau(181) correlated positively with the amount of cortical Pittsburgh compound B binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau to Abeta1-42 and p-tau(181) to Abeta1-42 outperformed any single analyte, including Abeta1-42, in discriminating individuals with vs without cortical amyloid. CONCLUSIONS: The INNOTEST and INNO-BIA CSF platforms perform equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cutoff values. PMID- 21555604 TI - Effect of APOE epsilon4 status on intrinsic network connectivity in cognitively normal elderly subjects. AB - OBJECTIVE: To examine default mode and salience network functional connectivity as a function of APOE epsilon4 status in a group of cognitively normal age-, sex , and education-matched older adults. DESIGN: Case-control study. SUBJECTS: Fifty six cognitively normal APOE epsilon4 carriers and 56 age-, sex- and education matched cognitively normal APOE epsilon4 noncarriers. MAIN OUTCOME MEASURE: Alterations in in-phase default mode and salience network connectivity in APOE epsilon4 carriers compared with APOE epsilon4 noncarriers ranging from 63 to 91 years of age. RESULTS: A posterior cingulate seed revealed decreased in-phase connectivity in regions of the posterior default mode network that included the left inferior parietal lobe, left middle temporal gyrus, and bilateral anterior temporal lobes in the epsilon4 carriers relative to APOE epsilon4 noncarriers. An anterior cingulate seed showed greater in-phase connectivity in the salience network including the cingulate gyrus, medial prefrontal cortex, bilateral insular cortex, striatum, and thalamus in APOE epsilon4 carriers vs noncarriers. There were no groupwise differences in brain anatomy. CONCLUSIONS: The observation of functional alterations in default mode and salience network connectivity in the absence of structural changes between APOE epsilon4 carriers and noncarriers suggests that alterations in connectivity may have the potential to serve as an early biomarker. PMID- 21555605 TI - Stroke-related translational research. AB - Stroke-related translational research is multifaceted. Herein, we highlight genome-wide association studies and genetic studies of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1 mutations, and cerebral cavernous malformations; advances in molecular biology and biomarkers; newer brain imaging research; and recovery from stroke emphasizing cell-based and other rehabilitative modalities. PMID- 21555606 TI - Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. AB - OBJECTIVE: To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab. DESIGN: Case study. SETTING: Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver. PATIENTS: Four patients developing PML in the setting of rituximab therapy for RA. INTERVENTION: Rituximab therapy. MAIN OUTCOME MEASURES: Clinical and pathological observations. RESULTS: Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjogren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease. CONCLUSION: These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low. PMID- 21555607 TI - Risk factors for visual field progression in treated glaucoma. AB - OBJECTIVE: To determine intraocular pressure (IOP)-dependent and IOP-independent variables associated with visual field (VF) progression in treated glaucoma. DESIGN: Retrospective cohort of the Glaucoma Progression Study. METHODS: Consecutive, treated glaucoma patients with repeatable VF loss who had 8 or more VF examinations of either eye, using the Swedish Interactive Threshold Algorithm (24-2 SITA-Standard, Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc, Dublin, California), during the period between January 1999 and September 2009 were included. Visual field progression was evaluated using automated pointwise linear regression. Evaluated data included age, sex, race, central corneal thickness, baseline VF mean deviation, mean follow-up IOP, peak IOP, IOP fluctuation, a detected disc hemorrhage, and presence of beta-zone parapapillary atrophy. RESULTS: We selected 587 eyes of 587 patients (mean [SD] age, 64.9 [13.0] years). The mean (SD) number of VFs was 11.1 (3.0), spanning a mean (SD) of 6.4 (1.7) years. In the univariable model, older age (odds ratio [OR], 1.19 per decade; P = .01), baseline diagnosis of exfoliation syndrome (OR, 1.79; P = .01), decreased central corneal thickness (OR, 1.38 per 40 MUm thinner; P < .01), a detected disc hemorrhage (OR, 2.31; P < .01), presence of beta-zone parapapillary atrophy (OR, 2.17; P < .01), and all IOP parameters (mean follow-up, peak, and fluctuation; P < .01) were associated with increased risk of VF progression. In the multivariable model, peak IOP (OR, 1.13; P < .01), thinner central corneal thickness (OR, 1.45 per 40 MUm thinner; P < .01), a detected disc hemorrhage (OR, 2.59; P < .01), and presence of beta-zone parapapillary atrophy (OR, 2.38; P < .01) were associated with VF progression. CONCLUSIONS: IOP-dependent and IOP independent risk factors affect disease progression in treated glaucoma. Peak IOP is a better predictor of progression than is IOP mean or fluctuation. PMID- 21555608 TI - Association of narrow angles with anterior chamber area and volume measured with anterior-segment optical coherence tomography. AB - OBJECTIVES: To describe the measurement of anterior chamber area and anterior chamber volume by anterior-segment optical coherence tomography and to investigate the association of these parameters with the presence of narrow angles. METHODS: This was a cross-sectional study of subjects aged at least 50 years without ophthalmic symptoms recruited from a community clinic. All participants underwent standardized ocular examination and anterior-segment optical coherence tomography. Customized software was used to measure anterior chamber area (cross-sectional area bounded by the corneal endothelium, anterior surface of iris, and lens within the pupil) and anterior chamber volume (calculated by rotating the anterior chamber area 360 degrees around a vertical axis through the midpoint of the anterior chamber area). An eye was considered to have narrow angles if the posterior pigmented trabecular meshwork was not visible for at least 180 degrees on gonioscopy with the eye in the primary position. RESULTS: A total of 1922 subjects were included in the final analyses, 317 (16.5%) of whom had narrow angles. Mean anterior chamber area (15.6 vs 21.1 mm(2); P < .001) and anterior chamber volume (97.6 vs 142.1 mm(3); P < .001) were smaller in eyes with narrow angles compared with those in eyes without narrow angles. After adjusting for age, sex, anterior chamber depth, axial length, and pupil size, smaller anterior chamber area (odds ratio, 53.2; 95% confidence interval, 27.1-104.5) and anterior chamber volume (odds ratio, 40.2; 95% confidence interval, 21.5-75.2) were significantly associated with the presence of narrow angles. CONCLUSION: Smaller anterior chamber area and anterior chamber volume were independently associated with narrow angles in Singaporeans, even after controlling for other known ocular risk factors. PMID- 21555609 TI - Retinal pigment epithelium tears secondary to age-related macular degeneration: a simultaneous confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography study. AB - OBJECTIVE: To describe the morphology of retinal pigment epithelium (RPE) tears secondary to age-related macular degeneration by using high-resolution, spectral domain optical coherence tomography (SD-OCT). METHODS: For simultaneous topographic and tomographic in vivo imaging, confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography were applied in combination. Retina over the RPE-denuded area was particularly examined for signs of viable photoreceptors. RESULTS: A total of 26 patients (28 eyes) were included in the study. The mean (SD) age of patients was 78 (8) years (age range, 62-91 years). In cases with recent RPE tears, external limiting membrane, photoreceptor inner and outer segment junction, and nonatrophic outer nuclear layer could be identified in the retina on the RPE-denuded area. Intact external limiting membrane, photoreceptor inner and outer segment junction, and nonatrophic outer nuclear layer could be seen in 1 patient for up to 325 days after the RPE tear. In fibrotic older RPE tears, these structures were atrophic. CONCLUSIONS: In this study, signs for viable photoreceptors could be identified for up to 325 days after an RPE tear using spectral-domain optical coherence tomography. This finding is important to consider in future therapies aimed at rescuing photoreceptors after RPE tears. PMID- 21555610 TI - Pattern electroretinography in age-related macular degeneration. AB - OBJECTIVE: To determine whether prolonged vascular endothelial growth factor inhibition is toxic to the retina by using pattern electroretinographic imaging in participants with neovascular age-related macular degeneration (AMD). METHODS: We performed a prospective, single-arm clinical trial of 17 eyes in 17 treatment naive participants with subfoveal choroidal neovascularization from AMD. On-label intravitreous ranibizumab was injected monthly for 6 months. Then pattern electroretinographic imaging was performed before and at 1 month, 3 months, and 6 months after first treatment, and results were interpreted by a trained reader masked to the clinical data. The primary outcome measure was the change in pattern electroretinographic imaging (positive wave peaking at 50 milliseconds [P50] and negative wave peaking at 95 milliseconds [N95] values) from baseline at 6 months. The secondary outcome measure was the change in visual acuity at 6 months. RESULTS: The mean participant age was 79.6 years (range, 69.5-90.4 years). At baseline, mean (SD) P50 and N95 amplitudes were 1.3 (0.69) MUV and 1.5 (0.71) MUV, respectively. By 6 months, no decrease in P50 or N95 amplitudes from baseline was observed (1.4 [0.47] MUV, P = .46; and 1.8 [0.96] MUV, P = .14, respectively). Mean visual acuity before treatment was 20/85 with improvement to a mean of 20/55 (P = .004) at 6 months. CONCLUSIONS: This study found no decrease in P50 and N95 amplitudes in participants treated with ranibizumab for neovascular AMD. These findings indicate that vascular endothelial growth factor inhibition with monthly injections of ranibizumab for 6 months likely does not lead to retinal damage. Trial Registration clinicaltrials.gov Identifier: NCT00500344. PMID- 21555611 TI - Sutureless triplanar sclerotomy for 23-gauge vitrectomy. AB - OBJECTIVES: To describe and test the intraoperative integrity of triplanar sclerotomies. METHODS: A prospective consecutive case series of 180 sclerotomies in 60 eyes was studied. After conjunctival dissection, triplanar transscleral wounds were created with a 23-gauge trocar using a standardized technique. At the conclusion of surgery, an air-fluid exchange was performed, and cannulas were removed. Then, unsutured scleral wound integrity was tested for permeability to vitreous, gas, and fluid by application of a cellulose sponge, observation of gas escape, and examination by the Seidel method, respectively. Postoperative intraocular pressure was recorded. Laboratory studies with fresh human donor globes were conducted to evaluate the histologic characteristics of triplanar sclerotomies. RESULTS: Unsutured triplanar wounds were closed to vitreous, gas, and fluid in 169 of 180 sclerotomies (93.9%). Eleven sclerotomies were open and showed positive results using only 1 testing method each. In these cases, vitreous was detected in 1 wound, gas escaped from 8 wounds, and Seidel test results were positive in 2 wounds. Complex retinal detachment repairs had a higher rate of wounds requiring suture placement. One patient had transient postoperative day 1 hypotony. CONCLUSIONS: It is possible to achieve high rates of unsutured wound closure with triplanar transscleral sclerotomies. No single method of evaluating wound leakage appeared to be the most sensitive. More complex cases requiring longer surgical times, more instrument passes, and increased wound manipulation resulted in higher rates of wound leakage. Leakage can be subtle, and surgeons should use multiple methods to adequately assess sclerotomy closure. PMID- 21555612 TI - Predictive value of pre-plus disease in retinopathy of prematurity. AB - OBJECTIVES: To investigate prospectively whether the presence of pre-plus disease predicts progression to severe retinopathy of prematurity (ROP) requiring laser treatment. METHODS: Posterior retinal video recordings were obtained during 710 indirect ophthalmoscopy examinations of 214 premature infants over a period of 5 years. Two masked experts reviewed short video recordings and determined whether there was plus disease, pre-plus disease, or neither. The primary analysis included results of one examination of the right eye at 33 to 34 weeks' postmenstrual age. The primary outcome was a comparison of the proportion of eyes subsequently requiring laser treatment between the group graded as having pre plus disease vs the group graded as having neither plus disease nor pre-plus disease. RESULTS: Of 10 eyes with pre-plus disease at 33 to 34 weeks' postmenstrual age, 7 (70%) subsequently required laser treatment; of 154 eyes without pre-plus disease or plus disease at 33 to 34 weeks' postmenstrual age, 14 (9%) subsequently required laser treatment (risk ratio, 7.7; 95% confidence interval, 4.1-14.8; P < .001). The mean time between the examination diagnosing pre-plus disease and laser treatment was 1.6 weeks (range, 1.0-2.4 weeks). When adjusting for birth weight, gestational age, ROP location (zone), and ROP severity (stage), the presence of pre-plus disease at 33 to 34 weeks' postmenstrual age independently predicted the need for laser treatment (adjusted odds ratio, 7.6; 95% confidence interval, 1.4-42.3; P = .02). CONCLUSIONS: Pre plus disease observed early during the course of ROP is strongly associated with the development of severe ROP requiring laser treatment. The diagnosis of pre plus disease has prognostic value beyond that already provided by birth weight, gestational age, ROP zone, and ROP stage. Eyes with pre-plus disease should be closely observed to allow optimal timing of intervention. PMID- 21555613 TI - Fundus autofluorescence in autosomal dominant occult macular dystrophy. AB - OBJECTIVE: To characterize fundus autofluorescence (FAF) images of eyes with autosomal dominant occult macular dystrophy (OMD). METHODS: All patients received a comprehensive ophthalmologic examination for diagnosis of OMD. We evaluated the FAF images in 13 eyes of 7 patients with autosomal dominant OMD by confocal scanning laser ophthalmoscopy with excitation at 488 nm and emission more than 500 nm. RESULTS: The FAF images showed unspecific weak foveal hyperfluorescence in 4 eyes of 2 patients; one showed a thin hyperfluorescence in the temporal fovea bilaterally and the other showed weak hyperfluorescence in the fovea bilaterally. The optical coherence tomographic images showed abnormalities of the photoreceptor inner segment-outer segment line and cone outer segment tip line in all patients. However, 5 patients had normal FAF images regardless of morphological abnormalities of the photoreceptor. CONCLUSIONS: Fundus autofluorescence is a useful method to acquire additional information of photoreceptor/retinal pigment epithelium function in eyes with OMD. Fundus autofluorescence will be also helpful for the differential diagnosis of eyes with OMD vs eyes with other dystrophies that have a distinctive FAF pattern. PMID- 21555614 TI - Cost-effectiveness of 2 approaches to managing nasolacrimal duct obstruction in infants: the importance of the spontaneous resolution rate. AB - OBJECTIVE: To assess the impact of the rate of spontaneous resolution of congenital nasolacrimal duct obstruction on the relative cost-effectiveness of deferred nasolacrimal duct probing in a surgical facility (DFPS) compared with an immediate office-based probing surgery (IOPS). METHODS: Data from the literature, Medicare 2009 fee schedule, and consensus assumptions were combined to populate a model of outcomes of 2 treatment strategies: immediate office-based probing (IOPS) and deferred facility-based probing (DFPS) (deferred for 6 months). Sensitivity analyses were conducted, varying the 6-month spontaneous resolution rate from 50% to 90%. Additional factors varied during analyses included surgical cost and each procedure's probability of success. Outcomes measured were overall cost of treatment, chance of cure, and months of symptoms avoided by 18 months of life. RESULTS: Under the base case, assuming a 75% spontaneous resolution rate during 6 months prior to deferred probing, IOPS is more expensive ($771 vs $641) and slightly less effective (93.0% vs 97.5%) than DFPS, although IOPS costs only $44 per month of symptoms avoided. At spontaneous resolution rates between 50% and 68%, IOPS costs less than DFPS (from $2 to $342 less), although it also is slightly less effective (from 2.0% to 3.8% less). At a 90% spontaneous resolution rate, IOPS costs $169 per month of symptoms avoided. As the rate of spontaneous resolution falls, the cost per additional success for DFPS increases to $16 709 at a 50% spontaneous resolution rate. CONCLUSION: The relative cost-effectiveness of these strategies for treatment of nasolacrimal duct obstruction depends on the spontaneous resolution rate after diagnosis. PMID- 21555615 TI - Object detection in the ring scotoma of a monocular bioptic telescope. AB - OBJECTIVE: To evaluate the ability of the fellow eye to detect stimuli in the area corresponding to the ring scotoma (blind area) of a monocular bioptic telescope in simple conditions (conventional perimetry) and in more visually demanding conditions. METHODS: A computerized dichoptic perimeter enabled separate stimuli to be presented to each eye of 7 bioptic users and 7 nonusers. The bioptic ring scotoma was mapped by presenting the stimulus to the telescope eye only. Detection tests were then conducted under binocular viewing, with stimuli presented only to the fellow eye in a 2 * 2 * 2 design with or without telescope, on plain gray or patterned (spatial noise) background, and with passive (looking at cross) or active (reading letters) fixation task. RESULTS: No significant differences were noted in fellow-eye detection with (86%) and without (87%) a bioptic. The detection rate was significantly reduced on the patterned background and in the active fixation task. CONCLUSIONS: To our knowledge, this is the first study to demonstrate fellow-eye detection in the area of the ring scotoma with a monocular bioptic telescope under more realistic and visually demanding conditions than conventional perimetry. These results should ease the concern that the monocular ring scotoma might cause blindness to traffic outside the field of the telescope. PMID- 21555616 TI - Advancing the treatment of conjunctival scarring: a novel ex vivo model. AB - OBJECTIVES: To develop and validate a novel ex vivo model of conjunctival contraction. METHODS: Ex vivo segments of conjunctiva were maintained in culture for 4 weeks in permeable support plates. Digital images were obtained twice a week to monitor contraction using tissue area changes and weekly weight measurements. Investigated were the effects of known contraction stimulators (fetal bovine serum and transforming growth factor beta(2)) and of the matrix metalloproteinase inhibitor GM6001. Microscopic contraction, tissue organization, and cell viability (using the cell vital dye carboxyfluorescein diacetate) were monitored by confocal reflection and 2-photon microscopy, revealing detailed real time kinetics of tissue remodeling. RESULTS: Fetal bovine serum and transforming growth factor beta(2) induced significant tissue contraction in conjunctiva segments, with no changes in cell viability. This correlated with dramatic and specific degradation of the collagen component in the tissue. Contraction and collagen degradation were reduced in the presence of GM6001. CONCLUSIONS: Ex vivo segments of conjunctiva can be used as an integral model system to provide a higher level of understanding about the efficacy of antiscarring therapies and can help bridge the current gap between in vitro and in vivo models. CLINICAL RELEVANCE: Scarring leads to the failure of several ocular surgical procedures. This novel ex vivo model recapitulates tissue contraction (with kinetics close to that of in vivo scarring) and allows for a more physiological analysis of conjunctival scarring, which could better evaluate potential therapeutic targets. PMID- 21555617 TI - Pilot study of the delivery of microcollimated pars plana external beam radiation in porcine eyes. AB - OBJECTIVE: To investigate the effects of a novel stereotactic radiosurgical system for pars plana delivery of microcollimated x-rays to the retina and determine the retinal radiological dose response and toxicity threshold in a pig model. METHODS: The x-rays were delivered through the pars plana to the maculae of Yucatan miniswine to verify the targeting and safety of a cornea-scleral, stabilized, office-based delivery system. Twelve eyes were randomized to receive 0, 16, 24, 42, 60, or 90 Gy in a single dose to the retina. Eye examinations, fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were obtained at days 7, 30, 60, and 90. Indocyanine green angiography was done at day 90. RESULTS: Through day 90 interim analysis, no abnormalities of external structures were noted. A small cortical lens opacity was noted in the 60-Gy group. Fundus evaluation revealed no abnormalities at 16 or 24 Gy. Beginning at day 30, circular pale retinal lesions with sharp margins were noted in the maculae of the eyes that received 42, 60, and 90 Gy. Higher dose lesions showed late staining on fluorescein angiography, choroidal hypoperfusion on indocyanine green angiography, and defined photoreceptor loss and retinal thinning on spectral-domain optical coherence tomography. CONCLUSION: Transscleral stereotactic radiation dosing of porcine eyes demonstrates no apparent clinical abnormalities in doses less than 24 Gy. Doses of 42 Gy or higher led to focal choroidal and retinal damage within the target area. CLINICAL RELEVANCE: Radiation can induce small-blood vessel closure and thereby has therapeutic potential in neovascular diseases such as age-related macular degeneration. PMID- 21555618 TI - Prevalence of dry eye disease in an elderly Korean population. AB - OBJECTIVE: To evaluate the prevalence of and risk factors for dry eye disease (DED) in an elderly Korean population. METHODS: This population-based study in Yongin, Korea, included 657 individuals 65 years or older randomly selected from an official household registration database. Dry eye symptoms were assessed using a 6-item questionnaire, and DED was defined as having 1 or more dry eye symptoms often or all the time. Dry eye tests, including the Schirmer test, tear film break-up time measured using fluorescein, cornea fluorescein staining, and examination for meibomian gland dysfunction, were performed. RESULTS: The crude prevalence of DED was 30.3%, and the age-, sex-, and region (urban vs rural) adjusted prevalence was 33.2%. Women (P = .01) and urban dwellers (P = .001) were more likely to have DED. Of those with DED, 85.1% had tear film break-up time of 10 seconds or less, 54.1% had meibomian gland dysfunction, 39.2% had a fluorescein score of 1 or greater, and 32.8% had a Schirmer test score of 5 mm or less. A low Schirmer score was correlated with increased prevalence of DED, although sensitivity was low. CONCLUSIONS: Dry eye disease is common in elderly Koreans; female sex and living in an urban region were strongly correlated with its frequency. We also noted a positive correlation between low Schirmer test scores and symptom-based DED. PMID- 21555619 TI - Two novel CHN1 mutations in 2 families with Duane retraction syndrome. AB - OBJECTIVE: To determine the genetic cause of Duane retraction syndrome (DRS) in 2 families segregating DRS as a dominant trait. METHODS: Members of 2 unrelated pedigrees were enrolled in a genetic study. Linkage analysis was performed on the CHN1 locus. Probands and family members were screened for CHN1 mutations. RESULTS: The 6 affected individuals in the 2 pedigrees have DRS. Both pedigrees are consistent with linkage to the locus. Sequence analysis revealed 2 novel heterozygous missense CHN1 mutations, c.422C>T and c.754C>T, predicted to result in alpha2-chimaerin amino acid substitutions P141L and P252S, respectively. CONCLUSIONS: Genetic analysis of 2 pedigrees revealed 2 novel DRS mutations, bringing the number of DRS pedigrees known to harbor CHN1 from 7 to 9. Both mutations alter residues that participate in intramolecular interactions that stabilize the inactive, closed conformation of alpha2-chimaerin and, thus, are predicted to result in its hyperactivation. Moreover, amino acid residue P252 was previously reported to be altered to a different residue in a previously reported DRS pedigree; thus, this is the first report of 2 CHN1 mutations altering the same residue, further supporting a gain-of-function etiology. CLINICAL RELEVANCE: Members of families segregating DRS as an autosomal dominant trait should be screened for mutations in the CHN1 gene, enhancing genetic counseling and permitting earlier diagnosis. PMID- 21555620 TI - Interview with Alfred Sommer, MD, MHS by George B Bartley. PMID- 21555621 TI - The curious blindness of Charles F. Lummis. AB - Generations of disabled persons were inspired by the miraculous recovery Charles Fletcher Lummis made following a series of devastating strokes that began at the age of 28. The famed author, editor, and social activist was struck by misfortune again at 51 when he went bilaterally blind. At the height of his career, Lummis never let the loss of vision interfere with his many professional responsibilities or his personal life. The cause of Lummis's stroke and blindness has been the subject of speculation for nearly a century and involves one of the most sensitive and perplexing diagnoses in medicine. PMID- 21555622 TI - Ocular pathologic features and gadolinium deposition in nephrogenic systemic fibrosis. PMID- 21555623 TI - Mitochondrial DNA mutations in oncocytic adnexal lacrimal glands of the conjunctiva. PMID- 21555624 TI - Possible in vitro model of toxic epidermal necrolysis. PMID- 21555625 TI - Elevation of intraocular pressure in patients with uveitis treated with topical difluprednate. PMID- 21555626 TI - Intraocular pressure elevation during radioactive plaque brachytherapy for uveal melanoma. PMID- 21555627 TI - Photoreceptor recovery following laser photocoagulation and albendazole in diffuse unilateral subacute neuroretinitis. PMID- 21555628 TI - Peripheral retinal nonperfusion in septo-optic dysplasia (de Morsier syndrome). PMID- 21555629 TI - Analysis of clinical misdiagnoses in children treated with enucleation. PMID- 21555632 TI - Letter from the DSMC regarding a clinical trial of lutein in patients with retinitis pigmentosa. PMID- 21555633 TI - Movement disorders emergencies. Part 1: Hypokinetic disorders. AB - Movement disorders usually do not require emergent intervention; nevertheless, there are acute/subacute clinical settings in which the neurologist is consulted. It is in these circumstances that the neurologist must be prepared to accurately diagnose and properly treat the patient. We have reviewed the literature regarding movement disorder emergencies and divided them into hypokinetic (part 1) and hyperkinetic (part 2) presentations. In part 1, drug-induced syndromes including neuroleptic malignant syndrome, parkinsonism hyperpyrexia syndrome, and serotonin syndrome will be discussed. Emergency complications related to the management of Parkinson disease, including falling, motor fluctuations, and psychiatric issues, will also be reviewed. PMID- 21555634 TI - Test-retest reliability of memory task functional magnetic resonance imaging in Alzheimer disease clinical trials. AB - OBJECTIVE: To examine the feasibility and test-retest reliability of encoding task functional magnetic resonance imaging (fMRI) in mild Alzheimer disease (AD). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Memory clinical trials unit. PARTICIPANTS: We studied 12 patients with mild AD (mean [SEM] Mini-Mental State Examination score, 24.0 [0.7]; mean Clinical Dementia Rating score, 1.0) who had been taking donepezil hydrochloride for more than 6 months from the placebo arm of a larger 24-week study (n = 24, 4 scans on weeks 0, 6, 12, and 24, respectively). INTERVENTIONS: Placebo and 3 face-name, paired associate encoding, block-design blood oxygenation level-dependent fMRI scans in 12 weeks. MAIN OUTCOME MEASURES: We performed whole-brain t maps (P < .001, 5 contiguous voxels) and hippocampal regions-of-interest analyses of extent (percentage of active voxels) and magnitude (percentage of signal change) for novel-greater-than-repeated face-name contrasts. We also calculated intraclass correlation coefficients and power estimates for hippocampal regions of interest. RESULTS: Task tolerability and data yield were high (95 of 96 scans yielded favorable-quality data). Whole-brain maps were stable. Right and left hippocampal regions-of-interest intraclass correlation coefficients were 0.59 to 0.87 and 0.67 to 0.74, respectively. To detect 25.0% to 50.0% changes in week-0 to week-12 hippocampal activity using left-right extent or right magnitude with 80.0% power (2-sided alpha = .05) requires 14 to 51 patients. Using left magnitude requires 125 patients because of relatively small signal to variance ratios. CONCLUSIONS: Encoding-task fMRI was successfully implemented in a single-site, 24-week, AD randomized controlled trial. Week 0 to 12 whole-brain t maps were stable, and test-retest reliability of hippocampal fMRI measures ranged from moderate to substantial. Right hippocampal magnitude may be the most promising of these candidate measures in a leveraged context. These initial estimates of test-retest reliability and power justify evaluation of encoding-task fMRI as a potential biomarker for signal of effect in exploratory and proof-of-concept trials in mild AD. Validation of these results with larger sample sizes and assessment in multisite studies is warranted. PMID- 21555635 TI - Telephone-based identification of mild cognitive impairment and dementia in a multicultural cohort. AB - BACKGROUND: Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people. OBJECTIVE: To determine the accuracy of a telephone interview in classifying (1) demented from nondemented participants, (2) cognitively impaired participants from cognitively normal participants, and (3) participants with mild cognitive impairment (MCI) from those with normal cognition or (4) MCI from dementia among an ethnically and educationally diverse community-based sample. METHOD: The sample consisted of 377 (30.5% non-Hispanic white, 34.7% non-Hispanic black, and 33.7% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and MCI based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave. RESULTS: The sample included 256 people (67.9%) with normal cognition, 68 (18.0%) with MCI, and 53 (14.1%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non Hispanic blacks, and Hispanics. Among non-Hispanic whites, the DQ had better discrimination of those with dementia from those without dementia and from those with MCI than among other racial/ethnic groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (88% sensitivity and 87% specificity for the TICS; 66% sensitivity and 89% specificity for DQ) and when used to differentiate cognitively normal participants from those with cognitive impairment (ie, MCI and dementia combined; 73% sensitivity and 77% specificity for the TICS; 49% sensitivity and 82% specificity for DQ). When demographics and prior memory test performance were used to calculate pretest probability, consideration of the telephone measures significantly improved diagnostic validity. CONCLUSIONS: The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition. PMID- 21555636 TI - Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic aspects. AB - BACKGROUND: Cerebral folate deficiency may be amenable to therapeutic supplementation. Diverse metabolic pathways and unrelated processes can lead to cerebrospinal fluid 5-methyltetrahydrofolate (5-MTHF) depletion, the hallmark of cerebral folate deficiency. OBJECTIVE: To analyze cerebral folate abundance in a large prospective series of children diagnosed with any neurologic disorder for which a diagnostic lumbar puncture was indicated. DESIGN: We studied the spectrum and frequency of disorders associated with cerebral folate deficiency by measuring cerebrospinal fluid 5-MTHF, biogenic amines, and pterins. Direct sequencing of the FOLR1 transporter gene was also performed in some patients. SETTING: Academic pediatric medical center. PARTICIPANTS: We studied 134 individuals free of neurometabolic disease and 584 patients with any of several diseases of the central nervous system. RESULTS: Of 584 patients, 71 (12%) exhibited 5-MTHF deficiency. Mild to moderate deficiency (n = 63; range, 19-63 nmol/L) was associated with perinatal asphyxia, central nervous system infection, or diseases of probable genetic origin (inborn errors of metabolism, white matter disorders, Rett syndrome, or epileptic encephalopathies). Severe 5-MTHF depletion (n = 8; range, 0.6-13 nmol/L) was detected in severe MTHF reductase deficiency, Kearns-Sayre syndrome, biotin-responsive striatal necrosis, acute necrotizing encephalitis of Hurst, and FOLR1 defect. A strong correlation was observed between cerebrospinal fluid and plasma folate levels in cerebral folate deficiency. CONCLUSIONS: Of the 2 main forms of cerebral folate deficiency identified, mild to moderate 5-MTHF deficiency was most commonly associated with disorders bearing no primary relation to folate metabolism, whereas profound 5 MTHF depletion was associated with specific mitochondrial disorders, metabolic and transporter defects, or cerebral degenerations. The results suggest that 5 MTHF can serve either as the hallmark of inborn disorders of folate transport and metabolism or, more frequently, as an indicator of neurologic dysfunction. PMID- 21555637 TI - The APOE gene locus in frontotemporal dementia and primary progressive aphasia. AB - OBJECTIVE: To investigate the role of the apolipoprotein E (APOE) locus in frontotemporal dementia (FTD) and primary progressive aphasia (PPA). DESIGN: Case control study. SETTING: Neurology clinic, Rome, Italy. PATIENTS: Eighty-six patients with a clinical diagnosis of sporadic FTD, including 32 patients with a clinical diagnosis of PPA, and 99 nondemented cognitively intact control subjects. MAIN OUTCOME MEASURES: Genotype analysis of the 3 single-nucleotide polymorphisms rs449647, rs769446, and rs405509 in the promoter region of the APOE gene and of the 2 single-nucleotide polymorphisms rs429358 and rs7412 forming the common apoE polymorphism. RESULTS: Significant associations with FTD were observed for genotypes rs449647 A/T (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.5), rs769446 T/C (OR, 4.4; 95% CI, 1.9-10.2), and APOE epsilon3/epsilon4 (OR, 4.1; 95% CI, 1.6-10.9). Significant associations with PPA were also observed for genotypes APOE epsilon3/epsilon4 (OR, 22.5; 95% CI, 1.2 229.4) and epsilon4/epsilon4 (OR, 7.5; 95% CI, 2.6-21.6). Significant associations with FTD were observed for haplotypes A-C-G-C-C (OR, 5.6; 95% CI, 1.4-21.5) and T-T-T-C-C (OR, 5.2; 95% CI, 1.1-24.0). Significant associations with PPA were also observed for haplotypes A-T-T-T-C (OR, 0.4; 95% CI, 0.2-0.9) and A-T-T-C-C (OR, 5.2; 95% CI, 1.4-19.3). CONCLUSION: Although the physiological role of apoE in FTD and PPA needs further investigations, our results suggest an involvement of the APOE gene locus in the genetics of FTD and PPA. PMID- 21555638 TI - Mild cognitive impairment, dementia, and their subtypes in oldest old women. AB - BACKGROUND: The population of oldest old is increasing, but the prevalence of cognitive impairment is not well characterized in this group. OBJECTIVES: To determine the prevalence of mild cognitive impairment (MCI), dementia, and their subtypes in oldest old women and to examine whether some groups of oldest old women were more likely to have cognitive impairment. DESIGN: Prospective cohort study. SETTING: Women Cognitive Impairment Study of Exceptional Aging. PARTICIPANTS: A total of 1299 oldest old (>=85 years) women. MAIN OUTCOME MEASURES: All the women completed a neuropsychological test battery. Those who screened positive for possible cognitive impairment (n = 634) were further assessed for a diagnosis of dementia, MCI, or normal cognition. The remaining women (n = 665) were considered cognitively normal. Dementia and MCI subtypes were determined using standard criteria. RESULTS: The women had a mean age of 88.2 years, and 27.0% were 90 years or older; 231 women (17.8%) were diagnosed as having dementia and 301 (23.2%) as having MCI, for a combined cognitive impairment prevalence of 41.0%. Clinical features consistent with Alzheimer disease and mixed dementia were most common, each accounting for 40% of dementia cases. Amnestic multiple domain and nonamnestic single domain were the most common MCI types, accounting for 33.9% and 28.9% of cases, respectively. Cognitive impairment was more frequent in women 90 years or older compared with those 85 to 89 years (dementia, 28.2% vs 13.9%, P < .001; MCI, 24.5% vs 22.7%, P = .02) and was more common in women with less education, a history of stroke, and prevalent depression. CONCLUSIONS: In this large sample of oldest old women, 41.0% had clinically adjudicated cognitive impairment. Subtypes of dementia and MCI were similar to those in younger populations. Women in the fastest growing demographic, the oldest old, should be screened for cognitive disorders, especially high-risk groups. PMID- 21555639 TI - SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. AB - BACKGROUND: Deletions in ITPR1, coding for the inositol-triphosphate receptor type 1, have been recently identified in spinocerebellar ataxia type 15 (SCA15). OBJECTIVE: To determine the frequency and the phenotypical spectrum of SCA15. DESIGN: Taqman polymerase chain reaction (258 index cases) or single-nucleotide polymorphism genome-wide genotyping (75 index cases). SETTING: A collaboration between the Centre de Recherche de l'Institut de Cerveau et de la Moelle Epiniere of the Salpetriere Hospital (Paris, France) and the Molecular Genetics Unit of the National Institute of Aging (Bethesda, Maryland). Patients Index cases of 333 families with autosomal dominant cerebellar ataxia negative for CAG repeat expansions in coding exons. MAIN OUTCOME MEASURES: Detection of ITPR1 copy number alterations. RESULTS: A deletion of ITPR1 was found in 6 of 333 families (1.8%), corresponding to 13 patients with SCA15. Age at onset ranged from 18 to 66 years (mean [SD] age, 35 [16] years). The symptom at onset was cerebellar gait ataxia, except in 1 patient with isolated upper limb tremor. Although families were tested irrespective of their phenotype, patients with SCA15 had a homogeneous phenotype and were characterized by a slowly progressive cerebellar ataxia. However, pyramidal signs (2 patients) and mild cognitive problems (2 patients) were occasionally present. Radiologic findings showed global or predominant vermian cerebellar atrophy in all patients. CONCLUSIONS: In this series, ITPR1 deletions were rare and accounted for approximately 1% of all autosomal dominant cerebellar ataxias. The SCA15 phenotype mostly consists of a slowly progressive isolated cerebellar ataxia with variable age at onset; an additional pyramidal syndrome and problems in executive functions may be present. PMID- 21555640 TI - Longitudinal patterns of beta-amyloid deposition in nondemented older adults. AB - BACKGROUND: High levels of beta-amyloid (Abeta) characterize Alzheimer disease. OBJECTIVE: To investigate whether longitudinal changes in Abeta deposition can be detected in vivo in older adults without dementia (hereafter referred to as nondemented). DESIGN: Prospective study. SETTING: Community-dwelling older adults. PARTICIPANTS: Twenty-four nondemented participants (4 with a baseline Clinical Dementia Rating Scale score of 0.5; mean [SD] age, 79.2 [8.1] years) in the Baltimore Longitudinal Study of Aging underwent serial carbon 11-labeled Pittsburgh Compound B-positron emission tomography ([(11)C]PiB-PET) (follow-up at a mean [SD] of 1.5 [0.5] years), with 5 participants undergoing a third [(11)C]PiB-PET examination. MAIN OUTCOME MEASURES: Annual changes in distribution volume ratio (DVR) were evaluated using a global index of cortical DVR (cDVR) and region-of-interest analyses. Given the variability of cDVR at the initial PiB PET, annual changes in cDVR in those with minimal vs those with elevated initial cDVR were compared. RESULTS: In nondemented older adults, annual increase in [(11)C]PiB retention is 0.011 DVR per year (0.9%; P = .01), which localizes to the prefrontal, parietal, lateral temporal, occipital, and anterior and posterior cingulate cortices. Annual change in cDVR is greater in older adults with elevated cDVR than in those with a minimal initial cDVR (P = .006). CONCLUSIONS: Fibrillar Abeta detected by [(11)C]PiB-PET increases over time even in nondemented older adults. Individuals with higher initial [(11)C]PiB retention have greater rates of Abeta deposition, providing evidence of differential rates of Abeta deposition. Moreover, regional vulnerabilities to Abeta deposition allow for more targeted investigation of early Abeta changes. PMID- 21555641 TI - Huntington chorea presenting with motor neuron disease. AB - BACKGROUND: There have been a few case reports of motor neuron disease in association with Huntington disease (HD). OBJECTIVE: To describe a patient presenting with prominent fasciculations, chorea, and possible amyotrophic lateral sclerosis (ALS) in whom genetic testing revealed HD mutation. DESIGN: Case report. SETTING: University of Texas Southwestern Medical Center, Dallas. Patient A 69-year-old man with chorea and fasciculations. INTERVENTIONS: Genetic and electrophysiologic testing. MAIN OUTCOME MEASURES: Genetic test result, electrophysiologic test result, and physical examination. RESULTS: A 69-year-old man with long-standing depression and failing memory presented with muscle twitches of 8 months' duration. He was found to have choreoathetoid movements and distal weakness on neurological examination. Electrophysiologic studies revealed evidence of motor neuron disease. Genetic test showed CAG repeat of 40 on chromosome 4, confirming the diagnosis of HD. CONCLUSION: Motor neuron disease can rarely occur in patients with HD and could be one of its presenting features. PMID- 21555642 TI - SCA3 presenting as an isolated axonal polyneuropathy. AB - OBJECTIVES: To highlight an unexpected clinical presentation and to review the associated polyneuropathy phenotypes of SCA3. DESIGN: Clinical follow-up. SETTING: Neurological referral center. PATIENT: Middle-aged man with no family history for SCA3. RESULTS: Presentation with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy for 6 years before developing a cerebellar syndrome prompting genetic testing for SCA3. CONCLUSION: SCA3 can present with an isolated axonal, distal, symmetric, sensorimotor polyneuropathy. PMID- 21555643 TI - Lobar distribution of cerebral microbleeds: the Rotterdam Scan Study. AB - OBJECTIVE: To investigate the distribution of lobar microbleeds over the different lobes, taking into account lobar volume and clustering effects of multiple microbleeds. DESIGN: Population-based, cross-sectional analysis. SETTING: The Rotterdam Scan Study. PARTICIPANTS: A total of 198 persons (age range, 61-95 years) with lobar microbleeds. MAIN OUTCOME MEASURES: Distribution of microbleeds over different lobes. RESULTS: We found that lobar cerebral microbleeds occurred significantly more often in the temporal lobe, a region known to be more affected in cerebral amyloid angiopathy. CONCLUSION: This study corroborates the presumed association of lobar microbleeds with cerebral amyloid angiopathy. PMID- 21555644 TI - In-flight seizures and fatal air embolism: the importance of a chest radiograph. AB - OBJECTIVE: To describe for the first time, to our knowledge, a case of recurrent in-flight-dependent seizures related to commercial airline flight in which the patient experienced a fatal air embolism secondary to a giant bronchogenic cyst. DESIGN: Case report. SETTING: University hospital. PATIENT: A female airline passenger presented with a seizure, then unconsciousness and death. The patient had experienced 2 previous episodes of in-flight seizures without any sequelae. RESULTS: The patient had an air embolism proved by findings on cranial computed tomography (CT) and a CT perfusion study. The embolism was secondary to a giant bronchogenic cyst that was evident on chest CT. The patient was examined after the previous episodes of in-flight seizures, but no chest radiography had been performed. CONCLUSIONS: We propose minor air embolism as a cause of in-flight seizures. This type of seizure can signify the existence of a giant bronchogenic cyst. We believe that obtaining a chest radiograph can be useful in patients with a history of in-flight seizures to rule out the presence of a bronchogenic cyst and to prevent a possibly fatal air embolism. PMID- 21555645 TI - Novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. AB - OBJECTIVE: To characterize a novel SCN1A mutation in a proband with malignant migrating partial seizures of infancy. DESIGN: Genomic DNA was isolated from blood and submitted for commercial testing. The identified missense mutation was confirmed in brain DNA obtained at autopsy. Genomic DNA from the brain of the proband was analyzed by comparative genome hybridization, and the coding exons of SCN9A were amplified. Quantitation studies of the mutant transcript were performed. SETTING: Children's National Medical Center and Yale University School of Medicine. PROBAND: A full-term female infant who experienced seizure onset at age 10 weeks, with progression of hemiclonic, apneic, and multifocal migrating partial seizures leading to recurrent status epilepticus and death at age 9 months. MAIN OUTCOME MEASURES: Electroencephalographic and magnetic resonance imaging results, quantitative RNA expression, and secondary mutation test results. RESULTS: The heterozygous missense mutation c.C5006C>A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the SCN1A sodium channel protein Na(v)1.1. The mutant transcript is found to be expressed at levels comparable to the wild type allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containing SCN1A or elsewhere in the genome. No mutations were detected in the linked sodium channel gene SCN9A, which has been reported to act as a modifier of SCN1A mutations. CONCLUSION: This report expands the spectrum of SCN1A epileptic channelopathies to include malignant migrating partial seizures of infancy. PMID- 21555646 TI - Multiple pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia complicated by embolic strokes. PMID- 21555647 TI - Hemidystonia in uncontrolled type 2 diabetes mellitus. PMID- 21555648 TI - Fibrous cap enhancement in symptomatic atherosclerotic basilar artery stenosis. PMID- 21555649 TI - Magnetic resonance imaging-based intravenous thrombolysis 6 hours after onset of minor cerebellar stroke. PMID- 21555650 TI - Critical role of PINK1 in regulating Parkin protein levels in vivo. PMID- 21555651 TI - Blood-based biomarkers in Alzheimer disease. PMID- 21555652 TI - Colorectal cancer screening protocols and procedures: comment on "Overuse of screening colonoscopy in the Medicare population" and "Long-term outcomes following positive fecal occult blood test results in older adults". PMID- 21555653 TI - Overuse of screening colonoscopy in the Medicare population. AB - BACKGROUND: All relevant authorities recommend an interval of 10 years between normal screening colonoscopies. We assessed the timing of repeated colonoscopies after a negative screening colonoscopy finding in a population-based sample of Medicare patients. METHODS: A 5% national sample of Medicare enrollees from 2000 through 2008 was used to identify average-risk patients undergoing screening colonoscopy between 2001 and 2003. Colonoscopy was classified as a negative screening examination finding if no indication other than screening were in the claims and if no biopsy, fulguration, or polypectomy was performed. Time to repeated colonoscopy was calculated. RESULTS: Among 24,071 Medicare patients who had a negative screening colonoscopy finding in 2001 through 2003, 46.2% underwent a repeated examination in fewer than 7 years. In 42.5% of these patients (23.5% of the overall sample), there was no clear indication for the early repeated examination. In patients aged 75 to 79 years or 80 years or older at the time of the initial negative screening colonoscopy result, 45.6% and 32.9%, respectively, received a repeated examination within 7 years. In multivariable analyses, male sex, more comorbidities, and colonoscopy by a high volume colonoscopist or in an office setting were associated with higher rates of early repeated colonoscopy without clear indication, while those 80 years or older had a reduced risk. There were also marked geographic variations, from less than 5% in some health referral regions to greater than 50% in others. CONCLUSIONS: A large proportion of Medicare patients who undergo screening colonoscopy do so more frequently than recommended. Current Medicare regulations intending to limit reimbursement for screening colonoscopy to every 10 years would not appear to be effective. PMID- 21555654 TI - Hypomagnesemia and proton pump inhibitors: below the tip of the iceberg. AB - Severe magnesium deficiency associated with proton pump inhibitors (PPIs) has been described recently with clinical presentations varying from life-threatening conditions to muscle cramps and paresthesias. Probably milder cases go undetected. We report an asymptomatic case of hypomagnesemia associated with chronic use of PPIs in a 67-year-old woman. She had had symptoms of gastroesophageal reflux disease for several years, which abated partially with PPIs, and denied any other symptoms or medications. Her initial evaluation showed an unexplained hypomagnesemia with a very low magnesium excretion rate in urine. Serum calcium, phosphorus, potassium, and glucose levels and renal function were normal. After PPI withdrawal, serum and urinary magnesium levels normalized. PMID- 21555655 TI - Long-term outcomes following positive fecal occult blood test results in older adults: benefits and burdens. AB - BACKGROUND: In the United States, older adults have low rates of follow-up colonoscopy after a positive fecal occult blood test (FOBT) result. The long-term outcomes of these real world practices and their associated benefits and burdens are unknown. METHODS: Longitudinal cohort study of 212 patients 70 years or older with a positive FOBT result at 4 Veteran Affairs (VA) facilities in 2001 and followed up through 2008. We determined the frequency of downstream outcomes during the 7 years of follow-up, including procedures, colonoscopic findings, outcomes of treatment, complications, and mortality based on chart review and national VA and Medicare data. Net burden or benefit from screening and follow-up was determined according to each patient's life expectancy. Life expectancy was classified into 3 categories: best (age, 70-79 years and Charlson-Deyo comorbidity index [CCI], 0), average, and worst (age, 70-84 years and CCI, >=4 or age, >=85 years and CCI, >=1). RESULTS: Fifty-six percent of patients received follow-up colonoscopy (118 of 212), which found 34 significant adenomas and 6 cancers. Ten percent experienced complications from colonoscopy or cancer treatment (12 of 118). Forty-six percent of those without follow-up colonoscopy died of other causes within 5 years of FOBT (43 of 94), while 3 died of colorectal cancer within 5 years. Eighty-seven percent of patients with worst life expectancy experienced a net burden from screening (26 of 30) as did 70% with average life expectancy (92 of 131) and 65% with best life expectancy (35 of 51) (P = .048 for trend). CONCLUSIONS: Over a 7-year period, older adults with best life expectancy were less likely to experience a net burden from current screening and follow-up practices than are those with worst life expectancy. The net burden could be decreased by better targeting FOBT screening and follow-up to healthy older adults. PMID- 21555656 TI - Shared norms and their explanation for the social clustering of obesity. AB - OBJECTIVES: We aimed to test the hypothesized role of shared body size norms in the social contagion of body size and obesity. METHODS: Using data collected in 2009 from 101 women and 812 of their social ties in Phoenix, Arizona, we assessed the indirect effect of social norms on shared body mass index (BMI) measured in 3 different ways. RESULTS: We confirmed Christakis and Fowler's basic finding that BMI and obesity do indeed cluster socially, but we found that body size norms accounted for only a small portion of this effect (at most 20%) and only via 1 of the 3 pathways. CONCLUSIONS: If shared social norms play only a minor role in the social contagion of obesity, interventions targeted at changing ideas about appropriate BMIs or body sizes may be less useful than those working more directly with behaviors, for example, by changing eating habits or transforming opportunities for and constraints on dietary intake. PMID- 21555657 TI - Life-threatening ST-segment elevation without coronary artery disease. PMID- 21555659 TI - The implications of therapeutic complexity on adherence to cardiovascular medications. AB - BACKGROUND: Patients with chronic disease often take many medications multiple times per day. Such regimen complexity is associated with medication nonadherence. Other factors, including the number of pharmacy visits patients make to pick up their prescriptions, may also undermine adherence. Our objective was to estimate the extent of prescribing and filling complexity in patients prescribed a cardiovascular medication and to evaluate its association with adherence. METHODS: The study population comprised individuals prescribed a statin (n = 1 827 395) or an angiotensin- converting enzyme inhibitor or renin angiotensin receptor blocker (ACEI/ARB) (n = 1 480 304) between June 1, 2006, and May 30, 2007. We estimated complexity by measuring the number of medications, prescribers, pharmacies, pharmacy visits, and refill consolidation (a measure of the number of visits per fill) during the 3 months from the first prescription. The number of daily doses was also measured in ACEI/ARB users. After this period, adherence was evaluated over the subsequent year. The relationship between complexity and adherence was assessed with multivariable linear regression. RESULTS: The statin cohort had a mean age of 63 years and were 49% male. On average, during the 3-month complexity assessment period, statin users filled 11.4 prescriptions for 6.3 different medications, had prescriptions written by 2 prescribers, and made 5.0 visits to the pharmacy. Results for ACEI/ARB users were similar. Greater prescribing and filling complexity was associated with lower levels of adherence. In adjusted models, patients with the least refill consolidation had adherence rates that were 8% lower over the subsequent year than patients with the greatest refill consolidation. CONCLUSION: Medication use and prescription filling for patients with cardiovascular disease is complex, and strategies to reduce this complexity may help improve medication adherence. PMID- 21555660 TI - Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. AB - BACKGROUND: Computed tomographic pulmonary angiography (CTPA) may improve detection of life-threatening pulmonary embolism (PE), but this sensitive test may have a downside: overdiagnosis and overtreatment (finding clinically unimportant emboli and exposing patients to harms from unnecessary treatment). METHODS: To assess the impact of CTPA on national PE incidence, mortality, and treatment complications, we conducted a time trend analysis using the Nationwide Inpatient Sample and Multiple Cause-of-Death databases. We compared age-adjusted incidence, mortality, and treatment complications (in-hospital gastrointestinal tract or intracranial hemorrhage or secondary thrombocytopenia) of PE among US adults before (1993-1998) and after (1998-2006) CTPA was introduced. RESULTS: Pulmonary embolism incidence was unchanged before CTPA (P = .64) but increased substantially after CTPA (81% increase, from 62.1 to 112.3 per 100,000; P < .001). Pulmonary embolism mortality decreased during both periods: more so before CTPA (8% reduction, from 13.4 to 12.3 per 100,000; P < .001) than after (3% reduction, from 12.3 to 11.9 per 100,000; P = .02). Case fatality improved slightly before (8% decrease, from 13.2% to 12.1%; P = .02) and substantially after CTPA (36% decrease, from 12.1% to 7.8%; P < .001). Meanwhile, CTPA was associated with an increase in presumed complications of anticoagulation for PE: before CTPA, the complication rate was stable (P = .24), but after it increased by 71% (from 3.1 to 5.3 per 100,000; P < .001). CONCLUSIONS: The introduction of CTPA was associated with changes consistent with overdiagnosis: rising incidence, minimal change in mortality, and lower case fatality. Better technology allows us to diagnose more emboli, but to minimize harms of overdiagnosis we must learn which ones matter. PMID- 21555661 TI - Acute pulmonary embolism: comment on "time trends in pulmonary embolism in the United States". PMID- 21555662 TI - Clinician attitudes about commercial support of continuing medical education: results of a detailed survey. AB - BACKGROUND: Pharmaceutical and medical device company funding supports up to 60% of accredited continuing medical education (CME) costs in the United States. Some have proposed measures to limit the size, scope, and potential influence of commercial support for CME activities. We sought to determine whether participants at CME activities perceive that commercial support introduces bias, whether this is affected by the amount or type of support, and whether they would be willing to accept higher fees or fewer amenities to decrease the need for such funding. METHODS: We delivered a structured questionnaire to 1347 participants at a series of 5 live CME activities about the impact of commercial support on bias and their willingness to pay additional amounts to eliminate the need for commercial support. RESULTS: Of the 770 respondents (a 57% response rate), most (88%) believed that commercial support introduces bias, with greater amounts of support introducing greater risk of bias. Only 15%, however, supported elimination of commercial support from CME activities, and less than half (42%) were willing to pay increased registration fees to decrease or eliminate commercial support. Participants who perceived bias from commercial support more frequently agreed to increase registration fees to decrease such support (2- to 3 fold odds ratio). Participants greatly underestimated the costs of ancillary activities, such as food, as well as the degree of support actually provided by commercial funding. CONCLUSION: Although the medical professionals responding to this survey were concerned about bias introduced from commercial funding of CME, many were not willing to pay higher fees to offset or eliminate such funding sources. PMID- 21555663 TI - Continuing medical education: comment on "clinician attitudes about commercial support of continuing medical education". PMID- 21555664 TI - On patient autonomy and physician responsibility in end-of-life care. AB - In current medical practice, excessive or reflexive deference to an unreflective concept of patient autonomy may inadvertently compromise patient autonomy by placing unwanted and unreasonable responsibility for technical medical decisions on patients or their surrogate decision makers rather than on their physicians. Such practices can harm patients by depriving them of the expert, professional advice they both need and deserve to make important decisions about their health care. We describe herein how the patient-physician relationship has evolved in recent decades as more life-sustaining and life-saving treatments, such as cardiopulmonary resuscitation, have become available. We then examine respect for patient autonomy and describe how patient autonomy can be promoted while the physician's responsibility for technical medical decisions is simultaneously affirmed. The patient is the expert on his or her values, goals, and preferences, while the physician is the expert on the medical means for honoring the patient's perspective. We conclude that an intervention, such as cardiopulmonary resuscitation, should not be offered when, based on the patient's own criteria, it promises no physical or psychosocial benefit or would be far more harmful than beneficial. PMID- 21555665 TI - A swinging pendulum: comment on "on patient autonomy and physician responsibility in end-of-life care". PMID- 21555666 TI - The ability of intensive care units to maintain zero central line-associated bloodstream infections. PMID- 21555667 TI - Reducing heart failure readmissions by teaching patient-centered care to internal medicine residents. PMID- 21555668 TI - Effect of admission medication reconciliation on adverse drug events from admission medication changes. PMID- 21555669 TI - When conventional medical providers recommend unconventional medicine: results of a national study. PMID- 21555670 TI - Influence of therapeutic complexity on medication adherence in the Netherlands. PMID- 21555671 TI - Use of PPIs are not associated with mortality in institutionalized older people. PMID- 21555672 TI - A true believer's flawed analysis. PMID- 21555673 TI - Reducing drugs in older adults is more. PMID- 21555674 TI - Reducing polypharmacy: is hospitalization the right time? PMID- 21555675 TI - Adipose tissue-derived soluble fms-like tyrosine kinase 1 is an obesity-relevant endogenous paracrine adipokine. AB - Adipose tissue growth depends on angiogenesis. We tested the hypothesis that adipose tissue produces factors relevant to angiogenesis. We obtained fat biopsies in 2 different patient cohorts, cultured adipose-derived stem cells and studied mature adipocytes. We performed microarray, RT-PCR, and Western blotting; studied a rat obesity/metabolic syndrome model; and conducted viral gene transfer experiments in leptin-deficient mice. The microarray identified the splice variant of the vascular endothelial growth factor receptor, the soluble fms-like tyrosine kinase 1 (sFlt-1), as an antiangiogenesis candidate. We verified the expression findings and found that sFlt-1 was secreted by isolated mature human adipocytes. Tumor necrosis factor-alpha decreased sFlt-1 expression in mature adipocytes, whereas hypoxia had no effect. Separating cells from adipose tissue showed that the highest sFlt-1 expression was present in adipose-tissue nonfat cells rather than in the adipocytes themselves. We also found that sFlt-1 expression and sFlt-1 release by adipose-tissue explants were inversely correlated with body mass index of the corresponding patients but was directly correlated with adiponectin expression. In the obesity/metabolic syndrome rat model, we observed that circulating sFlt-1 levels and sFlt-1 expression in adipose tissue were also inversely correlated with body weight. To model our putative antiangiogenic factor further, we next overexpressed sFlt-1 by viral transfer in a mouse genetic model of leptin deficiency and observed that the transfected mice gained less weight than controls. We suggest that sFlt-1 could act as a paracrine factor inhibiting adipose tissue growth. Local sFlt-1 may regulate angiogenic potential and thereby influence adipose tissue mass. PMID- 21555677 TI - Effects of weight loss on structural and functional alterations of subcutaneous small arteries in obese patients. AB - Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media:lumen ratio, are frequently present in hypertensive and/or diabetic patients and may represent the earliest alteration observed. In addition, media:lumen ratios of small arteries have a strong prognostic significance. However, no data are available about the structure of small resistance arteries of obese patients, particularly after weight loss. We have investigated 27 patients with severe obesity. Twelve of them were normotensive, and 15 were hypertensive. All of the obese patients underwent bariatric surgery. We compared results obtained with those observed in 13 normotensive lean controls and in 13 hypertensive lean patients. All of the subjects and patients underwent a biopsy of subcutaneous fat during surgical intervention. In 8 obese patients, a second biopsy was obtained after consistent weight loss, during a surgical intervention for abdominoplasty. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and structural parameters were measured. A concentration-response curve to acetylcholine was performed to evaluate endothelial function. Obese patients, independent from the presence of hypertension, show the presence of an increased media:lumen ratio and media cross sectional area, together with an impaired endothelial-dependent vasodilatation. After surgical correction of obesity and consistent weight loss, a significant improvement of microvascular structure and of some oxidative stress/inflammation markers were observed. In conclusion, our data suggest that the presence of obesity is associated with structural alterations of subcutaneous small resistance arteries, mainly characterized by hypertrophic remodeling. Weight loss may improve microvascular structure. PMID- 21555676 TI - Limitations of analyses based on achieved blood pressure: lessons from the African American study of kidney disease and hypertension trial. AB - Blood pressure (BP) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials. The objective of this article was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression. Participants (n=1094) in the African American Study of Kidney Disease and Hypertension Trial were randomly assigned to either usual BP goal defined by a mean arterial pressure goal of 102 to 107 mm Hg or lower BP goal defined by a mean arterial pressure goal of <=92 mm Hg. Median follow-up was 3.7 years. Primary outcomes were rate of decline in measured glomerular filtration rate and a composite of a decrease in glomerular filtration rate by >50% or >25 mL/min per 1.73 m(2), requirement for dialysis, transplantation, or death. Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in glomerular filtration rate or the clinical composite outcome. In contrast, the achieved BP analyses showed that each 10-mm Hg increment in mean follow-up achieved mean arterial pressure was associated with a 0.35 mL/min per 1.73 m(2) (95% CI: 0.08 to 0.62 mL/min per 1.73 m(2); P=0.01) faster mean glomerular filtration rate decline and a 17% (95% CI: 5% to 32%; P=0.006) increased risk of the clinical composite outcome. Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses, attributed in part to confounding of achieved BP with comorbidities, disease severity, and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP. PMID- 21555678 TI - Poor sleep and cardiovascular function in children. AB - We investigated whether sleep quantity and quality were related to 24-hour ambulatory blood pressure and cardiovascular reactivity in children. We studied term-born, healthy 8.0-year olds (SD: 1.4 years) without sleep-disordered breathing (231 and 265 children provided valid data for analyses of ambulatory blood pressure and cardiovascular reactivity, respectively). Sleep was registered with an actigraph for 6 nights on average (SD: 1.2; range: 3 to 13 nights). Ambulatory blood pressure was measured for 24-hours (41% nonschool days) with an oscillometric device. The children underwent the Trier Social Stress Test for Children, during which blood pressure, electrocardiography, and thoracic impedance were recorded and processed offline to give measures of cardiovascular and autonomic function. Neither quantity nor quality of sleep was related to 24 hour ambulatory blood pressure or cardiovascular reactivity after accounting for major covariates (sex, age, height, body mass index, and parental education). Although lower sympathetic nervous system activation and higher cardiac activation under stress were found in the group of children who slept for short duration when they were compared with the average sleep duration group, these associations were not significant after correction for multiple testing and were not seen in linear regression models of the effects of sleep duration. These findings do not support the mainstream of epidemiological findings, derived from samples more heterogeneous in age, sociodemographic characteristics, and health, suggesting that poor sleep is associated with an unhealthy cardiovascular phenotype. PMID- 21555679 TI - Mixed messages on blood pressure goals. PMID- 21555680 TI - Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study. AB - The associations between blood pressure and dementia have been inconclusive. We followed up a total of 668 community-dwelling Japanese individuals without dementia, aged 65 to 79 years, for 17 years and examined the associations of late life and midlife hypertension with the risk of vascular dementia and Alzheimer disease using the Cox proportional hazards model. During the follow-up, 76 subjects experienced vascular dementia and 123 developed Alzheimer disease. The age- and sex-adjusted incidence of vascular dementia significantly increased with elevated late-life blood pressure levels (normal: 2.3, prehypertension: 8.4, stage 1 hypertension: 12.6, and stage 2 hypertension: 18.9 per 1000 person-years; P(trend)<0.001), whereas no such association was observed for Alzheimer disease (P(trend)=0.88). After adjusting for potential confounding factors, subjects with prehypertension and stage 1 or stage 2 hypertension had 3.0-fold, 4.5-fold, and 5.6-fold greater risk of vascular dementia, respectively, compared with subjects with normal blood pressure. Likewise, there was a positive association of midlife blood pressure levels with the risk of vascular dementia but not with the risk of Alzheimer disease. Compared with those without hypertension in both midlife and late life, subjects with midlife hypertension had an ~5-fold greater risk of vascular dementia, regardless of late-life blood pressure levels. Our findings suggest that midlife hypertension and late-life hypertension are significant risk factors for the late-life onset of vascular dementia but not for that of Alzheimer disease in a general Japanese population. Midlife hypertension is especially strongly associated with a greater risk of vascular dementia, regardless of late-life blood pressure levels. PMID- 21555681 TI - KRAS-mutation positive, metastatic tonsil carcinoma with cancer stem-like cell features and long-term response to gefitinib: a case report and review of the literature. PMID- 21555682 TI - Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. AB - PURPOSE: Non-small-cell lung cancer (NSCLC) commonly expresses the epidermal growth factor receptor (EGFR), which is associated with poor clinical outcome. Cetuximab is a chimerized monoclonal antibody that targets the EGFR and, in preclinical models, it demonstrates radiosensitization properties. We report a phase II trial testing the combination of cetuximab with chemoradiotherapy (CRT) in unresectable stage III NSCLC. PATIENTS AND METHODS: Eligibility criteria included unresectable stage III NSCLC, Zubrod performance status <= 1, weight loss <= 5%, forced expiratory volume in 1 second >= 1.2 L, and adequate organ function. Patients received an initial dose of cetuximab (400 mg/m(2)) on day 1 of week 1 and then weekly doses of cetuximab (250 mg/m(2)) until completion of therapy (weeks 2 through 17). During week 2, patients started CRT (63 Gy in 35 fractions) with weekly carboplatin at area under the [concentration-time] curve (AUC) 2 and six doses of paclitaxel at 45 mg/m(2) followed by carboplatin (AUC 6) and two cycles of paclitaxel (200 mg/m(2)) during weeks 12 through 17. Primary end points included safety and compliance of concurrent cetuximab and CRT. RESULTS: In all, 93 patients were enrolled and 87 were evaluable. Median follow up was 21.6 months. Response rate was 62% (n = 54), median survival was 22.7 months, and 24-month overall survival was 49.3%. Adverse events related to treatment included 20% grade 4 hematologic toxicities, 8% grade 3 esophagitis, and 7% grade 3 to 4 pneumonitis. There were five grade 5 events. CONCLUSION: The combination of cetuximab with CRT is feasible and shows promising activity. The median and overall survival achieved with this regimen were longer than any previously reported by the Radiation Therapy Oncology Group. PMID- 21555683 TI - Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. AB - PURPOSE: To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)). PATIENTS AND METHOD: RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old. RESULTS: NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies. CONCLUSION: We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions. PMID- 21555684 TI - Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. AB - PURPOSE: Aromatase inhibitors are effective as endocrine treatment for patients with hormone receptor-positive breast cancer. According to the hypothesis that overweight patients have higher levels of aromatase enzyme availability, we investigated the influence of body mass index (BMI) on the efficacy of adjuvant endocrine therapy in premenopausal patients in a retrospective analysis of the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 trial. PATIENTS AND METHODS: ABCSG-12 examined the efficacy of ovarian suppression using goserelin (3.6 mg subcutaneously every 28 days) in combination with anastrozole or tamoxifen with or without zoledronic acid (4 mg intravenously every 6 months) in premenopausal women with endocrine-responsive breast cancer. BMI was calculated using the prospectively collected data on patients' height and weight at study entry. BMI categories have been differentiated according to the WHO definition. RESULTS: Overweight patients treated with anastrozole had a 60% increase in the risk of disease recurrence (hazard ratio [HR], 1.60; 95% CI, 1.06 to 2.41; P = .02) and more than a doubling in the risk of death (HR, 2.14; 95% CI, 1.17 to 3.92; P = .01) compared with normal weight patients treated with anastrozole. In the overweight group, patients treated with anastrozole had a nearly 50% increase in the risk of disease recurrence (HR, 1.49; 95% CI, 0.93 to 2.38; P = .08) and a three-fold increase in the risk of death (HR, 3.03; 95% CI, 1.35 to 6.82; P = .004) compared with patients treated with tamoxifen. CONCLUSION: BMI significantly impacts on the efficacy of anastrozole plus goserelin in premenopausal patients with breast cancer, probably through influencing aromatase availability and/or ovarian suppression by goserelin. PMID- 21555685 TI - How fine a slice: treatment of newly diagnosed glioblastoma with an epidermal growth factor receptor variant III peptide vaccine. PMID- 21555686 TI - Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. AB - PURPOSE: This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP). RESULTS: In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support. CONCLUSION: The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy. PMID- 21555687 TI - Altered biodistribution of somatostatin analogues after first cycle of Peptide receptor radionuclide therapy. PMID- 21555688 TI - Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin based chemotherapy. AB - PURPOSE: Cisplatin-based combination chemotherapy is considered standard first line treatment for patients with metastatic urothelial carcinoma. However, a large proportion of patients with metastatic urothelial carcinoma are considered "unfit" for cisplatin. The purpose of this review is to define unfit patients and to identify treatment options for this subgroup of patients. PATIENTS AND METHODS: In this review, the criteria used to define unfit patients are explored and the results of prospective clinical trials evaluating chemotherapeutic regimens in unfit patients are summarized. RESULTS: Several phase II trials and a single, large phase III trial have explored chemotherapeutic regimens for the treatment of unfit patients with metastatic urothelial carcinoma. Heterogeneous eligibility criteria have been used to define unfit patients in these studies. A uniform definition of unfit is proposed on the basis of the results of a survey of genitourinary medical oncologists. According to this definition, unfit patients would meet at least one of the following criteria: Eastern Cooperative Oncology Group performance status of 2, creatinine clearance less than 60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, and/or New York Heart Association Class III heart failure. CONCLUSION: Additional studies to optimize treatment for this important subset of patients are needed. A uniform definition of unfit patients will lead to more uniform clinical trials, enhanced ability to interpret the results of these trials, and a greater likelihood of developing a viable strategy for regulatory approval. PMID- 21555689 TI - Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. AB - PURPOSE: Preoperative aromatase inhibitor (AI) treatment promotes breast conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. PATIENTS AND METHODS: Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. RESULTS: On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). CONCLUSION: Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling. PMID- 21555690 TI - Risk of recurrent venous thromboembolism and mortality in patients with cancer incidentally diagnosed with pulmonary embolism: a comparison with symptomatic patients. AB - PURPOSE: The routine use of modern computed tomography scanners has led to an increased detection of incidental pulmonary embolism (PE), in particular in patients with cancer. The clinical relevance of these incidental findings is unknown. PATIENTS AND METHODS: In this retrospective cohort study, oncology patients in whom PE was objectively proven between 2004 and 2010 and anticoagulant treatment was started, were included. Fifty-one patients with incidental PE and 144 with symptomatic PE were observed for 1 year to compare the risks of recurrent venous thromboembolism (VTE), bleeding complications, and mortality. Kaplan-Meier and Cox survival analyses were performed. RESULTS: Incidental and symptomatic patients did not differ with respect to mean age, sex, cancer type and stage, and risk factors for VTE. As a result from evolving treatment guidelines, approximately half of the patients in both groups received long-term treatment with vitamin K antagonists in stead of currently recommended low-molecular-weight heparin. The 12-month cumulative incidence of recurrent VTE was 13.3% in the incidental group versus 16.9% in the symptomatic group (P = .77). Notably, 20% VTE events recurred after premature termination of anticoagulant therapy. The risk of major bleeding complications was also comparable in the two groups (12.5% for incidental patients and 8.6% for symptomatic patients; P = .5). The respective 12-month mortality risks were 52.9% and 53.3% (P = .7). CONCLUSION: Our findings suggest that oncology patients diagnosed with and treated for incidental PE, have similar high rates of recurrent VTE, bleeding complications, and mortality, as compared with oncology patients who develop symptomatic PE. PMID- 21555691 TI - Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. AB - We review how overall survival (OS) comparisons should be interpreted with increasing availability of effective therapies that can be given subsequently to the treatment assigned in a randomized clinical trial (RCT). We examine in detail how effective subsequent therapies influence OS comparisons under varying conditions in RCTs. A subsequent therapy given after tumor progression (or relapse) in an RCT that works better in the standard arm than the experimental arm will lead to a smaller OS difference (possibly no difference) than one would see if the subsequent therapy was not available. Subsequent treatments that are equally effective in the treatment arms would not be expected to affect the absolute OS benefit of the experimental treatment but will make the relative improvement in OS smaller. In trials in which control arm patients cross over to the experimental treatment after their condition worsens, a smaller OS difference could be observed than one would see without cross-overs. In particular, use of cross-over designs in the first definitive evaluation of a new agent in a given disease compromises the ability to assess clinical benefit. In disease settings in which there is not an intermediate end point that directly measures clinical benefit, OS should be the primary end point of an RCT. The observed difference in OS should be considered the measure of clinical benefit to the patients, regardless of subsequent therapies, provided that the subsequent therapies used in both treatment arms follow the current standard of care. PMID- 21555692 TI - Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. AB - PURPOSE: To investigate response, survival, and safety profile of the somatostatin-based radiopeptide (90)yttrium-labeled tetraazacyclododecane tetraacetic acid modified Tyr-octreotide ([(90)Y-DOTA]-TOC) in neuroendocrine cancers. PATIENTS AND METHODS: In a clinical phase II single-center open-label trial, patients with neuroendocrine cancers were treated with repeated cycles of [(90)Y-DOTA]-TOC. Each cycle consisted of a single intravenous injection of 3.7GBq/m(2) body-surface [(90)Y-DOTA]-TOC. Additional cycles were withheld in case of tumor progression and/or permanent toxicity. RESULTS: Overall, 1,109 patients received 2,472 cycles of [(90)Y-DOTA]-TOC (median, two; range, one to 10 cycles per patient). Of the 1,109 patients, 378 (34.1%) experienced morphologic response; 172 (15.5%), biochemical response; and 329 (29.7%), clinical response. During a median follow-up of 23 months, 491 patients (44.3%) died. Longer survival was correlated with each: morphologic (hazard ratio [HR], 0.46; 95% CI, 0.38 to 0.56; median survival, 44.7 v 18.3 months; P < .001), biochemical (HR, 0.75; 95% CI, 0.59 to 0.96; 35.3 v 25.7 months; P = .023), and clinical response (HR, 0.68; 95% CI, 0.56 to 0.82; 36.8 v 23.5 months; P < .001). Overall, 142 patients (12.8%) developed grade 3 to 4 transient hematologic toxicities, and 103 patients (9.2%) experienced grade 4 to 5 permanent renal toxicity. Multivariable regression revealed that tumoral uptake in the initial imaging study was predictive for overall survival (HR, 0.45; 95% CI, 0.29 to 0.69; P < .001), whereas the initial kidney uptake was predictive for severe renal toxicity (HR, 1.59; 95% CI, 1.17 to 2.17; P = .003). CONCLUSION: This study documents the long term outcome of [(90)Y-DOTA]-TOC treatment in a large cohort. Response to [(90)Y DOTA]-TOC is associated with longer survival. Somatostatin receptor imaging is predictive for both survival after [(90)Y-DOTA]-TOC treatment and occurrence of renal toxicity. PMID- 21555693 TI - Breast cancer adjuvant therapy: time to consider its time-dependent effects. PMID- 21555694 TI - Persistence of cytogenetic abnormalities at complete remission after induction in patients with acute myeloid leukemia: prognostic significance and the potential role of allogeneic stem-cell transplantation. AB - PURPOSE: To determine the prognostic impact of persistent cytogenetic abnormalities at complete remission (CR) on relapse-free survival (RFS) and overall survival (OS) in patients with acute myeloid leukemia (AML) and to examine the potential role of allogeneic stem-cell transplantation (SCT) in this setting. PATIENTS AND METHODS: Data from 254 adult patients with AML (excluding acute promyelocytic leukemia) who achieved CR after induction chemotherapy on various first-line protocols were examined. RESULTS: Median follow-up for surviving patients was 43 months. Patients with cytogenetic abnormalities at CR (n = 71) had significantly shorter RFS (P = .001) and OS (P < .001) compared with patients with normal cytogenetics at CR (n = 183); 3-year RFS was 15% and 45%, and 3-year OS was 15% and 56%, respectively. Among the patients with persistent cytogenetic abnormalities at CR, those who underwent SCT in first CR (CR1; n = 15) had better RFS and OS compared to those without SCT (n = 56; P = .04 and .06, respectively). In multivariate analysis, persistent cytogenetic abnormalities at CR was an independent predictor for RFS (P < .001) and OS (P = .001), but among patients with persistent cytogenetic abnormalities at CR, no significant differences in OS (P = .25) was observed between those who did or did not receive SCT with a trend favoring SCT for RFS (P = .08). CONCLUSION: Persistent cytogenetically abnormal cells at CR predict a significantly shorter RFS and OS. SCT in CR1 may improve the clinical outcome of patients lacking cytogenetic remission after induction although this depends on patient selection. PMID- 21555695 TI - Lymph nodes, tumor deposits, and TNM: are we getting better? AB - PURPOSE: New editions of the TNM staging system for colorectal cancer have been subject to extensive criticism. In the current study, we evaluate each edition of TNM and analyze stage migration caused by the different versions. PATIENTS AND METHODS: Two independent test populations were used: participants derived from a randomized surgical trial from the United Kingdom (n = 455) and patients from a population-based series from Sweden (n = 505). All slides from these patient cases were reviewed with special attention for the presence of tumor deposits. Tumor deposits were classified according to the fifth, sixth, and seventh editions of TNM and correlated with prognosis. RESULTS: Every change in edition of TNM led to a stage migration of between 33% and 64% in patients with tumor deposits. Reproducibility was best in the fifth edition of TNM. The prognostic value of the seventh edition was best only when all tumor deposits irrespective of size or contour were included as lymph nodes. The prognostic value of the fifth edition was better than that of the sixth. CONCLUSION: We demonstrate there is a place for tumor deposits in the staging of patients with colorectal cancer. However, many questions remain about their definition and the reproducibility and use of this category in special situations, such as after neoadjuvant treatment. These should be the subject of additional research before use as a factor in TNM staging. This work demonstrates the necessity of testing modifications before their introduction. PMID- 21555696 TI - Metastatic and locally advanced pancreatic endocrine carcinomas: analysis of factors associated with disease progression. AB - PURPOSE: Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. PATIENTS AND METHODS: In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. RESULTS: Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P < .001) and tumor differentiation (P < .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P < .001). Overall 5-year survival was 44.1%. CONCLUSION: The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies. PMID- 21555697 TI - Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease. AB - PURPOSE: To describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castleman's disease (MCD) in a sizeable mature cohort. METHODS: From a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide. RESULTS: At MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively. CONCLUSION: HIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates. PMID- 21555698 TI - Anti-vascular endothelial growth factor therapy for breast cancer: can we pick the winners? PMID- 21555699 TI - Long-term use of acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs and risk of hematologic malignancies: results from the prospective Vitamins and Lifestyle (VITAL) study. AB - PURPOSE: Among previous studies examining the associations of over-the-counter analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs) and incident hematologic malignancies, results were inconsistent for NSAIDs but suggested an increased risk with acetaminophen (paracetamol). Herein, we used a large prospective cohort study to examine these associations. PATIENTS AND METHODS: In total, 64,839 men and women age 50 to 76 years were recruited from 2000 to 2002 to the Vitamins and Lifestyle (VITAL) study. Incident hematologic malignancies (n = 577) were identified through December 2008 by linkage to the Surveillance, Epidemiology and End Results cancer registry. Hazard ratios (HRs) associated with use of analgesics for total incident hematologic malignancies and cancer subcategories were estimated by Cox proportional hazards models. Models were adjusted for age, sex, race/ethnicity, education, smoking, self-rated health, arthritis, chronic musculoskeletal pain, migraines, headaches, fatigue, and family history of leukemia/lymphoma. RESULTS: After adjustment, there was an increased risk of incident hematologic malignancies associated with high use (>= 4 days/week for >= 4 years) of acetaminophen (HR, 1.84; 95% CI, 1.35 to 2.50 for high use; P trend = .004). This association was seen for myeloid neoplasms (HR, 2.26; 95% CI, 1.24 to 4.12), non-Hodgkin's lymphomas (HR, 1.81; 95% CI, 1.12 to 2.93), and plasma cell disorders (HR, 2.42; 95% CI, 1.08 to 5.41), but not chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; HR, 0.84; 95% CI, 0.31 to 2.28). By comparison, there was no association with risk of incident hematologic malignancies for increasing use of aspirin, nonaspirin NSAIDs, or ibuprofen. CONCLUSION: High use of acetaminophen was associated with an almost two-fold increased risk of incident hematologic malignancies other than CLL/SLL. Neither aspirin nor nonaspirin NSAIDs are likely useful for prevention of hematologic malignancies. PMID- 21555700 TI - Longitudinal perceptions of prognosis and goals of therapy in patients with metastatic non-small-cell lung cancer: results of a randomized study of early palliative care. AB - PURPOSE: Understanding of prognosis among terminally ill patients impacts medical decision making. The aims of this study were to explore perceptions of prognosis and goals of therapy in patients with metastatic non-small-cell lung cancer (NSCLC) and to examine the effect of early palliative care on these views over time. PATIENTS AND METHODS: Patients with newly diagnosed metastatic NSCLC were randomly assigned to receive either early palliative care integrated with standard oncology care or standard oncology care alone. Participants completed baseline and longitudinal assessments of their perceptions of prognosis and the goals of cancer therapy over a 6-month period. RESULTS: We enrolled 151 participants on the study. Despite having terminal cancer, one third of patients (46 of 145 patients) reported that their cancer was curable at baseline, and a majority (86 of 124 patients) endorsed getting rid of all of the cancer as a goal of therapy. Baseline perceptions of prognosis (ie, curability) and goals of therapy did not differ significantly between study arms. A greater percentage of patients assigned to early palliative care retained or developed an accurate assessment of their prognosis over time (82.5% v 59.6%; P = .02) compared with those receiving standard care. Patients receiving early palliative care who reported an accurate perception of their prognosis were less likely to receive intravenous chemotherapy near the end of life (9.4% v 50%; P = .02). CONCLUSION: Many patients with newly diagnosed metastatic NSCLC hold inaccurate perceptions of their prognoses. Early palliative care significantly improves patient understanding of prognosis over time, which may impact decision making about care near the end of life. PMID- 21555701 TI - Granulocytic sarcoma in a patient with blast crisis mimicking a chronic subdural hematoma. PMID- 21555702 TI - Identification and classification of acute cardiac rejection by intragraft transcriptional profiling. AB - BACKGROUND: Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation. METHODS AND RESULTS: Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings. CONCLUSION: The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies. PMID- 21555703 TI - Less than a minute or two. PMID- 21555704 TI - Sensitivity of the aortic dissection detection risk score, a novel guideline based tool for identification of acute aortic dissection at initial presentation: results from the international registry of acute aortic dissection. AB - BACKGROUND: In 2010, the American Heart Association and American College of Cardiology released guidelines for the diagnosis and management of patients with thoracic aortic disease, which identified high-risk clinical features to assist in the early detection of acute aortic dissection. The sensitivity of these risk markers has not been validated. METHODS AND RESULTS: We examined patients enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2009. The number of patients with confirmed acute aortic dissection who presented with 1 or more of 12 proposed clinical risk markers was determined. An aortic dissection detection (ADD) risk score of 0 to 3 was calculated on the basis of the number of risk categories (high-risk predisposing conditions, high-risk pain features, high-risk examination features) in which patients met criteria. The ADD risk score was tested for sensitivity. Of 2538 patients with acute aortic dissection, 2430 (95.7%) were identified by 1 or more of 12 proposed clinical risk markers. With the use of the ADD risk score, 108 patients (4.3%) were identified as low risk (ADD score 0), 927 patients (36.5%) were intermediate risk (ADD score 1), and 1503 patients (59.2%) were high risk (ADD score 2 or 3). Among 108 patients with no clinical risk markers present (ADD score 0), 72 had chest x rays recorded, of which 35 (48.6%) demonstrated a widened mediastinum. CONCLUSIONS: The clinical risk markers proposed in the 2010 thoracic aortic disease guidelines and their application as part of the ADD risk score comprise a highly sensitive clinical tool for the detection of acute aortic dissection. PMID- 21555705 TI - CaMKII inhibition: breaking the cycle of electrical storm? PMID- 21555707 TI - Ethnic differences in out-of-hospital fatal pulmonary embolism. AB - BACKGROUND: In-hospital pulmonary embolism (PE) has been extensively studied in large populations; however, out-of-hospital fatal PE studies are rare. Here, we systematically evaluated a large number of decedents who suffered fatal PE outside of hospitals and were subsequently investigated by the New York City Office of Chief Medical Examiner. METHODS AND RESULTS: A total of 578 consecutive out-of-hospital fatal PE cases were analyzed. All underwent autopsy, toxicology, microbiology, and genetic testing. Incidence rates and baseline characteristics were analyzed. Race-adjusted incidence rates of out-of-hospital fatal PE (per 100 000 people per year) were as follows: blacks, 3.73 (95% confidence interval, 3.31 to 4.11); whites, 1.15 (95% confidence interval, 0.96 to 1.33); and Hispanics, 0.93 (95% confidence interval, 0.72 to 1.10). Overall, obesity (body mass index >=30 kg/m(2)) was 2.5- to 3-fold higher in fatal PE cases than in the New York City population as a whole. Carrier frequencies for prothrombin G20210A in fatal PE were 2- to 10-fold higher than reported frequencies in ethnically matched controls. Cumulative distribution curves showed that compared with whites, blacks and Hispanics died at significantly younger ages (P<0.001). Univariate and multiple linear regression analyses showed that in addition to nonwhite ethnicity, heterozygous carriers for factor V Leiden (P=0.001) and obesity (P=0.002) are significantly associated with younger age at death. CONCLUSION: There are unique epidemiological differences in out-of-hospital fatal PE between ethnic groups in New York City. PMID- 21555706 TI - Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines. AB - BACKGROUND: We hypothesize that left-sided low-level vagus nerve stimulation (LL VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. METHODS AND RESULTS: We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P=0.033) in group 1. The reduction was most apparent at 8 am, along with a significantly reduced heart rate (P=0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 MUm(2)/mm(2) (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 MUm(2)/mm(2) (95% CI, 154 956 to 218 166; P=0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P=0.001 and 22.0/d [95% CI, 19.1 to 25.5], P<0.001, respectively). CONCLUSIONS: Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS. PMID- 21555708 TI - Venous thromboembolism: why does ethnicity matter? PMID- 21555709 TI - Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm. AB - BACKGROUND: Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca(2+)-related protein alterations in ES. METHODS AND RESULTS: We studied 37 rabbits with complete atrioventricular block for ~80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (>=3 VF episodes per 24-hour period; 103+/-23 VF episodes per rabbit). Expression/phosphorylation of Ca(2+)-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca(2+)/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca(2+) channel alpha-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca(2+)/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction. CONCLUSIONS: ES causes Ca(2+)/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES. PMID- 21555710 TI - Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. AB - BACKGROUND: Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). METHODS AND RESULTS: Patients >=30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). CONCLUSIONS: Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view. PMID- 21555711 TI - Nontraditional risk factors and biomarkers for cardiovascular disease: mechanistic, research, and clinical considerations for youth: a scientific statement from the American Heart Association. AB - The rapid increase in the prevalence and severity of obesity in children is likely to lower the age of onset and increase the incidence of cardiovascular disease worldwide. Understanding the pathophysiology and improving the clinical management of cardiovascular disease involve a knowledge of novel risk factors and biomarkers. The clinical and mechanistic roles of these novel biological factors during childhood are currently being investigated. The goals of this scientific statement are to present the existing knowledge and theoretical framework of nontraditional risk factors for cardiovascular disease as they relate to children and adolescents, to describe the relevance and weight of available experimental and clinical evidence and the therapeutic implications pertaining to nontraditional risk factors in the pediatric population, and to stimulate further research with a goal of developing valid and reliable approaches to identify and validate novel risk factors that will aid in the clinical evaluation and perhaps prediction of cardiovascular disease in the pediatric population. Although several biomarkers are promising, substantial research is required before nontraditional risk factors can be used to identify and reduce cardiovascular disease risk in children and adolescents. PMID- 21555712 TI - Endothelium-derived hyperpolarizing factor determines resting and stimulated forearm vasodilator tone in health and in disease. AB - BACKGROUND: We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit K(+)(Ca) channel activation and fluconazole was used to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by K(+)(Ca) channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. METHODS AND RESULTS: In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N(G)-monomethyl-l-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001); however, the vasoconstrictor response to L-NMMA was greater (P=0.04) and to TEA was lower (P=0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K(+)(Ca) channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects but was significantly attenuated in hypercholesterolemia (P<0.04). CONCLUSIONS: First, by activating TEA-inhibitable K(+)(Ca) channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of K(+)(Ca) channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of K(+)(Ca) channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates K(+)(Ca) channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K(+)(Ca) channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00166166. PMID- 21555713 TI - Endothelium-derived neuregulin protects the heart against ischemic injury. AB - BACKGROUND: Removal of cardiac endothelial cells (EC) has been shown to produce significant detrimental effects on the function of adjacent cardiac myocytes, suggesting that EC play a critical role in autocrine/paracrine regulation of the heart. Despite this important observation, the mediators of the protective function of EC remain obscure. Neuregulin (NRG, a member of the epidermal growth factor family) is produced by EC and cardiac myocytes contain receptors (erbB) for this ligand. We hypothesized that NRG is an essential factor produced by EC, which promotes cardioprotection against ischemic injury. METHODS AND RESULTS: We demonstrate that human cardiac EC express and release NRG in response to hypoxia reoxygenation. Under conditions where hypoxia--reoxygenation causes significant cardiac myocyte cell death, NRG can significantly decrease apoptosis of isolated adult ventricular myocytes. Coculturing adult murine myocytes with human umbilical vein, murine lung microvascular, or human coronary artery EC can also protect myocytes against hypoxia--reoxygenation--induced apoptosis. These protective effects are abolished by NRG gene deletion or silencing of NRG expression in EC. Finally, endothelium-selective deletion of NRG in vivo leads to significantly decreased tolerance to ischemic insult, as demonstrated by impaired postischemic contractile recovery in a perfused whole-organ preparation and larger infarct sizes after coronary artery ligation. CONCLUSION: Together, these data demonstrate that EC-derived NRG plays an important role in cardiac myocyte protection against ischemic injury in the heart and supports the idea that manipulation of this signaling pathway may be an important clinical target in this setting. PMID- 21555714 TI - Problems with risk reclassification methods for evaluating prediction models. AB - For comparing the performance of a baseline risk prediction model with one that includes an additional predictor, a risk reclassification analysis strategy has been proposed. The first step is to cross-classify risks calculated according to the 2 models for all study subjects. Summary measures including the percentage of reclassification and the percentage of correct reclassification are calculated, along with 2 reclassification calibration statistics. The author shows that interpretations of the proposed summary measures and P values are problematic. The author's recommendation is to display the reclassification table, because it shows interesting information, but to use alternative methods for summarizing and comparing model performance. The Net Reclassification Index has been suggested as one alternative method. The author argues for reporting components of the Net Reclassification Index because they are more clinically relevant than is the single numerical summary measure. PMID- 21555715 TI - Risk of osteoporotic fractures after discontinuation of menopausal hormone therapy: results from the E3N cohort. AB - While current use of menopausal hormone therapy (MHT) reduces the risk of osteoporotic fractures, epidemiologic studies suggest that protection wears off rapidly after discontinuation of treatment. The authors identified 5,589 first osteoporotic fractures (2,235 major osteoporotic fractures) among 70,182 postmenopausal women from the French E3N cohort (1992-2008) and used Cox multivariate proportional hazards regression models to estimate hazard ratios. Persistence of protection against major osteoporotic fractures after MHT discontinuation was only observed when MHT had been used for at least 5 years, with a slightly more important decrease within the 5 years after discontinuation (compared with never use of MHT, hazard ratio = 0.68, 95% confidence interval: 0.50, 0.92) than beyond 5 years (hazard ratio = 0.83, 95% confidence interval: 0.69, 0.99); the P value for homogeneity between the 2 estimates was not significant. Oral estrogen use and transdermal estrogen use conveyed similar estimates in past users. Among current users, the authors confirmed a protective effect of MHT against risk of osteoporotic fractures. These findings, which relied on a number of MHT combinations, suggested that such therapies should be used for 5 years or more for reducing risk of fracture after treatment discontinuation. PMID- 21555716 TI - Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. AB - In this paper, the authors describe different instrumental variable (IV) estimators of causal risk ratios and odds ratios with particular attention to methods that can handle continuously measured exposures. The authors present this discussion in the context of a Mendelian randomization analysis of the effect of body mass index (BMI; weight (kg)/height (m)(2)) on the risk of asthma at age 7 years (Avon Longitudinal Study of Parents and Children, 1991-1992). The authors show that the multiplicative structural mean model (MSMM) and the multiplicative generalized method of moments (MGMM) estimator produce identical estimates of the causal risk ratio. In the example, MSMM and MGMM estimates suggested an inverse relation between BMI and asthma but other IV estimates suggested a positive relation, although all estimates had wide confidence intervals. An interaction between the associations of BMI and fat mass and obesity-associated (FTO) genotype with asthma explained the different directions of the different estimates, and a simulation study supported the observation that MSMM/MGMM estimators are negatively correlated with the other estimators when such an interaction is present. The authors conclude that point estimates from various IV methods can differ in practical applications. Based on the theoretical properties of the estimators, structural mean models make weaker assumptions than other IV estimators and can therefore be expected to be consistent in a wider range of situations. PMID- 21555717 TI - Seasonal variations in sleep problems at latitude 63 degrees -65 degrees in Norway: The Nord-Trondelag Health Study, 1995-1997. AB - Most studies on seasonal variability in sleep have asked participants if they think their sleep quality varies with the seasons, which reveals the research hypothesis to the participants. To date, the hypothesis of seasonal variation in sleep has not been tested in a large population-based fully blinded study. The aim of the current study was to investigate monthly variations in sleep problems in a geographic region of Norway with large seasonal differences in daytime light. Using data from a general health survey, the authors had access to information on sleep in the general population, collected across the seasons over 2 years without linking sleep to seasonal variation. In all, 43,045 participants (mean age, 44.6 years) of the Nord-Trondelag Health Study, 1995-1997 (referred to as "HUNT-2"), provided reports of insomnia symptoms and time in bed in all months except July. The mean prevalence of insomnia symptoms was 12.4%. No evidence of a seasonal variation on reports of insomnia symptoms or time in bed was found. These null findings are in marked contrast to previous seasonality studies of sleep. Previous studies reporting seasonal variations in sleep and insomnia might have been subject to publication biases and lack of blinding to the research hypothesis. PMID- 21555718 TI - Large aortic pseudoaneurysm, from left coronary ostium, with aortopulmonary fistula 10 years after aortic root replacement for type a aortic dissection. PMID- 21555719 TI - An unusual heart failure: cardiac amyloidosis due to light-chain myeloma. PMID- 21555720 TI - Letter by McEvoy regarding article, "Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both". PMID- 21555721 TI - Letter by Poullis regarding article, "Visceral arterial compromise during intra aortic balloon counterpulsation therapy". PMID- 21555722 TI - Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. PMID- 21555724 TI - Natriuretic peptide testing in heart failure. PMID- 21555725 TI - The broken heart. PMID- 21555723 TI - Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. PMID- 21555726 TI - Clinical reasoning: a 79-year-old man with polyneuropathy and dysautonomia. PMID- 21555728 TI - A family with Parkinsonism, essential tremor, restless legs syndrome, and depression. AB - BACKGROUND: Previous epidemiologic and genetic studies have suggested a link between Parkinson disease (PD), essential tremor (ET), and restless legs syndrome (RLS). METHODS: We describe the clinical, PET, and pathologic characteristics of an extensive kindred from Arkansas with hereditary PD, ET, and RLS. The pedigree contains 138 individuals. Sixty-five family members were examined neurologically up to 3 times from 2004 to 2010. Clinical data were collected from medical records and questionnaires. Genetic studies were performed. Five family members underwent multitracer PET. Two individuals with PD were examined postmortem. RESULTS: Eleven family members had PD with generally mild and slowly progressive symptoms. Age at onset was between 39 and 74 years (mean 59.1, SD 13.4). All individuals treated with l-dopa responded positively. Postural or action tremor was present in 6 individuals with PD, and in 19 additional family members. Fifteen persons reported symptoms of RLS. PET showed reduced presynaptic dopamine function typical of sporadic PD in a patient with PD and ET, but not in persons with ET or RLS. The inheritance pattern was autosomal dominant for PD and RLS. No known pathogenic mutation in PD-related genes was found. Fourteen of the family members with PD, ET, or RLS had depression. Neuropathologic examination revealed pallidonigral pigment spheroid degeneration with ubiquitin-positive axonal spheroids, TDP43-positive pathology in the basal ganglia, hippocampus, and brainstem, and only sparse Lewy bodies. CONCLUSION: Familial forms of PD, ET, RLS, and depression occur in this family. The genetic cause remains to be elucidated. PMID- 21555729 TI - Behavioral therapy to treat urinary incontinence in Parkinson disease. AB - OBJECTIVE: To assess the feasibility and efficacy of exercise-based behavioral therapy to treat urinary incontinence (UI) in older adults with Parkinson disease (PD). METHODS: Participants with PD >=50 years with >=4 UI episodes on a 7-day bladder diary were recruited from movement disorders clinics. In 5 visits over 8 weeks, participants learned pelvic floor muscle exercises using computer-assisted EMG biofeedback, and bladder control strategies including urge suppression. Bladder diaries were used to reinforce techniques and monitor the primary outcome of UI frequency. Secondary outcomes included additional reporting of lower urinary tract symptoms, symptom bother, and quality of life (QOL) using the International Consultation on Incontinence Questionnaire for overactive bladder (ICIQ-OAB). RESULTS: Twenty participants were enrolled (90% male, age 66.5 +/- 6.2 [mean +/- SD], with PD for 6.9 +/- 5.4 years) and 17 completed the study. The median (interquartile range) weekly frequency of baseline UI episodes was 9 (4 11) and following intervention was 1 (0-3), representing an 83.3% reduction (45.5 100.0, p = 0.0001). QOL scores on the ICIQ-OAB improved from 71.1 +/- 23.9 to 54.7 +/- 15.4 (p = 0.002). CONCLUSIONS: In this uncontrolled pilot study of an exercise-based, biofeedback-assisted behavioral intervention, older participants with PD demonstrated statistically significant and clinically meaningful reductions in frequency of UI and improvement in QOL. Randomized controlled trials to assess behavioral therapies for UI in patients with PD are warranted. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that exercise based, biofeedback-assisted behavioral intervention can reduce UI frequency in patients >50 years old with PD. PMID- 21555732 TI - Acquired pendular nystagmus in multiple sclerosis and oculopalatal tremor. AB - OBJECTIVE: Acquired pendular nystagmus occurs mainly in multiple sclerosis (MS) and focal brainstem lesions. In the later case, it is part of the syndrome of oculopalatal tremor. Even though pathophysiology of acquired pendular nystagmus has been clearly characterized experimentally in both etiologies, there is a persisting ambiguity in clinical literature, which leads one to consider both clinical conditions as a common entity. The objective of our work was to compare in a prospective study clinical features, eye movement recording, and functional consequences of acquired pendular nystagmus in 14 patients with oculopalatal tremor and 20 patients with MS. METHODS: Besides complete neurologic evaluation, evaluation of visual function, 3-dimensional eye movement recording, and functional scores of the Visual Function Questionnaire were recorded. RESULTS: One patient with oculopalatal tremor and 15 patients with MS disclosed signs of optic neuropathy. The nystagmus in the oculopalatal group showed significant larger mean amplitude (8 deg vs 1 deg), higher mean peak velocity (16 deg/s vs 6 deg/s), lower mean frequency (1-3 Hz vs 4-6 Hz), and larger asymmetry and irregularity of ocular oscillations compared to the MS group. The vision-specific health-related quality of life was more deteriorated in the oculopalatal tremor group than in the MS group. CONCLUSIONS: This study emphasizes the need to consider acquired pendular nystagmus in MS and oculopalatal tremor as 2 different clinical entities. This is of particular importance regarding the future evaluation of potential specific effects of pharmacologic agents. PMID- 21555731 TI - A new device to quantify tactile sensation in neuropathy. AB - OBJECTIVE: To devise a rapid, sensitive method to quantify tactile threshold of finger pads for early detection and staging of peripheral neuropathy and for use in clinical trials. METHODS: Subjects were 166 healthy controls and 103 patients with, or at risk for, peripheral neuropathy. Subjects were screened by questionnaire. The test device, the Bumps, is a checkerboard-like smooth surface with 12 squares; each square encloses 5 colored circles. The subject explores the circles of each square with the index finger pad to locate the one circle containing a small bump. Bumps in different squares have different heights. Detection threshold is defined as the smallest bump height detected. In some subjects, a 3-mm skin biopsy from the tested finger pad was taken to compare density of Meissner corpuscles (MCs) to bump detection thresholds. RESULTS: The mean (+/-SEM) bump detection threshold for control subjects was 3.3 +/- 0.10 MUm. Threshold and test time were age related, older subjects having slightly higher thresholds and using more time. Mean detection threshold of patients with neuropathy (6.2 +/- 0.35 MUm) differed from controls (p < 0.001). A proposed threshold for identifying impaired sensation had a sensitivity of 71% and specificity of 74%. Detection threshold was higher when MC density was decreased. CONCLUSIONS: These preliminary studies suggest that the Bumps test is a rapid, sensitive, inexpensive method to quantify tactile sensation of finger pads. It has potential for early diagnosis of tactile deficiency in subjects suspected of having neuropathy, for staging degree of tactile deficit, and for monitoring change over time. PMID- 21555733 TI - CSF opening pressure in children with optic nerve head edema. AB - BACKGROUND: We previously reported that an abnormal CSF opening pressure (OP) in children was greater than 28 cm H(2)O. Since elevated intracranial pressure can cause optic nerve head edema (ONHE), we would expect that most patients with ONHE would have an OP greater than 28 cm H(2)O. This study describes the range of OP for children with ONHE and compared them to age-matched controls without ONHE. METHODS: Case subjects were children (1-18 years of age) enrolled in a prospective study of CSF OP that demonstrated ONHE at time of lumbar puncture and that the ONHE later resolved. Patients with ONHE secondary to infectious, inflammatory, or ischemic conditions were excluded. Control subjects from the same study, but without ONHE, were matched to cases. RESULTS: Of the 472 subjects enrolled in the study, 41 OP measurements were obtained from 33 patients with ONHE who did not have any exclusionary criteria and matched to 41 control subjects without ONHE. Case subjects had a significantly higher OP (mean, 41.4 cm H(2)0; range, 22-56) than control subjects (mean, 18.9 cm H(2)O; range, 9-29; p < 0.01). Forty of 41 (97.6%) case subjects and 2 of 41 (4.8%) control subjects had OP measures >28 cm H(2)O. CONCLUSIONS: Children with ONHE not related to infectious, inflammatory, or ischemic causes typically have an OP >28 cm H(2)O, significantly higher than age-matched controls without ONHE. This study provides further support to our previously published findings that suggests an abnormal OP in children is typically above 28 cm H(2)O. PMID- 21555734 TI - Population-based study of wake-up strokes. AB - OBJECTIVE: Previous studies have estimated that wake-up strokes comprise 8%to 28% of all ischemic strokes, but these studies were either small or not population based. We sought to establish the proportion and event rate of wake-up strokes in a large population-based study and to compare patients who awoke with stroke symptoms with those who were awake at time of onset. METHODS: First-time and recurrent ischemic strokes among residents of the Greater Cincinnati/Northern Kentucky region (population 1.3 million) in 2005 were identified using International Classification of Diseases-9 codes 430-436 and verified via study physician review. Ischemic strokes in patients aged 18 years and older presenting to an emergency department were included. Baseline characteristics were ascertained, along with discharge modified Rankin Scale scores and 90-day mortality. RESULTS: We identified 1,854 ischemic strokes presenting to an emergency department, of which 273 (14.3%) were wake-up strokes. There were no differences between wake-up strokes and all other strokes with regard to clinical features or outcomes except for minor differences in age and baseline retrospective NIH Stroke Scale score. The adjusted wake-up stroke event rate was 26.0/100,000. Of the wake-up strokes, at least 98 (35.9%) would have been eligible for thrombolysis if arrival time were not a factor. CONCLUSIONS: Within our population, approximately 14% of ischemic strokes presenting to an emergency department were wake-up strokes. Wake-up strokes cannot be distinguished from other strokes by clinical features or outcome. We estimate that approximately 58,000 patients with wake-up strokes presented to an emergency department in the United States in 2005. PMID- 21555736 TI - Did General Douglas MacArthur have Parkinson disease? A video and archival analysis. AB - BACKGROUND: Historians have suggested that MacArthur had Parkinson disease (PD), and that this may have influenced his military judgment. There is little evidence to support or to refute this suggestion. OBJECTIVE: We aimed in this article to review multiple cinematic images, as well as the personal writings of Douglas MacArthur to determine the likelihood that he had PD. METHODS: A complete review of the Western literature on Douglas MacArthur, including YouTube, Google Scholar/Google Images/Google Video, PubMed, and HighWirePress was undertaken. Over 200 minutes of film footage was analyzed, including such factors as MacArthur's facial profiles, facial expression, gait, posture, and movement. Handwriting samples from over 6 decades were compared for evidence of micrographia. Videos and handwriting samples were independently reviewed by 3 fellowship-trained movement disorders neurologists. RESULTS: Examination of video footage showed evidence of progression of head tremors, postural action tremors, and voice tremors. There were no clear indications of a masked face, rigidity, bradykinesia, or a resting tremor on film footage recorded from 1906 to 1964. There was no evidence of micrographia in handwriting samples. Oral testimony and letters written by an attending gastroenterologist present at MacArthur's death in 1964 revealed no evidence of parkinsonian features. CONCLUSIONS: We conclude that MacArthur had mild essential tremor that was more evident in his postmilitary career. There was no evidence to suggest that he had a clinical diagnosis of progressive PD. PMID- 21555737 TI - Copper deficiency myeloneuropathy in a patient with Wilson disease. PMID- 21555738 TI - Dominant vertebral artery occlusion during ipsilateral head tilt. PMID- 21555739 TI - Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties. PMID- 21555740 TI - Teaching Video NeuroImages: complex partial seizure evolving into a psychogenic nonepileptic seizure. PMID- 21555741 TI - Activation of hypoxia-inducible factor-1alpha (Hif-1alpha) delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. AB - The oxygen-sensing transcription factor hypoxia-inducible factor-1alpha (HIF 1alpha) plays a critical role in the regulation of myeloid cell function. The mechanisms of regulation are not well understood, nor are the phenotypic consequences of HIF modulation in the context of neutrophilic inflammation. Species conservation across higher metazoans enables the use of the genetically tractable and transparent zebrafish (Danio rerio) embryo to study in vivo resolution of the inflammatory response. Using both a pharmacologic approach known to lead to stabilization of HIF-1alpha, and selective genetic manipulation of zebrafish HIF-1alpha homologs, we sought to determine the roles of HIF-1alpha in inflammation resolution. Both approaches reveal that activated Hif-1alpha delays resolution of inflammation after tail transection in zebrafish larvae. This delay can be replicated by neutrophil-specific Hif activation and is a consequence of both reduced neutrophil apoptosis and increased retention of neutrophils at the site of tissue injury. Hif-activated neutrophils continue to patrol the injury site during the resolution phase, when neutrophils would normally migrate away. Site-directed mutagenesis of Hif in vivo reveals that hydroxylation of Hif-1alpha by prolyl hydroxylases critically regulates the Hif pathway in zebrafish neutrophils. Our data demonstrate that Hif-1alpha regulates neutrophil function in complex ways during inflammation resolution in vivo. PMID- 21555742 TI - Structural basis of thrombin-mediated factor V activation: the Glu666-Glu672 sequence is critical for processing at the heavy chain-B domain junction. AB - Thrombin-catalyzed activation of coagulation factor V (FV) is an essential positive feedback reaction within the blood clotting system. Efficient processing at the N- (Arg(709)-Ser(710)) and C-terminal activation cleavage sites (Arg(1545) Ser(1546)) requires initial substrate interactions with 2 clusters of positively charged residues on the proteinase surface, exosites I and II. We addressed the mechanism of activation of human factor V (FV) using peptides that cover the entire acidic regions preceding these cleavage sites, FV (657-709)/ (FVa2) and FV(1481-1545)/(FVa3). FVa2 appears to interact mostly with exosite I, while both exosites are involved in interactions with the C-terminal linker. The 1.7-A crystal structure of irreversibly inhibited thrombin bound to FVa2 unambiguously reveals docking of FV residues Glu(666)-Glu(672) to exosite I. These findings were confirmed in a second, medium-resolution structure of FVa2 bound to the benzamidine-inhibited proteinase. Our results suggest that the acidic A2-B domain linker is involved in major interactions with thrombin during cofactor activation, with its more N-terminal hirudin-like sequence playing a critical role. Modeling experiments indicate that FVa2, and likely also FVa3, wrap around thrombin in productive thrombin.FV complexes that cover a large surface of the activator to engage the active site. PMID- 21555743 TI - Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. AB - CREB-binding protein (CREBBP) is important for the cell-autonomous regulation of hematopoiesis, including the stem cell compartment. In the present study, we show that CREBBP plays an equally pivotal role in microenvironment-mediated regulation of hematopoiesis. We found that the BM microenvironment of Crebbp(+/-) mice was unable to properly maintain the immature stem cell and progenitor cell pools. Instead, it stimulates myeloid differentiation, which progresses into a myeloproliferation phenotype. Alterations in the BM microenvironment resulting from haploinsufficiency of Crebbp included a marked decrease in trabecular bone that was predominantly caused by increased osteoclastogenesis. Although CFU fibroblast (CFU-F) and total osteoblast numbers were decreased, the bone formation rate was similar to that found in wild-type mice. At the molecular level, we found that the known hematopoietic modulators matrix metallopeptidase-9 (MMP9) and kit ligand (KITL) were decreased with heterozygous levels of Crebbp. Lastly, potentially important regulatory proteins, endothelial cell adhesion molecule 1 (ESAM1) and cadherin 5 (CDH5), were increased on Crebbp(+/-) endothelial cells. Our findings reveal that a full dose of Crebbp is essential in the BM microenvironment to maintain proper hematopoiesis and to prevent excessive myeloproliferation. PMID- 21555744 TI - Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. AB - Replacement therapy with factor IX (FIX) concentrates is the recommended treatment for patients with hemophilia B, an X-linked bleeding disorder occurring in 1:25,000 male births. N9-GP is a recombinant FIX molecule with a prolonged half-life which is obtained by site-directed glycoPEGylation where a 40-kDa polyethylene glycol molecule is attached to the activation peptide of FIX. This first human dose trial in patients with hemophilia B investigated the safety and pharmacokinetic properties of a single IV dose of N9-GP. Sixteen previously treated patients received one dose of their previous FIX product followed by one dose of N9-GP at the same dose level (25, 50, or 100 U/kg). None of the patients developed inhibitors. One patient developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from pharmacokinetic analyses. In the remaining 15 patients, N9-GP was well-tolerated. The half-life was 93 hours, which was 5 times higher than the patient's previous product. The incremental recovery of N9-GP was 94% and 20% higher compared with recombinant and plasma derived products, respectively. These results indicate that N9-GP has the potential to reduce dosing frequency while providing effective treatment of bleeding episodes with a single dose. The trial was registered at www.clinicaltrials.gov as NCT00956345. PMID- 21555746 TI - Can CME save lives? The results of a Swedish, evidence-based continuing education intervention. PMID- 21555745 TI - Barriers to mucosal transmission of immunodeficiency viruses. AB - Lentiviruses such as HIV have a daunting challenge in gaining access to a new host predominantly through the penile, rectal, or vaginal/cervical mucosal tissue after sexual exposure. Multiple mechanisms have evolved to help prevent such infections, including anatomical barriers, innate inhibitors, and adaptive immune responses. For lentiviruses, it appears that in naive or even conventionally vaccinated hosts, typical adaptive immune responses are generally too little and too late to prevent infection. Nevertheless, a combination of anatomical barriers and innate immune responses may limit transmission, especially in patients without predisposing conditions such as mucosal lesions or preexisting sexually transmitted infections. Furthermore, when infection does occur, most often the primary viremia of the acute infection can be traced back genetically to a single founder virus. Unfortunately, even a single virion can establish an infection that will ultimately lead to the demise of the host. This review seeks to describe the biology of and barriers to establishment of systemic, disseminated productive infection with HIV after sexual exposure and to discuss the possible mechanisms leading to infection by a single viral variant. Understanding the initial events of infection, before systemic spread, could provide insights into strategies for reducing acquisition or ameliorating clinical outcome. PMID- 21555747 TI - Balancing the risks and benefits of proton pump inhibitors. PMID- 21555748 TI - Case-based training of evidence-based clinical practice in primary care and decreased mortality in patients with coronary heart disease. AB - PURPOSE: We investigated the 10-year mortality rates in a trial that tested a case-based intervention in primary care aimed at reducing the gap between evidence-based goals and clinical practice in patients with coronary heart disease (CHD). METHODS: A prospective randomized controlled pragmatic trial was undertaken in a primary care setting. New evidence-based guidelines, with intensified lipid-lowering recommendations in CHD, were mailed to all general practitioners in the region and presented at a lecture in 1995. General practitioners (n = 54) and patients with CHD (n = 88) were assigned according to their primary health care center to 2 balanced groups and randomly allocated to usual care as a control or to an active intervention. General practitioners in the intervention group participated in repeated case-based training during a 2 year period. Patients whose CHD was treated by specialists (n = 167) served as an internal specialist comparison group. Altogether, 255 consecutive patients were included. Cox regression analysis was used to detect any survival benefit of the intervention. RESULTS: At 10 years, 22% of the patients in the intervention group had died as compared with 44% in the control group (P = .02), with a hazard ratio of 0.45 (95% confidence interval, 0.20-0.95). This difference was mainly due to reduced cardiovascular mortality in the intervention group (P = .01). In addition, the mortality rate of 22% in the intervention group was comparable to the rate of 23% seen in patients treated by a specialist. CONCLUSIONS: Use of case-based training to implement evidence-based practice in primary care was associated with decreased mortality at 10 years in patients with CHD. PMID- 21555749 TI - Racial differences in primary care opioid risk reduction strategies. AB - PURPOSE: Racial disparities in treating pain with opioids are widely reported; however, differences in use of recommended strategies to reduce the risk of opioid misuse by race/ethnicity have not been evaluated. METHODS: In a retrospective cohort of black and white patients with chronic noncancer pain prescribed opioid analgesics for at least 3 months, we assessed physicians' use of 3 opioid risk reduction strategies: (1) urine drug testing, (2) regular office visits (at least 1 visit per 6 months on opioids and within 30 days of an opioid change), and (3) restricted early opioid refills (receipt of a refill >1 week early less than twice). Nonlinear mixed effect regression models accounted for clustering within physician and adjusted additively for demographics, substance abuse, mental health and medical comorbidities, health care factors, and practice site. RESULTS: Of the 1,612 patients studied, 62.1% were black. Black patients were more likely than white patients to receive urine drug testing (10.4% vs 4.1%), regular office visits (56.4% vs 39.0%), and restricted early refills (79.4% vs 72.0%) (P <.001 for each). In fully adjusted models, black patients had significantly higher odds than their white counterparts of receiving regular office visits (odds ratio = 1.51; 95% confidence interval, 1.06-2.14) and restricted early refills (odds ratio = 1.55; 95% confidence interval, 1.03-2.32), but not urine drug testing (odds ratio = 1.41; 95% confidence interval, 0.78 2.54). CONCLUSIONS: In this cohort of primary care patients receiving opioid analgesics on a long-term basis, use of risk reduction strategies was very limited overall; however, black patients were more likely than white patients to receive 2 of 3 guideline-recommended strategies. These data raise questions about lax monitoring, especially for white patients taking opioids long term. PMID- 21555750 TI - Corticosteroid injections for greater trochanteric pain syndrome: a randomized controlled trial in primary care. AB - PURPOSE: We undertook a study to evaluate the effectiveness of corticosteroid injections in primary care patients with greater trochanteric pain syndrome (GTPS). METHODS: We evaluated the effect of corticosteroid injections compared with expectant treatment (usual care) in a pragmatic, multicenter, open-label, randomized clinical trial in the Netherlands. Patients (aged 18 to 80 years) with GTPS visiting 81 participating primary care physicians were randomly allocated to receive either local corticosteroid injections (n = 60) or usual care (n = 60). Primary outcomes of pain severity (numerical rating scale 0 to 10) and recovery (yes or no total or major recovery) were evaluated at 3-month and 12-month follow up visits. Adverse events were collected at 6 weeks. RESULTS: At the 3-month follow-up visit, 34% of the patients in the usual care group had recovered compared with 55% in the injection group (adjusted OR = 2.38; 95% CI, 1.14-5.00, number needed to treat = 5). Pain severity at rest and on activity decreased in both groups, but the decrease was greater in the injection group, for an adjusted difference in pain at rest of 1.18 (95% CI, 0.31-2.05) and in pain with activity of 1.30 (95% CI, 0.32-2.29). At the 12-month follow-up, 60% of the patients in the usual care group had recovered compared with 61% in the injection group (OR = 1.05; 95% CI, 0.50-2.27). Pain severity at rest and on activity decreased in both groups and the 12-month follow-up showed no significant differences, with adjusted differences of 0.14 (95% CI, -0.75 to 1.04) for pain at rest and 0.45 (95% CI, -0.55 to 1.46) for pain with activity. Aside from a short period with superficial pain at the site of the injection, no differences in adverse events were found. CONCLUSION: In this first randomized controlled trial assessing the effectiveness of corticosteroid injections vs usual care in GTPS, a clinically relevant effect was shown at a 3-month follow-up visit for recovery and for pain at rest and with activity. At a 12-month follow-up visit, the differences in outcome were no longer present. PMID- 21555751 TI - Understanding patients' experiences of treatment burden in chronic heart failure using normalization process theory. AB - PURPOSE: Our goal was to assess the burden associated with treatment among patients living with chronic heart failure and to determine whether Normalization Process Theory (NPT) is a useful framework to help describe the components of treatment burden in these patients. METHODS: We performed a secondary analysis of qualitative interview data, using framework analysis, informed by NPT, to determine the components of patient "work." Participants were 47 patients with chronic heart failure managed in primary care in the United Kingdom who had participated in an earlier qualitative study about living with this condition. We identified and examined data that fell outside of the coding frame to determine if important concepts or ideas were being missed by using the chosen theoretical framework. RESULTS: We were able to identify and describe components of treatment burden as distinct from illness burden using the framework. Treatment burden in chronic heart failure includes the work of developing an understanding of treatments, interacting with others to organize care, attending appointments, taking medications, enacting lifestyle measures, and appraising treatments. Factors that patients reported as increasing treatment burden included too many medications and appointments, barriers to accessing services, fragmented and poorly organized care, lack of continuity, and inadequate communication between health professionals. Patient "work" that fell outside of the coding frame was exclusively emotional or spiritual in nature. CONCLUSIONS: We identified core components of treatment burden as reported by patients with chronic heart failure. The findings suggest that NPT is a theoretical framework that facilitates understanding of experiences of health care work at the individual, as well as the organizational, level. Although further exploration and patient endorsement are necessary, our findings lay the foundation for a new target for treatment and quality improvement efforts toward patient-centered care. PMID- 21555752 TI - 'Meeting people where they're at': experiences of family physicians engaging women who use illicit drugs. AB - PURPOSE: There is little research exploring the experiences of family physicians caring for women who use illicit drugs. This study explores the experiences of these physicians in order to better understand the process of engaging these women in the patient-physician relationship. METHODS: We conducted a phenomenologic, qualitative study using individual, in-depth interviews with 10 family physicians working in inner-city Toronto and Ottawa, Ontario. An iterative and interpretive analysis was used. RESULTS: Three broad themes emerged from the analysis. The predominant theme was that of the patient-physician relationship, which consisted of 2 phases: the engagement phase and the maintenance phase. During the engagement phase, issues such as access and women's experiences of trauma and violence were evident and impeded participants' ability to engage with this population. As such, the patient-physician relationship during the engagement phase was tenuous. Trust and presence were paramount during this phase. Once a family physician engaged a woman, the transition to the maintenance phase was made. Within the maintenance phase, 2 subthemes were identified: continuity of care and "meeting people where they're at" (finding common ground). CONCLUSIONS: This study identified a 2-phase process of the patient-physician relationship from the perspective of family physicians caring for women using illicit drugs: the engagement and maintenance phases. Our findings identified strategies to support the patient-physician relationship during each of these phases that have implications for improving the health of these women. PMID- 21555753 TI - Preventing life-sustaining treatment by default. AB - Many physicians will at some point care for patients who will receive life sustaining treatment by default, because there are no instructions available from the patient as to what kind of care is preferred, and because surrogates are likely to ask for everything to be done when they do not know a patient's preferences. We use the methods of ethics informed by qualitative focus group research to identify 5 pathways to life-sustaining treatment by default originating with the patient's preferred decision-making style: deciding for oneself or letting others decide. We emphasize preventing the ethically unwelcome outcome of life-sustaining treatment by default by increasing the frequency with which patients make clear decisions or clearly express their values and goals that they then communicate to physicians or surrogates. PMID- 21555754 TI - Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. AB - PURPOSE: Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis. METHODS: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta analysis, because of heterogeneity. RESULTS: Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk. CONCLUSIONS: We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors. PMID- 21555755 TI - Nasruddin and the coin. AB - Many problems can be solved through following clinical guidelines and algorithms. In this essay, however, I explore the importance of narrative by connecting an ancient Middle Eastern teaching fable to a contemporary story of healing. A middle-aged Latina, Magdalena, comes to my residency clinic with chronic hypertension, cerebrovascular disease, and depression. Using standard biomedical approaches, I attempt to manage and cure these chronic conditions. After several months of failure, I seek the guidance of an eccentric mentor, who points me toward broader and deeper interactions with my patient. Ultimately, Magdalena heals herself through revisiting her past. Her story suggests that the cause of illness may sometimes be found outside the usual biomedical framework of explanation. PMID- 21555756 TI - Education of students and residents in Patient Centered Medical Home (PCMH): preparing the way. PMID- 21555757 TI - Innovation in family medicine residencies: struggling to create classics for the future. PMID- 21555758 TI - Family medicine, NAPCRG, and the Great Mandella. PMID- 21555759 TI - Match shows med students believe in specialty's future. PMID- 21555760 TI - ABFM's Physicians Quality Reporting System registry. PMID- 21555761 TI - STFM and CAFM create task force to assist residencies in measuring residency competency. PMID- 21555762 TI - Establishment of a novel model of onychomycosis in rabbits for evaluation of antifungal agents. AB - We developed a novel model of onychomycosis in which we observed fungi in the deep layer of the nail, and we used the model to evaluate the efficacy of two topical antifungal drugs. To establish an experimental, in vivo model of onychomycosis, we applied Trichophyton mentagrophytes TIMM2789 to the nails of the hind limbs of rabbits that underwent steroid treatment. The nails were taken from the rabbits' feet at 0, 2, and 6 weeks after a 2-week infection. The localization of the fungi was evaluated histopathologically. Some fungi were seen to penetrate to the nail bed, and the infection rate in the sample at 0, 2, and 6 weeks after infection was 57, 87, and 93%, respectively. In addition, fungi proliferated and moved proximally into the nail plate in a manner that depended on the duration of infection. Second, using this model we evaluated antifungal efficacy both by the culture recovery method and histopathological examination. Two topical antifungal drugs, 8% ciclopirox nail lacquer and 5% amorolfine nail lacquer, were applied to the nail for 4 weeks in each group. On histopathological examination, two antifungal treatment groups showed no significant difference against the nontreated control group. However, there were a significantly low fungus-positive rate and intensity of the recovery of fungi on culture between antifungal treatment and nontreated control groups. We therefore suggest that we have established an in vivo model of onychomycosis that is useful for the evaluation of the efficacy of antifungal agents. PMID- 21555763 TI - Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. AB - With increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m(2). Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of >= 1.0 mg/liter. PMID- 21555764 TI - Effects of etravirine alone and with ritonavir-boosted protease inhibitors on the pharmacokinetics of dolutegravir. AB - Dolutegravir (DTG) is an unboosted, once-daily integrase inhibitor currently in phase 3 trials. Two studies evaluated the effects of etravirine (ETR) alone and in combination with ritonavir (RTV)-boosted protease inhibitors (PIs) on DTG pharmacokinetics (PK) in healthy subjects. DTG 50 mg every 24 h (q24h) was administered alone for 5 days in period 1, followed by combination with ETR at 200 mg q12h for 14 days in period 2 (study 1) or with ETR/lopinavir (LPV)/RTV at 200/400/100 mg q12h or ETR/darunavir (DRV)/RTV at 200/600/100 mg q12h for 14 days in period 2 (study 2). PK samples were collected on day 5 in period 1 and day 14 in period 2. All of the treatments were well tolerated. ETR significantly decreased exposures of DTG, with geometric mean ratios of 0.294 (90% confidence intervals, 0.257 to 0.337) for the area under the curve from time zero until the end of the dosage interval (AUC(0-tau)), 0.484 (0.433 to 0.542) for the observed maximum plasma concentration (C(max)), and 0.121 (0.093 to 0.157) for the plasma concentration at the end of the dosage interval (C(tau)). ETR combined with an RTV-boosted PI affected the exposure of DTG to a lesser degree: ETR/LPV/RTV treatment had no effect on the DTG plasma AUC(0-tau) and C(max), whereas the C(tau) increased by 28%. ETR/DRV/RTV modestly decreased the plasma DTG AUC(0 tau), C(max), and C(tau) by 25, 12, and 37%, respectively. Such effects of ETR/LPV/RTV and ETR/DRV/RTV are not considered clinically relevant. The combination of DTG and ETR alone should be avoided; however, DTG may be coadministered with ETR without a dosage adjustment if LPV/RTV or DRV/RTV is concurrently administered. PMID- 21555765 TI - JNJ-Q2, a new fluoroquinolone with potent in vitro activity against Staphylococcus aureus, including methicillin- and fluoroquinolone-resistant strains. AB - JNJ-Q2 is a broad-spectrum bactericidal fluoroquinolone with potent activity against Gram-positive and -negative pathogens. In this study, the in vitro activity of JNJ-Q2 was evaluated against 511 selected Staphylococcus aureus samples isolated in 2008-2009 from patients with acute bacterial skin and skin structure infections in the United States by using reference methodology. JNJ-Q2 was the most potent fluoroquinolone tested overall (MIC(50) and MIC(90), 0.12 and 0.5 MUg/ml, respectively) and against methicillin- and fluoroquinolone-resistant subgroups in direct comparisons to moxifloxacin, levofloxacin, and ciprofloxacin (each being >= 16-fold less potent than JNJ-Q2). PMID- 21555766 TI - Characteristic resistance mechanism of Mycobacterium tuberculosis to DC-159a, a new respiratory quinolone. AB - A G88C mutation in GyrA is one of the key alterations by which Mycobacterium tuberculosis mutants acquire DC-159a resistance in vitro. A novel double mutation in GyrA, G88C D94H, conferred high DC-159a resistance. Different mutation patterns in GyrA were demonstrated for DC-159a-resistant mutants and quinolone resistant multidrug-resistant (QR-MDR) M. tuberculosis isolates, with a mutation either at position 90 or 94 and double mutations at 90 and 91 or at 90 and 94. DC 159a might be promising for QR M. tuberculosis treatment. PMID- 21555767 TI - Implication of the NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid pH and in resistance to moxifloxacin. AB - Staphylococcus aureus is an important pathogen that adapts and survives in low-pH environments. One component of this adaptation involves the regulation of genes encoding bacterial transporters that could affect response to antibiotics under these conditions. We previously demonstrated that the transcriptional regulator MgrA in its phosphorylated form (MgrA-P) represses the expression of norB, encoding the NorB multidrug resistance efflux pump. In this study, we focused on changes in the expression of mgrA at the transcriptional and posttranslational levels, following a shift from pH 7.0 to pH 4.5. We then correlated those changes with modifications in transcript levels of norB and to resistance to moxifloxacin, a substrate of NorB. At pH 4.5, S. aureus MgrA increased 2-fold and MgrA-P decreased 4-fold, associated with an 8-fold increase in norB transcripts and a 6-fold reduction in bacterial killing by moxifloxacin, and the phenomenon was dependent on intact mgrA. Taken together, these new data showed that phosphoregulation of MgrA at low pH reverses its repression of norB expression, conferring resistance to moxifloxacin. PMID- 21555768 TI - Dissemination of clinical isolates of Klebsiella oxytoca harboring CMY-31, VIM-1, and a New OXY-2-type variant in the community. AB - The aim of the present study was to investigate the epidemiological link of multidrug-resistant Klebsiella oxytoca isolates causing community-onset infections among patients attending our outpatient department and to investigate the underlying resistance mechanisms. The isolates were tested by agar dilution MICs, phenotypic carbapenemase testing, enterobacterial repetitive intergenic consensus-PCR, and pulsed-field gel electrophoresis (PFGE). PCR assays and nucleotide sequencing were employed for the identification of bla gene types and the mapping of the integron-containing metallo-beta-lactamase (MBL) gene. During the study period (January 2005 to April 2007), nine broad-spectrum cephalosporin resistant K. oxytoca clinical isolates were prospectively collected from separate outpatients with urinary tract infections. In all cases, the patients had been hospitalized or exposed to health care facilities during the preceding year. Molecular typing revealed that all isolates belonged to the same K. oxytoca clonal type, which contained five PFGE subtypes. A novel chromosomal OXY-2 beta lactamase type variant (OXY-2-9) was detected in all isolates, but no mutations in the promoter region justifying bla(OXY) gene overproduction were detected. In addition, all isolates harbored the plasmidic CMY-31 (LAT-4) AmpC cephalosporinase, while three of them harbored VIM-1 MBL in a class 1 integron structure. This is the first study to present the dissemination in the community of multidrug-resistant K. oxytoca isolates causing extrahospital infections. PMID- 21555769 TI - Symmetry requirements for effective blocking of pore-forming toxins: comparative study with alpha-, beta-, and gamma-cyclodextrin derivatives. AB - We compared the abilities of structurally related cationic cyclodextrins to inhibit Bacillus anthracis lethal toxin and Staphylococcus aureus alpha hemolysin. We found that both beta- and gamma-cyclodextrin derivatives effectively inhibited anthrax toxin action by blocking the transmembrane oligomeric pores formed by the protective antigen (PA) subunit of the toxin, whereas alpha-cyclodextrins were ineffective. In contrast, alpha-hemolysin was selectively blocked only by beta-cyclodextrin derivatives, demonstrating that both symmetry and size of the inhibitor and the pore are important. PMID- 21555770 TI - Exploring the inhibition of CTX-M-9 by beta-lactamase inhibitors and carbapenems. AB - Currently, CTX-M beta-lactamases are among the most prevalent and most heterogeneous extended-spectrum beta-lactamases (ESBLs). In general, CTX-M enzymes are susceptible to inhibition by beta-lactamase inhibitors. However, it is unknown if the pathway to inhibition by beta-lactamase inhibitors for CTX-M ESBLs is similar to TEM and SHV beta-lactamases and why bacteria possessing only CTX-M ESBLs are so susceptible to carbapenems. Here, we have performed a kinetic analysis and timed electrospray ionization mass spectrometry (ESI-MS) studies to reveal the intermediates of inhibition of CTX-M-9, an ESBL representative of this family of enzymes. CTX-M-9 beta-lactamase was inactivated by sulbactam, tazobactam, clavulanate, meropenem, doripenem, ertapenem, and a 6-methylidene penem, penem 1. K(i) values ranged from 1.6 +/- 0.3 MUM (mean +/- standard error) for tazobactam to 0.02 +/- 0.01 MUM for penem 1. Before and after tryptic digestion of the CTX-M-9 beta-lactamase apo-enzyme and CTX-M-9 inactivation by inhibitors (meropenem, clavulanate, sulbactam, tazobactam, and penem 1), ESI-MS and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identified different adducts attached to the peptide containing the active site Ser70 (+52, 70, 88, and 156 +/- 3 atomic mass units). This study shows that a multistep inhibition pathway results from modification or fragmentation with clavulanate, sulbactam, and tazobactam, while a single acyl enzyme intermediate is detected when meropenem and penem 1 inactivate CTX-M-9 beta-lactamase. More generally, we propose that Arg276 in CTX-M-9 plays an essential role in the recognition of the C(3) carboxylate of inhibitors and that the localization of this positive charge to a "region of the active site" rather than a specific residue represents an important evolutionary strategy used by beta-lactamases. PMID- 21555771 TI - Trends towards lower antimicrobial susceptibility and characterization of acquired resistance among clinical isolates of Brachyspira hyodysenteriae in Spain. AB - The antimicrobial susceptibility of clinical isolates of Brachyspira hyodysenteriae in Spain was monitored, and the underlying molecular mechanisms of resistance were investigated. MICs of tylosin, tiamulin, valnemulin, lincomycin, and tylvalosin were determined for 87 B. hyodysenteriae isolates recovered from 2008 to 2009 by broth dilution. Domain V of the 23S rRNA gene and the ribosomal protein L3 gene were sequenced in 20 isolates for which the tiamulin MIC was >= 4 MUg/ml, presenting decreased susceptibility, and in 18 tiamulin-susceptible isolates (MIC <= 0.125 MUg/ml), and all isolates were typed by multiple-locus variable-number tandem repeats analysis. A comparison with antimicrobial susceptibility data from 2000 to 2007 showed an increase in pleuromutilin resistance over time, doubling the number of isolates with decreased susceptibility to tiamulin. No alteration in susceptibility was detected for lincomycin, and the MIC of tylosin remained high (MIC(50) > 128 MUg/ml). The decreased susceptibility to tylosin and lincomycin can be explained by mutations at position A2058 of the 23S rRNA gene (Escherichia coli numbering). A2058T was the predominant mutation, but A2058G also was found together with a change of the neighboring base pair at positions 2057 to 2611. The role of additional point mutations in the vicinity of the peptidyl transferase center and mutations in the L3 at amino acids 148 and 149 and their possible involvement in antimicrobial susceptibility are considered. An association between G2032A and high levels of tiamulin and lincomycin MICs was found, suggesting an increasing importance of this mutation in antimicrobial resistance of clinical isolates of B. hyodysenteriae. PMID- 21555772 TI - Penetration of intact blood-brain barrier by doripenem. PMID- 21555773 TI - Short-term teriparatide delivery and osseointegration: a clinical feasibility study. AB - Teriparatide is an anabolic osteoporosis therapeutic agent that can improve healing after fractures and periodontal surgeries. Clinical studies investigating the effects of teriparatide on the osseointegration of titanium implants have not been performed. We conducted an open-label randomized controlled feasibility study and included 24 individuals with edentulous lower jaws. The participants received 2 study implants in the mandible during interforaminal dental implant surgery. They were randomly assigned to receive either 20 ug of teriparatide once daily for 28 days or no treatment. Study implants were retrieved from 23 participants after 9 weeks and were subjected to histomorphometric analyses. Endpoints were new bone-volume-per-tissue-volume (NBV/TV) and new bone-to-implant contact (NBIC). We report here that median values of NBV/TV in the control and the teriparatide groups were 15.4% vs. 17.6% in the periosteal compartment, 11.3% vs. 16.5% in the cortical compartment, and 7.3% vs. 12.0% in the medullary compartment, respectively. NBIC median values in the control and the teriparatide groups were 3.3% vs. 4.1% in the periosteal compartment, 5.0% vs. 4.4% in the cortical compartment, and 0.3% vs. 1.4% in the medullary compartment, respectively. The results provide the first histological data on the osseointegration of titanium study implants in individuals treated with teriparatide. ClinicalTrials.gov number, NCT00089674. PMID- 21555774 TI - The impact of vitamin D status on periodontal surgery outcomes. AB - Vitamin D regulates calcium and immune function. While vitamin D deficiency has been associated with periodontitis, little information exists regarding its effect on wound healing and periodontal surgery outcomes. This longitudinal clinical trial assessed outcomes of periodontal surgery and teriparatide administration in vitamin-D-sufficient and -insufficient individuals. Forty individuals with severe chronic periodontitis received periodontal surgery, daily calcium and vitamin D supplements, and self-administered teriparatide or placebo for 6 wks to correspond with osseous healing time. Serum 25(OH)D was evaluated at baseline, 6 wks, and 6 mos post-surgery. Clinical and radiographic outcomes were evaluated over 1 yr. Placebo patients with baseline vitamin D deficiency [serum 25(OH)D, 16-19 ng/mL] had significantly less clinical attachment loss (CAL) gain (-0.43 mm vs. 0.92 mm, p < 0.01) and probing depth (PPD) reduction (0.43 mm vs. 1.83 mm, p < 0.01) than vitamin-D-sufficient individuals. Vitamin D levels had no significant impact on CAL and PPD improvements in teriparatide patients at 1 yr, but infrabony defect resolution was greater in teriparatide-treated vitamin-D sufficient vs. -deficient individuals (2.05 mm vs. 0.87 mm, p = 0.03). Vitamin D deficiency at the time of periodontal surgery negatively affects treatment outcomes for up to 1 yr. Analysis of these data suggests that vitamin D status may be critical for post-surgical healing. (ClinicalTrials.gov number, CT00277706). PMID- 21555775 TI - Electrical implications of corrosion for osseointegration of titanium implants. AB - The success rate of titanium implants for dental and orthopedic applications depends on the ability of surrounding bone tissue to integrate with the surface of the device, and it remains far from ideal in patients with bone compromised by physiological factors. The electrical properties and electrical stimulation of bone have been shown to control its growth and healing and can enhance osseointegration. Bone cells are also sensitive to the chemical products generated during corrosion events, but less is known about how the electrical signals associated with corrosion might affect osseointegration. The metallic nature of the materials used for implant applications and the corrosive environments found in the human body, in combination with the continuous and cyclic loads to which these implants are exposed, may lead to corrosion and its corresponding electrochemical products. The abnormal electrical currents produced during corrosion can convert any metallic implant into an electrode, and the negative impact on the surrounding tissue due to these extreme signals could be an additional cause of poor performance and rejection of implants. Here, we review basic aspects of the electrical properties and electrical stimulation of bone, as well as fundamental concepts of aqueous corrosion and its electrical and clinical implications. PMID- 21555776 TI - Improving fatigue damage resistance of alumina through surface grading. AB - Porcelain-veneered alumina crown restorations often fail from bulk fracture resulting from radial cracks that initiate at the cementation surface with repeated flexure of the stiffer crown layers on the soft dentin support. We hypothesized that bulk fracture may be substantially mitigated by grading the elastic modulus at the crown surfaces. In this study, we fabricated graded structures by infiltrating glass into dense alumina plates, resulting in a diminished modulus at the surface layers. The plates were then bonded to polycarbonate substrates and subjected to fatigue loading in water. Tests were terminated when fracture occurred at the cementation tensile surface or at the fatigue endurance limit (1 million cycles). Infiltrated specimens showed a significant increase in fatigue fracture loads over non-infiltrated controls. Our results indicate that controlled elastic gradients at the surface could be highly beneficial in the design of fracture-resistant alumina crowns. PMID- 21555777 TI - Ear, nose, and throat manifestations during pregnancy. AB - OBJECTIVE: The objective of this clinical review is to highlight the otolaryngological symptoms that occur in pregnancy. Where available, the authors discuss the current evidence of the etiology and management of the various presentations. While it is appreciated that many of these complaints are transient, their impact on the maternal quality of life can be significant, and therefore, medical practitioners should be aware of what to expect in order to provide reassurance to patients and also to safely manage such symptoms. DATA SOURCES: MEDLINE and EMBASE databases were searched for publications related to otolaryngology and pregnancy. REVIEW METHODS: All literature was searched for and reviewed by 2 authors independently. Search results were then cross-examined, and any differences were settled by consensus. RESULTS: Pregnancy leads to circulatory changes and increased susceptibility to viral reactivation, and along with the exertion of parturition, it can lead to tinnitus, facial palsies, and deafness. Rising levels of sex hormones and heightened sensitivity to allergens may influence the nasal mucosa, precipitating epistaxis and rhinitis. Increased progesterone and the increased intra-abdominal pressure of the growing fetus can lead to symptoms and sequelae of laryngopharyngeal reflux. Evidence for the treatment of pregnancy-induced symptoms is principally restricted to case reports and retrospective studies. CONCLUSION: Recognition and understanding of pregnancy related ear, nose, and throat complaints will allow otolaryngologists to reassure and manage these patients, improving their experience of the gestational period. High-quality evidence for their management is limited, with further research required. PMID- 21555778 TI - Treatment of pediatric status migrainosus: can we prevent the "bounce back"? AB - The impact of treatment given upon discharge on the "bounce back" rate was ascertained in children presenting at the emergency department for treatment of status migrainosus. All children ages 8 to 17 years old presenting to an emergency department in 2008 who were treated for status migrainosus and discharged home were included. Of the total of 187 patients, 21 patients (11.2%) bounced back. Treatment given was not associated with the bounce back rate. The only factors reaching significance were the presence of a migraine equivalent in 28.6% of patients who bounced back as compared with only 6.7% in patients without recurrence (P = .006); brain imaging study in the emergency department (52.4% vs. 16.9%, P = .001); and an arranged physician follow-up (66.6% vs. 36.3%, P = .01). The results appear to suggest that no current treatment given to children presenting to the emergency department with status migrainosus seems to alter the immediate recurrence rate. PMID- 21555779 TI - Behavior therapy for tics in children: acute and long-term effects on psychiatric and psychosocial functioning. AB - Children (n = 126) ages 9 to 17 years with chronic tic or Tourette disorder were randomly assigned to receive either behavior therapy or a control treatment over 10 weeks. This study examined acute effects of behavior therapy on secondary psychiatric symptoms and psychosocial functioning and long-term effects on these measures for behavior therapy responders only. Baseline and end point assessments conducted by a masked independent evaluator assessed several secondary psychiatric symptoms and measures of psychosocial functioning. Responders to behavior therapy at the end of the acute phase were reassessed at 3-month and 6 month follow-up. Children in the behavior therapy and control conditions did not differentially improve on secondary psychiatric or psychosocial outcome measures at the end of the acute phase. At 6-month posttreatment, positive response to behavior therapy was associated with decreased anxiety, disruptive behavior, and family strain and improved social functioning. Behavior therapy is a tic-specific treatment for children with tic disorders. PMID- 21555780 TI - Solitary tumefactive demyelinating lesions in children. AB - Solitary tumefactive demyelination is rare in children, and the diagnosis is often conferred after brain biopsy. The authors report 3 children with solitary tumefactive demyelination and provide clinical and paraclinical clues to aid the clinician in reaching a diagnosis using a noninvasive approach. PMID- 21555783 TI - MicroRNAs and glial cell development. AB - Mounting evidence indicates that microRNAs (miRNAs) play important roles in the control of glial cell development in the central nervous system. Suppression of miRNA formation disrupts the initial generation of oligodendrocyte progenitor cells from the ventricular neuroprogenitor cells in the embryonic spinal cord. miRNAs also regulate the later events of oligodendrocyte development, including cell proliferation, maturation, and myelin formation. In addition, miRNAs are essential for the development of astrocytes, and inhibition of miRNA genesis completely blocks astrogliogenesis in the spinal cord. PMID- 21555784 TI - Breast feeding and child behaviour in the Millennium Cohort Study. AB - OBJECTIVE: To examine whether breast feeding is associated with behavioural development in children aged 5 years. DESIGN: The authors used data from a large, prospective, nationally representative UK cohort, the Millennium Cohort Study. PARTICIPANTS: 10 037 mother-child pairs from white ethnic background (9525 term and 512 preterm children) were included in the analyses. METHODS: Duration of breast feeding (at all or exclusively) was ascertained from parental interview at study baseline, when the children were aged 9 months. Child behaviour was assessed using a parent-completed questionnaire, the Strengths and Difficulties Questionnaire (SDQ). The authors used logistic regression to investigate the associations of breastfeeding duration with abnormal parent-rated SDQ total and subscores at age 5 in term and preterm children separately. RESULTS: Abnormal SDQ scores were less common in term children (n=1129/9525, 12%) than pre-term (n=78/512, 15%) children. Term children breast fed for 4 months or longer (n=2741/9525, 29%) had lower odds of an abnormal total SDQ score (multivariable adjusted OR compared with never breastfed children (n=3292/9525, 35%) 0.67, 95% CI: 0.54 to 0.83). This effect was similar for all the SDQ subscores. In preterm children, longer duration of breast feeding was generally associated with lower odds of abnormal SDQ total and subscores but the effect estimates were imprecise. The associations between exclusive breast feeding and abnormal SDQ scores were similar to those of any breast feeding and abnormal SDQ scores. CONCLUSIONS: The findings suggest that, at least in term children, longer duration of breast feeding is associated with fewer parent-rated behavioural problems in children aged 5 years. PMID- 21555786 TI - To work or not to work: motivation (not low IQ) determines symptom validity test findings. AB - Social Security Disability Determinations Service (DDS) claimants are seeking compensation for an inability to work (Chafetz, 2010). These usually low functioning claimants fail Symptom Validity Tests (SVTs) at high rates (Chafetz, 2008), typically over 40%. In contrast, claimants for the Rehabilitation Service in Louisiana (LRS) are seeking to work. Individuals referred by the Department of Child and Family Services (DCFS) are seeking reunification with their children. All three groups consisted of equivalently low-IQ claimants when considering only those who passed SVTs. Only the DDS group failed SVTs at high rates, whereas LRS claimants failed at minimal rates and DCFS claimants did not fail. Thus, intrinsic motivation explains effort in this particular study of low-functioning claimants: those seeking to work or to look good to reunify with their children pass SVTs at high rates. PMID- 21555785 TI - Mechanism of amylin fibrillization enhancement by heparin. AB - We characterized the interaction of amylin with heparin fragments of defined length, which model the glycosaminoglycan chains associated with amyloid deposits found in type 2 diabetes. Binding of heparin fragments to the positively charged N-terminal half of monomeric amylin depends on the concentration of negatively charged saccharides but is independent of oligosaccharide length. By contrast, amylin fibrillogenesis has a sigmoidal dependence on heparin fragment length, with an enhancement observed for oligosaccharides longer than four monomers and a leveling off of effects beyond 12 monomers. The length dependence suggests that the negatively charged helical structure of heparin electrostatically complements the positively charged surface of the fibrillar amylin cross-beta structure. Fluorescence resonance energy transfer and total internal reflection fluorescence microscopy experiments indicate that heparin associates with amylin fibrils, rather than enhancing fibrillogenesis catalytically. Short heparin fragments containing two- or eight-saccharide monomers protect against amylin cytotoxicity toward a MIN6 mouse cell model of pancreatic beta-cells. PMID- 21555787 TI - Test-retest reliability and practice effect of the oral-format Symbol Digit Modalities Test in patients with stroke. AB - The Symbol Digit Modalities Test (SDMT) is commonly used to evaluate an individual's switching attention and processing speed. However, its test-retest reliability and practice effect are not well known in patients with stroke, limiting its utility in both clinical and research settings. The present study examined the two aforementioned psychometric properties of the oral-format SDMT on a group of 30 outpatients with stroke. The oral-format SDMT demonstrated excellent test-retest reliability (ICC = 0.89) and a small practice effect (Cohen's d = 0.26) within a 1-week interval. A practice effect-corrected reliable change index [-5.29, 10.89] was also provided to help clinicians and researchers interpret their clients' test results. Patients' characteristics and the test retest interval should be considered before applying the findings of the present study to clinical settings. PMID- 21555788 TI - Efficient cloning of alternatively polyadenylated transcripts via hybridization capture PCR. AB - Cloning of alternatively polyadenylated transcripts is crucial for studying gene expression and function. Recent transcriptome analysis has mainly focused on large EST clone collections. However, EST sequencing techniques in many cases are incapable of isolating rare transcripts or address transcript variability. In most cases, 3' RACE is applied for the experimental identification of alternatively polyadenylated transcripts. However, its application may result in nonspecific amplification and false positive products due to the usage of a single gene specific primer. Additionally, internal poly(A) stretches primed by oligo(dT) primer in mRNAs with AU-rich 3'UTR may generate truncated cDNAs. To overcome these limitations, we have developed a simple and rapid approach combining SMART technology for the construction of a full length cDNA library and hybrid capture PCR for the selection and amplification of target cDNAs. Our strategy is characterized by enhanced specificity compared to other conventional RT-PCR and 3' RACE procedures. PMID- 21555789 TI - Mitochondrial compartmentalized protein folding and tumor cell survival. AB - Molecular chaperones are master regulators of protein folding quality control, and it is widely accepted that these functions are aberrantly exploited in human tumors. What has also emerged in recent years is that chaperone control of protein folding does not occur randomly in cells, but is spatially compartmentalized in subcellular organelles and specialized microenvironments. Fresh experimental evidence has now uncovered a role for mitochondrial localized chaperones to oversee the protein folding environment within the organelle, selectively in tumor cells. Perturbation of this compartmentalized chaperone network triggers an array of compensatory responses that aims at restoring homeostasis, while also providing novel opportunities for rational cancer therapy. PMID- 21555790 TI - Behavioral response to pain in drowsy and sleeping neonates: a randomized control study. AB - In a randomized controlled design, 100 healthy, term neonates in the first week of life, undergoing heel prick for routine screening were randomized to receive a heel prick in either the drowsy/sleeping state or the awake (but not fussy or crying) state. 48 babies in sleeping or drowsy states and 47 in the awake states were analyzed. Infants in the drowsy/sleeping states scored significantly lower on the Neonatal Infant Pain Score (NIPS) (median score 5) at 30 seconds post stimulus compared with infants in higher states of alertness (median score 6). They also had a shorter total duration of cry (29.17 sec +/- 8.95 vs 32.67 sec +/ 9.82). However, there was no difference in the NIPS score between the two groups at 45 seconds post stimulus. We concluded that babies in the drowsy/sleeping states of alertness at the time of a painful stimulus appear to show a less intense behavioral response to pain as compared to those in the awake state. PMID- 21555791 TI - Efficacy and safety of azithromycin for uncomplicated typhoid fever: an open label non-comparative study. AB - An open-labelled, non-comparative study was conducted in 117 children aged 2-12 years to evaluate the efficacy and safety of azithromycin (20mg/ kg/day for 6 days) for the treatment of uncomplicated typhoid fever. Of the patients enrolled based on a clinical definition of typhoid fever, 109 (93.1%) completed the study.Mean (SD) of duration of fever at presentation was 9.1(4.5) days. Clinical cure was seen in 102 (93.5%) subjects, while 7 were withdrawn from the study because of clinical deterioration. Mean day of response was 3.45+/-1.97. BACTEC blood culture was positive for Salmonella typhi in 17/109 (15.5%) and all achieved bacteriological cure. No serious adverse event was observed. Global well being assessed by the investigator and subjects was good in 95% cases which was done at the end of the treatment. Azithromycin was found to be safe and efficacious for the management of uncomplicated typhoid fever. PMID- 21555792 TI - Significance of family survey of index case for detection of tuberculosis. AB - Tuberculosis is highly prevalent amongst children in India. Contact survey has not received much attention in the Revised National Tuberculosis Control Program guidelines. This study was conducted to look for tuberculosis in asymptomatic family members of pediatric tuberculosis patients at a government hospital attached to a medical college in Central India. 168 siblings and 162 parents of 86 index cases of tuberculosis were studied. 64 tuberculosis infected siblings and 7 sputum positive parents were identified. PMID- 21555793 TI - Foot length as a marker of pubertal onset. AB - This observational study was conducted on 973 healthy children between 8 and 16 years to evaluate the relation between changes in foot length and pubertal maturation. The right foot length of study children was recorded and SMR staging was done. The difference in mean foot length was statistically significant between SMR 1 and 2 (P<;0.0001). No significant difference in the mean foot lengths was found thereafter. Smoothed standard deviation curves were constructed for foot length as a function of SMR stage using the LMS method. Foot length was found to rise sharply in SMR 2, which coincides with the onset of puberty. PMID- 21555794 TI - Ultrasound profile of hips of South Indian infants. AB - One thousand consecutive infants, 437 girls and 563 boys, attending their first DPT vaccination at a mean age of 48 days underwent ultrasonological screening of the hips by Graf's technique at the immunization clinic of a tertiary hospital in South India. Graf I (mature) hips were seen bilaterally in 925 children. The incidence of Graf type II hips was 74/1000 infants. The incidence of sonographically abnormal hips (II, III and IV) in this population was 7.5%. The hip dislocation rate was 1 in 1000 (0.1%). PMID- 21555795 TI - Benign partial seizures of adolescence. AB - Benign partial seizures of adolescence (BPSA) presents as partial seizures with or without secondary generalization occurring isolated or in a cluster in the first 24 to 48 hours after onset in adolescents. Correct recognition of this entity can avoid use of antiepileptic drugs and associated risks. We conducted retrospective review of charts to identify seven cases of BPSA between 11-15 years at presentation who did not have generalized epilepsy, benign rolandic epilepsy, benign occipital epilepsy, an epileptogenic lesion on neuroimaging, or unprovoked recurrent tonic-clonic seizures. All of them had partial seizures, normal neuroimaging and electroencephalogram with no recurrence of seizures despite no treatment. PMID- 21555796 TI - Prognostic value of plasma pro-adrenomedullin and antithrombin levels in neonatal sepsis. AB - The aim of this study was to clarify the prognostic value of serum pro Adrenomedullin level (pro-ADM) and Anti thrombin level in neonatal sepsis. 40 term neonates with sepsis were enrolled in this study including 20 cases with mild sepsis and 20 cases with severe sepsis. Twenty healthy matched neonates served as a control group. Serum levels of Pro ADM and Antithrombin were measured in all patients and the control group. Serum Pro ADM level was higher in neonates with sepsis than control group, higher in severe than mild sepsis, and was higher in non survivors. Antithrombin concentrations were lower in sepsis cases than control, lower in severe than mild sepsis, and lower in non-survivors. PMID- 21555797 TI - Rescue high frequency oscillation in neonates with acute respiratory failure. AB - The aim was to study the efficacy of rescue High Frequency Oscillatory Ventilation (HFOV) in improving the oxygenation and ventilation in neonates with acute respiratory failure after failing Conventional Mechanical Ventilation (CMV). Primary outcome was short term oxygenation, lung recruitment, and ventilation and secondary outcome studied was survival. 675 babies were ventilated and 97 of them received HFOV. HFOV significantly improved oxygenation index, alveolar-arterial oxygen gradient, pH, PCO2, PO2 and caused better lung recruitment within 2 hours. Fifty seven babies (58.77%) survived and the mortality was more in <28 weeks, babies with pulmonary hemorrhage, sepsis and CDH. PMID- 21555798 TI - Childhood T-lineage acute lymphoblastic leukemia: management and outcome at a tertiary care center in North India. AB - OBJECTIVE: To assess the clinical features, prognostic factors and outcome of childhood T-ALL in comparison with B-lineage ALL, treated with a uniform treatment regimen (MCP 841). SETTING: Pediatric oncology division of a tertiary care institution in Northern India. DESIGN: Retrospective analysis of clinical data and survival outcome. PARTICIPANTS: 60 children with T-ALL and 139 with B- lineage ALL, and less than 15 years of age treated over 15 years. RESULTS: T-ALL was observed in 30%. High risk features at presentation (age >10 years, WBC >50,000/mm3, mediastinal mass, and CNS leukemia) were significantly more frequent in T-ALL as compared to B-lineage ALL (P=0.049, P<0.001, P<0.001 and P=0.02, respectively). Fifty five of 60 T-ALL patients (91.7%) achieved complete remission after induction therapy. There were 3 induction and 10 remission deaths while 11 (18.3%) relapsed. The overall survival and event-free survival of T-lineage ALL (61.5+/-7.6 and 49.9+/-7.4, respectively) were similar to that of B lineage patients (68.7+/-4.7 and 47.1+/-5.1, respectively). National Cancer Institute risk groups emerged as significant prognostic factor for event free survival only in B-lineage patients. CONCLUSIONS: Even though high risk features were significantly more frequent in T-ALL, survival outcome was similar to that of B-lineage patients. None of the routinely described prognostic parameters significantly impacted survival. PMID- 21555799 TI - Clinical Pulmonary Infection Score to diagnose ventilator-associated pneumonia in children. AB - BACKGROUND: There is a need to validate and suggest easy clinical method for diagnosis of ventilator-associated pneumonia (VAP) in developing countries. OBJECTIVES: To validate the use of simplified Clinical Pulmonary Infection Score (CPIS) for the diagnosis of VAP. DESIGN: Prospective study. SETTING: Pediatric intensive care unit of a tertiary care teaching hospital. SUBJECTS: 30 children receiving mechanical ventilation for more than 48 hours and with simplified CPIS=6. METHODS: All patients underwent flexible bronchoscopy to obtain bronchoalveolar lavage which was analyzed quantitatively. Colony count = 10(4) cfu/mL was considered reference standard for definite VAP. RESULTS: Of the five variables used for simplified CPIS, only patients temperature (P=0.013) and PaO2/FiO2 ratio were significant (P<0.001) to differentiate the presence of definite VAP. Patients with definite VAP (BAL colony count = 10(4) cfu/mL) had CPIS of 8.4 while in no definite VAP group it was 6.4 (P=0.007). CPIS of 8 was found to have sensitivity of 80%, specificity 80%, PPV 86.9%, NPV 70.5% and accuracy 80%. The area under Receiver operating characteristic curve of CPIS against reference standard was 0.81+/- 0.069 (P=0.001). CONCLUSION: Simplified CPIS is useful in patients on mechanical ventilation to diagnose ventilator associated pneumonia. PMID- 21555800 TI - Waist circumference and waist for height percentiles in urban South Indian children aged 3-16 years. AB - OBJECTIVES: To develop age and gender specific waist circumference references for urban Indian children aged 3 -16 years. DESIGN: Cross-sectional study. SETTING: Urban preschools and schools of Bangalore. PARTICIPANTS: 9060 children (5172 boys and 3888 girls) in the age group of 3-16 years. METHODS: Weight, height, and waist circumference were measured using standard anthropometric methodology. Percentiles for waist circumference and Waist/height ratio (W/Ht) for each age and gender were constructed and smoothed using the LMS method. RESULTS: Mean waist circumference increased with age for both girls and boys. The upper end of curve in boys continued to increase, whereas in the girls it tended to plateau at 14 years. The waist circumference of the Indian children from the present study was higher than age and sex matched European children. The proportion of children with W/Ht ratio greater than 0.5 decreased as their age increased. CONCLUSIONS: These curves represent the first waist and waist height ratio percentiles for Indian children and could be used as reference values for urban Indian children. We suggest that for a start, the 75th percentile of waist circumference from this study be used as an action point for Indian children to identify obesity (as a tautological argument), while retaining the cut-off of 0.5 for the W/Ht ratio; however this underlines the need to derive biologically rational cut-offs that would relate to different levels of risk for adult cardiovascular disease. PMID- 21555801 TI - Effectiveness of Muskaan Ek Abhiyan (the smile campaign) for strengthening routine immunization in bihar, India. AB - BACKGROUND: In Bihar State, proportion of fully immunized children was only 19% ;in Coverage Evaluation Survey of 2005. In October 2007, a special campaign called Muskaan Ek Abhiyan (The Smile Campaign) was launched under National Rural Health Mission to give a fillip to the immunization program. OBJECTIVES: To evaluate improvement in the performance and coverage of the Routine Immunization Program consequent to the launch of Muskaan Ek Abhiyan INTERVENTION: The main strategies of the Muskaan campaign were reviewing and strengthening immunization micro-plans, enhanced inter-sectoral coordination between the Departments of Health, and Women and Child Development, increased involvement of women groups in awareness generation, enhanced political commitment and budgetary support, strengthening of monitoring and supervision mechanisms, and provision of performance based incentive to service providers. METHODS: Immunization Coverage Evaluation Surveys conducted in various states of India during 2005 and 2009 were used for evaluation of the effect of Muskaan campaign by measuring the increase in immunization coverage in Bihar in comparison to other Empowered Action Group (EAG) states using the difference-in-difference method. Interviews of the key stakeholders were also done to substantiate the findings. RESULTS: The proportion of fully immunized 12-23 month old children in Bihar has increased significantly from 19% ;in 2005 to 49% ;in 2009. The coverage of BCG also increased significantly from 52.8% to 82.3%, DPT-3 from 36.5 to 59.3%, OPV-3 from 27.1% ;to 61.6% ;and measles from 28.4 to 58.2%. In comparison to other states, the coverage of fully immunized children increased significantly from 16 to 26% ;in Bihar. CONCLUSIONS: There was a marked improvement in immunization coverage after the launch of the Campaign in Bihar. Therefore, best practices of the Campaign may be replicated in other areas where full immunization coverage is low. PMID- 21555802 TI - Profile of HIV infected children from Delhi and their response to antiretroviral treatment. AB - OBJECTIVES: (i) To study the clinical and immunological profile of HIV infected children attending the ART centre; (ii) To correlate CD4 count with clinical staging at diagnosis; and, iii) To study the clinical and immunological response to antiretroviral treatment. SETTING: Antiretroviral therapy (ART) centres of two tertiary care hospitals of Delhi. PATIENTS: 100 children attending the centres between December 2008 to June 2009. METHODS: The clinical features, immunological profile (CD4 count) and response to ART were recorded in a structured proforma. DESIGN: Prospective follow-up. RESULTS: Average age of enrolled children was 6.24 y (range 1-14 years) and mode of transmission was parent to child in 92%. Most common clinical presentation was fever (83%), cough (50.8%) and diarrhea (38.9%). Tuberculosis was the most common opportunistic infection seen in 11% of children. 59% of enrolled children were malnourished. Antiretroviral treatment (ART) was initiated in 33 children. Children who were initiated on ART had a significant improvement in both clinical and immunological staging at the 6 months follow up. Immunological response (rise in CD4 count) to ART was better in children with lesser degree of immunosuppression. The measure of agreement between the clinical and immunological stage at presentation was poor. CONCLUSIONS: Baseline CD4 counts rather than clinical staging can be a primary determinant for initiation of antiretroviral treatment in HIV infected children. PMID- 21555803 TI - Validation of IMNCI algorithm for young infants (0-2 months) in India. AB - OBJECTIVE: To check the validity of Integrated Management of Neonatal and Childhood Illness (IMNCI) algorithm for young infants (0-2 months). DESIGN: Prospective observational study. SETTING: The outpatient department and emergency room of a medical college attached hospital. METHODS: 419 infants (176 between 0 7 days, 243 between 7 days to 2 months) underwent a detailed diagnostic assessment and treatment as per the standard protocol of treating unit. These infants also underwent assessment, classification and identification of treatment as per IMNCI algorithm. The diagnostic and therapeutic agreement between standard protocol and IMNCI was computed to assess the validity of IMNCI algorithm. RESULTS: The IMNCI algorithm performed well in identifying sick young infants with sensitivity of 97%, 94% and 95%, and specificity of 85%, 87% and 87% in 0 7 days, 7 days to 2 months and 0-2 months age groups, respectively. The algorithm covered majority (80%) of recorded diagnoses, and could identify bacterial infection with 88.5% sensitivity and 57.4% specificity. Complete diagnostic agreement with gold standard was seen in 50%; overdiagnosis and under diagnosis was seen in 13% and 19%, respectively. Low birthweight and upper respiratory infection were the main reasons for overdiagnosis whereas surgical conditions resulted in under diagnoses in majority. CONCLUSION: IMNCI algorithm for evaluation and management of young infants has good sensitivity and specificity for referring cases with severe illness. PMID- 21555804 TI - Characteristics of radiographically diagnosed pneumonia in under-5 children in Salvador, Brazil. AB - OBJECTIVE: To assess the association of demographic and clinical aspects with radiographically diagnosed pneumonia. DESIGN: By active surveillance, the admitted pneumonia cases by the pediatrician on duty were identified in a 2 year period. Demographic, clinical and radiographic data were registered into standardized forms. SETTING: A public university pediatric hospital in Salvador, Northeast Brazil. PATIENTS: Children <5 years-old. MAIN OUTCOME MEASURES: Radiographically diagnosed pneumonia based on detection of pulmonary infiltrate/ consolidation. RESULTS: 301 cases had the chest X-ray evaluated by a pediatric radiologist blinded to clinical information, among whom pulmonary infiltrate and consolidation were described in 161 (54%) and 119 (40%), respectively. Chest X ray was read normal for 140 cases. Overall, the median age was 17 months (mean 20+/-14, range 12 days-59 months). Pulmonary infiltrate was less frequently described among patients aged under 1 year (41.3% vs 59.9%, P=0.002, OR [95% CI] = 0.47 [0.29-0.76]) and hyperinflation was significantly more frequent in this age group (27.9% vs 4.1%, P<0.001, OR [95% CI] = 9.14 [4.0-20.9]). By multiple logistic regression, fever on admission was independently associated with pulmonary infiltrate (OR [95% CI] = 1.68 [1.03-2.73]) or consolidation (1.79 [1.10-2.92]), wheezing was independently associated with absence of pulmonary infiltrate (0.53 [0.33-0.86]) or of consolidation (0.53 [0.33-0.87]). The positive likelihood ratio of fever on examination for pulmonary infiltrate and consolidation was 1.49 (95% CI:1.11-1.98) and 1.49 (95% CI: 1.14-1.94), respectively. CONCLUSION: Presence of fever enhanced 2.5 times the chance of children hospitalized with lower respiratory tract disease to have radiographically diagnosed pneumonia. PMID- 21555805 TI - Pattern of growth faltering and recovery in under 5 children in India using WHO growth standards--a study on First and Third National Family Health Survey. AB - OBJECTIVE: To examine the pattern of growth faltering in preschool children, using World Health Organization (WHO) growth standards 2006 from the available datasets of first and third National Family Health Survey (NFHS 1 and 3). DESIGN: Data-analysis of two large-scale cross-sectional surveys done at a gap of 15 years. SETTING: General community. SUBJECTS: Preschool children included in NFHS 1 (n = 37,768) and NFHS 3 (n = 41,306). MAIN OUTCOME MEASURES: Weight for age Z scores (WAZ), height for age Z scores (HAZ) and weight for height Z scores (WHZ) based on WHO growth standards for the first four years of life. RESULTS: Mean WAZ score at 0 month during first and third surveys were -1.15 (n=268) and -0.76 (n=184), respectively. Of the total growth faltering in weight for age Z (WAZ) score by the end of third year, 55% and 44% of the growth faltering was already present at birth for the first and third survey, respectively. There was no change in weight for height Z (WHZ) score for the first three years during both the surveys. CONCLUSIONS: A good part of the total growth faltering in India has already taken place at birth. Much of the growth faltering in early life can be attributed to faltering in HAZ scores or stunting. Understanding the causal role of stunting and its prevention as well as improving birth weight appears to be the key for better efficacy of public health programs in preventing under-5 malnutrition in India. PMID- 21555806 TI - Serum Nevirapine and Efavirenz concentrations and effect of concomitant rifampicin in HIV infected children on antiretroviral therapy. AB - OBJECTIVE: To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. METHODS: A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. RESULTS: Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9+/-59.8 mg/m2/day (on simultaneous rifampicin) and 309.2+/-54.6 mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9+/-1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. CONCLUSION: Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine is increased by 20-30%. Formulation of drugs does not alter the blood levels provided drug administered is in the recommended dose. PMID- 21555807 TI - Rickettsial diseases in central India: proposed clinical scoring system for early detection of spotted fever. AB - OBJECTIVES: To report a series of cases of rickettsial infections from central India and to develop a clinical scoring system for its early detection. DESIGN: Retrospective review of children hospitalized during one year period with fever without a source, and presence of one or more of the clinical features suggestive of rickettsial infection. Diagnosis of rickettsial disease was made by classical clinical features and detection of IgM antibody by ELISA. A clinical scoring system was developed to diagnose spotted fever group by using classical clinical and laboratory findings. RESULTS: 161 patients were admitted and met the inclusion criteria, 75 (45.6%) were diagnosed with rickettsial diseases. 52 (69.3%) had spotted fever group and 23 (30.7%) scrub typhus. The mortality rate with rickettsial diseases was 9%. By using proposed clinical scoring system, a score of 14 has sensitivity and specificity of 96.15% and 98.84%, respectively in making a diagnosis of spotted fever group. CONCLUSION: Rickettsial diseases are common in the central part of India and should be included in the differential diagnosis of patients with fever of undetermined source. The proposed scoring system can be used for early detection, treatment and prevention of mortality and morbidity from spotted fever group. PMID- 21555808 TI - Determinants of vitamin A deficiency amongst children in Aligarh District, Uttar Pradesh. AB - OBJECTIVES: To determine the prevalence and determinants of xerophthalmia among children aged 0-60 months . METHODS: This cross-sectional study included 3571 children under 5 years of age from six villages and four periurban areas. Children with xerophthalmia were identified and severity graded using the WHO classification. The main outcome measures were socio-demographic, nutritional and comorbidity related risk factors of xerophthalmia. A pretested questionnaire carrying information on the above factors was administered to the caregivers. Univariate and multivariate binary logistic regression analyses were performed to examine the association of each of these factors with xerophthalmia. RESULTS: The overall prevalence of xerophthalmia was of serious public health importance at 9.1%. Prevalence of both mild (night blindness, and Bitots spots) and severe forms (corneal changes) of xerophthalmia increased with age. Bitots spots and night blindness were the commonest manifestations. Rural dwelling, lower social class, maternal illiteracy and occupation outside home were significant antecedent socio-demographic risk factors on univariate analysis. Multivariate analysis revealed low intake of proteins and vitamin A containing foods as well as predominant maize diet to be significant dietary factors. Nutritional wasting and a preceding history of measles were significant comorbid determinants (P<0.05). None of the socio-demographic variables emerged significant on multivariate analysis. CONCLUSIONS: Vitamin A deficiency remains a significant public health problem in Aligarh district. The proximal factors in a child's milieu viz nutrition and comorbidities were more significantly associated with xerophthalmia than the distal socio-demographic factors, thereby making a case for their cost effective prevention. The high magnitude of the problem calls for intensification of existing prophylactic measures in these areas. PMID- 21555809 TI - Echocardiographic parameters of patent ductus arteriosus in preterm infants. AB - OBJECTIVE: To analyze cardiovascular parameters by echocardiography in preterm infants with patent ductus arteriosus (PDA). SETTING: Tertiary-care pediatric university hospital. DESIGN: Cross-sectional, hospital-based study. PARTICIPANTS: 58 preterm infants, gestational age less than 33 weeks. MEASUREMENTS: A complete 2-dimension, M-mode, color doppler echocardiography was performed in each preterm infant at approximately 48 hours of life. RESULTS: Each preterm was categorized into hemodynamically significant PDA (hsPDA) (n=17, 29.3%), non-hemodynamically significant PDA (non-hsPDA) (n = 12, 20.7%), and no PDA (non-PDA) (n=29, 50%). Gestational age (29.4 +/- 1.2 wk) and birth weight (1237 +/- 358 g) of infants in hsPDA were significantly lower than those in non-PDA group (30.8 +/- 1.3 wk, 1543 +/- 361 g, P = 0.001), as compared to those in the non-hsPDA group (29.5 +/- 2.3 wk, 1296 +/- 462 g). Cardiovascular parameters including left atrium/aorta ratio, left atrium volume index, left ventricular dimensions and volumes, stroke volume, and cardiac output in hsPDA were significantly greater than those in non-hsPDA and nonPDA. LV systolic and diastolic functions were not significantly different in each group. LV global function in hsPDA (0.34 +/- 0.13) was significantly lower than that in non-PDA (0.45 +/- 0.13, P = 0.01). CONCLUSIONS: In preterm infants with hsPDA, there was a volume load of the left heart causing increased stroke volume and cardiac output. The hsPDA could be detected by echocardiography even in the first 48 hours. The left atrial volume index may be a better indicator of the volume load of the heart. PMID- 21555810 TI - Is there a need for liver disease monitoring in HIV patients in Africa? AB - Liver disease is one of the leading causes of death in HIV-infected individuals from Europe and North America and has been attributed mainly to coinfection with hepatotropic viruses. Little data, however, has so far become available on liver disease in HIV-infected individuals from Africa. Results from a first study on liver disease staging by Fibroscan((r)) in a large group of HIV-infected patients from rural Uganda suggest unexpectedly high rates of advanced fibrosis. These results were independent from hepatitis status, initiating a discussion on the need for future liver disease monitoring in these particular patient groups. PMID- 21555811 TI - Evidence of a significant role for Fas-mediated apoptosis in HCV clearance during pegylated interferon plus ribavirin combination therapy. AB - BACKGROUND: The role of apoptosis in treatment-induced HCV clearance is controversial. We sought to assess the kinetics of serum apoptosis-related cytokines during pegylated interferon-alpha2a or -alpha2b plus weight-based ribavirin therapy for genotype 1 chronic HCV infection. METHODS: Serum levels of soluble Fas (sFas), soluble Fas ligand (sFasL) and soluble tumour necrosis factor receptor I (sTNF-RI) were measured at baseline, week 12 and 24 weeks after the end of therapy. RESULTS: Sustained virological response (SVR) was achieved in 46% of the 164 included patients, 29% had a non-response (NR) and 25% had relapse (RR). NR patients presented with higher levels of sFasL at baseline and lower levels of sTNF-RI at week 12 as compared to RR and SVR patients. Lower concentrations of sFas were observed in SVR patients 24 weeks after treatment as compared to RR and NR patients. An increase in sFas at week 12 followed by a significant drop 24 weeks after therapy was observed among SVR patients. An increase in sFasL during and after treatment was observed in RR and SVR patients. NR patients exhibited an earlier drop in sTNF-RI levels as compared to RR and SVR patients. CONCLUSIONS: Virological response during HCV therapy was associated with an increase of sFas and sFasL, and maintenance of increased concentrations of sTNF-RI. PMID- 21555812 TI - Two patterns of alanine aminotransferase increase to predict long-term viral response in chronic hepatitis B patients: virus- or host-induced? AB - BACKGROUND: Serum alanine aminotransferase (ALT) increase is a well-known phenomenon during interferon treatment for chronic hepatitis B. However, little is known about these increases during nucleoside/nucleotide treatment and the effects on long-term clinical outcomes. METHODS: A total of 170 treatment-naive hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients were treated with a nucleoside/nucleotide analogue for at least 2 years and followed up for 1 more year post-treatment. Clinical characteristics were detected and analysed at baseline and at every 3-month interval. RESULTS: Two patterns of ALT increase, virus- and host-induced, were detected. Virus-induced increases were characterized by a rapid increase in serum ALT and HBV DNA typically after 2 years of treatment, and were more common than host-induced ALT increases (15.9% versus 6.5%; P<0.05) with a median ALT increase of 5.7-fold the upper limit of normal (ULN). Host-induced ALT increases were characterized by moderately increased ALT (median 2.5-fold ULN) with a slow decrease in HBV DNA that occurred mainly in the first year of treatment (63.6%). Most importantly, host-induced increases were associated with favourable long-term treatment outcomes in HBV DNA undetectable rate (82% versus 0%), HBeAg seroconversion (82% versus 7%) and histological improvement. Moreover, interferon-gamma-expressing T-helper cells were increased in patients with host-induced ALT increases. CONCLUSIONS: Two patterns of ALT increases may occur during nucleoside/nucleotide analogue treatment. Host induced ALT increases, accompanied by decreased HBV DNA, lead to better long-term clinical outcomes. PMID- 21555813 TI - Inhibition of respiratory syncytial virus in vitro and in vivo by the immunosuppressive agent leflunomide. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis and pneumonia in infants and young children worldwide and is often the cause of infections in bone marrow, solid organ transplant, cystic fibrosis and congenital heart disease patients, as well as respiratory tract disease in elderly adults. Treatment options are limited to ribavirin, which is only marginally effective, and passive immunoprophylaxis, which is very expensive. The immunosuppressive agent leflunomide has been shown to exert potent antiviral activity against several herpesviruses and polyomavirus BK. In the current study we have tested the hypothesis that leflunomide exerts antiviral activity against RSV. METHODS: Human Hep-2 or small airway epithelial cells were inoculated with RSV and treated with A77 1726, the active metabolite of leflunomide. Syncytia formation was assessed by immunohistochemical staining, and virus yield was measured by plaque assay. Cotton rats were intranasally inoculated with RSV, treated with leflunomide by gavage, and pulmonary viral loads were measured by plaque assay of lung homogenates. RESULTS: Phase contrast microscopy and immunohistochemical staining demonstrated profound attenuation of RSV-induced syncytia formation in infected cultures treated with A77 1726, the active metabolite of leflunomide. Plaque assays of virus yield in RSV-inoculated cell cultures demonstrated potent, dose-dependent A77-mediated antiviral activity. Likewise, pulmonary viral loads in RSV-inoculated cotton rats were reduced by >3 log by leflunomide compared with vehicle-treated controls, even when leflunomide treatment was delayed until day 3 post-inoculation. CONCLUSIONS: These findings suggest promise for leflunomide as a convenient, orally administered addition to the growing arsenal of antiviral therapeutics. While specific antiviral mechanisms remain to be elucidated, leflunomide shows unique bifunctional potential to both reduce viral load and, by virtue of its well-documented anti inflammatory activity, attenuate the destructive inflammation associated with RSV disease. PMID- 21555814 TI - Mutations in gp41 are correlated with coreceptor tropism but do not improve prediction methods substantially. AB - BACKGROUND: The main determinants of HIV-1 coreceptor usage are located in the V3 loop of gp120, although mutations in V2 and gp41 are also known. Incorporation of V2 is known to improve prediction algorithms; however, this has not been confirmed for gp41 mutations. METHODS: Samples with V3 and gp41 genotypes and Trofile assay (Monogram Biosciences, South San Francisco, CA, USA) results were taken from the HOMER cohort (n=444) and from patients screened for the MOTIVATE studies (n=1,916; 859 with maraviroc outcome data). Correlations of mutations with tropism were assessed using Fisher's exact test and prediction models trained using support vector machines. Models were validated by cross-validation, by testing models from one dataset on the other, and by analysing virological outcome. RESULTS: Several mutations within gp41 were highly significant for CXCR4 usage; most strikingly an insertion occurring in 7.7% of HOMER-R5 and 46.3% of HOMER-X4 samples (MOTIVATE 5.7% and 25.2%, respectively). Models trained on gp41 sequence alone achieved relatively high areas under the receiver-operating characteristic curve (AUCs; HOMER 0.713 and MOTIVATE 0.736) that were almost as good as V3 models (0.773 and 0.884, respectively). However, combining the two regions improved predictions only marginally (0.813 and 0.902, respectively). Similar results were found when models were trained on HOMER and validated on MOTIVATE or vice versa. The difference in median log viral load decrease at week 24 between patients with R5 and X4 virus was 1.65 (HOMER 2.45 and MOTIVATE 0.79) for V3 models, 1.59 for gp41-models (2.42 and 0.83, respectively) and 1.58 for the combined predictor (2.44 and 0.86, respectively). CONCLUSIONS: Several mutations within gp41 showed strong correlation with tropism in two independent datasets. However, incorporating gp41 mutations into prediction models is not mandatory because they do not improve substantially on models trained on V3 sequences alone. PMID- 21555815 TI - Haemoglobin and anaemia in the SMART study. AB - BACKGROUND: Data from randomized trials on the development of anaemia after interruption of therapy are not well-described. METHODS: A total of 2,248 patients from the SMART study were included. We used Cox proportional hazards models to investigate development of new (<=12 mg/dl for females and <=14 mg/dl for males) or worsening (<=8 mg/dl if anaemic at randomization) anaemia and Poisson regression analyses to explore the relationship between anaemia and the development of AIDS, death or non-AIDS events. RESULTS: Overall, 759 patients developed new or worsening anaemia: 420/1,106 (38.0%) in the drug conservation (DC) arm and 339/1127 (30.1%) in the viral suppression (VS) arm (P<0.0001). At 4 months after randomization, patients in the DC arm had a significantly increased risk of developing new or worsening anaemia (adjusted relative hazard 1.56, 95% CI 1.28-1.89). Currently anaemic patients had an increased incidence of AIDS (adjusted incidence rate ratio [IRR] 2.31, 95% CI 1.34-3.98), death (adjusted IRR 2.19, 95% CI 1.23-3.87) and non-AIDS events (adjusted IRR 2.98, 95% CI 2.01-4.40) compared to non-anaemic patients. CONCLUSIONS: Patients who interrupted combination antiretroviral therapy had a higher risk of new or worsening anaemia. Anaemic patients had a higher incidence of AIDS, non-AIDS defining events or deaths, possibly due to deteriorating health and subclinical disease. PMID- 21555816 TI - Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial. AB - BACKGROUND: Selection of first-line antiretroviral therapy requires consideration of efficacy as well as effects on lipids given the increased concern about cardiovascular risk in HIV-1 patients. METHODS: ARTEN is a randomized, open label, non-inferiority trial that compares nevirapine (NVP) 200 mg twice daily or 400 mg once daily to atazanavir/ritonavir (ATZ/r) 300 mg/100 mg once daily, each combined with fixed-dose tenofovir disoproxil fumarate (TDF) 300 mg/emtricitabine (FTC) 200 mg once daily, in antiretroviral-naive HIV-1 patients with CD4(+) T cell counts <400 (men) and <250 cells/mm(3) (women). The primary end point was plasma HIV RNA<50 copies/ml at two consecutive visits prior to week 48. RESULTS: A total of 569 patients were randomized and treated. Overall, 66.8% of NVP and 65.3% of ATZ/r patients achieved the primary end point (difference 1.9%, 95% CI 5.9-9.8%). Similar rates of serious adverse events were observed (9.6% on NVP versus 8.8% on ATZ/r), although discontinuations due to adverse events were more frequent with NVP than ATZ/r (13.6% versus 3.6%, respectively). None of the 28 patients virologically failing ATZ/r selected resistance mutations, while they were selected in 29/44 patients virologically failing NVP. NVP induced a significantly greater increase in high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A1 from baseline than ATZ/r, whereas triglycerides increased significantly more with ATZ/r than NVP. Mean change from baseline in TC:HDL-c ratio was -0.24 for NVP and 0.13 for ATZ/r (P=0.0001). CONCLUSIONS: NVP demonstrated at week 48 non-inferior antiviral efficacy compared with ATZ/r when given along with TDF/FTC, despite more drug-related discontinuations with NVP than ATZ/r. NVP was associated with a lower atherogenic lipid profile than ATZ/r although resistance mutations were more frequently selected with NVP than ATZ/r. PMID- 21555817 TI - Maternal outcomes after HAART for the prevention of mother-to-child transmission in HIV-infected women in Brazil. AB - BACKGROUND: Information is lacking on outcomes in HIV-infected Brazilian women with CD4(+) T-cell counts >200 cells/mm(3) who initiate HAART for the prevention of mother-to-child transmission, and discontinue after delivery. METHODS: Clinical event rates after postpartum HAART discontinuation were calculated for all WHO stage 2-3 events, as well as for HIV progression warranting HAART re initiation, defined by a WHO stage 4 event and/or CD4(+) T-cell decrease to <=200 cells/mm(3). Predictors of the WHO stage 2-3 events and HIV progression outcomes were evaluated with Cox's proportional hazards models. RESULTS: A total of 120 women were followed for a mean of 1.5 years after delivery. Overall, 26 women had 30 events as follows: 20 developed WHO stage 2-3 events, yielding an incidence rate of 13/100 person-years (PY; 95% CI 8-20); 10 developed HIV progression requiring HAART re-initiation (incidence ratio 6/100 PY, 95% CI 3-11). Among progressors, a single woman developed a WHO stage 4 clinical event and the remainder had CD4(+) T-cell decreases. Women who had baseline CD4(+) T-cell counts between 200-500 cells/mm(3) had a hazard ratio for WHO stage 2-3 events of 2.5 compared to women with baseline >=500 cells/mm(3) (95% CI 1.0-6.3; P=0.05). The only significant predictor of HIV progression was baseline CD4(+) T-cell count (hazard ratio 0.99, 95% CI 0.98-0.99; P=0.02). CONCLUSIONS: In this observational study, a baseline CD4(+) T-cell count <500 cells/mm(3) was associated with an increased risk of postpartum WHO stage 2-3 clinical events and HIV disease progression. Randomized studies are needed to further evaluate the effect of postpartum treatment discontinuation on maternal health. PMID- 21555818 TI - Inhibitory effects of indigowoad root polysaccharides on porcine reproductive and respiratory syndrome virus replication in vitro. AB - BACKGROUND: Indigowoad root polysaccharide (IRPS) is a natural polysaccharide isolated from the traditional Chinese medicinal herb Radix Isatidis, and has many kinds of biological activities. However, the IRPS antiviral activity, especially the anti-porcine reproductive and respiratory syndrome virus (PRRSV) effect, has not been evaluated. METHODS: PRRSV was propagated in the MARC-145 cell line, and viral titre was determined by cytopathic effect and expressed as the 50% tissue culture infection dose (TCID(50)) in the current study. The cell cytotoxic effect of IRPS toward MARC-145 was evaluated by MTT assay firstly, then the inhibitory effects of IRPS on PRRSV replication in vitro were investigated by determining the effect of IRPS upon a single replicative cycle of PRRSV in MARC-145 cells. The effects of IRPS on viral RNA and protein synthesis in PRRSV-infected cells were investigated using real-time PCR and double-antibody (sandwich) ELISA. RESULTS: IRPS was able to effectively suppress the infectivity of the PRRSV in a dose-dependent manner, especially by adding IRPS during the PRRSV infection. IRPS could affect the attachment of PRRSV to MARC-145 cells, and also inhibit the viral RNA and protein synthesis. CONCLUSIONS: IRPS has an antiviral effect on PRRSV replication in MARC-145 cells and might be useful in medical development for antiviral research. However, the precise mechanism of the host and viral targets of IRPS are unknown, so further studies should be conducted to investigate the precise mechanism of IRPS inhibitory effect on PRRSV infection. PMID- 21555819 TI - Decreased mitochondrial DNA content in subcutaneous fat from HIV-infected women taking antiretroviral therapy as measured at delivery. AB - BACKGROUND: Increasing numbers of pregnant HIV-positive women are receiving combination antiretroviral regimens for preventing mother-to-child virus transmission or for treating the infection itself. Several studies have demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by several mechanisms, including depletion of mitochondrial DNA (mtDNA). By the quantification of mtDNA levels, we studied mitochondrial toxicity in HIV-positive women at delivery and the possible correlations with antiretroviral regimens, viroimmunological and metabolic parameters. METHODS: We analysed 68 HIV-positive women enrolled in the Italian Prospective Cohort Study on Efficacy and Toxicity of Antiretroviral in Pregnancy (TARGET Study); all were taking >=1 NRTI. We quantified mtDNA copies per cell in subcutaneous fat samples collected during delivery. At the 3rd, 6th and 9th month of pregnancy, we collected data concerning CD4(+) T-cell count, plasma HIV RNA, total and high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and triglycerides. As a control, we analysed mtDNA levels in abdominal subcutaneous fat samples from 23 HIV-seronegative women at delivery. RESULTS: mtDNA content was significantly lower in HIV-infected women when compared with HIV-negative controls. mtDNA content varied independently from viroimmunological, lipid and glucose parameters at the different months, with the exceptions of triglycerides at the 9th month and of HDL at the 6th month of pregnancy. CONCLUSIONS: In subcutaneous tissue from women taking NRTI-based antiretroviral regimens, we observed a significant decrease of mtDNA content, compared with uninfected women not on antiviral treatment. Moreover, a significant correlation was noted between mtDNA content and HDL cholesterol and triglycerides. PMID- 21555820 TI - Predicting antiretroviral drug resistance from the latest or the cumulative genotype. AB - BACKGROUND: This study evaluates the added benefit when estimating antiretroviral drug resistance of combining all available resistance test results in a cumulative genotype relative to using the latest genotype alone. METHODS: The prevalence of resistance and genotypic sensitivity scores (GSS) predicted by the latest and the cumulative genotype, together with virological outcomes after the latest genotype, were measured in treatment-experienced patients who underwent >=2 resistance tests in 1999-2008. RESULTS: Comparing the latest with the cumulative genotype in 227 patients, 4 (1.7%) versus 0 (0.0%) showed no major resistance mutations, whereas 74 (32.6%) versus 46 (20.3%), 88 (38.8%) versus 76 (33.5%) and 61 (26.9%) versus 105 (46.3%) showed single-class, dual-class and triple-class resistance mutations, respectively. The median (IQR) number of fully or partially active drugs was 6 (5-6) versus 5 (4-6) for the nucleoside/nucleotide reverse transcriptase inhibitors, 3 (1-3) versus 1 (1-3) for the non-nucleoside reverse transcriptase inhibitors and 7 (7-7) versus 7 (7 7) for the protease inhibitors, respectively. Among 163 patients who started a new regimen after the latest genotype, both the latest and the cumulative GSS were predictive of early (<=24 weeks) virological responses. The GSS decreased by median 1 unit (IQR 0.5-1.0) in the cumulative genotype and larger differences relative to the latest genotype corresponded to smaller decreases in viral load. CONCLUSIONS: The cumulative genotype offers a more comprehensive evaluation of the burden of resistance. This approach can guide small but appreciable improvements in the selection of antiretroviral regimens for treatment experienced patients. PMID- 21555821 TI - The guanine-quadruplex aptamer 93del inhibits HIV-1 replication ex vivo by interfering with viral entry, reverse transcription and integration. AB - BACKGROUND: We have previously identified the guanine-rich oligonucleotide (ODN) 93del as a potent inhibitor in vitro of HIV-1 integrase. Moreover, low nanomolar concentrations of ODN 93del have been shown to inhibit HIV-1 replication in infected cells. METHODS: To investigate the ex vivo mechanism of ODN 93del inhibition, we analysed its antiviral effects on the early steps of HIV-1 replication such as viral entry, reverse transcription and integration using quantitative PCR. RESULTS: In addition to the effect on viral entry previously described for other guanine-quadruplex ODNs, transfection experiments showed that ODN 93del severely affects the proviral integration step independently of the effect on viral entry. Moreover, incubation of viral particles with ODN 93del revealed a potential microbicide activity of the aptamer. CONCLUSIONS: Our data point to an original multimodal inhibition of HIV-1 replication by ODN 93del, strongly suggesting that targets of guanine-quartet-forming ODNs involve entry as well as other intracellular early steps of HIV-1 replication. PMID- 21555822 TI - Baseline CD4(+) T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients. AB - BACKGROUND: Maraviroc-containing regimens are known to achieve virological suppression in many treatment-experienced patients. This study aimed to evaluate a more rigorous methodological approach to resistance-response analysis in large clinical studies and to better establish which subpopulations of patients were most likely to benefit from maraviroc by refining and extending previous subgroup analyses from the MOTIVATE studies. METHODS: Individual weighted optimized background therapy (OBT) susceptibility scores were calculated by combining genotypic or phenotypic resistance testing with prior drug use information. Virological response (HIV-1 RNA<50 copies/ml at week 48) using each of these methods was compared with a commonly used method of counting active drugs. Baseline predictors of virological response, including weighted or unweighted scoring, maraviroc use, baseline CD4(+) T-cell count, HIV-1 plasma viral load and tropism, were assessed by logistic regression modelling. RESULTS: Genotypic or phenotypic weighted methods were similarly predictive of virological response and better than counting active drugs. Weighted scoring and baseline CD4(+) T-cell count were the strongest predictors of virological response (P<0.0001): ~70% of maraviroc patients with a weighted score >=2 had a virological response, rising to ~80% when the baseline CD4(+) T-cell count was >=50 cells/mm(3). CONCLUSIONS: Approximately 80% of patients with a CD4(+) T-cell count >=50 cells/mm(3) receiving maraviroc with the equivalent of at least two fully active agents achieved HIV-1 RNA<50 copies/ml at week 48 in the MOTIVATE studies. Genotypic and phenotypic weighted scores were similarly predictive of virological response. PMID- 21555823 TI - High prevalence of liver fibrosis associated with HIV infection: a study in rural Rakai, Uganda. AB - BACKGROUND: Liver disease is a leading cause of mortality among HIV-infected persons in the United States and Europe. However, data regarding the effects of HIV and antiretroviral therapy (ART) on liver disease in Africa are sparse. METHODS: A total of 500 HIV-infected participants in an HIV care programme in rural Rakai, Uganda were frequency-matched by age, gender and site to 500 HIV uninfected participants in a population cohort. All participants underwent transient elastography (FibroScan((r))) to quantify liver stiffness measurements (LSM) and identify participants with significant liver fibrosis, defined as LSM>=9.3 kPa (~ Metavir F>=2). Risk factors for liver fibrosis were identified by estimating adjusted prevalence risk ratios (adjPRR) and 95% CI using modified Poisson multivariate regression. RESULTS: The prevalence of hepatitis B coinfection in the study population was 5%. The prevalence of significant fibrosis was 17% among HIV-infected and 11% in HIV-uninfected participants (P=0.008). HIV infection was associated with a 50% increase in liver fibrosis (adjPRR 1.5, 95% CI 1.1-2.1; P=0.010). Fibrosis was also associated with male gender (adjPRR 1.4, 95% CI 1.0-1.9; P=0.045), herbal medicine use (adjPRR 2.0, 95% CI 1.2-3.3; P=0.005), heavy alcohol consumption (adjPRR 2.3, 95% CI 1.3-3.9; P=0.005), occupational fishing (adjPRR 2.5, 95% CI 1.2-5.3; P=0.019) and chronic HBV infection (adjPRR 1.7, 95% CI 1.0-3.1; P=0.058). Among HIV-infected participants, ART reduced fibrosis risk (adjPRR 0.6, 95% CI 0.4-1.0; P=0.030). CONCLUSIONS: The burden of liver fibrosis among HIV-infected rural Ugandans is high. These data suggest that liver disease may represent a significant cause of HIV-related morbidity and mortality in Africa. PMID- 21555824 TI - Natural polymorphisms associated with resistance to new antivirals against HCV in newly diagnosed HIV-HCV-coinfected patients. AB - BACKGROUND: Direct acting antivirals (DAA) targeting the HCV serine protease and RNA polymerase have recently entered clinical development. Information about primary resistance to these compounds in HIV-HCV-coinfected patients is scarce. METHODS: All individuals newly diagnosed with HIV-1 at several clinics in Madrid between 2000 and 2010 were tested for serum HCV antibody and HCV RNA. The NS3 protease and NS5B polymerase genes were sequenced in all HCV viraemic patients with genotype 1 (G1). RESULTS: From 1,684 individuals newly diagnosed with HIV-1 during the 10-year study period, 141 (8.4%) were positive for serum HCV RNA. Overall, 58% were infected with G1, being 1a in 64.2% of them. Altogether, 62% of G1a and 30% of G1b harboured HCV drug-resistant changes, with the most common being prQ80K (n=9), prV55A (n=2), polC316Y/N (n=3) and polV499A (n=24). Although no primary resistance mutations were identified for HCV protease inhibitors or nucleoside analogues, mutations C316Y/N and V499A conferring resistance to some non-nucleoside analogues were found in 6% and 51% of G1 patients, respectively. CONCLUSIONS: Natural DAA resistance-associated mutations are frequently seen in HIV-HCV-coinfected individuals. Changes polV499A and prQ80K seem to be natural polymorphisms and their effect on treatment outcomes warrants further examination. However, drug resistance testing in HCV drug-naive individuals coinfected with HIV currently does not seem to be warranted before using HCV protease inhibitors and nucleoside analogues. More information is needed for HCV non-nucleoside analogues. PMID- 21555825 TI - Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis. AB - BACKGROUND: Coadministration of rifampicin dramatically reduces the concentrations of protease inhibitors. A pharmacokinetic study in healthy adults showed that doubling the dose of coformulated lopinavir/ritonavir was able to overcome the inducing effect of rifampicin. We evaluated this strategy in children treated with rifampicin-based antituberculosis therapy attending antiretroviral clinics in South Africa. METHODS: Plasma concentrations of lopinavir were measured in children (aged 0.64-2.43 years) established on antituberculosis treatment who commenced antiretroviral therapy comprising double the usual recommended dose of lopinavir/ritonavir oral solution (460/115 mg/m(2) twice daily) plus two nucleoside reverse transcriptase inhibitors. Control children (0.57-4.23 years old) without tuberculosis received standard doses of lopinavir/ritonavir (230/57.5 mg/m(2) twice daily). RESULTS: Pre-dose lopinavir concentrations were reduced by >80% in children with tuberculosis (median 0.7 mg/l, IQR 0.1-2.0) compared with controls (4.2 mg/l, IQR 3.4-8.1; P<0.001) and were below the minimum recommended concentration of 1 mg/l in 12 of 20 (60%) children with tuberculosis versus 2 of 24 (8%) controls (P<0.001). CONCLUSIONS: Double doses of coformulated lopinavir/ritonavir results in inadequate lopinavir concentrations in young children treated concurrently with rifampicin. Suitable regimens are urgently needed for treating young children with HIV-associated tuberculosis. PMID- 21555826 TI - Decentralization of access to antiretroviral therapy in Cameroon: correlates of HIV physicians' knowledge in HIV care. AB - BACKGROUND: Good knowledge in HIV care among physicians is a necessary prerequisite to effective antiretroviral therapy (ART) scaling-up in Sub-Saharan Africa. METHODS: Between September 2006 and March 2007, a 27-item knowledge questionnaire was proposed to all HIV physicians working in 27 hospitals throughout six provinces of Cameroon. Physicians' responses were compared between the three levels of decentralization of the Cameroonian healthcare delivery system (chi(2) and Fisher tests). Correct responses were summed to build a knowledge score. Factors significantly associated with a higher score were identified using linear regression. RESULTS: In total, 93 physicians filled in the questionnaire. Level of knowledge was globally good (median score 23), with no significant difference between the three levels of decentralization. Gaps in knowledge were observed regarding the use of cotrimoxazole and the follow-up of ART-treated patients. Main factors independently associated with a higher knowledge score included training, involvement in therapeutic committees, satisfactory collaboration with other practitioners and establishment of strong relationships between patients and patients' associations. CONCLUSIONS: Overall knowledge in HIV care is good among HIV physicians working at all three levels of decentralization of healthcare in Cameroon. However, a national training policy should be set up to improve knowledge and practices in both ART follow-up and specific situations such as paediatric HIV. Collaboration between caregivers and external resources involved in HIV care should also be encouraged. PMID- 21555827 TI - High prevalence of antiretroviral drug resistance among HIV-1-untreated patients in Guinea-Conakry and in Niger. AB - BACKGROUND: The aim of the study was to assess the prevalence of antiretroviral drug resistance mutations in HIV-1 from recently diagnosed and untreated patients living in Conakry, Guinea-Conakry and in Niamey, Niger. METHODS: The study was performed in two countries of Western Africa - Guinea-Conakry and Niger - using the same survey method in both sites. All newly HIV-1 diagnosed patients, naive of antiretroviral drugs, were consecutively included during September 2009 in each of the two sites. Protease and reverse transcriptase sequencing was performed using the ANRS procedures. Drug resistance mutations were identified according to the 2009 update surveillance drug resistance mutations. RESULTS: In Conakry, 99 patients were included, most of whom (89%) were infected with CRF02_AG recombinant virus. Resistance analysis among the 93 samples showed that >=1 drug resistance mutation was observed in 8 samples, leading to a prevalence of primary resistance of 8.6% (95% CI 2.91-14.29%). In Niamey, 96 patients were included; a high diversity in HIV-1 subtypes was observed with 47 (51%) patients infected with CRF02_AG. Resistance analysis performed among the 92 samples with successful genotypic resistance test showed that >=1 drug resistance mutation was observed in 6 samples, leading to a prevalence of primary resistance of 6.5% (95% CI 1.50-11.50%). CONCLUSIONS: We reported the first antiretroviral drug resistance survey studies in antiretroviral-naive patients living in Guinea Conakry and in Niger. The prevalence of resistance was between 6% and 9% in both sites, which is higher than most of the other countries from Western Africa region. PMID- 21555828 TI - Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir. AB - The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care. PMID- 21555829 TI - A method for characterizing the biodiversity in bat pinnae as a basis for engineering analysis. AB - A quantitative analysis of the interspecific variability between beamforming baffle shapes in the biosonar system of bats is presented. The data set analyzed consisted of 100 outer ear (pinna) shapes from at least 59 species. A vector space representation suitable for principal component analysis (PCA) was constructed by virtue of a transform of the pinna surfaces into cylindrical coordinates. The central axis of the cylindrical transform was found by minimizing a potential function. The shapes were aligned by means of their respective axes and their center of gravity. The average pinna of the sample was a symmetrical, obliquely truncated horn. The first seven eigenvalues accounted already for two-thirds of the variability around the mean, which indicates that most of the biodiversity in the bat pinna can be understood in a more low dimensional space. The first three principal components show that most of the variability of the bat pinna sample is in terms of opening angle, left-right asymmetry, and selective changes in width at the top or the bottom of the pinna. The beampattern effects of these individual components have been characterized. These insights could be used to design bioinspired beamforming devices from the diversity in biosonar. PMID- 21555830 TI - Spin-spin indirect interaction at low-energy excitation in zero-dimensional cavities. AB - We solve the low-energy part of the spectrum of a model that describes a circularly polarized cavity mode strongly coupled to two exciton modes, each of which is coupled to a localized spin of arbitrary magnitude. In the regime in which the excitons and the cavity modes are strongly coupled, forming polaritons, the low-energy part of the spectrum can be described by an effective spin model, which contains a magnetic field, an axial anisotropy, and an Ising interaction between the localized spins. For detunings such that the low-energy states are dominated by nearly degenerate excitonic modes, the description of the low-energy states by a simple effective Hamiltonian ceases to be valid and the effective interaction tends to vanish. Finally, we discuss a possible application to two qubit quantum computing operations in a system of transition-metal impurities embedded in quantum dots inside a micropillar. PMID- 21555831 TI - Effects of electronic correlation on x-ray absorption and dichroic spectra at L(2, 3) edge. AB - We present a new theoretical approach to describe x-ray absorption and magnetic circular dichroism spectra in the presence of electron-electron correlation. Our approach provides an unified picture to include correlations in both charged and neutral excitations, namely in direct/inversion photoemission where electrons are removed/added, and photoabsorption where electrons are promoted from core levels to empty states. We apply this approach to the prototypical case of the L(2, 3) edge of 3d transition metals and we show that the inclusion of many-body effects in the core level excitations is essential to reproduce, together with satellite structures in core level photoemission, the observed asymmetric lineshapes in x ray absorption and dichroic spectra. PMID- 21555832 TI - Electromagnetic interaction in stacked split ring resonator arrays. AB - We theoretically demonstrate the coupling between the unit cells and the interaction between constituents within each cell in metamaterials consisting of stacked split ring resonator arrays which are embedded in a homogeneous dielectric. It is found that the resonant frequency due to plasmon hybridization depends on the symmetry of resonance modes. Both for the first and third order plasmon resonances, we show that the resonances at lower frequency are not sensitive to the variation of lattice density, while the resonances at higher frequency rely on the coupling between cells due to the symmetric distribution of current. The underlying physics is qualitatively interpreted according to the quasistatic electric and magnetic dipole coupling model combined by the calculated field distributions. PMID- 21555833 TI - Nonlinear emission dynamics of a GaAs microcavity with embedded quantum wells. AB - The emission dynamics of a GaAs microcavity at different angles of observation with respect to the sample normal under conditions of nonresonant picosecond pulse excitation is measured. At sufficiently high excitation densities, the decay time of the lower polariton emission increases with the polariton wavevector; at low excitation densities the decay time is independent of the wavevector. The effect of additional nonresonant continuous illumination on the emission originating from the bottom of the lower polariton branch is investigated. The additional illumination leads to a substantial increase in the emission intensity (considerably larger than the intensity of the photoluminescence excited by this illumination alone). This fact is explained in terms of acceleration of the polariton relaxation to the radiative states due to scattering by charge carriers created by the additional illumination. The results obtained show that, at large negative detunings between the photon and exciton modes, polariton-polariton and polariton-free carrier scattering are the main processes responsible for the filling of states near the bottom of the lower polariton branch. PMID- 21555834 TI - Sn/Pt(110) bimetallic surfaces: formation and oxygen adsorption. AB - Submonolayer coverage of Sn on a Pt(110) surface was studied by photoemission and low-energy electron diffraction. Deposition of less than 0.6 ML at 300 K gives rise to a c(2 * 2) surface reconstruction with weak diffraction spots at the very beginning of growth, and no other LEED patterns were found at this temperature. A new (4 * 1) Sn/Pt(110) surface structure was observed after flashing to 570 K a coverage of 0.64 ML. The total Sn coverage decreased to 0.58 ML after flashing as some of the atoms diffused into deeper layers. Different Sn phases were identified on the (4 * 1) Sn/Pt(110) surface: two types of surface Sn atoms in different adsorption sites, a subsurface Sn-Pt intermetallic layer and Sn-Pt surface islands. To investigate chemical reactivity, 0.25 ML Sn/Pt(110) and 0.58 ML (4 * 1) Sn/Pt(110) surfaces were exposed to 1000 L of O(2) at 300 K. Analyses of the photoemission data provide evidence for the formation of tin oxide. The interaction with oxygen of the two surfaces is similar, independent of surface structure and the composition of the subsurface layers. The Sn concentration in the interface intermetallic layer is the main factor which influences the oxygen adsorption. PMID- 21555835 TI - Magnetic phase diagram of multiferroic MnWO4 probed by ultrasound. AB - The magnetic phase diagram of multiferroic MnWO(4) is studied in magnetic fields up to 60 T using sound velocity and sound attenuation measurements. Anomalies are observed at temperatures T(N1) = 7.6 K, T(N2) = 12.6 K and T(N3) = 13.6 K that separate commensurate antiferromagnetic (AF1) to helical AF2 and commensurate AF3 to paramagnetic phases, respectively. The anomalies are significantly different and shed light on the spin-phonon coupling and evolution of the various order parameters in this multiferroic material. For temperatures below T(N2) pronounced field hysteresis effects are also observed in the sound velocity, indicating field-induced transformations. In the temperature dependence of the attenuation we observe anomalies distinctively different from the usual maxima related to relaxation effects. They are attributed to the combination of dispersion effects due to domain walls and the discontinuously changing sound velocity. In total, six different magnetic phases, at various temperatures and fields including a novel high-field phase, are revealed and analyzed. PMID- 21555836 TI - Thermal conductivity and thermal rectification in unzipped carbon nanotubes. AB - We study the thermal transport in completely unzipped carbon nanotubes, which are called graphene nanoribbons, partially unzipped carbon nanotubes, which can be seen as carbon-nanotube-graphene-nanoribbon junctions, and carbon nanotubes by using molecular dynamics simulations. It is found that the thermal conductivity of a graphene nanoribbon is much less than that of its perfect carbon nanotube counterparts because of the localized phonon modes at the boundary. A partially unzipped carbon nanotube has the lowest thermal conductivity due to additional localized modes at the junction region. More strikingly, a significant thermal rectification effect is observed in both partially unzipped armchair and zigzag carbon nanotubes. Our results suggest that carbon-nanotube-graphene-nanoribbon junctions can be used in thermal energy control. PMID- 21555837 TI - Structural stability of BaMF4 (M = Mg, Zn and Mn) at high pressures. AB - Piezoelectric fluorides of the composition BaMF(4) (M = Mg, Zn, Mn) have been studied in situ at high pressures in diamond anvil cells with single-crystal x ray diffraction and Raman spectroscopy. All three compounds crystallize in the acentric space group Cmc 2(1) at ambient pressure. BaMgF(4) undergoes a reversible second order phase transition to the paraelectric phase (space group Cmcm) at pressures between 5 and 6 GPa. BaZnF(4) undergoes a reversible first order phase transition to a monoclinic phase (space group P 11n). Both high- and low-pressure polymorphs coexist in the pressure range 5-7 GPa. BaMnF(4) maintains the Cmc 2(1) structure up to pressures of 4 GPa. Above this pressure the diffraction signal decreases rapidly and at 6 GPa no diffraction signal could be detected in our experiment. The compound does not recover its crystallinity on decompression. A comparison of the effects of external and chemical pressure is presented. PMID- 21555838 TI - Zero-(n) non-Bragg gap plasmon-polariton modes and omni-reflectance in 1D metamaterial photonic superlattices. AB - A theoretical study of the photonic band structure and transmission spectra for 1D periodic superlattices with an elementary cell composed of two layers of refractive indices n(a) and n(b), which may take on positive as well as negative values, has been performed within the transfer-matrix approach. The dependence on the angle of incidence of the electromagnetic wave for excitation of plasmon polaritons as well as the properties of the (n) = 0 gap were thoroughly investigated. Results are found for the generalized conditions that must be satisfied by the ratio a/b of the layer widths of metamaterial photonic superlattices, for both transverse electric and transverse magnetic polarizations, in order to have an omnidirectional (n) = 0 gap. The present study indicates new perspectives in the design and development of future optical devices. PMID- 21555839 TI - The autocorrelation function for island areas on self-affine surfaces. AB - The spatial distribution of regions that lie above contours of constant height through a self-affine surface is studied as a function of the Hurst exponent H. If the surface represents a landscape, these regions correspond to islands. When the surface represents the height difference for contacting surfaces, the regions correspond to mechanical contacts in the common bearing area model. The autocorrelation function C(Deltar) is defined as the probability that points separated by Deltar are both within islands. The scaling of C has important implications for the stiffness and conductance of mechanical contacts. We find that its Fourier transform C(q) scales as a power of the wavevector magnitude q: [Formula: see text] with MU = 2 + H rather than the value MU = 2 + 2H reported previously. An analytic argument for MU = 2 + H is presented using the distribution of areas contained in disconnected islands. PMID- 21555840 TI - Critical magnetic transition in TbNi2Mn--magnetization and Mossbauer spectroscopy. AB - The structural and magnetic properties of the TbNi(2)Mn(x) series (0.9 <= x <= 1.10) have been investigated using x-ray diffraction, field- and temperature dependent AC magnetic susceptibility, DC magnetization (5-340 K; 0-5 T) and (57)Fe Mossbauer spectroscopy (5-300 K). TbNi(2)Mn(x) crystallizes in the MgCu(2) type structure (space group Fd3m). The additional contributions to the magnetic energy terms from transition-metal-transition-metal interactions (T-T) and rare earth-transition-metal interactions (R-T) in RNi(2)Mn compounds contribute to their increased magnetic ordering temperatures compared with RNi(2) and RMn(2). Both the lattice constant a and the Curie temperature T(C) exhibit maximal values at the x = 1 composition indicating strong magnetostructural coupling. Analyses of the AC magnetic susceptibility and DC magnetization data of TbNi(2)Mn around the Curie temperature T(C) = 147 K confirm that the magnetic transition is second order with critical exponents beta = 0.77 +/- 0.12, gamma = 1.09 +/- 0.07 and delta = 2.51 +/- 0.06. These exponents establish that the magnetic interactions in TbNi(2)Mn are long range despite mixed occupancies of Tb and Mn atoms at the 8a site and vacancies. The magnetic entropy - DeltaS(M) around T(C) is proportional to (MU(0)H/T(C))(2/3) in agreement with the critical magnetic analyses. The Mossbauer spectra above T(C) are fitted by two sub-spectra in agreement with refinement of the x-ray data while below T(C) three sub-spectra are required to represent the three inequivalent local magnetic environments. PMID- 21555841 TI - Interaction of tungsten with CeO2(111) layers as a function of temperature: a photoelectron spectroscopy study. AB - The interaction of tungsten with CeO(2)(111) layers grown on Cu(111) was studied in the temperature range between 300 and 870 K by photoelectron spectroscopy of the core levels and resonant valence band spectroscopy. The interaction was found to be very strong even at 300 K, leading to the formation of cerium tungstate Ce(6)WO(12) in which the metal atoms were in Ce(3+) and W(6+) chemical states. The growth was limited by the diffusion of W atoms into the ceria layer, so subsequent tungsten deposition led to formation of W suboxides with consecutively lower chemical oxidation states, i.e. W(4+), W(2+) and metallic W(0) with an almost negligible contribution of W(5+). Step-wise annealing of the layer showed that due to stimulated diffusion of tungsten into ceria at higher temperature, Ce(6)WO(12) was formed more easily. Larger W overlayer thicknesses needed higher annealing temperature to promote diffusion. The thickest sample studied, 1.4 nm W/CeO(2), was transformed by annealing to 870 K to the Ce(6)WO(12)/W system with a tungsten monoxide (WO) interface, whereas the rest of the tungsten was converted to the W(6 + ) oxidation state. PMID- 21555842 TI - TiO2 -enriched polymeric powder coatings support human mesenchymal cell spreading and osteogenic differentiation. AB - Novel polymeric powder coatings (PPC) were prepared by ultrafine powder coating technology and shown to support human mesenchymal cell attachment and growth. PPC surfaces enriched with nano-TiO(2) (nTiO(2)) showed enhanced cellular responses, and were compared to commercially pure titanium (cpTi). After cell attachment and growth, osteogenic differentiation and bone matrix formation ensures osseointegration for implantable biomaterials. Therefore, the objective of this study was to determine if mesenchymal cells grown on PPC could undergo osteogenic differentiation by inducing Runx2 and bone matrix proteins, and then initiate mineralization. Atomic force microscopy revealed intricate three-dimensional micro-topographies, and the measures of nano-roughness and porosity were similar for all PPC surfaces. Scanning electron microscopy showed that the cells attached and spread out over all of the surfaces. After 1 week in osteogenic media, RT-PCR analysis showed the induction of Runx2, the up-regulation of type I collagen, and the initial detection of alkaline phosphatase and bone sialoprotein. After 4 weeks, Alizarin Red staining showed mineral deposition. However, cell spreading and osteogenic differentiation were significantly (P < 0.05) higher on the cpTi controls than on the PPC surfaces. Furthermore, spreading and differentiation were consistently higher on the titanium-enriched PPC-2, -3 and -4 than on the titanium-free PPC-1. Therefore, despite the presence of complex micro topographies and nano-features, titanium-enrichment enhanced the cellular response, and pure titanium still provided the best substrate. These findings confirm the cytocompatibility of these novel polymeric coatings and suggest that titanium-enrichment and nTiO(2) additives may enhance their performance. PMID- 21555843 TI - Improved human tenocyte proliferation and differentiation in vitro by optimized silk degumming. AB - Tendon disorders are common clinical conditions. Tendon tissue engineering provides a new approach for tendon repair by integrating engineered substitutes with their native counterparts. Silk is considered to be a promising candidate for tendon engineering because of its biological and mechanical properties. However, a major concern with using silk for biomedical applications is the immune responses generated by sericin, a glue-like protein that coats the silk fibres. This study improves the existing protocols for silk 'degumming' which removes sericin and enables preparation of silk that is suitable for tendon regeneration. Bombyx mori silks were treated by sequential treatments with different proteases. The efficiency of degumming was determined by measuring weight loss, picric acid and carmine staining and scanning electron microscopy. To evaluate the cellular responses after degumming, the growth and differentiation of human tenocytes on silks were examined. The results showed that sequential protease treatment effectively degummed raw silks. The sequentially degummed silks showed enhanced tenocyte proliferation and upregulated mRNA levels of tendon markers. Thick cell multilayers formed on the treated silks, with cells and collagen fibres penetrating into the spaces in individual silk filaments, resulting in a structure resembling human tendon. PMID- 21555844 TI - Running over unknown rough terrain with a one-legged planar robot. AB - The ability to traverse unknown, rough terrain is an advantage that legged locomoters have over their wheeled counterparts. However, due to the complexity of multi-legged systems, research in legged robotics has not yet been able to reproduce the agility found in the animal kingdom. In an effort to reduce the complexity of the problem, researchers have developed single-legged models to gain insight into the fundamental dynamics of legged running. Inspired by studies of animal locomotion, researchers have proposed numerous control strategies to achieve stable, one-legged running over unknown, rough terrain. One such control strategy incorporates energy variations into the system during the stance phase by changing the force-free leg length as a sinusoidal function of time. In this research, a one-legged planar robot capable of implementing this and other state of-the-art control strategies was designed and built. Both simulated and experimental results were used to determine and compare the stability of the proposed controllers as the robot was subjected to unknown drop and raised step perturbations equal to 25% of the nominal leg length. This study illustrates the relative advantages of utilizing a minimal-sensing, active energy removal control scheme to stabilize running over rough terrain. PMID- 21555845 TI - Colloidal suspensions. PMID- 21555846 TI - Two communication lines in a 3 * 3 matrix speller. AB - In a matrix speller both eye fixation and attention are reflected in the event related potentials to highlighting of characters. We consider the question of whether this can be used to open up two parallel channels by dissociating the attended character from the fixated one. Complementary classifiers for both characters are established and their relationship is investigated. PMID- 21555847 TI - SSVEP-based Bremen-BCI interface--boosting information transfer rates. AB - In recent years, there has been increased interest in using steady-state visual evoked potentials (SSVEP) in brain-computer interface (BCI) systems; the SSVEP approach currently provides the fastest and most reliable communication paradigm for the implementation of a non-invasive BCI. This paper presents recent developments in the signal processing of the SSVEP-based Bremen BCI system, which allowed one of the subjects in an online experiment to reach a peak information transfer rate (ITR) of 124 bit min(-1). It is worth mentioning that this ITR value is higher than all values previously published in the literature for any kind of BCI paradigm. PMID- 21555848 TI - Desynchronizing anti-resonance effect of m: n ON-OFF coordinated reset stimulation. AB - This computational study is devoted to the optimal parameter calibration for coordinated reset (CR) stimulation, a stimulation technique suggested for an effective desynchronization of pathological neuronal synchronization. We present a detailed study of the parameter space of the CR stimulation method and show that CR stimulation can induce cluster states, desynchronization and oscillation death. The stimulation-induced cluster states (at CR offset) cause the longest desynchronizing post-stimulus transients, which constitute an essential part of the CR stimulation effect. We discover a desynchronization-related anti-resonance response of the stimulated oscillators induced by a periodic ON-OFF CR stimulation protocol with m cycles ON stimulation followed by n cycles OFF stimulation. The undesired collective oscillations are effectively desynchronized if the stimulation is administered at resonant frequencies of the controlled ensemble, which is in complete contrast to the typical effect of the usual periodic forcing. PMID- 21555849 TI - Ethical guidance for the management of conflicts of interest for researchers, engineers and clinicians engaged in the development of therapeutic deep brain stimulation. AB - The clinical promise of deep brain stimulation (DBS) for neuropsychiatric conditions is coupled with the potential for ethical conflicts of interest because the work is so heavily reliant upon collaborations between academia, industry and the clinic. To foster transparency and public trust, we offer ethical guidance for the management of conflicts of interest in the conduct of DBS research and practice so that this nascent field can better balance competing goods and engineer new and better strategies for the amelioration of human suffering. We also hope that our ethical analysis will be of relevance to those working with other related neuroprosthetic devices, such brain-computer interfaces and neural arrays, which naturally share many of the same concerns. PMID- 21555850 TI - Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts. AB - Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen positive (PSMA-positive) cells to IR. siRNA library screens identified DNA activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa. PMID- 21555851 TI - Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. AB - In chronic viral infections, CD8+ T cells become functionally deficient and display multiple molecular alterations. In contrast, only little is known of self and tumor-specific CD8+ T cells from mice and humans. Here we determined molecular profiles of tumor-specific CD8+ T cells from melanoma patients. In peripheral blood from patients vaccinated with CpG and the melanoma antigen Melan A/MART-1 peptide, we found functional effector T cell populations, with only small but nevertheless significant differences in T cells specific for persistent herpesviruses (EBV and CMV). In contrast, Melan-A/MART-1-specific T cells isolated from metastases from patients with melanoma expressed a large variety of genes associated with T cell exhaustion. The identified exhaustion profile revealed extended molecular alterations. Our data demonstrate a remarkable coexistence of effector cells in circulation and exhausted cells in the tumor environment. Functional T cell impairment is mediated by inhibitory receptors and further molecular pathways, which represent potential targets for cancer therapy. PMID- 21555852 TI - Mitochondrial dysfunction in patients with primary congenital insulin resistance. AB - Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels. PMID- 21555853 TI - Growth hormone receptor regulates beta cell hyperplasia and glucose-stimulated insulin secretion in obese mice. AB - Insulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) play key roles in the regulation of beta cell growth and function. Although beta cells express the GH receptor, the direct effects of GH on beta cells remain largely unknown. Here we have employed a rat insulin II promoter-driven (RIP-driven) Cre recombinase to disrupt the GH receptor in beta cells (betaGHRKO). betaGHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in beta cell mass. When challenged with a high-fat diet, betaGHRKO mice showed evidence of a beta cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucose-stimulated insulin secretion. Interestingly, betaGHRKO mice were impaired in beta cell hyperplasia in response to a high-fat diet, with decreased beta cell proliferation and overall reduced beta cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and beta cell compensation in response to a high-fat diet. PMID- 21555854 TI - The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice. AB - Cardiac hypertrophy and failure are accompanied by a reprogramming of gene expression that involves transcription factors and chromatin remodeling enzymes. Little is known about the roles of histone methylation and demethylation in this process. To understand the role of JMJD2A, a histone trimethyl demethylase, in cardiac hypertrophy, we generated mouse lines with heart-specific Jmjd2a deletion (hKO) and overexpression (Jmjd2a-Tg). Jmjd2a hKO and Jmjd2a-Tg mice had no overt baseline phenotype, but did demonstrate altered responses to cardiac stresses. While inactivation of Jmjd2a resulted in an attenuated hypertrophic response to transverse aortic constriction-induced (TAC-induced) pressure overload, Jmjd2a-Tg mice displayed exacerbated cardiac hypertrophy. We identified four-and-a-half LIM domains 1 (FHL1), a key component of the mechanotransducer machinery in the heart, as a direct target of JMJD2A. JMJD2A bound to the FHL1 promoter in response to TAC, upregulated FHL1 expression, and downregulated H3K9 trimethylation. Upregulation of FHL1 by JMJD2A was mediated through SRF and myocardin and required its demethylase activity. The expression of JMJD2A was upregulated in human hypertrophic cardiomyopathy patients. Our studies reveal that JMJD2A promotes cardiac hypertrophy under pathological conditions and suggest what we believe to be a novel mechanism for JMJD2A in reprogramming of gene expression involved in cardiac hypertrophy. PMID- 21555855 TI - Engagement of S1P1-degradative mechanisms leads to vascular leak in mice. AB - GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although highly efficacious, dose-dependent increases in adverse events have tempered its utility. We show here that FTY720P induces phosphorylation of the C-terminal domain of S1P receptor 1 (S1P1) at multiple sites, resulting in GPCR internalization, polyubiquitinylation, and degradation. We also identified the ubiquitin E3 ligase WWP2 in the GPCR complex and demonstrated its requirement in FTY720-induced receptor degradation. GPCR degradation was not essential for the induction of lymphopenia, but was critical for pulmonary vascular leak in vivo. Prevention of receptor phosphorylation, internalization, and degradation inhibited vascular leak, which suggests that discrete mechanisms of S1P receptor regulation are responsible for the efficacy and adverse events associated with this class of therapeutics. PMID- 21555856 TI - Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape. AB - Induction of virus-specific CD8+ T cell responses is critical for the success of vaccines against chronic viral infections. Despite the large number of potential MHC-I-restricted epitopes located in viral proteins, MHC-I-restricted epitope generation is inefficient, and factors defining the production and presentation of MHC-I-restricted viral epitopes are poorly understood. Here, we have demonstrated that the half-lives of HIV-derived peptides in cytosol from primary human cells were highly variable and sequence dependent, and significantly affected the efficiency of cell recognition by CD8+ T cells. Furthermore, multiple clinical isolates of HLA-associated HIV epitope variants displayed reduced half-lives relative to consensus sequence. This decreased cytosolic peptide stability diminished epitope presentation and CTL recognition, illustrating a mechanism of immune escape. Chaperone complexes including Hsp90 and histone deacetylase HDAC6 enhanced peptide stability by transient protection from peptidase degradation. Based on empirical results with 166 peptides, we developed a computational approach utilizing a sequence-based algorithm to estimate the cytosolic stability of antigenic peptides. Our results identify sequence motifs able to alter the amount of peptide available for loading onto MHC-I, suggesting potential new strategies to modulate epitope production from vaccine immunogens. PMID- 21555857 TI - Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque. AB - High levels of HIV-1 replication during the chronic phase of infection usually correlate with rapid progression to severe immunodeficiency. However, a minority of highly viremic individuals remains asymptomatic and maintains high CD4+ T cell counts. This tolerant profile is poorly understood and reminiscent of the widely studied nonprogressive disease model of SIV infection in natural hosts. Here, we identify transcriptome differences between rapid progressors (RPs) and viremic nonprogressors (VNPs) and highlight several genes relevant for the understanding of HIV-1-induced immunosuppression. RPs were characterized by a specific transcriptome profile of CD4+ and CD8+ T cells similar to that observed in pathogenic SIV-infected rhesus macaques. In contrast, VNPs exhibited lower expression of interferon-stimulated genes and shared a common gene regulation profile with nonpathogenic SIV-infected sooty mangabeys. A short list of genes associated with VNP, including CASP1, CD38, LAG3, TNFSF13B, SOCS1, and EEF1D, showed significant correlation with time to disease progression when evaluated in an independent set of CD4+ T cell expression data. This work characterizes 2 minimally studied clinical patterns of progression to AIDS, whose analysis may inform our understanding of HIV pathogenesis. PMID- 21555858 TI - Phenotypic variation of fluoride responses between inbred strains of mice. AB - Excessive systemic exposure to fluoride (F) can lead to disturbances in bone homeostasis and dental enamel development. We have previously shown strain specific responses to F in the development of dental fluorosis (DF) and in bone formation/mineralization. The current study was undertaken to further investigate F responsive variations in bone metabolism and to determine possible relationships with DF susceptibility. Seven-week-old male mice from FVB/NJ, C57BL/6J, C3H/HeJ, A/J, 129S1/SvImJ, AKR/J, DBA/2J, and BALB/cByJ inbred strains were exposed to NaF (0 or 50 ppm as F(-)) in drinking water for 60 days. Sera were collected for F, Ca, Mg, PO(4), iPTH, sRANKL, and ALP levels. Bone marrow cells were subjected to ex vivo cell culture for osteoclast potential and CFU colony assays (CFU-fibroblast, CFU-osteoblast, CFU erythrocyte/granulocyte/macrophage/megakaryocyte, CFU-granulocyte/macrophage, CFU macrophage, and CFU-granulocyte). Femurs and vertebrae were subjected to micro-CT analyses, biomechanical testing, and F, Mg, and Ca content assays. DF was evaluated using quantitative fluorescence and clinical criteria. Strain-specific responses to F were observed for DF, serum studies, ex vivo cell culture studies, and bone quality. Among the strains, there were no patterns or significant correlations between DF severity and the actions of F on bone homeostasis (serum studies, ex vivo assays, or bone quality parameters). The genetic background continues to play a role in the actions of F on tooth enamel development and bone homeostasis. F exposure led to variable phenotypic responses between strains involving dental enamel development and bone metabolism. PMID- 21555859 TI - On the formation and functions of high and very high magnesium calcites in the continuously growing teeth of the echinoderm Lytechinus variegatus: development of crystallinity and protein involvement. AB - Sea urchin teeth grow continuously and develop a complex mineralized structure consisting of spatially separate but crystallographically aligned first stage calcitic elements of high Mg content (5-15 mol% mineral). These become cemented together by epitaxially oriented second stage very high Mg calcite (30-40 mol% mineral). In the tooth plumula, ingressing preodontoblasts create layered cellular syncytia. Mineral deposits develop within membrane-bound compartments between cellular syncytial layers. We seek to understand how this complex tooth architecture is developed, how individual crystalline calcitic elements become crystallographically aligned, and how their Mg composition is regulated. Synchrotron microbeam X-ray scattering was performed on live, freshly dissected teeth. We observed that the initial diffracting crystals lie within independent syncytial spaces in the plumula. These diffraction patterns match those of mature tooth calcite. Thus, the spatially separate crystallites grow with the same crystallographic orientation seen in the mature tooth. Mineral-related proteins from regions with differing Mg contents were isolated, sequenced, and characterized. A tooth cDNA library was constructed, and selected matrix-related proteins were cloned. Antibodies were prepared and used for immunolocaliztion. Matrix-related proteins are acidic, phosphorylated, and associated with the syncytial membranes. Time-of-flight secondary ion mass spectroscopy of various crystal elements shows unique amino acid, Mg, and Ca ion distributions. High and very high Mg calcites differ in Asp content. Matrix-related proteins are phosphorylated. Very high Mg calcite is associated with Asp-rich protein, and it is restricted to the second stage mineral. Thus, the composition at each part of the tooth is related to architecture and function. PMID- 21555860 TI - DMP1 and DSPP: evidence for duplication and convergent evolution of two SIBLING proteins. AB - Since first being proposed as a tandem gene family in 2001, the relatedness of the 5 SIBLING proteins (BSP, DMP1, DSPP, MEPE, and SPP1/OPN) has predominantly depended on arguments involving shared intron/exon properties as well as conserved protein biochemical properties (e.g. unstructured and acidic) and specific peptide motifs (e.g. phosphorylation and integrin-binding RGD). This report discusses the evidence that an ancient DMP1 gene underwent a simple duplication in the common ancestor of mammals and reptiles and then separately evolved into DSPP-like paralogs in the 2 classes. Genomic sequence analyses show that different copies of the original DMP1 duplication process were selected by mammalian and reptilian (anole lizard) classes to acquire genetically different but biochemically similar phosphoserine-rich repeat domains by convergent evolution. Mammals, for example, expanded phosphoserine motifs encoded exclusively using motifs containing AGC/T serine codons while the reptile line's repeats also used TCN-encoding serine codons. A similar analysis of the origins of the other 4 SIBLINGs will require even more detailed analysis as genome sequences of various fish and amphibia become available. PMID- 21555861 TI - Citrate modulates calcium oxalate crystal growth by face-specific interactions. AB - Because of its ability to inhibit the growth of calcium oxalate monohydrate (COM) crystals, citrate plays an important role in preventing the formation of kidney stones. To determine the mechanism of inhibition, we studied the citrate-COM interaction using a combination of microscopic and simulation techniques. Using scanning confocal interference microscopy, we found that addition of citrate preferentially inhibits crystal growth in <100> and, to a lesser extent, <001> directions, suggesting that citrate adsorbs to the faces of COM in the order {100} > {121} > {010}. Scanning electron microscopy showed that the resulting crystals are plate shaped, with large {100} faces and rounded ends. Molecular dynamics simulations predicted, however, that citrate interacts with the faces of COM in a different order, i.e. {100} > {010} > {121}. Our simulations showed that citrate molecules align with the rows of Ca2+ ions on the {010} face but do not form close contacts, presumably because of electrostatic repulsion by the carboxylate groups that project from the Ca2+-rich plane. We propose that this weak interaction is responsible for citrate's limited inhibition of COM growth in <010> directions. Overall, these findings indicate that electrostatic interactions with the Ca2+-rich faces of COM crystals are responsible for the growth-modulating properties of citrate. PMID- 21555862 TI - Urodynamic parameters development and complications of clean intermittent self catheterization in Chinese schoolchildren with neurogenic underactive bladder. AB - OBJECTIVE: To evaluate the urodynamic parameters, development of bladder function and complications of clean intermittent self-catheterization (CIC) in Chinese schoolchildren with neurogenic underactive bladder. METHODS: Ninety-three children with neurogenic underactive bladder were successfully treated with CIC or combined with oxybutynin for two years follow-up. According to bladder compliance before CIC, they were subdivided into a normal bladder compliance (NBC) group and a low bladder compliance (LBC) group. Urodynamic parameters and complications were recorded. RESULTS: At follow-up, the incidence of neurogenic detrusor overactivity was found to have significantly decreased in both groups. Moreover, maximum cystometric capacity (CC) and relatively safe CC in the NBC group was significantly higher than those before CIC. However, relatively safe CC was significantly lower than that before CIC, and detrusor leakage point pressure was significantly higher than that before CIC in the LBC group. The incidences of bacteriuria, vesicureteral reflux (VUR), febrile urinary tract infections (UTI) and macroscopic hematuria were, respectively, 62, 13, 25 and 15%, and those of VUR and febrile UTI in the LBC group were significantly higher than those in the NBC group. CONCLUSION: For these cases, the complications of CIC are rare, and bladder compliance seems to be correlated with the development of bladder function and complications during CIC. PMID- 21555863 TI - Roles of DMP1 processing in osteogenesis, dentinogenesis and chondrogenesis. AB - Dentin matrix protein 1 (DMP1) is an acidic protein that plays critical roles in osteogenesis and dentinogenesis. Protein chemistry studies have demonstrated that DMP1 primarily exists as processed NH2- and COOH-terminal fragments in the extracellular matrix of bone and dentin. Our earlier work showed that the substitution of Asp213 (a residue at a cleavage site) by Ala213 blocks the processing of mouse DMP1 in vitro. Recently, we generated transgenic mice expressing this mutant DMP1 (designated 'D213A-DMP1'). By crossbreeding these transgenic mice with Dmp1-knockout (Dmp1-KO) mice, we obtained mice expressing the D213A-DMP1 transgene in the Dmp1-null background (named 'Dmp1-KO/D213A-Tg' mice). In this study, we analyzed the long bone, mandible, dentin, and cartilage of Dmp1-KO/D213A-Tg mice in comparison with wild-type, Dmp1-KO, and Dmp1-KO mice expressing the normal DMP1 transgene (Dmp1-KO/normal-Tg). Our results showed that D213A-DMP1 was barely cleaved in the dentin matrix of Dmp1-KO/D213A-Tg mice and the expression of D213A-DMP1 failed to rescue the developmental defects in Dmp1 null mice. Interestingly, enlarged growth plates and condylar cartilages were observed in Dmp1-KO/D213A-Tg mice, indicating a potential role of the full-length form of DMP1 in chondrogenesis. PMID- 21555864 TI - Ectopic expression of Col2.3 and Col3.6 promoters in the brain and association with leptin signaling. AB - The collagen 2.3 and 3.6 promoters have been used to drive Cre expression for generation of conditional transgenic mutant mice. Within the bone, Col3.6 is expressed by mesenchymal precursor cells and their downstream progeny, while Col2.3 is more osteoblast specific. Our generation of transgenic mice with Col2.3 Cre- and Col3.6-Cre-driven deletion of the long-form leptin receptor (ObRb) necessitated a thorough analysis of the nonspecific expression of these promoters in the central nervous system. Both Col2.3 and Col3.6 were capable of forcing loxP recombination in the brain as demonstrated by EGFP expression in ROSA reporter mice. Expression of Col2.3 was limited to the central base of the brain near the third ventricle. In contrast, robust expression of Col3.6 was noted throughout the brain, centering near the distal third ventricle, third ventricle, and aqueduct. We subsequently analyzed the colocalization of leptin-responsive P Stat3 neurons with Col3.6-expressing neurons. Approximately 5-10% colocalization was noted in leptin-responsive brain areas such as the arcuate nucleus, dorsal medial hypothalamus, ventral premammillary nucleus, and lateral hypothalamus. Injection of 3.6(Cre+F/F) ObRb knockout mice with leptin confirmed the presence of an intact P-Stat3 response that was dampened in the lateral hypothalamus (p < 0.050). This test was done to explore the contribution of neural leptin signaling to the bone phenotype of the 3.6(Cre+F/F) mice. Our analysis indicates that neural ObRb deletion, while present, is likely not the sole driver of femoral changes through traditional sympathetic circuits. PMID- 21555865 TI - Public perspectives on returning genetics and genomics research results. AB - BACKGROUND: The debate about returning research results has revealed different perspectives among researchers, participants and advisory groups with participants generally interested in obtaining their results. Given this preference, policies regarding return of individual research results may affect whether a potential subject chooses to participate in a study. Public attitudes, particularly those of African-Americans, toward this issue have been understudied. METHODS: In 2008-2009, we convened 10 focus groups in Durham, N.C. to explore attitudes about returning research results and how different policies might influence their likelihood to participate in genetic/genomic studies. Transcripts were complimented by a short anonymous survey. Of 100 participants, 73% were female and 76% African-American with a median age of 40-49 years. RESULTS: Although there was general interest in obtaining genetics research results, particularly individual results, discussants recognized many potential complexities. The option to obtain research results (individual or summary) was clearly valued and lack thereof was potentially a deterrent for genetic/genomic research enrollment. CONCLUSIONS: Providing the option to learn research results may help strengthen relationships between investigators and participants and thereby serve as a positive influencing factor for minority communities. Consideration of the broader implications of returning research results is warranted. Engaging diverse publics is essential to gain a balance between the interests and burdens of participants and investigators. PMID- 21555866 TI - sigma receptor 1 is preferentially involved in modulation of N-methyl-D-aspartate receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells. AB - Using patch-clamp whole-cell recording, we investigated how activation of the sigma receptor 1 (sigmaR1) modulates light-evoked excitatory postsynaptic currents (eEPSCs) of ganglion cells (GCs) in rat retinal slice preparations. Bath application of the sigmaR1 agonist SKF10047 (SKF) suppressed N-methyl-D-aspartate (NMDA) receptor-mediated eEPSCs at different holding potentials in ON, OFF and ON OFF GCs, and the effects were blocked when the preparations were pre-incubated with the sigmaR1 antagonist BD1047. In contrast, SKF had no effects on alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated eEPSCs of these GCs. Furthermore, application of SKF did not affect AMPA receptor mediated miniature EPSCs of GCs, suggesting that activation of sigmaR1 did not change the release of glutamate from bipolar cells. These results suggest that sigmaR1 may be involved in the regulation of output signaling of GCs by preferentially modulating NMDA receptor-mediated eEPSCs of these retinal neurons. PMID- 21555867 TI - Bronchodilation and smoking interaction in COPD: a cohort pilot study to assess cardiovascular risk. AB - BACKGROUND: Smoking and bronchodilator treatment are both extensively studied as key elements in patients with chronic obstructive pulmonary disease. However, little is known about whether or not these elements interact in terms of developing cardiovascular diseases in patients with COPD. OBJECTIVES: To explore to what extent the risk of developing ischemic cardiovascular disease in COPD patients is mediated by smoking status, use of bronchodilators and--specifically- their interaction. METHODS: We performed an observational pilot study on a relatively healthy Dutch COPD cohort from a primary care diagnostic center database with full information on spirometry tests, smoking status, bronchodilator use and other prescribed medication. We defined first ischemic cardiovascular events as primary outcome, measured by first prescription of antiplatelet drugs and/or nitrates. Unadjusted analyses by Kaplan-Meier were followed by adjusted Cox' proportional hazards. RESULTS: 845 COPD patients, totaling 2,169 observation years, were included in the analyses. We observed an increased risk for nonfatal ischemic cardiovascular events by smoking (adjusted HR=3.58, p=0.001) and a protective effect of bronchodilators (adjusted HR=0.43, p=0.01). Although the protective effect of bronchodilators appears to be substantially minimized in patients that persist in smoking, we could not statistically confirm a hazardous interaction between bronchodilators and smoking (HR 2.50, p=0.21). CONCLUSION: Our study reveals bronchodilators may protect from ischemic cardiovascular events in a relatively 'healthy' COPD population. We did not confirm a hazardous interaction between bronchodilators and smoking, although we observed current smokers benefit substantially less from the protective effect of bronchodilators. PMID- 21555868 TI - Pneumocyte biomarkers KL-6 and surfactant protein D reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia. AB - BACKGROUND: Serum levels of pneumocyte biomarkers KL-6 and surfactant protein D (SP-D) are useful diagnostic markers for interstitial lung diseases. However, associations of serum KL-6 and SP-D with radiologic findings in nonspecific interstitial pneumonia (NSIP) remain unclear. OBJECTIVES: To determine whether serum levels of KL-6 and SP-D reflect fibrotic and/or inflammatory processes in NSIP, we investigated the correlation between high-resolution computed tomography (HRCT) findings and serum KL-6 and SP-D levels. METHODS: Serum levels of KL-6 and SP-D were measured in 21 patients with biopsy-confirmed NSIP. The radiographic extent of 6 HRCT patterns and total HRCT score, defined as the scored fibrotic index, were assessed. Changes in the levels of serum markers and CT findings during follow-up were also monitored. RESULTS: Serum levels of KL-6 in NSIP positively correlated with the total HRCT score and overall extent of interstitial disease. Serum levels of SP-D in NSIP showed a positive correlation with the area of ground-glass attenuation without traction bronchiectasis and the inflammatory CT pattern, but the levels were inversely correlated with the area of ground-glass attenuation with traction bronchiectasis and the fibrotic CT pattern. The follow-up CT and serum marker changes after treatment showed that percent change of disease extent was reflected in both markers, especially KL-6. Further, the decreased fibrotic pattern correlated with both biomarkers. CONCLUSIONS: The results indicate that serum levels of KL-6 in NSIP reflect the overall extent of interstitial lesions, which include both inflammatory and fibrotic lesions, while the levels of SP-D mainly reflect the extent of inflammatory lesions. PMID- 21555869 TI - A 38-year-old pregnant woman with hemoptysis and acute renal failure. Microscopic polyangiitis. PMID- 21555870 TI - Bronchorrhea in bronchioloalveolar carcinoma. PMID- 21555871 TI - The influence of tissue factor and tissue factor pathway inhibitor polymorphisms on thrombin generation in stable coronary artery disease. AB - In patients with stable coronary heart disease (n = 1,001) we investigated the influence of tissue factor (TF) and TF pathway inhibitor (TFPI) polymorphisms on thrombin generation in vivo, measured by prothrombin fragment (F) 1 and 2, and the potential to generate thrombin ex vivo, measured by the calibrated automated thrombogram assay. Additionally, circulating levels of TF and TFPI were correlated to the different parameters of thrombin generation. The TF 5466 and TFPI -399 polymorphisms associated with higher thrombin generation in vivo, the latter also with a prolonged lag time of the thrombin generation ex vivo(p < 0.05 for all).The TF -1812 TT and the TF -603 GG genotypes were associated with lower peak thrombin and a decreased average net rate of thrombin activation during the propagation phases (p <= 0.05), and the TFPI -33 TC genotype with prolonged lag time (p < 0.05) and additionally time to peak (p = 0.06). Strong correlations between TFPI levels, prothrombin fragment 1 and 2 as well as calibrated automated thrombogram parameters were observed. PMID- 21555872 TI - Splenomegaly in primary antiphospholipid syndrome without accompanying portal hypertension or comorbidity. AB - OBJECTIVE: To demonstrate the presence of splenomegaly in primary antiphospholipid syndrome (PAPS) patients without accompanying portal hypertension or comorbidity. METHODS: Twelve patients (7 women) aged 23-65 years followed upon the diagnosis of PAPS were enrolled in the study. We documented the identified causes of splenomegaly in patients with PAPS, and searched for the potential causes of splenomegaly in patients with spleen enlargement. PAPS patients with or without splenomegaly were evaluated in terms of demographic and clinical findings. RESULTS: Splenomegaly was present in 6 of the 12 patients. In these patients, there were no infections, hematological disorders, portal hypertension or malignancy that might lead to splenomegaly. The long axis of spleen was found to be in the range of 137-155 mm in patients with splenomegaly. Splenomegaly was more frequently determined in female PAPS patients. The splenomegaly group had a longer duration of disease (median 5.5 vs. 0.75 years) and a higher number of thrombotic events (median 3 vs. 1.5). The splenomegaly group was especially composed of patients who never received any anticoagulant and acetylsalicylic acid, or who used these agents irregularly for very short periods. CONCLUSION: Splenomegaly was observed in association with disease duration, frequency of thrombotic events and irregular antiaggregant or anticoagulant treatment in patients with PAPS, in the absence of comorbidity or portal hypertension. PMID- 21555873 TI - Evidence for integrity of parental genomes in the diploid hybridogenetic water frog Pelophylax esculentus by genomic in situ hybridization. AB - The Western Palearctic water frogs Pelophylax ridibundus and P. lessonae were identified as parental (sexual) species and P. esculentus as their interspecific, hybridogenetically reproducing hybrid with hemiclonal heredity. We used genomic in situ hybridization (GISH) to identify parental chromosomes of P.lessonae and P.ridibundus in diploid P. esculentus karyotypes (2n = 26). GISH probes were made by fluorochrome labeling of total genomic DNA extracted from the sexual progenitors. The labeled probe from one species was hybridized to chromosomes of P. esculentus in the presence of excess of unlabeled genomic DNA from the other species. Thus, the P. lessonae probe was blocked by P. ridibundus unlabeled DNA, and vice versa. We successfully discriminated each of the 13 respective parental chromosomes in metaphase complements of the hybrids according to species-specific hybridization signals. GISH enabled us to confirm additional differences between parental chromosomes in size (smaller chromosomes belong to P. lessonae) and in the presence of DAPI-positive centromeric heterochromatin (detected in chromosomes of P. ridibundus, but not in P. lessonae). The fact that no visible intergenomic exchanges were found in metaphase chromosomes of diploid P. esculentus provides important information on the genomic integrity of hemiclonal transmission and supports hybridogenesis as a reproductive mode at the chromosome level for the specimens examined. PMID- 21555874 TI - Variation in missegregation rates among human chromosomes in hybrid cells. AB - Chinese hamster ovary-human hybrid cells containing chromosomes 16, 18, X, or 21 have been used to test the ability of human kinetochores to successfully bind to spindle microtubules and to be distributed to daughter cells. The intrinsic rates of non-disjunction among these human chromosomes have been determined and compared to non-disjunction rates in cells presented with taxol as a mitotic challenge. Cells grown on culture slides were fixed and processed for immunofluorescence and fluorescence in situ hybridization. Daughter cell pairs were identified by staining with anti-alpha-tubulin to identify midbodies. DNA probes specific for human centromeres were used to test for the successful passage of human chromosomes to daughter cells. Our data indicate that different human kinetochores vary in their ability to properly engage the spindle and to be successfully distributed. In addition, our data indicate that the 4 human chromosomes studied can be divided into 2 groups, based on their overall intrinsic rate of non-disjunction and their response to microtubule perturbation. The mechanism of this effect is not yet known. PMID- 21555875 TI - Impact of fatigue on outcomes in the hemodialysis (HEMO) study. AB - BACKGROUND: Fatigue is a common debilitating symptom in chronic kidney disease patients on maintenance hemodialysis. However, little is known about its pathogenesis and association with survival. METHODS: This study examines the correlates and outcomes of fatigue among 1,798 hemodialysis patients enrolled in the HEMO study. Fatigue was assessed using the SF-36 vitality scale. Multivariable analysis was used to assess independent associations of demographic and clinical characteristics with baseline fatigue and longitudinal changes in fatigue. The association of fatigue with all-cause and cause-specific mortality and cardiac hospitalizations was also assessed. RESULTS: Higher index of coexistent diseases (ICED) score, diabetes, non-African-American race, lower serum albumin, use of medications for sleep and poor sleep quality were found to be significantly associated with more fatigue at baseline. In longitudinal analyses, patients who were older, had been on dialysis longer, had higher ICED score, and reported using medications for sleep were more likely to experience worsening fatigue, whereas higher serum albumin was strongly associated with an improvement in level of fatigue. A 10-point increase in vitality score was associated with 10% increase in mean survival (p < 0.0001). CONCLUSIONS: Demographic and clinical factors have significant associations with fatigue, which itself predicts mortality. Improving fatigue in the end-stage renal disease population may positively impact patient well-being and survival. PMID- 21555876 TI - A methodological section in cerebrovascular diseases: why? PMID- 21555877 TI - Molecular cytogenetic analysis of a gliosarcoma with osseous metaplasia. AB - Gliosarcoma, a rare glioblastoma variant, is composed of a glial and a mesenchymal component. Though the mesenchymal portion most commonly resembles a fibrosarcoma, other differentiation patterns have been observed. We present the first genomic characterisation (karyotyping followed by FISH and array comparative genomic hybridisation analysis) of a gliosarcoma with osseous metaplasia. In addition to chromosomal changes often found in gliomas (+7, -10, 13, and -22), the tumour cells also harboured a hitherto unknown t(3;21)(q13~21;q21~22). PMID- 21555878 TI - Cytogenetic mapping of rRNAs and histone H3 genes in 14 species of Dichotomius (Coleoptera, Scarabaeidae, Scarabaeinae) beetles. AB - Standard cytogenetic analyses and chromosomal mapping of the genes for 18S and 5S rRNAs and histone H3 were performed in 14 species of beetles of the genus Dichotomius (Coleoptera, Scarabaeidae, Scarabaeinae). Conserved karyotypes with 2n = 18 and biarmed chromosomes were observed in all species. Moreover, the presence of a large metacentric pair (pair 1) was characteristic in the studied species, evidencing a remarkable synapomorphy for this genus, which probably originated by an ancient fusion of 2 autosomes while the ancestral sex-chromosome pair remained conserved. FISH showed that the 5S rRNA and histone H3 genes are located in the proximal region of pair 2, with the 2 genes co-located. However, the major rDNA cluster probed by the 18S rRNA gene mapped to 1-3 bivalents, being exclusively autosomal, associated with sex elements, or both. In most species, the major rDNA cluster was observed in pair 3, and it was frequently (64.3%) located in the distal region regardless of the chromosome. The conserved number and position of the 5S rDNA/H3 histone cluster seems to be an ancient pattern shared by all of the studied species. In contrast, the major rDNA clusters apparently tolerate distinct patterns of diversification in the karyotypes of the species that could be associated with small inversions, ectopic recombination, and transposition. Moreover, we reinforced the association/co-localization between the 5S rRNA and histone H3 genes in this group contributing thus to the knowledge about the chromosomal organization and diversification patterns of multigene families in beetles and insects. PMID- 21555879 TI - Genetic compensation abilities of Aegilops speltoides chromosomes for homoeologous B-genome chromosomes of polyploid wheat in disomic S(B) chromosome substitution lines. AB - The S genome of Aegilops speltoides is closely related to the B and G genomes of polyploid wheats. However, little work has been reported on the genetic relationships between the S-genome and B-genome chromosomes of polyploid wheat. Here, we report the isolation of a set of disomic substitutions (DS) of S-genome chromosomes for the B-genome chromosomes and their effects on gametophytic and sporophytic development. Ae. speltoides chromosomes were identified by their distinct C-banding and fluorescence in situ hybridization patterns with the Ae. speltoides-derived clone pGc1R-1. Although no large structural differences between S-genome and B-genome chromosomes exist, significant differences in gametophytic compensation were observed for chromosomes 1S, 3S, 5S and 6S. Similarly, chromosomes 1S, 2S, 4S, 5S and 6S affected certain aspects of sporophytic development in relation to spike morphology, fertility and meiotic pairing. The DS5S(5B) had disturbed meiosis with univalents/multivalents and suffered chromosome elimination in the germ tissues leading to haploid spikes in 50% of the plants. The effect of the Ph1 gene on meiosis is well known, and these results provide evidence for the role of Ph1 in the maintenance of polyploid genome integrity. These and other data are discussed in relation to the structural and functional differentiation of S- and B-genome chromosomes and the practical utility of the stocks in wheat improvement. PMID- 21555880 TI - Activation of rye 5RL neocentromere by an organophosphate pesticide. AB - An interstitial constriction located on the long arm of rye chromosome 5R (5RL) shows neocentromeric activity at meiosis. In some meiocytes this region is strongly stretched orienting with the true centromere to opposite poles at metaphase I, and keeping sister chromatid cohesion at anaphase I. We found previously that the frequency of neocentric activity varied dramatically in different generations suggesting the effect of environmental factors. Here we studied the behavior of the 5RL neocentromere in mono- and ditelosomic 5RL, and mono-, and disomic 5R wheat-rye addition lines, untreated and treated with an organophosphate pesticide. The treated plants form neocentromeres with an about 4.5-fold increased frequency compared to untreated ones, demonstrating that the pesticide promotes neocentric activity. The neocentromere was activated irrespectively of the pairing configuration or the presence of a complete or truncated 5R centromere. Fluorescence in situ hybridization (FISH) with 2 repetitive sequences (UCM600 and pSc119.2) present at the constriction showed kinetic activity at several locations within this region. Immunostaining with anti-alpha-tubulin showed that treated plants have abnormal spindles in 46% of the metaphase I cells, indicating that disturbances in spindle formation might promote neocentromere activation. PMID- 21555881 TI - Simulated infusion of paclitaxel with in-line filters. AB - BACKGROUND: Paclitaxel is one of the most effective anticancer drugs ever developed. To prevent hazards associated with intravenous (IV) administration which include the formation of microbubbles, microbiological contamination and particulate matter, the suppliers recommend that an in-line IV filter should be used during the infusion of the chemotherapeutic agent. METHODS: To rule out the possibility that polyethersulfone (PES) membranes retain the paclitaxel during filtration, we carried out specific tests. Paclitaxel retention by PES in-line IV filters was evaluated by a simulated-drug IV infusion and high-performance liquid chromatography analysis. RESULTS: In our model of study, no variation of paclitaxel concentration was revealed before and after filtration using two different filter devices. CONCLUSIONS: The results suggest that, under our experimental conditions, paclitaxel concentration in saline solution remains constant before and after filtration. Indeed, our study indicates that the filters analyzed herein, other than preventing hazards associated with IV administration, do not retain paclitaxel, thus avoiding the reduction of the drug concentration and potency during filtration. PMID- 21555882 TI - The changes in residual cancer burden after interval debulking surgery are effective in evaluating the response to adjuvant chemotherapy. AB - OBJECTIVE: To study the clinical significance of the change of residual cancer burden (RCB) of epithelial ovarian carcinoma (EOC) between primary (PDS) and interval debulking surgery (IDS) in order to evaluate the effectiveness of adjuvant chemotherapy. METHODS: Thirty-eight EOC patients with suboptimal PDS with adjuvant chemotherapy were selected for this retrospective study and divided into pathologically negative (group A) and pathologically positive (group B) groups based on the histopathological examination and the change of size of residual disease after IDS. Patients in group B were further divided into groups B1 (partial remission criteria, n = 9), B2 (consistent with stable disease, n = 12) and B3 (consistent with disease progression, n = 4) based on the changes in RCB between PDS and IDS and the guidelines to evaluate the response to treatment in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST). The responses to chemotherapy evaluated by pathological examination of RCB versus by CA-125, recurrence patterns, and prognoses were analyzed. RESULTS: The clinical benefit rates evaluated by pathological assessment for groups A, B1, B2 and B3 were 100, 100, 100 and 0%, respectively (p < 0.01), whereas the rates were not statistically different when evaluated by CA-125 (100, 100, 91.7 and 100%, respectively; p > 0.05). The median progression-free survival (PFS) for patients in groups A and B was 36 and 6 months, respectively (p < 0.05); the median overall survival (OS) was 93 and 42 months, respectively (p < 0.05). There were no significant differences in median PFS or OS among patients in groups B1, B2 and B3 (PFS: 16, 6 and 1.5 months; OS: 52, 31 and 30.5 months, respectively; all p > 0.05), but there were significant differences in median PFS or OS between B1 and B3. There was no significant difference in recurrence rates between groups A and B (53.8 vs. 72.0%, p > 0.05), but there were significant differences in the rate of drug-resistant recurrence [28.6% (2/7) vs. 72.2% (13/18), p < 0.05] and in median PFS of relapsed patients (19 vs. 4 months, p < 0.05). CONCLUSION: The histopathological assessment of RCB between PDS and IDS may be used to evaluate and predict the response to adjuvant chemotherapy in EOC. PMID- 21555883 TI - Common polymorphisms in KCNJ5 [corrected] are associated with early-onset lone atrial fibrillation in Caucasians. AB - OBJECTIVES: The aim of this study was to screen lone atrial fibrillation (AF) patients for mutations in the genes KCNJ2, KCNJ3 and KCNJ5, all encoding potassium channels. Furthermore, we wanted to replicate the prior association of two single-nucleotide polymorphisms (SNPs) in KCNJ5, C171T (rs6590357) and G810T (rs7118824), with lone AF in Han Chinese. METHODS: We sequenced the coding region and splice site of KCNJ2, KCNJ3 and KCNJ5 in 187 early-onset lone-AF patients screening for mutations and counting SNP frequencies for the two noted SNPs in KCNJ5. RESULTS: No mutations were found in KCNJ2, KCNJ3 or KCNJ5. Both genotype distribution and allele frequencies of the SNPs rs6590357 and rs7118824 significantly differed between the AF and control group (p(genotype) = 0.0067, p(allele) = 0.0021 and p(genotype) = 0.014, p(allele) = 0.0101, respectively). On allele level, the OR for lone AF for rs6590357 was 1.77 (95% CI 1.16-2.73, p = 0.009) and for rs7118824 it was 1.71 (95% CI 1.13-2.57, p = 0.01) in a model adjusted for age and gender. CONCLUSIONS: Our findings indicate that rs6590357 and rs7118824 in KCNJ5 are associated with early-onset lone AF in Caucasians. No mutations were found in the exon or splice site of KCNJ2, KCNJ3 or KCNJ5. PMID- 21555884 TI - MR coronary angiography, back to the future? PMID- 21555885 TI - To develop new or to improve existing tools for risk stratification in acute coronary syndromes? PMID- 21555886 TI - Prediction of life-threatening arrhythmias--still an unresolved problem. AB - A major challenge in current cardiology is to predict who will die suddenly from ventricular arrhythmias. Ventricular arrhythmias are the most common cause of sudden cardiac death, occurring in about 1-2:1,000 inhabitants yearly, and is most frequently due to coronary artery disease. Patients with increased risk of ventricular arrhythmias can be offered medical treatment and ultimately an implantable cardioverter defibrillator (ICD). Left ventricular ejection fraction (EF) is currently the main risk stratification tool used to select patients for ICD therapy. However, EF is insufficient in predicting arrhythmic risk. A number of techniques have been presented to improve arrhythmic risk stratification without having reached clinical utility. Conduction abnormalities and dispersion of action potential duration forms the substrate for malignant ventricular arrhythmias in infarcted tissue as in several cardiomyopathies. The ability to assess electrical dispersion in patients noninvasively has been limited. Myocardial strain by echocardiography has been presented as an accurate tool for assessing myocardial function and timing. Inhomogeneous and dispersed myocardial contraction has been related to the occurrence of ventricular arrhythmias and seems to be a promising tool in risk stratification. This review focuses on arrhythmia mechanisms and novel echocardiographic tools for assessing risk of ventricular arrhythmias. PMID- 21555887 TI - Dementia staging across three different methods. AB - BACKGROUND/AIMS: To investigate the effectiveness of an item response theory (IRT)-based approach to staging dementia. METHODS: IRT estimates of dementia severity in 1,485 patients were used to stage dementia and then compared to dementia staging using the classic Clinical Dementia Rating Scale (CDR) algorithm and the Sum of the Boxes (SOB) approach. RESULTS: Measurement imprecision was highest when dementia stages were determined based on the classic algorithm (48% of sample), lower when they were determined based on the SOB approach (12%), and lowest when determined using IRT-based staging (0%). CONCLUSION: The classic CDR algorithm weights boxes largely according to clinical experience. The SOB approach weights all boxes equally. The IRT approach weights boxes according to their actual ability to identify dementia severity and therefore provides the most precise information for staging dementia. PMID- 21555888 TI - Familial semantic dementia with P301L mutation in the Tau gene. AB - BACKGROUND/AIMS: Semantic dementia (SD) is a clinical subclassification of frontotemporal lobar degeneration. Patients with 'pure SD' present with semantic memory impairment preceding the frontal symptoms, and there have been no reports of familial cases. METHODS: We evaluated the clinical features of, and performed neuropsychological examinations on, the proband and two affected family members. Then we performed neuroimaging and genetic analysis of MAPT and other dementia related genes in the proband. RESULTS: All three cases had semantic memory impairment with loss of word meanings as the primary early symptom. We diagnosed all cases as pure SD and identified a P301L mutation in the MAPT gene of the proband. CONCLUSION: Although the P301L mutation identified here has been previously described as pathogenic for frontotemporal dementia with parkinsonism 17 (FTDP-17), the proband and his two affected relatives showed different clinical symptoms from those of typical FTDP-17 cases who carry the P301L mutation. Pathologically, pure SD usually shows a TAR DNA-binding protein proteinopathy, but the molecular understanding of SD is not well established. Although our cases were clinically pure SD, the proband has a tau gene mutation, which would lead to tauopathy. These findings suggest that reconsideration of the molecular understanding of SD is warranted. PMID- 21555889 TI - Clinical significance of lymph node ratio and location of nodal involvement in patients with right colon cancer. AB - BACKGROUND/AIMS: Increasing negative lymph node count has been reported to be associated with better outcomes in patients with colon cancer. The present study aimed to clarify the clinical significance of the lymph node ratio (LNR) and location of lymph node metastasis (LNM) in patients with stage III right colon cancer. METHODS: We enrolled 820 patients who had undergone curative resection due to colon cancer at a single institution between 1991 and 2005. Among them, 197 underwent curative resection for T2-T4 right colon cancer. We evaluated the oncological outcomes according to LNR (quartiles) and distribution of LNM (n1 = LNM adjacent to the colon or along the vascular arcades of the marginal arteries; n2 = LNM along the major vessels; n3 = LNM near the roots of the major vessels). RESULTS: The rates of LNM in T2, T3 and T4 right colon cancer were 11.1, 38.6 and 58.0%, respectively (p < 0.0001). Recurrence rates were 27.3, 37.5 and 57.1% in patients with n1, n2 and n3 LNM, respectively (p < 0.0001). LNR (p < 0.0001) and distribution of LNM (p = 0.046) were independent risk factors for recurrence in patients with stage III right colon cancer. CONCLUSIONS: Some patients with extensive LNM benefited from lymph node dissection with high ligation. Those with T3-T4 right colon cancer are suitable candidates for lymph node dissection with high ligation. Adding the concept of LNR and location of LNM to conventional TNM staging could improve the accuracy of evaluating nodal status. PMID- 21555890 TI - Renal Association Clinical Practice Guideline on anaemia of chronic kidney disease. PMID- 21555891 TI - Renal Association Clinical Practice Guideline on cardiovascular disease in CKD. PMID- 21555892 TI - Renal Association Clinical Practice Guideline development policy manual. PMID- 21555893 TI - Renal Association Clinical Practice Guideline in mineral and bone disorders in CKD. PMID- 21555894 TI - Renal Association Clinical Practice Guideline on nutrition in CKD. PMID- 21555895 TI - Renal Association Clinical Practice Guideline on prevention of blood borne virus infection in the renal unit. PMID- 21555896 TI - Renal Association Clinical Practice Guideline on planning, initiating and withdrawal of renal replacement therapy. PMID- 21555897 TI - Renal Association Clinical Practice Guideline on the assessment of the potential kidney transplant recipient. PMID- 21555898 TI - Renal Association Clinical Practice Guideline on vascular access for haemodialysis. PMID- 21555899 TI - Renal Association Clinical Practice Guideline on haemodialysis. PMID- 21555900 TI - Summary of the 5th edition of the Renal Association Clinical Practice Guidelines (2009-2012). PMID- 21555901 TI - Renal Association Clinical Practice Guideline on peritoneal dialysis. PMID- 21555902 TI - Renal Association Clinical Practice Guideline on post-operative care of the kidney transplant recipient. PMID- 21555903 TI - Renal Association Clinical Practice Guidelines on acute kidney injury. PMID- 21555904 TI - Executive summary of the fifth edition of the Renal Association Clinical Practice Guidelines (2009-2012). PMID- 21555905 TI - Renal Association Clinical Practice Guideline on detection, monitoring and management of patients with CKD. PMID- 21555906 TI - Quantitative assessment of photoreceptor layer in eyes with resolved edema after pars plana vitrectomy with internal limiting membrane removal for diabetic macular edema. AB - BACKGROUND/AIMS: To evaluate the correlation between visual acuity (VA) and photoreceptor integrity in eyes with resolved diabetic macular edema (DME) after pars plana vitrectomy (PPV). METHODS: Eleven eyes with resolved macular edema following PPV with internal limiting membrane removal for DME were included in this retrospective study. The integrity of the external limiting membrane (ELM) and inner and outer segments (IS/OS) of the photoreceptor junction was evaluated by spectral domain optical coherence tomography. The main outcome measures were percentage of disrupted ELM and IS/OS lines, and correlation between VA and photoreceptor integrity. RESULTS: The mean time after PPV was 78 +/- 17 months. The mean lengths of the disrupted ELM and IS/OS lines were 223 +/- 167 MUm (63%) and 189 +/- 175 MUm (54%) in the foveola, and 900 +/- 522 MUm (60%) and 835 +/- 582 MUm (55%) in the fovea, respectively. Intact ELM and IS/OS lines were positively correlated with VA in both the fovea (p = 0.09 and p = 0.02, respectively) and foveola (p = 0.004 and p = 0.03, respectively). Linear regression analysis showed a statistically significant association of intact ELM and IS/OS lines with VA in the fovea. Disrupted ELM and IS/OS lines had a strong correlation with each other in both the fovea (r = -0.71, p = 0.013) and foveola (r = 0.81, p = 0.02). CONCLUSIONS: The integrity of the ELM and IS/OS lines was positively correlated with VA in eyes with resolved DME after PPV. PMID- 21555907 TI - Transsellar transsphenoidal encephalocele: a case report. AB - Basal encephaloceles are rare, accounting for about 1.5% of all encephaloceles. Transsellar transsphenoidal encephaloceles are the rarest variety of basal encephaloceles. We report a rare case of transsellar transsphenoidal encephalocele managed by a transnasal transseptal approach. PMID- 21555908 TI - Harvey Cushing's surgical treatment of a pediatric patient with an intraventricular glioma. AB - BACKGROUND/AIMS: The combination of inadequate technology and incomplete nomenclature systems created challenges for early neurosurgeons, and contributed to the dismal prognosis for brain tumors, particularly within the pediatric population. METHODS: Following IRB approval, and by the courtesy of the Alan Mason Chesney Archives, we reviewed the Johns Hopkins Hospital surgical files from 1896 to 1912. A single case of a pediatric patient with an intraventricular glioma was selected for further review. RESULTS: Here we report the case of a 10 year-old girl who presented to the Johns Hopkins Hospital in 1907, with a 7-year history of subtle symptoms of increased intracranial pressure, secondary to a tumor. Dr. Harvey Cushing operated upon her, and during surgical intervention resected a large parenchymal and intraventricular glioma. CONCLUSIONS: High-grade gliomas are rare occurrences in pediatric patients, with intraventricular gliomas described in only a handful of cases. Although advances in neuroimaging, hemostasis and understanding of the cerebrospinal fluid system have allowed neurosurgeons to resect intraventricular gliomas more safely, the surgical approaches in use today are still fraught with challenges. Here we describe a case of attempted resection of an intraventricular glioma in a pediatric patient, which predates the earliest published report of intraventricular gliomas by 30 years. PMID- 21555909 TI - Supratentorial extraventricular anaplastic ependymoma in a 10-year-old girl. PMID- 21555910 TI - The role of holocarboxylase synthetase in genome stability is mediated partly by epigenomic synergies between methylation and biotinylation events. AB - Holocarboxylase synthetase (HLCS) catalyzes the covalent binding of biotin to histones. Biotinylated histones are gene repression marks and are particularly enriched in long terminal repeats, telomeres, and other repeat regions. The effects of HLCS in gene regulation are mediated by its physical interactions with chromatin proteins such as histone H3, DNMT1, MeCP2, and EHMT-1. It appears that histone biotinylation depends on prior methylation of cytosines. De-repression of long terminal repeats in biotin- or HLCS-deficient cell cultures and organisms is associated with genome instability. PMID- 21555911 TI - Heritability and role for the environment in DNA methylation in AXL receptor tyrosine kinase. AB - DNA methylation in AXL, a receptor tyrosine kinase relevant in cancer and immune function, is reportedly highly heritable. We present evidence to suggest that heritability of DNA methylation in AXL is variable, dependent on population characteristics and cell type studied. Moreover, environmental exposures in utero, particularly exposure to maternal smoking, contributes to variation in DNA methylation of select CpG loci that can affect calculations of heritability. Children exposed to maternal smoking in utero had a 2.3% increase (95 % CI 0.3, 4.2) in DNA methylation in AXL, which was magnified in girls as compared to boys. These results present compelling evidence that environmental exposure to tobacco smoke during pregnancy may alter DNA methylation levels in subtle but potentially important ways, and that these changes are persistent years after birth. PMID- 21555912 TI - Quality control in oocytes: domain-domain interactions regulate the activity of p63. PMID- 21555913 TI - Inflammasome-mediated suppression of inflammation-induced colorectal cancer progression is mediated by direct regulation of epithelial cell proliferation. AB - Chronic inflammation is a risk factor for many types of human cancers, yet the precise mechanism of this strong association is largely unknown. The inflammasome is a multiprotein complex that has recently been shown to orchestrate multiple innate and adaptive immune responses, yet its potential role in inflammation induced cancer has been little studied. We recently reported a surprising link between the inflammasome and colorectal inflammation-induced tumorigenesis. In the model, the role of caspase-1 and NLRC4 in tumorigenesis was found to be mediated by direct and profound effects on colonic epithelial cell proliferation and cell death, rather than through regulation of colonic inflammation. Herein, we discuss the recent advances and discoveries related to the role of inflammasome in inflammation-induced colorectal tumorigenesis. PMID- 21555914 TI - SRSF2 is required for sodium butyrate-mediated p21(WAF1) induction and premature senescence in human lung carcinoma cell lines. AB - Sodium butyrate (NaBu) is a histone deacetylase inhibitor that exhibits numerous antiproliferative activities in various cancer cell lines, notably through the accumulation of the well-known cyclin-dependent kinase inhibitor p21(WAF1) . SRSF2 belongs to the family of SR proteins that are crucial regulators of constitutive and alternative pre-mRNA splicing. Previous studies demonstrated that NaBu alters pre-mRNA splicing patterns through upregulation of SR proteins expression in non-tumor cells. In this study, we show that NaBu also induces the accumulation of SRSF2 in human lung carcinoma cell lines. We recently identified a signaling network involving the acetyltransferase TIP60, the deacetylase HDAC6 and the SRPK kinases that regulates SRSF2 protein turnover through phosphorylation/acetylation modifications in response to cisplatin. Here, we show that the same signaling pathway controls SRSF2 protein expression upon NaBu treatment. Importantly, we further demonstrate that SRSF2 is required for the accumulation of p21(WAF1) at both mRNA and protein levels in response to NaBu. Finally, we provide evidence that a long-term NaBu-treatment triggers senescence in our cellular models, a phenomenon that is prevented by the knockdown of SRSF2. Altogether, these results unravel a new function of SRSF2 in the process of cellular senescence and identify the cyclin-Cdk inhibitor p21(WAF1) as a key target of SRSF2 in this setting. PMID- 21555915 TI - mTOR signaling in protein homeostasis: less is more? AB - A proper balance between synthesis, maturation and degradation of cellular proteins is crucial for cells to maintain physiological functions. The costly process of protein synthesis is tightly coupled to energy status and nutrient levels by the mammalian target of rapamycin (mTOR), whereas the quality of newly synthesized polypeptides is largely maintained by molecular chaperones and the ubiquitin-proteasome system. There is a wealth of evidence indicating close ties between the nutrient signaling pathway and the intracellular stress response. Dysregulation of both systems has been implicated in aging and age-associated pathologies. In this review, we describe molecular mechanisms underlying the connection between mTOR and the chaperone network and discuss the importance of their functional interaction in growth and aging. PMID- 21555916 TI - Hiding from intracellular pattern recognition receptors, a passive strategy of flavivirus immune evasion. AB - Tick-borne encephalitis virus (TBEV) is a medically important flavivirus in Europe and Asia, causing meningitis and encephalitis in thousands of people annually. Despite its relevance for public health, the interaction of TBEV with the type I interferon (IFN) system is poorly characterized. Induction of these antiviral cytokines is normally triggered by cytoplasmic recognition of viral signature molecules such as double-stranded (ds) RNA. In a recent paper, we showed that TBEV infection leads to formation of intracellular membrane vesicles which protect the viral dsRNA from cellular recognition. This delays the onset of antiviral IFN production sufficiently enough for an unhindered release of progeny viruses over 24 h. Thus, TBEV has evolved a stealth strategy to outrun the antiviral IFN response. PMID- 21555917 TI - The role of horizontal gene transfer in Staphylococcus aureus host adaptation. AB - Staphylococcus aureus is an important human pathogen that also causes economically important infections of livestock. In a recent paper, we employed a population genomic approach to investigate the molecular basis of ruminant host adaptation by S. aureus. The data suggest that the common pathogenic clone associated with small ruminants originated in humans but has since adapted to its adopted host through a combination of allelic diversification, gene loss and acquisition of mobile genetic elements. In particular, a new subfamily of staphylococcal pathogenicity islands (SaPI) was identified encoding a novel von Willebrand factor-binding protein (vWBP) with ruminant-specific coagulase activity. The wide distribution of vWBP-encoding SaPIs among ruminant strains implies an important role in host-adaptation. In the current article we summarize the findings of the paper and comment on the implications of the study for our understanding of the molecular basis of bacterial host adaptation. PMID- 21555918 TI - Apoptotic and autophagic responses to photodynamic therapy in 1c1c7 murine hepatoma cells. AB - Photodynamic therapy (PDT) is a process that can induce apoptosis, autophagy or both depending on the cell phenotype. Apoptosis is a pathway to cell death while autophagy can protect from photokilling or act as a death pathway. In a previous study, we reported a cytoprotective effect of autophagy in murine leukemia cell lines where both autophagy and apoptosis occur within minutes after irradiation of photosensitized cells. In this study, we examined the effects of mitochondrial photodamage catalyzed by low (<= 1 MUM) concentrations of the photosensitizing agent termed benzoporphyrin derivative (BPD, Verteporfin) on murine hepatoma 1c1c7 cells. Apoptosis was not observed until several hours after irradiation of photosensitized cells. Autophagy was clearly cytoprotective since PDT efficacy was significantly enhanced in a knockdown sub-line (KD) in which the level of a critical autophagy protein (Atg7) was markedly reduced. This result indicates that autophagy can protect from phototoxicity even when apoptosis is substantially delayed. Much higher concentrations (>= 10 MUM) of BPD had previously been shown to inhibit autophagosome formation. Phototoxicity studies performed with 10 MUM BPD and a proportionally reduced light dose were consistent with the absence of an autophagic process in wild-type (WT) cells under these conditions. PMID- 21555919 TI - Hepatic stellate cells and astrocytes: Stars of scar formation and tissue repair. AB - Scar formation inhibits tissue repair and regeneration in the liver and central nervous system. Activation of hepatic stellate cells (HSCs) after liver injury or of astrocytes after nervous system damage is considered to drive scar formation. HSCs are the fibrotic cells of the liver, as they undergo activation and acquire fibrogenic properties after liver injury. HSC activation has been compared to reactive gliosis of astrocytes, which acquire a reactive phenotype and contribute to scar formation after nervous system injury, much like HSCs after liver injury. It is intriguing that a wide range of neuroglia-related molecules are expressed by HSCs. We identified an unexpected role for the p75 neurotrophin receptor in regulating HSC activation and liver repair. Here we discuss the molecular mechanisms that regulate HSC activation and reactive gliosis and their contributions to scar formation and tissue repair. Juxtaposing key mechanistic and functional similarities in HSC and astrocyte activation might provide novel insight into liver regeneration and nervous system repair. PMID- 21555923 TI - Relative source contribution of perchlorate and other goitrogens in newborn thyroid function. PMID- 21555920 TI - Disulfide mapping reveals the domain swapping as the crucial process of the structural conversion of prion protein. AB - Prion diseases are infectious conformational diseases. Despite the determination of many native prion protein (PrP) structures and in vitro production of infectious prions from recombinant PrP the structural background of PrP conversion remains the largest unsolved problem. The aggregated state of PrP (Sc) makes it inaccessible to high resolution techniques, therefore indirect methods have to be used to investigate the conversion process. We engineered disulfide bridges into the structured domain of PrP in order to determine the secondary structure elements that remain conserved upon conversion. Rather surprisingly, introduction of disulfides into each or both of the subdomains B1-H1-B2 and H2-H3 of the C-terminal globular domain retained the robust ability to convert into fibrils with increased content of beta-structure, indistinguishable from the wild type PrP. On the other hand disulfide bridges tethering the two subdomains completely prevented conversion, while their reduction reversed their conversion ability. The same conversion propensity was replicated also in prion infected cell lines. Experiments with combinations of engineered cysteine residues further support that domain swapping, centered on the B2-H2 loop, previously associated to species barrier, leads to PrP swapped dimers as the building block of prion fibrils. PMID- 21555925 TI - Assault rates and implementation of a workplace violence prevention program in the Veterans Health Care Administration. AB - OBJECTIVE: This study examined the relationship between changes in assault rates over time and the implementation of a workplace violence prevention (WVP) program in 138 Department of Veterans Affairs health care facilities. METHODS: Data on WVP implementation were assessed for each facility by a three-person team. We computed three WVP dimension scores: training, workplace practices, and environmental control and security. We obtained 6 years of assault rate data from the national injury system. Using a linear mixed model, we analyzed whether the WVP implementation was associated with lower assault rates controlling for time and organizational characteristics. RESULTS: Training implementation was negatively associated with assault rates. Facilities with smaller bed sizes and without academic affiliates had lower assault rates. CONCLUSIONS: Particular attention should be given to these dimensions because they may be associated with lower facility-level assault rates. PMID- 21555926 TI - Spirometry in the occupational health setting--2011 update. PMID- 21555927 TI - How can I get managers in my organizations to make their employee referrals to me effective? PMID- 21555930 TI - Neoadjuvant accelerated concomitant boost radiotherapy and multidrug chemotherapy in locally advanced rectal cancer: a dose-escalation study. AB - OBJECTIVES: To determine the maximal and safely dose of preoperative radiotherapy and concurrently intensified chemotherapy regimen (raltitrexed plus oxaliplatin) in locally advanced rectal cancer patients. METHODS: Patients with cT3-T4 and/or cN>=1 or locally recurrent rectal cancer were sequentially assigned to 4 treatment schedules of chemoradiation: standard radiotherapy (50.4 Gy/5.5 wk) plus raltitrexed (cohort A), accelerated radiotherapy (55 Gy/5 wk) plus raltitrexed (cohort B), standard radiotherapy plus raltitrexed and oxaliplatin (cohort C), accelerated radiotherapy plus raltitrexed and oxaliplatin (cohort D). Patients were treated in cohorts of 6 to 12 per group. The maximal tolerated dose was exceeded if more than one-third of patients in a given cohort experienced dose-limiting toxicity (DLT). DLT was defined as any grade >=3 toxicity according to the Radiation Therapy Oncology Group criteria. RESULTS: Forty-six consecutive patients were enrolled. In cohort A, 6 patients received the planned treatment with no DLT. In cohort B, 1 of 8 patients experienced a DLT. In cohort C, a DLT occurred in 2 of 6 patients and therefore, a cohort expansion was required. Three of 16 patients treated at this dose level experienced a DLT. In addition, cohort D was expanded and DLT was found in 4 of 16 patients. Therefore, the maximal tolerated dose was not exceeded at any treatment level. CONCLUSIONS: An intensified regimen of chemoradiotherapy delivering raltitrexed and oxaliplatin concurrently with concomitant boost radiotherapy (55 Gy/5 wk) can be safely administered in patients with locally advanced rectal cancer. On the basis of these results, this intensified regimen could be tested in a phase II study. PMID- 21555931 TI - Management of single malignant lung nodules in elderly patients (70 years or older) who are not candidates for lobectomy. AB - PURPOSE: The aim of this study was to evaluate and compare sublobar resection plus intraoperative seed implant (IOS) versus stereotactic body radiation therapy (SBRT) in patients with single malignant lung nodules in patients 70 years of age or older. MATERIALS AND METHODS: A retrospective chart review was performed and 47 patients with adequate information were selected for analysis. Thirty patients with single malignant lung nodules received SBRT. Seventeen patients received limited surgical resection plus radioactive seed implantation for solitary malignant lung nodules. Univariate statistical analysis showed a significant difference only for the age in the 2 groups: the mean age in the radioactive seed group, 78.8 years versus 76.1 years in the SBRT group (2-sided, P=0.05). RESULTS: There was high local control and minimal toxicity with either treatment modality and no significant difference among the 2 groups in terms of local control, survival, and toxicity. However, the distant failure was higher but not statistically significant in the SBRT group (9 of 30 patients in SBRT vs. 0 of 17 in IOS, P=0.1). CONCLUSIONS: Our study has shown excellent outcomes and limited toxicity in both IOS and SBRT for treatment of single malignant lung nodules in patients who are not candidates for lobectomy. However, a randomized trial is needed in this group of elderly patients to determine the most appropriate treatment. PMID- 21555932 TI - Gemcitabine and docetaxel for hepatocellular carcinoma: a phase II North Central Cancer Treatment Group clinical trial. AB - OBJECTIVES: Few effective options are available for the treatment of unresectable hepatocellular carcinoma (HCC). Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel. METHODS: Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m (later reduced to 30 mg/m) and gemcitabine 800 mg/m on days 1 and 8 every 3 weeks. Twenty-five patients were enrolled in 26 months. Median age was 64 (range, 27-078), 17 were male, 14 had liver-only disease, and 11 had extrahepatic disease. RESULTS: Of 25 patients evaluable for the primary end point (response), 2 (8%) have a confirmed partial response. The median time to progression is 2.76 months (95% confidence interval, 1.84-6.64 mo). Median survival was 12.8 months (95% confidence interval, 5.26-28.00). Two patients died on study owing to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. Twenty patients (81%) have experienced grade 3+ adverse events, including 11 with grade 4+ adverse events, primarily neutropenia, thrombocytopenia, diarrhea, and fatigue. CONCLUSIONS: Although this combination seems to have potential benefit, as measured by overall survival, its toxicity and the recent introduction of sorafenib has further limited the use of chemotherapy. Approaches other than chemotherapy are likely to be of the greatest potential benefit. PMID- 21555933 TI - Phase I study of pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced non-small cell lung cancer. AB - OBJECTIVES: Concurrent chemoradiotherapy in well-selected locally advanced non small cell lung cancer (LANSCLC) is considered as standard therapy. However, the choice of anticancer agents is still unresolved. Our objectives were to determine the maximum tolerated dose and recommended dose of pemetrexed in combination with cisplatin, with concurrent late course accelerated hyperfractionated (LCAF) intensity modulated radiotherapy (IMRT) in patients with LANSCLC and to investigate the safety and efficacy. METHODS: The chemotherapy was cisplatin (25 mg/m(2) * 3 days) plus pemetrexed with doses escalating from 400 to 500 mg/m(2). The dose level was increased every 3 patients. The gross tumor volumes of concurrent LCAF IMRT were delineated according to [(18)F] fluorodeoxyglucose positron emission tomography computed tomography imaging. To spare functional lung, single photon emission photography lung perfusion imaging was used to optimize the plans. The total radiation dose was limited such that the V20 of bilateral lung is no more than 35%. RESULTS: Nine patients with LANSCLC were enrolled in this study. The median radiation dose was 70.8 Gy. The response rate was 66.7% with a complete remission rate of 33.3%. Toxicity was mild with only 1 patient experiencing dose limiting toxicity in 500 mg/m(2) level. Obviously, the maximum tolerated dose was not reached as per the definition. As the systemically active chemotherapy dose was reached, further dose escalation was discontinued, and the recommended dose of pemetrexed for a phase II study was 500 mg/m(2). CONCLUSIONS: The combination of pemetrexed and cisplatin with concurrent LCAF IMRT optimized based on single photon emission photography lung perfusion imaging is well tolerated in patients with LANSCLC. Full therapeutic doses of the chemotherapy can be safely administered. The initial results showed signs of efficacy. PMID- 21555934 TI - Spinal anesthesia in infant rats: development of a model and assessment of neurologic outcomes. AB - BACKGROUND: Previous studies in infant rats and case-control studies of human infants undergoing surgery have raised concerns about potential neurodevelopmental toxicities of general anesthesia. Spinal anesthesia is an alternative to general anesthesia for some infant surgeries. To test for potential toxicity, a spinal anesthesia model in infant rats was developed. METHODS: Rats of postnatal ages 7, 14, and 21 days were assigned to no treatment, 1% isoflurane for either 1 h or 6 h, or lumbar spinal injection of saline or bupivacaine at doses of 3.75 mg/kg (low dose) or 7.5 mg/kg (high dose). Subgroups of animals underwent neurobehavioral testing and blood gas analysis. Brain and lumbar spinal cord sections were examined for apoptosis using cleaved caspase-3 immunostaining. The lumbar spinal cord was examined histologically.Rats exposed to spinal or general anesthesia as infants underwent Rotarod testing of motor performance as adults. Data were analyzed using ANOVA with general linear models, Friedman tests, and Mann-Whitney U tests, as appropriate. RESULTS: Bupivacaine 3.75 mg/kg was effective for spinal anesthesia in all age groups. Impairments in sensory and motor function recovered in 40-60 min. Blood gases were similar among groups. Brain and spinal cord apoptosis increased in rats receiving 6 h of 1% isoflurane, but not among the other treatments. All groups showed intact motor performance at adulthood. CONCLUSIONS: Spinal anesthesia is technically feasible in infant rats and appears benign in terms of neuroapoptotic and neuromotor sequelae. PMID- 21555935 TI - Case scenario: anesthesia for maternal-fetal surgery: the Ex Utero Intrapartum Therapy (EXIT) procedure. PMID- 21555936 TI - An evaluation of using population pharmacokinetic models to estimate pharmacodynamic parameters for propofol and bispectral index in children. AB - BACKGROUND: To study propofol pharmacodynamics in a clinical setting a pharmacokinetic model must be used to predict drug plasma concentrations. Some investigators use a population pharmacokinetic model from existing literature and minimize the pharmacodynamic objective function. The purpose of the study was to determine whether this method selects the best-performing pharmacokinetic model in a set and provides accurate estimates of pharmacodynamic parameters in models for bispectral index in children after propofol administration. METHODS: Twenty eight children classified as American Society of Anesthesiologists physical status 1 who were given general anesthesia for dental treatment were studied. Anesthesia was given using target-controlled infusion of propofol based on the Kataria model. Propofol target plasma concentration was 7 MUg/ml for 15 min, followed by 1 MUg/ml for 15 min or until signs of awakening, followed by 5 MUg/ml for 15 min. Venous blood samples were taken 1, 2, 5, 10, and 15 min after each change in target. A classic pharmacokinetic-pharmacodynamic model was estimated, and the methodology of other studies was duplicated using pharmacokinetic models from the literature and (re-)estimating the pharmacodynamic models. RESULTS: There is no clear relationship between pharmacokinetic precision and the pharmacodynamic objective function. Low pharmacodynamic objective function values are not associated with accurate estimation of the pharmacodynamic parameters when the pharmacokinetic model is taken from other sources. CONCLUSION: Minimization of the pharmacodynamic objective function does not select the most accurate pharmacokinetic model. Using population pharmacokinetic models from the literature instead of the 'true' pharmacokinetic model can lead to better predictions of bispectral index while incorrectly estimating the pharmacodynamic parameters. PMID- 21555937 TI - Bronchopleural fistulae and pulmonary ossification in posttraumatic acute respiratory distress syndrome: successful treatment with extracorporeal support. AB - We report a case of severe posttraumatic acute respiratory distress syndrome (ARDS) complicated by bronchopleural fistulae (BPF). The stiff ARDS lung and huge air leaks from BPF resulted in the failure of different protective mechanical ventilation strategies to provide viable gas exchange. Lung rest, achieved by extracorporeal carbon dioxide removal (ECCO2R), allowed weaning from mechanical ventilation, closure of BPF, and resumption of spontaneous breathing. PMID- 21555938 TI - Dissociable effects of ultralow-dose naltrexone on tolerance to the antinociceptive and cataleptic effects of morphine. AB - Ultralow-dose opioid antagonists augment the antinociceptive effect of morphine and block the development of tolerance to repeated morphine injections in rodents, but the effects are not reliably reproduced in humans. One explanation for this discrepancy is that preclinical studies of ultralow-dose antagonism in rodents generally use reflex-withdrawal tests of antinociception, which may be affected by cataleptic effects of morphine. We tested this hypothesis by examining whether ultralow-dose naltrexone alters the cataleptic effect of morphine or the development of tolerance to morphine-induced catalepsy. Rats (N=56) were randomly assigned to saline, morphine (10 mg/kg), cotreatments of morphine plus naltrexone (molar ratios of 1,000,000 : 1; 500,000 : 1; 100,000 : 1), or naltrexone-alone groups. Rats were injected with drug for 7 consecutive days; on each day, catalepsy and antinociception were assessed 30 and 60 min postinjection, using the bar and tail-flick tests, respectively. Ultralow-dose naltrexone (500,000 : 1) extended the antinociceptive effect of morphine within a session and attenuated the development of tolerance to the antinociceptive effect of morphine across sessions. Naltrexone alone had no effect on either test. These data show that the paradoxical effect of ultralow-dose naltrexone on antinociception is not the product of morphine-induced catalepsy, pointing to an important role for agonist-antagonist combinations in the clinical treatment of pain. PMID- 21555940 TI - Biomarker profiles as descriptors of left ventricular remodeling after acute myocardial infarction. AB - BACKGROUND: Biomarker expression can predict subsequent cardiovascular events. The goal of this study was to determine the pattern of expression in blood of a broad array of cytokines and growth factors taken 24-72 h after an ST elevation myocardial infarction (STEMI) involving the left anterior descending (LAD) coronary artery. METHODS: Blood was taken from 16 patients with LAD STEMI. Cytokine and growth factor expressions were quantified with the use of a Milliplex cytokine/chemokine array analysis that tested 42 analytes. Results from patients were compared with those in blood from 20 healthy volunteers. RESULTS: Most (15/16) participants had positive remodeling without reduction in left ventricular function during follow-up. Analytes were grouped based on their function into those that activate class 1 T-helper cells (Th1 activates cell mediated immunity), those that activated a Th2 response (activates humoral immunity and attenuates cell-mediated immunity), chemokines (attract leukocytes), and growth factors (promote a healing response). Elevation of cytokines involved in the Th2 response predominated over the Th1 response demonstrating a balance favoring tolerance and limiting activation of cell-mediated immunity. The concentration of selected chemokines favoring cell-mediated immunity was not elevated. The concentration of selected growth factors was increased. CONCLUSION: The cytokine expression, 24-72 h after an LAD STEMI, suggests that positive ventricular remodeling is associated with growth factor expression and limitation of cell-mediated immunity. Subsequent studies are warranted to determine whether deviation from this pattern identifies patients at an increased risk of adverse remodeling after myocardial infarction. PMID- 21555939 TI - Admission with metabolic disorder is a useful predictor of the 1-year prognosis for patients with unstable angina, but not for patients with acute myocardial infarction: east-Osaka acute coronary syndrome registry. AB - BACKGROUND: For patients with acute myocardial infarction (AMI), several studies have examined the relationship between the metabolic syndrome and prognostic outcome. However, few studies have revealed an association between the metabolic syndrome and clinical outcomes in patients with unstable angina (UA). This study compared the differences in the usefulness of recognizing metabolic disorders for the prediction of a 1-year prognosis in patients with UA and AMI. METHODS: The study cohort consisted of 1173 patients with a mean age of 67 years. The focus was on general prognostic factors and five metabolic disorders (body mass index; hypertension; blood glucose/diabetes mellitus; and, serum concentrations of triglycerides and high-density lipoprotein cholesterol) at the time of admission. RESULTS: According to multivariate logistic regression analysis, metabolic scores on admission positively related to 1-year mortality or major adverse cardiovascular events (MACE) for patients with UA, but not for those with AMI, with an increase in either all-causes mortality or MACE being associated with the degree of metabolic dysfunction. No other general prognostic factors were related to either 1-year mortality or MACE in patients with UA. By contrast, general prognostic factors such as age and the Killip classification had a positive effect on 1-year mortality or on MACE for the patients with AMI. CONCLUSION: Accumulation of the effects of each metabolic disorder may affect mortality and MACE for patients with UA. PMID- 21555941 TI - Adult post-transplant lymphoproliferative disease in the liver graft in patients with recurrent hepatitis C. AB - AIM: The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft. METHODS: Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2). RESULTS: The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0+/-2.1 vs. 2.0+/-0.7, P=0.037), fibrosis stage (2.4+/-0.5 vs. 0.7+/-0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6+/-14.8% vs. 1.1+/-2.3%, P=0.0002). CONCLUSION: When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft. PMID- 21555942 TI - Active choice but not too active: public perspectives on biobank consent models. AB - PURPOSE: Despite important recent work, US public attitudes toward specific biobank consent models are not well understood. Public opinion data can help shape efforts to develop ethically sound and publicly trusted mechanisms for informing and consenting prospective biobank donors. The purpose of this study was to explore public perspectives toward a range of consent models currently being used or considered for use among comprehensive US biobanks. METHODS: The study used an exploratory mixed-methods design, using focus groups and telephone surveys. Eligible participants were English-speaking residents in the catchment area of a comprehensive biobank being developed at the University of Iowa. RESULTS: Forty-eight participants in seven focus groups and 751 survey participants were recruited. Biobanks were unfamiliar to almost all study participants but were seen as valuable resources. Most focus group (63%) and survey (67%) participants preferred a prospective opt-in over an opt-out consent approach. Broad, research-unspecific consent was preferred over categorical and study-specific consent models for purposes of approving future research use. CONCLUSION: Many individuals may want to make an active and informed choice at the point of being approached for biobank participation but are prepared to consent broadly to future research use and to forego additional choices as a result. PMID- 21555943 TI - Clinical trials for pharmacogenomics testing for warfarin dosing: relevance to general community practices. PMID- 21555944 TI - Educational needs about cancer family history and genetic counseling for cancer risk among frontline healthcare clinicians in New York City. AB - PURPOSE: This study investigated the educational needs of frontline healthcare clinicians about cancer family history and genetic counseling for cancer risk. METHODS: We conducted a voluntary, anonymous survey among (1) general medicine clinicians, (2) obstetrics/gynecology clinicians, and (3) nurse practitioners at Mount Sinai School of Medicine in New York City. RESULTS: A total of 143 clinicians completed the survey (response rate 81%). The majority of clinicians (77.5%) reported regularly completing family histories on cancer risk for their patients, but only 1.7% considered themselves "experts" in interpreting risk to make prevention, screening, and treatment recommendations. Numerous barriers to cancer family history collection were noted. More than half (55.8%) reported referring patients to genetic counseling, although only 14.3% reported confidence in their ability to make appropriate referrals. The majority reported that they would apply genetic counseling for cancer risk in their practice if they had the skills (84.9%). There was some variability found regarding specialty. CONCLUSION: Despite widespread use of family histories for cancer risk, barriers remain to appropriate cancer risk management among frontline healthcare clinicians. Development of educational training programs to assist clinicians with collection of cancer family history information, interpretation, and appropriate referral along with teaching direct application of a modified form of genetic counseling for low-medium risk patients and referral of patients at genetic risk is warranted. PMID- 21555945 TI - Comparison of compliance for colorectal cancer screening and surveillance by colonoscopy based on risk. AB - PURPOSE: To compare colonoscopy screening/surveillance rates by level of risk for colorectal cancer based on age, personal history of adenomatous polyps or colorectal cancer, or family history of colorectal cancer. METHODS: Participants were aged 30-90 years, were seen within 5 years at Intermountain Healthcare, and had family history in the Utah Population Database. Colonoscopy rates were measured for those with/without risk factors. RESULTS: Among those aged 60-69 years, 48.4% had colonoscopy in the last 10 years, with rates declining after age 70 years. Percentages of those having had a colonoscopy in the last 10 years generally increased by risk level from 38.5% in those with a familial relative risk <1.0 to 47.6% in those with a familial relative risk >3.0. Compared with those with no family history, the odds ratio for being screened according to guidelines was higher for those with one first-degree relative diagnosed with colorectal cancer >= 60 years or two affected second-degree relatives (1.54, 95% confidence interval: 1.46-1.61) than those with one affected first-degree relative diagnosed <60 years or >=2 affected first-degree relatives (1.25, 95% confidence interval: 1.14-1.37). CONCLUSIONS: Compliance with colonoscopy guidelines was higher for those with familial risk but did not correspond with the degree of risk. PMID- 21555946 TI - Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report. AB - Approximately 1.1 billion people currently live in countries where consanguineous marriages are customary, and among them one in every three marriages is between cousins. Opinions diverge between those warning of the possible health risks to offspring and others who highlight the social benefits of consanguineous marriages. A consanguinity study group of international experts and counselors met at the Geneva International Consanguinity Workshop from May 3, 2010, to May 7, 2010, to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. The group highlighted the importance of evidence-based counseling recommendations for consanguineous marriages and of undertaking both genomic and social research in defining the various influences and outcomes of consanguinity. Technological advances in rapid high-throughput genome sequencing and for the identification of copy number variants by comparative genomic hybridization offer a significant opportunity to identify genotype-phenotype correlations focusing on autozygosity, the hallmark of consanguinity. The ongoing strong preferential culture of close kin marriages in many societies, and among migrant communities in Western countries, merits an equivalently detailed assessment of the social and genetic benefits of consanguinity in future studies. PMID- 21555947 TI - Down syndrome: coercion and eugenics. AB - Experts agree that coercion by insurance companies or governmental authorities to limit reproductive choice constitutes a eugenic practice. We discuss discrimination against families of children with Down syndrome who chose not to have prenatal testing or chose to continue a pregnancy after a prenatal diagnosis. We argue that this discrimination represents economic and social coercion to limit reproductive choice, and we present examples of governmental rhetoric and policies condoning eugenics and commercial policies meeting criteria established by experts for eugenics. Our purpose is to sensitize the clinical genetics community to these issues as we attempt to provide the most neutral nondirective prenatal genetic counseling we can, and as we provide postnatal care and counseling to children with Down syndrome and their families. We are concerned that if eugenic policies and practices targeting individuals with Down syndrome and their families are tolerated by clinical geneticists and the broader citizenry, then we increase the probability of eugenics directed toward other individuals and communities. PMID- 21555948 TI - Phenylalanine hydroxylase deficiency. AB - Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120-360 MUmol/L (2-6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R tetrahydrobiopterin stereoisomer. Special consideration must be given to adult women with hyperphenylalaninemia because of the teratogenic effects of phenylalanine. Women with phenylalanine hydroxylase deficiency considering pregnancy should follow special guidelines and assure adequate energy intake with the proper proportion of protein, fat, and carbohydrates to minimize risks to the developing fetus. Molecular genetic testing of the phenylalanine hydroxylase gene is available for genetic counseling purposes to determine carrier status of at risk relatives and for prenatal testing. PMID- 21555949 TI - Complication during postacute rehabilitation: patients with posttraumatic hydrocephalus. AB - The objective of this study was to determine the incidence of posttraumatic hydrocephalus (PTH) among patients in our rehabilitation unit for traumatic brain injury. Furthermore, we aimed to assess the effect of shunt implantation and to identify the postoperative complication rate. This is a retrospective cohort study, in which between 2000 and 2009, data were collected from inpatients with traumatic brain injury complicated by PTH. During this period, 55 patients in our unit presented with PTH; all of these patients underwent ventricular shunt implantation. The incidence of PTH treated with shunt implantation was 4.8%. The mean age of the patients was 32 years (range 14-75 years). In 22 cases, the hydrocephalus was diagnosed in our rehabilitation unit (40%). Other patients were diagnosed and shunted before being transferred to our department. The median time of shunting was 80 days (range 20-270 days) after brain trauma. On the basis of scores of the functional independence measure, improvement could be observed in 43 cases (78%), the mean score improvement was 40 (2-81). Postoperative complications were seen in 10 patients (18%): four due to infections and six due to shunt failure. Revision was necessary in all 10 cases. Almost half of the diagnoses of PTH were established in the postacute rehabilitation unit, and all complications after shunt implantation were also recognized there. Precise clinical observation is necessary for diagnosis of PTH. Early diagnosis and treatment are important to prevent secondary complications. Teamwork and good cooperation between acute and postacute care are necessary for successful rehabilitation of patients with traumatic brain injury. PMID- 21555950 TI - Clostridium difficile diarrhea and fecal transplantation. PMID- 21555951 TI - What's in a name? Putting patients first: biofeedback for irritable bowel syndrome patients with dyssynergic defecation. PMID- 21555952 TI - The microbiota and colonic neoplasia: an emerging link? PMID- 21555953 TI - Current practice and perception of screening for medication adherence in inflammatory bowel disease. AB - BACKGROUND: Adherence to medication in inflammatory bowel disease (IBD) improves outcomes. Current practices of screening for adherence to IBD medications are unknown. The goal of this study was to determine current practice and perception of screening for medication adherence among US-based gastroenterologists. METHODS: A survey was mailed electronically to gastroenterologists whose electronic-mail address was listed in the American College of Gastroenterology database. Physicians who cared for IBD patients were invited to answer. RESULTS: About 6830 surveys were sent to gastroenterologists nationwide, and 395 physicians who cared for IBD patients completed the survey. The true response rate is unknown, as the number of physicians caring for IBD patients in the database is unknown. About 77% (n = 303) of physicians who responded stated they screen for adherence to medication. Of the 77% of physicians who screened for adherence, only 19% (n = 58) use accepted measures of screening for adherence (pill counts, prescription refill rates, or adherence surveys). The remaining 81% used patient interview to screen for adherence, a measure considered least accepted to determine adherence, as it overestimates adherence. The average number of IBD patients observed in 1 week had no statistical significance in predilection for screening (P = 0.82). Private practice physicians (P = 0.05), younger physicians (P = 0.03), and physicians with fewer years of experience (P = 0.02) all were more likely to screen. About 95% of responders thought determining a low adherer to medicine was important because an intervention can increase adherence. CONCLUSIONS: The majority of gastroenterologists surveyed recognize that adherence to medication is important and improves outcomes. The majority of physicians in this study are screening for nonadherence in IBD, but are not using accepted measures for adherence detection. If this study truly reflects the majority of physicians nationwide, changing the way physicians screen for adherence, may detect more low adherers to medication. PMID- 21555954 TI - Modified fecal transplantation. PMID- 21555955 TI - Treatment of irritable bowel syndrome with Saccharomyces boulardii. PMID- 21555956 TI - The changing yardstick in measurement of cognitive abilities in infancy. AB - There are concerns regarding accurate measurement of cognitive function in infants, particularly those at biologic risk. Herein we discuss these issues and make recommendations. Concerns include: 1) secular changes in test norms, referred to as the Flynn effect; 2) changes in the content of revised test versions; 3) recent findings of higher mean scores in newer test versions when compared to previous scores; and 4) correction for prematurity. Caution is necessary when comparing the same test scores over extended periods of time, and using different versions of the same test when mean scores of the tests vary or evaluate different areas of functioning. Ideal solutions are not readily apparent and thus we provide several suggestions: control groups are essential for longitudinal studies; clinicians should not rely totally on cognitive scores; and further investigation of the Flynn effect in different subgroups of children at different ages is necessary. PMID- 21555957 TI - The prevalence of gastrointestinal problems in children across the United States with autism spectrum disorders from families with multiple affected members. AB - OBJECTIVE: : To perform a large registry-based study to determine the relative prevalence of gastrointestinal (GI) problems in children with an autism spectrum disorder (ASD) from families with multiple affected members compared with their unaffected sibling(s). METHODS: : In-home structured retrospective medical history interviews by parent recall were conducted by a pediatric neurologist. Our analysis sample included information about GI health of 589 subjects with idiopathic, familial ASD and 163 of their unaffected sibling controls registered with Autism Genetic Resource Exchange. Individuals with ASD were subgrouped into 3 autism severity groups (Full Autism, Almost Autism, and Spectrum) based on their Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale scores. RESULTS: : Parents reported significantly more GI problems in children with ASD (249/589; 42%) compared with their unaffected siblings (20/163; 12%) (p < .001). The 2 most common Gl problems in children with ASD were constipation (116/589; 20%) and chronic diarrhea (111/589; 19%). Conditional logistic regression analysis showed that having Full Autism (adjusted odds ratio [AOR] = 14.28, 95% confidence interval [CI]: 6.22-32.77) or Almost Autism (AOR = 5.16, 95% CI 2.02-13.21) was most highly associated with experiencing GI problems. Increased autism symptom severity was associated with higher odds of GI problems (AOR for trend = 2.63, 95% CI: 1.56-4.45). CONCLUSIONS: : Parents report significantly more GI problems in children with familial ASD, especially those with Full Autism, than in their unaffected children. Increased autism symptom severity is associated with increased odds of having GI problems. PMID- 21555959 TI - Exercise-Induced Muscle Damage is Not Attenuated by Maximuscle beta-Hydroxy-beta Methylbutyrate-1000TM Supplementation. PMID- 21555958 TI - Infectious complications in pediatric acute liver failure. AB - OBJECTIVES: Acute liver failure (ALF) is rare in children but carries high mortality. Infectious complications (IC) in adults are an important cause of mortality; however, there are few data in the pediatric population. The aim of the study was to determine the incidence of IC and their effects on the outcome in children with ALF. MATERIALS AND METHODS: The present study is a retrospective review of the case records of children presenting with ALF to our center. All patients with ALF received antibiotics and antifungal as prophylaxis from day 1 and high-dose acyclovir was given to neonates only (stopped when herpes simplex was ruled out). Biochemical parameters, duration of ventilation and intensive care, overall hospital stay, and patient outcome were compared between patients with IC and non-IC. RESULTS: A total of 145 children (78 boys), median (range) age 4.22 (1 day-16 years) years, were studied. Thirty-seven of 145 (25%) patients had proven IC. The predominant infections included 14 episodes of bacteremia in 13 patients and lower respiratory tract infection and urinary tract infection in 10 and 8 patients, respectively. IC occurred in patients after a median (range) duration of 16 (0-54) days of admission. Median (range) duration of hospital stay in patients with IC was 38 (1-201) days and was significantly higher than in those without IC (10 [1-74] days), P < 0.0001. Overall mortality was 21% (31), of which 7% (11) was from the IC group and 14% (20) from the non-IC group; the difference was not statistically significant. CONCLUSIONS: Infections were more frequent after 2 weeks of admission. Patients with sepsis had longer hospital stays and prolonged ventilation. Invasive fungal infections were rare in pediatric ALF with adequate doses of antifungal prophylaxis. PMID- 21555960 TI - Effects of tai chi training in dynapenic and nondynapenic postmenopausal women. AB - OBJECTIVE: The purpose of the present study was to investigate the effects of a 12-week tai chi program in type I dynapenic and nondynapenic postmenopausal women. METHODS: Sixty-two postmenopausal women were recruited. Body composition, handgrip strength, functional capacities, cardiorespiratory functions (forced expiratory volume in 1 s and oxygen consumption per unit time peak), and quality of life (36-item Short-Form Health Survey) were measured before and after the intervention. RESULTS: Type I dynapenic postmenopausal women showed a significant decrease in body weight (P = 0.004), fat mass percentage (P = 0.02), and skeletal muscle mass (SM; in kilograms; P = 0.02), whereas handgrip strength (in kilograms per SMkg; P = 0.04), functional capacity test scores (P <= 0.050), and general health perception (P = 0.01) significantly increased. In nondynapenic postmenopausal women, we observed a significantly decreased waist circumference (P = 0.04) and a significantly increased chair-stand test (P < 0.001) and one-leg stance test (P = 0.04) scores. In addition, significantly lower systolic (P <= 0.001) and diastolic (P <= 0.005) blood pressures were observed in both groups after the intervention. Finally, type I dynapenic women showed a more pronounced general health perception increase compared with nondynapenic individuals (P = 0.03). CONCLUSIONS: Tai chi training improved body composition, muscle strength, functional capacities, and general health perception in postmenopausal women, and this last improvement was more pronounced in type I dynapenic individuals. Therefore, tai chi may be considered as an alternative physical training method in preventing the occurrence of disabilities and frailty in postmenopausal women with type I dynapenia. PMID- 21555961 TI - Performance of the American College of Obstetricians and Gynecologists' ovarian tumor referral guidelines with a multivariate index assay. AB - OBJECTIVE: The American College of Obstetricians and Gynecologists (the College) published referral guidelines for women with a pelvic mass that incorporate CA 125. A new multivariate index assay assesses the malignant risk of ovarian tumors before surgery. Our objective was to estimate the performance of the College guidelines with this new multivariate index assay. METHODS: This prospective, multi-institutional trial included 27 primary care and specialty sites throughout the United States. The College guidelines were evaluated in women scheduled for surgery for an ovarian mass. Clinical criteria and blood for biomarkers were collected before surgery. A standard CA 125-II assay was used and the value applied to the multivariate index assay algorithm and the CA 125 analysis. Study results were correlated with surgical pathology. RESULTS: Of the 590 women enrolled with ovarian mass on pelvic imaging, 516 were evaluable. There were 161 malignancies (45 premenopausal and 116 postmenopausal). The College referral criteria had a modest sensitivity in detecting malignancy. Replacing CA 125 with the multivariate index assay increased the sensitivity (77-94%) and negative predictive value (87-93%) while decreasing specificity (68-35%) and positive predictive value (52-40%). Similar trends were noted for premenopausal women and early-stage disease. CONCLUSION: Replacing CA 125 with the multivariate index assay improves the sensitivity and negative predictive value of the College referral guidelines while decreasing specificity and positive predictive value. The high sensitivity is maintained in premenopausal women and early-stage disease. PMID- 21555962 TI - A comparison of obstetric maneuvers for the acute management of shoulder dystocia. AB - OBJECTIVE: To assess the efficacy of obstetric maneuvers for resolving shoulder dystocia and the effect that these maneuvers have on neonatal injury when shoulder dystocia occurs. METHODS: Using an electronic database encompassing 206,969 deliveries, we identified all women with a vertex fetus beyond 34 0/7 weeks of gestation who incurred a shoulder dystocia during the process of delivery. Women whose fetuses had a congenital anomaly and women with an antepartum stillbirth were excluded. Medical records of all cases were reviewed by trained abstractors. Cases involving neonatal injury (defined as brachial plexus injury, clavicular or humerus fracture, or hypoxic-ischemic encephalopathy or intrapartum neonatal death attributed to the shoulder dystocia) were compared with those without injury. RESULTS: Among 132,098 women who delivered a term cephalic liveborn fetus vaginally, 2,018 incurred a shoulder dystocia (1.5%), and 101 (5.2%) of these incurred a neonatal injury. Delivery of the posterior shoulder was associated with the highest rate of delivery when compared with other maneuvers (84.4% compared with 24.3-72.0% for other maneuvers; P<.005 to P<.001) and similar rates of neonatal injury (8.4% compared with 6.1-14.0%; P=.23 to P=.7). The total number of maneuvers performed significantly correlated with the rate of neonatal injury (P<.001). CONCLUSION: Delivery of the posterior shoulder should be considered following the McRoberts maneuver and suprapubic pressure in the management of shoulder dystocia. The need for additional maneuvers was associated with higher rates of neonatal injury. PMID- 21555963 TI - Re: Biocompatibility of nitinol stapes prosthesis by Roosli, Christof; Schmid, Philipp; and Huber, Alex M. PMID- 21555964 TI - Novel mutation in the homeobox domain of transcription factor POU3F4 associated with profound sensorineural hearing loss. AB - BACKGROUND: Hearing loss affects 1 to 3 in 1,000 newborns, with 50% of these cases because of genetic causes. The majority of these are nonsyndromic (70%), and 2% are X linked. So far, 6 different X-linked loci have been mapped, but the causative gene POU3F4 has been identified only for the Locus DFN3. Clinical features of DFN3 often include a mixed, progressive hearing loss, temporal bone anomalies, and stapes fixation. POU3F4 belongs to a subfamily of transcription factors, which are characterized by 2 conserved deoxyribonucleic acid-binding domains, a POU and a HOX domain, both helix-turn-helix structural deoxyribonucleic acid-binding motifs.Several reports have described mutations of POU3F4 in patients with hearing loss and temporal bone abnormalities. In this study, we describe the clinical features and genetic analysis of a male child from a German family with congenital deafness and a novel POU3F4 mutation. METHOD: Mutational analysis of the affected individual and first-degree relatives was performed using direct sequencing of the coding exon and intron transitions of POU3F4. RESULT: The patient (II-1) had profound hearing loss, a severely dysplastic cochlea, and cerebrospinal fluid gusher during cochlear implantation. Sequence analysis of all family members demonstrated a novel missense mutation at nucleotide position 973, thymine to adenine (c.973 T>A), p.W325R in the patient (II-1), the mother (I-2), and sisters (II-2, II-3) heterozygous. The father (I-1) is not a carrier of the mutation. Conservation of the affected amino acid residue was seen across a number of different species. CONCLUSION: We identified a novel mutation in the third helix of the HOX domain of the POU3F4 transcription factor associated with congenital hearing loss. PMID- 21555965 TI - Lateral versus medial needle approach for ultrasound-guided supraclavicular block: a randomized controlled trial. AB - BACKGROUND: When performing a supraclavicular brachial plexus block (SCB) under ultrasound (US) guidance, the needle may approach the nerves in-plane with the US beam from 1 of 2 directions relative to the transducer, lateral-to-medial (lateral) or medial-to-lateral (medial). We aimed to compare the rates of sensory and motor block of the 4 major peripheral nerves of the upper extremity following a lateral or medial needle approach for US-guided SCB. METHODS: Eighty adult patients undergoing US-guided SCB for elective hand, wrist, forearm, or elbow procedures were randomized to either a lateral or medial needle approach. A 30-mL local anesthetic admixture (1:1 lidocaine 2%-bupivacaine 0.5% with 1:200,000 epinephrine) was injected to all patients. Sensory and motor function was assessed by a blinded observer at predetermined intervals. The primary outcome was the rate of sensory block in the distribution of the ulnar nerve measured 20 mins after block performance. RESULTS: Seventy-two patients were included in the final analysis. Patient characteristics were similar between groups. The rate of ulnar nerve sensory block at 20 mins was 63% in the lateral group and 62% in the medial group (P = 0.81). The rate of ulnar nerve sensory block at 30 mins increased to 89% in the lateral and 84% in the medial group (P = 0.96). The rates of both sensory and motor block in the distributions of the median, radial, and musculocutaneous nerves were high and did not differ between groups at any measured time interval. The block performance time and the postoperative pain scores were similar between the 2 groups. Complications were minor and transient and did not differ between groups. CONCLUSIONS: The rates of sensory and motor block of all 4 major peripheral nerves of the upper extremity did not differ at any time following a lateral compared with medial needle approach for US-guided SCB. Regardless of needle approach, the rate of ulnar nerve sensory block was less compared with the other peripheral nerves following US-guided SCB. PMID- 21555966 TI - Echotexture and correlated histologic analysis of peripheral nerves important in regional anesthesia. AB - BACKGROUND AND OBJECTIVES: Peripheral nerves in different body locations display different echotextures on ultrasound imaging, and knowledge of peripheral nerve echotexture is helpful for locating target nerves. However, the degree of echogenicity is often difficult to characterize. We aimed to define objectively the degree of echogenicity of peripheral nerves using grayscale measurements and compare nerve echotexture with matched histologic samples. METHODS: Ultrasound images of peripheral nerves in 12 body locations were obtained in 20 healthy subjects using linear 8- to 12-MHz and curved 3- to 5-MHZ transducers. Corresponding nerve segments from 2 cadavers were imaged in vitro before they were sectioned for histologic examination. Nerve echogenicity was assessed by an objective grayscale (G) and a subjective echogenicity index (SEI) determined by experienced evaluators. The results of G and SEI in selected peripheral nerves were compared and correlated with histologic morphometry. RESULTS: There is a close correlation between SEI and G (P < 0.05). Mixed echogenicity was seen in 30% of the peripheral nerves; 25.4% were predominantly hypoechogenic, and 44.5% hyperechogenic. Nerves in the neck and upper arm are more frequently hypoechoic, whereas those in the leg are more frequently hyperechoic. Histologically, differences in echogenicity are dependent on fascicle diameter and on nerve fascicular pattern, that is, differing ratios of fascicle number to total nerve area. CONCLUSIONS: This study suggests that grayscales can be used to objectively determine echogenicity and shows that grayscale measurements match well with subjective visual grading. Histologic analysis showed that both ratio of total fascicular area to whole nerve area and fascicular pattern are important determinants of echogenicity. PMID- 21555967 TI - Intravitreal bevacizumab versus combined intravitreal bevacizumab and triamcinolone for neovascular age-related macular degeneration: six-month results of a randomized clinical trial. AB - PURPOSE: To determine whether combined intravitreal bevacizumab (IVB) and triamcinolone (IVT) is more effective than IVB alone in neovascular age-related macular degeneration. METHODS: This was a prospective, randomized clinical trial performed at two centers. Eligible eyes were assigned randomly to one of the two study arms. In the IVB group, 3 consecutive injections of 1.25 mg of bevacizumab were given 6 weeks apart, while in the IVB/IVT group, the first of the triple IVB injections was combined with 2 mg of IVB. A fourth IVB was injected in eyes demonstrating active choroidal neovascularization at Week 24. RESULTS: Sixty and 55 eyes were in the IVB and IVB/IVT groups, respectively. Best-corrected visual acuity improved, and central macular thickness was reduced significantly in both groups at all time points. Visual improvement was more pronounced in the IVB/IVT group compared with the IVB group 6 weeks (8.5 +/- 14.4 vs. 3.8 +/- 8.9 letters, P = 0.04) and 12 weeks (11.8 +/- 16.6 vs. 6.2 +/- 10.8 letters, P = 0.03) after initiation of therapy. However, there was no significant difference in visual improvement at Week 24 (11.3 +/- 17.2 letters in the IVB/IVT group vs. 8.7 +/- 15.6 letters in the IVB group, P = 0.40). The IVB/IVT group showed significantly less need for a fourth injection at Week 24 (34.5% vs. 53.3% in the IVB/IVT and IVB groups, respectively, P = 0.04). CONCLUSION: Mandated therapy with IVB improved best-corrected visual acuity and decreased central macular thickness in neovascular age-related macular degeneration. The addition of low-dose IVT temporarily increased the therapeutic efficacy in the early postinjection period and resulted in fewer requirements for repeat IVB injections at 6 months; however, final levels of visual improvement were comparable in the 2 study groups. PMID- 21555968 TI - Combined 23-gauge sutureless vitrectomy and clear corneal phacoemulsification in patients with proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the results and complications of combined 23-gauge sutureless vitrectomy, clear corneal phacoemulsification, and intraocular lens implantation in patients with proliferative diabetic retinopathy. METHODS: This was a retrospective, consecutive, noncomparative, interventional case series of 136 eyes of 108 patients who underwent combined sutureless vitrectomy and clear corneal cataract surgery for the complications of proliferative diabetic retinopathy. The main outcome measures were visual outcomes and surgical complications. RESULTS: Main indications for the combined surgery were vitreous hemorrhage (78 eyes, 57.4%) and tractional retinal detachment (36 eyes, 28.7%). The logarithm of the minimum angle of resolution visual acuity (mean +/- SD) improved from 0.86 +/- 0.59 preoperatively to 0.39 +/- 0.52 six months postoperatively (P < 0.0001). Intraoperative retinal tear occurred in 7 eyes (5.1%) and postoperative vitreous hemorrhage in 10 eyes (7.5%). Even in the absence of suturing of sclerotomy sites, only 1 eye (0.7%) had postoperative hypotony (<6 mmHg). During the 6 months after surgery, only 1 eye (0.7%) developed neovascular glaucoma and 6 eyes (4.4%) required a repeat vitrectomy (3 for retinal detachment and 3 for vitreous hemorrhage). CONCLUSION: Combined 23 gauge sutureless vitrectomy and clear corneal phacoemulsification in patients with proliferative diabetic retinopathy was safe and effective. It may have not only the known advantages of conventional combined surgery but also additionally those such as faster visual rehabilitation and less conjunctival fibrosis. PMID- 21555969 TI - Intravitreal bevacizumab as supplemental treatment or monotherapy for severe retinopathy of prematurity. AB - PURPOSE: To investigate the benefit of intravitreal bevacizumab as supplemental or primary treatment for retinopathy of prematurity. METHODS: The files of nine consecutive infants treated with intravitreal bevacizumab for bilateral severe posterior retinopathy of prematurity were reviewed. RESULTS: Gestational age was 24 weeks to 27 weeks, and birth weight was 660 g to 1,131 g. Indications for treatment were retinopathy of prematurity progression from Stage 3 to 4A or 2 to 3 with extraretinal neovascularization despite laser treatment; active neovascular Stage 4A disease after laser and cryo-treatment; anterior segment neovascularization and bleeding after laser treatment; and aggressive posterior disease with tunica vasculosa lentis and vitreous haze, which prevented laser treatment. One patient (two eyes) underwent lens-sparing vitrectomy after bevacizumab treatment; one eye acquired macular fold. One patient underwent bilateral scleral buckle. Bevacizumab treatment was associated with subsidence of the active vascular component in all eyes. Anatomical results were favorable in 17 eyes. There were no local or systemic complications. CONCLUSION: Intravitreal bevacizumab may serve as a supplemental therapeutic agent for severe laser refractory retinopathy of prematurity or as monotherapy when media opacities preclude diode laser photocoagulation or the patient is too sick for lengthy laser treatment. PMID- 21555970 TI - The preferred retinal locus in macular disease: toward a consensus definition. AB - BACKGROUND: Eccentric viewing in macular disease has been described for half a century. However, a clear definition of eccentric viewing and preferred retinal locus (PRL) does not exist. Here, we determine how the PRL in macular disease is defined by researchers active in this field and, based on the responses received, propose a standardized definition of the preferred retinal locus. METHOD: A literature review of articles describing the PRL or eccentric viewing was performed. The first and senior authors of all identified publications were contacted and were asked to define the preferred retinal locus. Themes of responses were identified using inductive qualitative research techniques. RESULTS: Frequently recurring themes related to the definition of the PRL included 1) it is a retinal area used for fixation, 2) it is task specific, 3) more than one PRL can be used, 4) it is a well-defined region of retina, and 5) the same PRL is used on repeated testing. CONCLUSION: Based on the responses received, a consensus definition of the PRL is proposed. It is suggested that researchers define the PRL carefully in experimental reports and an instrument that images the retina is used to define the location of the PRL. PMID- 21555971 TI - Does haptoglobin genotype affect early onset of diabetic retinopathy in patients with type 2 diabetes? AB - PURPOSE: There are 2 common alleles for Hp (Hp-1 and Hp-2) and 3 common Hp genotypes: Hp1-1, Hp2-1, and Hp2-2. The haptoglobin genotype may play a dual role in morbidities of diabetes: Hp1-1, protective and Hp2-2, provocative. This study investigated the possible association of haptoglobin genotypes with onset of retinopathy in Type 2 diabetes (DM2). METHODS: The sample included 98 consecutive adults with DM2 under routine outpatient follow-up from 2007 to 2009 who met the criteria for either no retinopathy at >=10 years after diagnosis (Group 1) or proliferative retinopathy at <=10 years after diagnosis (Group 2). Blood samples were collected for haptoglobin genotyping by polymerase chain reaction. Findings were compared between and within groups. RESULTS: Eighty-four patients had no retinopathy and 14 had early proliferative retinopathy. The distributions of the Hp genotypes were as follows: no-retinopathy group: 28.6% Hp1-1, 35.7% Hp2-1, and 35.7% Hp2-2 and proliferative retinopathy group: 22.6% Hp1-1, 27.4% Hp2-1, and 50% Hp2-2 (NS). On statistical analysis (limited to the larger no-retinopathy group), a predominance of Hp1-1 was noted in older patients; Hp2-2 was associated with an increased rate of stroke. CONCLUSION: The Hp genotype apparently plays no role in the development or worsening of proliferative retinopathy in DM2. Hp1-1 may be involved in delaying the onset of diabetes. Hp2-2 may pose a microvascular risk. PMID- 21555972 TI - Everolimus for cardiac allograft vasculopathy--every patient, at any time? PMID- 21555973 TI - Pathophysiologic significance of B-cell clusters in chronically rejected grafts. AB - The role of antibodies in the pathogenesis of chronic rejection is increasingly acknowledged. In contrast, whether B-cell clusters, which have been recently identified in chronically rejected allografts, actively participate in the process or are only an epiphenomenon remain a matter of debate. Integrating recently published data, we put forward explanations that reconcile the conflicting conclusions of experimental and biopsy-based studies. Finally, we propose a unified model in which B-cell clusters as part of intragraft tertiary lymphoid tissue can play deleterious or regulatory roles and therefore actively modulate the kinetics of chronic rejection. PMID- 21555975 TI - RuCl3.3H2O catalyzed reactions: facile synthesis of bis(indolyl)methanes under mild conditions. AB - RuCl3.3H2O was found to be an effective catalyst for reactions of indoles, 2 methylthiophene, and 2-methylfuran with aldehydes to afford the corresponding bis(indolyl)methanes, bis(thienyl)methanes, and bis(fur-2-yl)methanes in moderate to excellent yields. Experimental results indicated that mono(indolyl)methanol is not the reaction intermediate under these reaction conditions. PMID- 21555974 TI - Impact of norovirus/sapovirus-related diarrhea in renal transplant recipients hospitalized for diarrhea. AB - BACKGROUND: Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients. METHODS: We undertook a retrospective study (2008-2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea. RESULTS: Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stool's clearance exhibited a prolonged viral shedding period with a median time of 289 days (107 581 days). CONCLUSIONS: Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment. PMID- 21555976 TI - Two new iridoid glycosides from the root barks of Sambucus williamsii Hance. AB - Chemical investigation of the ethanol extract of the root barks of Sambucus williamsii Hance collected in the Heilongjiang province of China resulted in the isolation of two new iridoid glycosides, williamsoside A (1) and williamsoside B (2). Their structures were elucidated on the basis of extensive spectroscopic analysis (1D, 2D-NMR and HRESIMS) and chemical studies. Iridoid glycosides have for a long time been considered as characteristic ingredients of S. williamsii. However, the presence of iridoid glycosides with apiofuranosyl moieties in S. williamsii is reported for the first time in this study. PMID- 21555977 TI - Anti-inflammatory activity of methyl salicylate glycosides isolated from Gaultheria yunnanensis (Franch.) Rehder. AB - Gaultheria yunnanensis (Franch.) Rehder is a kind of traditional Chinese herbal medicine used for the treatments of rheumatoid arthritis, swelling and pain. Two methyl salicylate glycosides, namely methyl benzoate-2-O-beta-D-xylopyranosyl(1 6)-O-beta-D-gluco-pyranoside (J12122) and methyl benzoate-2-O-beta-D xylopyranosyl(1-2)[O-beta-D-xylopyranosyl(1-6)]-O-beta-D-glucopyranoside (J12123), are natural salicylic derivatives isolated from Gaultheria yunnanensis. In this study, we investigated the anti-inflammatory activity of J12122 and J12123 on LPS-induced RAW264.7 macrophage cells by measuring the production of pro-inflammatory cytokines, accumulation of nitric oxide (NO), and level of reactive oxygen species (ROS). The results showed that both methyl salicylate glycosides dose-dependently inhibited the production of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6, respectively. Consistent with these observations, J12122 and J12123 significantly suppressed the accumulation of NO, with an inhibitory rate of 56.20% and 51.72% at 3.0 MUg/mL concentration, respectively. Furthermore, the two methyl salicylate glycosides reduced the level of ROS induced by LPS. These results showed that the isolated compounds possess anti-inflammatory properties through inhibition the production pro-inflammatory cytokines, NO, and ROS. PMID- 21555978 TI - Astragaloside IV improves metabolic syndrome and endothelium dysfunction in fructose-fed rats. AB - The prevalence of metabolic syndrome has increased in modern society and the condition is proving to be a common precursor of cardiovascular disease. The aim of the present study was to investigate whether astragaloside IV, a major active constituent of Astragalus membranaceus (Fisch) Bge., is able to prevent the development of hypertension and endothelial dysfunction in fructose-fed rats. Rats were fed with 10% fructose in their drinking water for 8 weeks. From the beginning of week 5, two groups of fructose-fed rats were treated with 0.5 or 2 mg/kg, i.p., astragaloside IV. Another group of fructose-fed rats, injected with the same volume of vehicle (dimethylsulfoxide, DMSO) from week 5, served as the control group. At the end of the treatment period, blood pressure, blood glucose, glucose tolerance, blood insulin and lipids were determined. In addition, in vitro experiments were conducted at the end of the eight week treatment period to evaluate endothelium-dependent aortic vasorelaxation, as well as myocardial and aortic tissue levels of nitrate and nitrite (NOx) and cGMP. Fructose-fed rats developed clustering signs of metabolic syndrome, such as increased bodyweight, mild hypertension, hyperinsulinaemia, hypertriglyceridaemia, impaired glucose tolerance and impaired endothelium-dependent vasorelaxation. Administration of astragaloside IV reduced blood pressure and triglyceride levels in fructose-fed rats and high dose of astragaloside IV also improved glucose tolerance and endothelium-dependent vasorelaxation. The astragaloside IV-induced improvement in vasorelaxation was associated with increased levels of aortic NOx and cGMP and was abrogated by blockade of nitric oxide synthase with NG-nitro-l-arginine methyl ester (l-NAME). On the basis of its favourable effects on lipid metabolism, endothelium-dependent vasorelaxation and the nitric oxide-cGMP related pathway, astragaloside IV may be useful in ameliorating food-induced metabolic syndrome. PMID- 21555979 TI - Effects of Thai medicinal herb extracts with anti-psoriatic activity on the expression on NF-kappaB signaling biomarkers in HaCaT keratinocytes. AB - Psoriasis is a chronic inflammatory skin disorder characterized by rapid proliferation of keratinocytes and incomplete keratinization. Discovery of safer and more effective anti-psoriatic drugs remains an area of active research at the present time. Using a HaCaT keratinocyte cell line as an in vitro model, we had previously found that ethanolic extracts from three Thai medicinal herbs, namely Alpinia galanga, Curcuma longa and Annona squamosa, possessed anti-psoriatic activity. In the current study, we aimed at investigating if these Thai medicinal herb extracts played a molecular role in suppressing psoriasis via regulation of NF-kappaB signaling biomarkers. Using semi-quantitative RT-PCR and report gene assays, we analyzed the effects of these potential herbal extracts on 10 different genes of the NF-kappaB signaling network in HaCaT cells. In accordance with our hypothesis, we found that the extract derived from Alpinia galanga significantly increased the expression of TNFAIP3 and significantly reduced the expression of CSF-1 and NF-kB2. Curcuma longa extract significantly decreased the expression of CSF-1, IL-8, NF-kB2, NF-kB1 and RelA, while Annona squamosa extract significantly lowered the expression of CD40 and NF-kB1. Therefore, this in vitro study suggested that these herbal extracts capable of functioning against psoriasis, might exert their activity by controlling the expression of NF-kappaB signaling biomarkers. PMID- 21555982 TI - Transfer of motor skill learning from the healthy hand to the paretic hand in stroke patients: a randomized controlled trial. AB - BACKGROUND: Bilateral transfer of a motor skill is a phenomenon based on the observation that the performance of a skill with one hand can "teach" the same skill to the other hand. AIM: In this study the ability of bilateral transfer to facilitate the motor skill of the paretic hand in patients that suffered a stroke was tested. DESIGN: In a randomized controlled trial subjects were randomly assigned to either the test group or the control group. SETTING: The experiment was performed in a general hospital rehabilitation facility for inpatients and outpatients. POPULATION: We studied 20 outpatients, who had their first stroke episode characterized by a brain lesion to a single hemisphere, at the end of their rehabilitation treatment. The criteria used for the selection were based on a physical examination, the time elapsed from the stroke and cognitive requirements. METHODS: The experiment consisted in training the healthy hand of each patient from the test group to execute the nine hole peg test 10 times a day, for three consecutive days, and then test the paretic hand with the same test and with bimanual tasks. The control group was not trained but went through the same analysis. RESULTS: The homogeneity of the two groups has been proven. In the test group we found that the execution speed of the nine hole peg test with the paretic hand, after training the healthy hand, was on average 22.6% faster than the value recorded at baseline. The training had a positive effect on the execution of bimanual tasks. Meanwhile, no significant difference was found in the control group. CONCLUSION: This is the first evidence that bilateral transfer of motor skills is present in patients that suffered a stroke, and that it improves the ability of the affected hand. CLINICAL REHABILITATION IMPACT: This observation could open the way to the development of a new approach for the rehabilitation of stroke patients. PMID- 21555983 TI - Physical exercise after hip fracture: an evidence overview. AB - Improving strategies for hip fracture rehabilitation among older people is an urgent public health challenge due to the increasing proportion of older people in the global population and therefore the increasing numbers of falls and fractures. Most older people who suffer a hip fracture experience a permanent decrease in physical functioning. It is now clear in the general older population that muscle strength and balance can be improved and falls can be prevented by well-designed exercise programs. Physical exercise has the potential to improve physical outcomes after hip fracture in older people. Increasingly, clinicians are being urged to seek guidance from clinical trials in order to make clinical decisions. This article presents: 1) an overview of clinical practice guidelines and systematic reviews about rehabilitation after hip fracture and 2) an overview of randomised trials of exercise for people after hip fracture indexed on the Physiotherapy Evidence Database (PEDro). The lack of well-designed large-scale trials of exercise after hip fracture means that current guidelines do not include detailed recommendations about exercise after hip fracture. The Cochrane reviews covering this field also do not draw firm conclusions. However, several individual trials have had promising findings and indicate some benefits of exercise after hip fracture. PMID- 21555984 TI - Effects of Thera-Band(r) elastic resistance-assisted gait training in stroke patients: a pilot study. AB - BACKGROUND: In stroke patients, it is difficult to manually assist dorsi-flexion during the normal gait cycle as it is a distal component. Furthermore, it is nearly impossible to simultaneously guard the patient and manually assist dorsi flexion during the swing phase of gait. However, one of the key benefits of Thera Band(r) Elastic Resistance-Assisted Gait Training is that it offers distal control of lower extremity during the normal gait sequence without jeopardizing patient safety. AIM: Aim of this study was to compare and measure the effects of Thera-Band(r) Elastic Resistance-Assisted Gait Training in stroke patients with respect to quality of gait and functional mobility. DESIGN: This was a pilot study. SETTING: The study was carried out at the Occupational Therapy Department, Mumbai, India. POPULATION: The study included 16 patients aged between 30-60 years with first episode of stroke or subacute stroke. METHODS: Following informed consent, as per inclusion criteria patients were randomly assigned in two groups: 1) control group: Conventional Occupational Therapy Intervention and Conventional Gait Training; 2) experimental group: Conventional Occupational Therapy and Thera-Band(r) Elastic Resistance Assisted Gait Training. Patients were assessed on: 1) Wisconsin Gait Scale; 2) Rivermead Mobility Index. Patients were reassessed as done initially at the end of third and sixth week. Patients received therapy three times a week for six weeks. RESULTS: Each group separately was associated with statistically significant improvement in quality of gait (P<0.001) as well as functional mobility (P<0.001). Thera-Band(r) Elastic Resistance-Assisted Gait Training had a more positive effect on improving the quality of gait, functional mobility in a short duration as compared to the conventional gait training. CONCLUSION: The use of Thera-Band(r) Elastic Resistance-Assisted Gait Training contributed to faster recovery as compared to the control group. Functionally patients showed improvement as compared to conventional therapy. CLINICAL REHABILITATION IMPACT: Thera-Band(r) Elastic Resistance-Assisted Gait Training facilitates dorsi-flexion during a single cycle of swing. PMID- 21555985 TI - Optimal setting and care organization in the management of older adults with hip fracture. AB - Hip fracture (HF) is a common event in the geriatric population and is often associated with significant morbidity, mortality and costs for the Healthcare Systems. The growing awareness of HF consequences and the expected rise in the total number of HF worldwide have led to the development and implementation of models of care alternative to the traditional ones for the acute and post-acute management of HF older adults. These services were set to minimize in-hospital complications, streamline hospital care and provide early discharge with the main objectives of improving functional and clinical outcomes, and reducing healthcare costs associated with hip and other fractures. Basically, the main feature that distinguishes these models is the different healthcare professional that retains the responsibility of the care during the acute and postacute phases. This review has been conceived to provide a brief description of the models implemented in the last twenty years, to describe their potential benefits on short- and long term outcomes, to define the strengths and limitations of these models and the areas of uncertain, and to make some consideration about the future. Actually, on the basis of available studies, it is not possible to define the best model of care for HF older adults. However, the more complex and sophisticated services, characterized by a multidisciplinary approach demonstrated, in randomized controlled and before-after observational studies, to produce better outcomes compared to the traditional or simplest models. Further research is warranted to confirm long-term functional and clinical benefits of these models and to evaluate their cost-effectiveness. PMID- 21555986 TI - Endovascular treatment of an early arch aneurysm rupture after open thoracoabdominal aortic repair. AB - Optimal treatment for synchronous aortic aneurysms is still debated. Staged repair is advocated as the standard of care. Its disadvantage however is the consistent risk of rupture of the untreated aortic segment during recovery; moreover a considerable percentage of patients either refuse the second stage or is lost to follow-up. We present the case of a patient with a ruptured aortic arch aneurysm after open-surgery for a type III thoracoabdominal aortic aneurysm. Our therapeutic decision is described and discussed, with all the related advantages and disadvantages. PMID- 21555987 TI - Primary aortoduodenal fistula in combination with aortoiliac occlusive disease: report of a rare case. AB - Most of the cases of aortoenteric fistula are due to aneurysm of the aorta, although infection, tumor, radiotherapy, gastric ulcers and foreign body ingestion have also been described in the literature. We report the case of a 62 year-old woman presenting with massive gastrointestinal bleeding with hematemesis and melaena. This case is unique in that the primary aortoduodenal (PADF) fistula formed as a result of complex atherosclerotic disease of the abdominal aorta and both iliacal arteries, also known as Leriche's syndrome, and not primarily due to an aneurysm. We will give a brief summary of the difficulties and challenges which the surgeon faced during the operation and a surprisingly uneventful postoperative course. PMID- 21555988 TI - Traumatic brain injury: Poor outcome after decompressive craniectomy. PMID- 21555991 TI - Epilepsy: Single-neuron activity in epilepsy. PMID- 21555992 TI - Parkinson disease: Could over-the-counter treatment protect against Parkinson disease? PMID- 21555993 TI - Multiple sclerosis: Benefits of alemtuzumab in MS. PMID- 21555994 TI - Pain: Statins--new treatment for neuropathic pain? PMID- 21555995 TI - Multiple sclerosis: Natalizumab improves neurological function in MS. PMID- 21555996 TI - Pathogenesis study of enterovirus 71 infection in rhesus monkeys. AB - Enterovirus 71 (EV71), a major pathogen that is responsible for causing hand-foot and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. HFMD that is caused by EV71 is usually characterized by vesicular lesions on the skin and oral mucosa and high morbidity rates in children; additionally, occasional fatal cases have been reported involving brainstem encephalitis and myelitis associated with cardiopulmonary collapse. Although viral pathogenesis in humans is unclear, previous animal studies have indicated that EV71, inoculated via various routes, is capable of targeting and injuring the central nervous system (CNS). We report here the pathogenic process of systemic EV71 infection in rhesus monkeys after inoculation via intracerebral, intravenous, respiratory and digestive routes. Infection with EV71 via these routes resulted in different rates of targeting to and injury of the CNS. Intracerebral inoculation resulted in pulmonary edema and hemorrhage, along with impairment of neurons. However, intravenous and respiratory inoculations resulted in a direct infection of the CNS, accompanied by obvious inflammation of lung tissue, as shown by impairment of the alveoli structure and massive cellular infiltration around the terminal bronchioles and small vessels. These pathological changes were associated with a peak of viremia and dynamic viral distribution in organs over time in the infected monkeys. Our results suggest that the rhesus monkey model may be used to study not only the basic pathogenesis of EV71 viral infections, but also to examine clinical features, such as neurological lesions, in the CNS and pathological changes in associated organs. PMID- 21555997 TI - Cell-specific effects of TNF-alpha and IL-1beta on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification. AB - Tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta stimulate tissue non specific alkaline phosphatase (TNAP) activity and mineralization in cultures of vascular smooth muscle cells (VSMCs). They are, therefore, considered as stimulators of vascular calcification in the context of atherosclerosis and diabetes type 2. In contrast, although ankylosing spondylitis (AS) leads to the formation of syndesmophytes, which are ectopic ossifications from entheses (where ligaments, tendons and capsules are attached to bone), anti-TNF-alpha therapies fail to block bone formation in this disease. In this context, our aims were to compare the effects of TNF-alpha and IL-1beta on TNAP activity and mineralization in entheseal cells and VSMCs. Organotypic cultures of mouse ankle entheses were treated or not with TNF-alpha and IL-1beta for 5 days. Micro-computed tomography was performed to determine trabecular bone parameters, and histology to assess TNAP activity and mineralization. Human mesenchymal stem cells cultured in pellets in chondrogenic conditions and human VSMCs were also used to determine the effects of cytokines on TNAP activity and expression, measured by quantitative PCR. In organotypic cultures, TNF-alpha and IL-1beta significantly reduced the tibia BV/TV ratio. They also inhibited TNAP activity in entheseal chondrocytes in situ, and in mouse and human chondrocytes in vitro. In contrast, TNF-alpha stimulated TNAP expression and activity in human VSMCs. These differences were likely due to cell-specific effects of peroxisome proliferator activated receptor gamma (PPARgamma), which is inhibited by TNF-alpha. Indeed, in human chondrocytes and VSMCs, the PPARgamma inhibitor GW-9662 displayed the same opposite effects as TNF-alpha on TNAP expression. In conclusion, whereas TNF alpha and IL-1beta stimulate TNAP activity in VSMCs, they inhibit it in entheseal cells in situ and on chondrocytes in vitro. The identification of PPARgamma as a likely mediator of cytokine effects deserves consideration for future research on the mechanisms of ectopic ossification. PMID- 21555998 TI - Induced pluripotent stem cells as a next-generation biomedical interface. AB - Recent advances in DNA sequencing technologies and subsequent progress in genome wide association study (GWAS) are rapidly changing the landscape of human diseases. Our knowledge on disease-gene linkage has been exponentially growing, and soon we will obtain complete maps of SNPs and mutations linked to nearly all major disease conditions. These studies will undoubtedly lead us to a more comprehensive understanding of how multiple genetic modifications link to human pathobiology. But what comes next after we discover these genetic linkages? To truly understand the mechanisms of how polygenic modifications identified through GWAS lead to disease conditions, we need an experimental interface to study their pathobiological effects. In this study, induced pluripotent stem cells (iPSCs), retaining all the genetic information from patients, will likely serve as a powerful resource. Indeed, pioneering studies have demonstrated that disease specific iPSCs are useful for understanding disease mechanisms. Moreover, iPSC derived cells, when recapitulating some disease phenotypes in vitro, can be a fast track screening tool for drug discovery. Further, with GWAS information, iPSCs will become a valuable tool to predict drug efficacy and toxicity for individuals, thus promoting personalized medicine. In this review, we will discuss how patient-specific iPSCs will become a powerful biomedical interface in clinical translational research. PMID- 21555999 TI - Hydrogen sulfide inhibits IL-8 expression in human keratinocytes via MAP kinase signaling. AB - Sulfur is able to penetrate the skin, and a sulfur-rich balneotherapy has been suggested to be effective in the treatment of psoriasis. Psoriasis is now considered a genetically programmed, immune-mediated, inflammatory disease, in which intralesional T lymphocytes trigger keratinocytes to proliferate and perpetuate the disease process. Interleukin (IL)-17 and IL-22 produced by Th1/Th17 lymphocytes induce IL-8 secretion by keratinocytes, a key event in the pathogenesis of the disease. It is now clear that mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinases (ERK) 1 and 2) activity is required for IL-17-induced IL-8 synthesis by keratinocytes, and, in fact, MAPK activity is increased in lesional psoriatic skin. Here, we demonstrate both in vitro and in vivo on primary psoriatic lesions that pharmacological inhibitors of ERKs as well as hydrogen sulfide not only reduce the basal expression and secretion of IL-8, but also interfere with IL-17- and IL-22-induced IL-8 production. These observations, together with the known anti-inflammatory activity of H2S, are relevant to understanding some previously unexplained biological effects exerted by sulfur therapy. PMID- 21556011 TI - Occurrence of identical NOTCH1 mutation in non-twinned sisters with T-cell acute lymphoblastic leukemia. PMID- 21556012 TI - Traumatic spinal cord injury among children and adolescents; a cohort study in western Norway. AB - OBJECTIVE: The objective of this study is to assess the temporal trends in the incidence and demographic characteristics of traumatic spinal cord injury (TSCI) among children and adolescents in a geographically defined cohort in western Norway during 1952-2001. METHODS: The patients included in this study were identified from the hospital records. RESULTS: Of 336 patients, 13 (3.9%) patients were 0-14 years at time of injury, and 44 (13.1%) patients were 15-19 years at time of injury. The average age-adjusted incidence was 2.4 per million children and 25.1 per million adolescents. Children were injured in car and pedestrian accidents, whereas adolescents were injured in car and motorcycle accidents. CONCLUSIONS: The age-adjusted incidence of TSCI among the adolescents increased, whereas the age-adjusted incidence among children remained low during the 50 years. TSCI was highly associated with car and pedestrian accidents among children. Among adolescents, TSCI was associated with car and motorcycle accidents. Awareness of these factors is important in prevention planning strategies. PMID- 21556001 TI - APOE and Alzheimer disease: a major gene with semi-dominant inheritance. AB - Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease. PMID- 21556013 TI - Earnings among people with spinal cord injury. AB - STUDY DESIGN: Secondary analysis of cross-sectional data. OBJECTIVES: To identify differences in earnings among participants with spinal cord injury (SCI) and their relation to demographic, injury, educational and employment-related factors. SETTING: People living with SCI in the community who were members of a disability support organization. METHODS: A total of 76 members who have had traumatic SCI for at least 2 years, between 15 and 64 years of age at time of study and were working before SCI were interviewed over the phone. The earnings were categorized as more, same or less than before SCI or no income for those unemployed. RESULTS: Of the 76 participants (who averaged about 15.1 years post SCI), only 13 participants (17.1%) were earning more than before injury, whereas majority were in the category of having no income, being unemployed at time of study, n=36 (47.4%). Factors positively related to earnings were having more years in education, both at time of injury and at time of survey. As anticipated, those currently in full time and paid employments were earning more while receipt of financial compensation was negatively related to earnings. CONCLUSION: Despite a lengthy period of time post SCI, only a minority were earning more, reflecting poorly on the quality of post SCI employment experience. The rehabilitation team should therefore focus on improving both educational and vocational opportunities for persons with SCI and aim for full time, paid employments. The current workers' compensation scheme renders the recipient at a static income and may need to be revised. PMID- 21556014 TI - Editorial note on: the importance of verification and beta testing. PMID- 21556015 TI - Human disease: something old, something new. PMID- 21556017 TI - Most B cells in non-lymphoid tissues are naive. AB - The current view of lymphocyte migration states that naive lymphocytes re circulate between the blood and the lymph via the lymph nodes, but are not able to access non-lymphoid tissues. We examined B lymphocytes in peripheral tissues and found that the majority were phenotypically similar to naive B cells in lymphoid tissues and were located within the parenchyma, not associated with blood vessels. The mutation rate within the Vh region of these cells was substantially less than the rate attributed to somatic hypermutation and was identical to that observed in naive B cells isolated from the lymph nodes, showing the presence of naive B cells in the non-lymphoid organs. Further, using FTY720-treated mice, we showed that naive B cells migrate through the peripheral tissues and, using pertussis toxin, that the entry of B cells was not controlled by chemokine-mediated signalling events. Overall, these results show that naive B lymphocytes constitute the majority of the total B-cell population in non lymphoid tissues and suggest that these cells may re-circulate through the periphery as part of their normal migration pathway. This has implications for the current view of the role of naive B cells in priming and tolerance. PMID- 21556016 TI - Understanding systems-level properties: timely stories from the study of clocks. AB - After several decades dominated by reductionist approaches in biology, researchers are returning to the study of complex biology with a litany of new and old techniques--this paradigm has been termed systems biology. Here we detail how systems biology is being used to uncover complex systems-level properties of the circadian clock. These properties include robustness, periodicity and temperature compensation. We describe how clock researchers are using systems biology techniques, such as genetic perturbations, kinetic luminescence imaging, synthetic biology and mathematical modelling, to untangle these complex properties in mammals, fungi and bacteria. The strategies developed in the context of circadian clocks may prove useful for tackling similar problems in other systems. PMID- 21556018 TI - Consequences of suboptimal priming are apparent for low-avidity T-cell responses. AB - The emergence of the novel reassortant A(H1N1)-2009 influenza virus highlighted the threat to the global population posed by an influenza pandemic. Pre-existing CD8(+) T-cell immunity targeting conserved epitopes provides immune protection against newly emerging strains of influenza virus, when minimal antibody immunity exists. However, the occurrence of mutations within T-cell antigenic peptides that enable the virus to evade T-cell recognition constitutes a substantial issue for virus control and vaccine design. Recent evidence suggests that it might be feasible to elicit CD8(+) T-cell memory pools to common virus mutants by pre emptive vaccination. However, there is a need for a greater understanding of CD8(+) T-cell immunity towards commonly emerging mutants. The present analysis focuses on novel and immunodominant, although of low pMHC-I avidity, CD8(+) T cell responses directed at the mutant influenza D(b)NP(366) epitope, D(b)NPM6A, following different routes of infection. We used a C57BL/6J model of influenza to dissect the effectiveness of the natural intranasal (i.n.) versus intraperitoneal (i.p.) priming for generating functional CD8(+) T cells towards the D(b)NPM6A epitope. In contrast to comparable CD8(+) T-cell responses directed at the wild type epitopes, D(b)NP(366) and D(b)PA(224), we found that the priming route greatly affected the numbers, cytokine profiles and TCR repertoire of the responding CD8(+) T cells directed at the D(b)NPM6A viral mutant. As the magnitude, polyfunctionality, and T-cell repertoire diversity are potential determinants of the protective efficacy of CD8(+) T-cell responses, our data have implications for the development of vaccines to combat virus mutants. PMID- 21556021 TI - Epidemiology: Count the dead, measure the living. PMID- 21556019 TI - Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. AB - Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist as they share the pathogenic abnormalities of excess adiposity and insulin resistance. Although type 1 diabetes mellitus (T1DM) is due to a relative lack of insulin, an increased prevalence of obesity and insulin resistance in this population means that NAFLD also commonly coexists with this condition. Both T2DM and NAFLD are associated with adverse outcomes of the other; T2DM is a risk factor for progressive liver disease and liver-related death in patients with NAFLD, whereas NAFLD may be a marker of cardiovascular risk and mortality in individuals with T2DM. Nonalcoholic steatohepatitis-a histological subtype of NAFLD characterized by hepatocyte injury and inflammation-is present in approximately 10% of patients with T2DM and is associated with an increased risk for the development of cirrhosis and liver-related death. Current treatment strategies aim to improve insulin resistance via weight loss and exercise, improve insulin sensitivity by the use of insulin-sensitizing agents (for example, pioglitazone) and reduce oxidative stress by the use of antioxidants, such as vitamin E. Pioglitazone and vitamin E supplementation show the most promise in improving hepatic steatosis and inflammation but have not yet been demonstrated to improve fibrosis, and concern remains regarding the toxicity of long-term use of both of these agents. PMID- 21556020 TI - Novel etiopathophysiological aspects of thyrotoxic periodic paralysis. AB - Thyrotoxicosis can lead to thyrotoxic periodic paralysis (TPP), an endocrine channelopathy, and is the most common cause of acquired periodic paralysis. Typically, paralytic attacks cease when hyperthyroidism is abolished, and recur if hyperthyroidism returns. TPP is often underdiagnosed, as it has diverse periodicity, duration and intensity. The age at which patients develop TPP closely follows the age at which thyrotoxicosis occurs. All ethnicities can be affected, but TPP is most prevalent in people of Asian and, secondly, Latin American descent. TPP is characterized by hypokalemia, suppressed TSH levels and increased levels of thyroid hormones. Nonselective beta adrenergic blockers, such as propranolol, are an efficient adjuvant to antithyroid drugs to prevent paralysis; however, an early and definitive treatment should always be pursued. Evidence indicates that TPP results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors (such as a high carbohydrate diet). We believe that excess T(3) modifies the insulin sensitivity of skeletal muscle and pancreatic beta cells and thus alters potassium homeostasis, but only leads to a depolarization-induced acute loss of muscle excitability in patients with inherited ion channel mutations. An integrated etiopathophysiological model is proposed based on molecular findings and knowledge gained from long-term follow-up of patients with TPP. PMID- 21556022 TI - Cancer: a roadmap for the land of small tumors. PMID- 21556023 TI - Obesity: BAI as a new measure of adiposity--throw away your scale? PMID- 21556024 TI - Targeted therapies: peaking beneath the surface of recent bevacizumab trials. PMID- 21556026 TI - Targeted therapies: denosumab--a new option for solid tumors metastatic to bone. PMID- 21556025 TI - Bone metastasis in prostate cancer: emerging therapeutic strategies. AB - Metastatic bone disease (MBD) in advanced-stage cancer increases the risk of intractable bone pain, pathological skeletal fracture, spinal-cord compression and decreased survival. The disease manifestation course during MBD is largely driven by homotypic and heterotypic cellular interactions between invading tumor cells, osteoblasts and osteoclasts. The outcome is a sustained vicious cycle of bone matrix remodeling. Osteoclast-mediated bone degradation and subsequent bone loss are the hallmarks of secondary bone metastases from most solid tumors. An additional complication in prostate cancer is the predominance of osteosclerotic lesions typified by inappropriate bone production. Successful therapeutic strategies for the treatment of osteolytic MBD include the administration of intravenous bisphosphonates or subcutaneous inhibitors of receptor activator of nuclear factor kappaB ligand (RANKL). Inhibitors of SRC and cABL kinases and cathepsin K are under clinical investigation as potential anti-osteolytics. In contrast to the rapid progress being made in the development of anti-osteolytic therapies, the treatment of osteosclerotic MBD remains restricted to palliative radiotherapy for symptomatic solitary lesions and systemic taxane-based chemotherapy for widespread multiple lesions. This Review discusses the complex pathology of bone lesions in metastatic castration-resistant prostate cancer and focuses on new therapeutic strategies and targets that are emerging in preclinical studies. PMID- 21556027 TI - Pathogenesis of antiphospholipid syndrome: understanding the antibodies. AB - Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Although the presence of aPL is a necessary pre-condition, APS-associated clotting is seemingly triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. beta(2) glycoprotein I (beta(2)GPI)-dependent aPL, the most important subset of these antibodies, mediate several--not necessarily alternative- thrombogenic mechanisms, mainly on the basis of their reactivity with beta(2)GPI expressed on the membrane of cells that participate in the coagulation cascade. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss suggests a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support a widespread inflammatory signature. beta(2)GPI dependent aPL are thought to recognize their antigen on placental tissues, inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. Characterization of the molecular basis of the pathogenic mechanisms involved, including the putative second hits and the role of complement activation, might offer an answer to this question. PMID- 21556028 TI - Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. AB - Glucocorticoids have been exploited therapeutically for more than six decades through the use of synthetic glucocorticoids as anti-inflammatory agents, and are still used in as many as 50% of patients suffering from inflammatory diseases such as rheumatoid arthritis (RA). Better understanding of the mechanisms of action of glucocorticoids could enable the development of therapies that dissociate the broad-spectrum benefits of glucocorticoids from their adverse metabolic effects. The glucocorticoid-induced leucine zipper protein (GILZ; also known as TSC22 domain family protein 3) is a glucocorticoid-responsive molecule whose interactions with signal transduction pathways, many of which are operative in RA and other inflammatory diseases, suggest that it is a key endogenous regulator of the immune response. The overlap between the observed effects of GILZ on the immune system and those of glucocorticoids strongly suggest GILZ as a critical mediator of the therapeutic effects of glucocorticoids. Observations of the immunomodulatory effects of GILZ in human RA synovial cells, and in an in vivo model of RA, support the hypothesis that GILZ is a key glucocorticoid induced regulator of inflammation in RA. Moreover, evidence that the effect of GILZ on bone loss might be in contrast to those of glucocorticoids suggests manipulation of GILZ as a potential means of dissociating the beneficial anti inflammatory effects of glucocorticoids from their negative metabolic repercussions. PMID- 21556029 TI - Rheumatoid arthritis: 2011 remission criteria are a new benchmark for RA therapy. PMID- 21556030 TI - Intravenous immunoglobulin therapy in rheumatic diseases. AB - Prepared from the collective plasma of several thousand people, therapeutic intravenous immunoglobulin (IVIg) consists mostly of human polyspecific IgG. In addition to its use in primary and secondary immune deficiencies, IVIg is used in the treatment of several rheumatic conditions, including Kawasaki disease, dermatomyositis and antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. In these diseases, IVIg therapy generally involves the use of 2 g/kg administered over either 2 or 5 consecutive days. However, dosage regimens have not been thoroughly explored, and indications for IVIg in most rheumatic diseases, such as systemic lupus erythematosus, polymyositis and catastrophic antiphospholipid syndrome, derive from its off-label usage. Randomized clinical trials are warranted to support the evidence-based use of IVIg, and to identify the ideal administration protocols to maximize the benefits of what is a limited resource. Further research to improve the therapeutic application of IVIg relies essentially on the conception of next-generation immunoglobulin preparations and optimization of combined therapies with immunomodulatory drugs and biologic agents. PMID- 21556032 TI - Clinical and pathophysiological concepts of neuralgic amyotrophy. AB - Neuralgic amyotrophy--also known as Parsonage-Turner syndrome or brachial plexus neuritis--is a distinct and painful peripheral neuropathy that causes episodes of multifocal paresis and sensory loss in a brachial plexus distribution with concomitant involvement of other PNS structures (such as the lumbosacral plexus or phrenic nerve) in a large number of patients. The phenotype can be limited or extensive and the amount of disability experienced also varies between patients, but many are left with residual disabilities that affect their ability to work and their everyday life. Both idiopathic and hereditary forms exist. The latter form is genetically heterogeneous, but in 55% of affected families, neuralgic amyotrophy is associated with a point mutation or duplication in the SEPT9 gene on chromosome 17q25. The disease is thought to result from an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus (possibly representing disturbance of the epineurial blood-nerve barrier), and an immune or autoimmune trigger for the attacks. The precise pathophysiological mechanisms are still unclear; treatment is empirical, and preventive measures are not yet available. This Review provides an overview of the current clinical and pathophysiological concepts and research topics in neuralgic amyotrophy. PMID- 21556033 TI - Parkinson disease: PD biomarkers-use of alpha-synuclein reaches new levels. AB - Biomarker development is important to the therapeutic imperative for neurodegenerative diseases, as biomarkers hold transformative promise for the design and conduct of clinical trials and, ultimately, for medical management of these diseases. Some of this promise is now being realized in Alzheimer disease, and progress in Parkinson disease is accelerating. PMID- 21556031 TI - Risk factors for and management of cognitive dysfunction in multiple sclerosis. AB - Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition. PMID- 21556034 TI - MicroRNA links obesity and impaired glucose metabolism. PMID- 21556035 TI - Imaging superoxide flash and metabolism-coupled mitochondrial permeability transition in living animals. AB - The mitochondrion is essential for energy metabolism and production of reactive oxygen species (ROS). In intact cells, respiratory mitochondria exhibit spontaneous "superoxide flashes", the quantal ROS-producing events consequential to transient mitochondrial permeability transition (tMPT). Here we perform the first in vivo imaging of mitochondrial superoxide flashes and tMPT activity in living mice expressing the superoxide biosensor mt-cpYFP, and demonstrate their coupling to whole-body glucose metabolism. Robust tMPT/superoxide flash activity occurred in skeletal muscle and sciatic nerve of anesthetized transgenic mice. In skeletal muscle, imaging tMPT/superoxide flashes revealed labyrinthine three dimensional networks of mitochondria that operate synchronously. The tMPT/superoxide flash activity surged in response to systemic glucose challenge or insulin stimulation, in an apparently frequency-modulated manner and involving also a shift in the gating mode of tMPT. Thus, in vivo imaging of tMPT-dependent mitochondrial ROS signals and the discovery of the metabolism-tMPT-superoxide flash coupling mark important technological and conceptual advances for the study of mitochondrial function and ROS signaling in health and disease. PMID- 21556036 TI - The p97 ATPase associates with EEA1 to regulate the size of early endosomes. AB - The AAA (ATPase-associated with various cellular activities) ATPase p97 acts on diverse substrate proteins to partake in various cellular processes such as membrane fusion and endoplasmic reticulum-associated degradation (ERAD). In membrane fusion, p97 is thought to function in analogy to the related ATPase NSF (N-ethylmaleimide-sensitive fusion protein), which promotes membrane fusion by disassembling a SNARE complex. In ERAD, p97 dislocates misfolded proteins from the ER membrane to facilitate their turnover by the proteasome. Here, we identify a novel function of p97 in endocytic trafficking by establishing the early endosomal autoantigen 1 (EEA1) as a new p97 substrate. We demonstrate that a fraction of p97 is localized to the early endosome membrane, where it binds EEA1 via the N-terminal C2H2 zinc finger domain. Inhibition of p97 either by siRNA or a pharmacological inhibitor results in clustering and enlargement of early endosomes, which is associated with an altered trafficking pattern for an endocytic cargo. Mechanistically, we show that p97 inhibition causes increased EEA1 self-association at the endosome membrane. We propose that p97 may regulate the size of early endosomes by governing the oligomeric state of EEA1. PMID- 21556037 TI - Regulation of erythroid differentiation by miR-376a and its targets. AB - Lineage differentiation is a continuous process during which fated progenitor cells execute specific programs to produce mature counterparts. This lineage restricted pathway can be controlled by particular regulators, which are usually exclusively expressed in certain cell types or at specific differentiation stages. Here we report that miR-376a participates in the regulation of the early stages of human erythropoiesis by targeting cyclin-dependent kinase 2 (CDK2) and Argonaute 2 (Ago2). Among various human leukemia cell lines, miR-376a was only detected in K562 cells which originated from a progenitor common to the erythroid and megakaryotic lineages. Enforced expression of miR-376a or silencing of CDK2 and Ago2 by RNAi inhibits erythroid differentiation of K562 cells. Hematopoietic progenitor cells transduced with miR-376a showed a significant reduction of their erythroid clonogenic capacity. MiR-376a is relatively abundant in erythroid progenitor cells, where it reduces expression of CDK2 and maintains a low level of differentiation due to cell cycle arrest and decreased cell growth. Following erythroid induction, miR-376a is significantly down-regulated and CDK2 is released from miR-376a inhibition, thereby facilitating the escape of progenitor cells from the quiescent state into erythroid differentiation. Moreover, our results establish a functional link between miR-376a and Ago2, a key factor in miRNA biogenesis and silencing pathways with novel roles in human hematopoiesis. PMID- 21556038 TI - High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. AB - OBJECTIVES: Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS: Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low grade or high-grade dysplasia or colorectal cancer. RESULTS: Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02). CONCLUSIONS: Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC. PMID- 21556039 TI - A novel method for the nonradiological assessment of ineffective swallowing. AB - OBJECTIVES: This validation study evaluates a new manometry impedance-based approach for the objective assessment of pharyngeal function relevant to postswallow bolus residue. METHODS: We studied 23 adult and pediatric dysphagic patients who were all referred for a videofluoroscopy, and compared these patients with 10 adult controls. The pharyngeal phase of swallowing of semisolid boluses was recorded with manometry and impedance. Fluoroscopic evidence of postswallow bolus residue was scored. Pharyngeal pressure impedance profiles were analyzed. Computational algorithms measured peak pressure (Peak P), pressure at nadir impedance (PNadImp), time from nadir impedance to PeakP (PNadImp-PeakP), the duration of impedance drop in the distal pharynx (flow interval), upper esophaghageal sphincter (UES) relaxation interval (UES-RI), nadir UES pressure (NadUESP), UES intrabolus pressure (UES-IBP), and UES resistance. A swallow risk index (SRI) was derived by the formula: SRI=(FI * PNadImp)/(PeakP * (TNadImp PeakP+1)) * 100. RESULTS: In all, 76 patient swallows (35 with residue) and 39 control swallows (12 with residue) were analyzed. Different functional variables were found to be altered in relation to residue. In both controls and patients, flow interval was longer in relation to residue. In controls, but not patients, residue was associated with an increased PNadImp (suggestive of increased pharyngeal IBP). Controls with residue had increased UES-IBP, NadUESP, and UES resistance compared with patients with residue. Residue in patients was related to a prolonged UES-RI. The SRI was elevated in relation to residue in both controls and patients and an average SRI of 9 was optimally predictive of residue (sensitivity 75% and specificity 80%). CONCLUSIONS: We present novel findings in control subjects and dysphagic patients showing that combined manometry and impedance recordings can be objectively analyzed to derive pressure-flow variables that are altered in relation to the bolus residual and can be combined to predict ineffective pharyngeal swallowing. PMID- 21556040 TI - The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. AB - OBJECTIVES: Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers. METHODS: A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum=155) and Zarit Burden Interview (ZBI)-Short Form (maximum=48) and questionnaires for depression, anxiety, and social support. RESULTS: A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32+/-14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%, P=0.0001) and financial status (85 vs. 61%, P=0.019) and posed a higher caregiver burden; PCB (75 vs. 65, P=0.019) and ZBI (16 vs. 11, P=0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score. CONCLUSIONS: Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family unit's daily functioning and medical adherence. A multidisciplinary approach to address this burden is required. PMID- 21556041 TI - The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis. AB - OBJECTIVES: Mexicans have an increased rate of alcohol abuse and alcoholic liver disease. Factors influencing the severity of alcoholic hepatitis (AH) in Mexicans are unknown. The aims of the present study were to identify the prognostic factors of short-term mortality in Mexican patients with AH and to validate the existing prognostic models. METHODS: One hundred seventy-five consecutive patients with AH were recruited from four hospital centers in Mexico. Demographic, clinical, and biochemical parameters were obtained at admission. Univariate and multivariate logistic regression analyses were used for the identification of prognostic factors. The accuracy of different models was evaluated by their area under the receiver operating characteristic (AUROC) curve and comparative risk analysis was performed using the Kaplan-Meier method. RESULTS: Age, serum creatinine, serum bilirubin, leukocyte count, and alcohol consumption >120 g/day were independently associated with short-term mortality. The impact of alcohol consumption was significant among patients with severe AH (48 vs. 72% risk of death, P=0.03). The AUROC (95% confidence interval) curves for the different scores were Maddrey's discriminant function 0.79 (0.72-0.86); model for end-stage liver disease (MELD) 0.83 (0.75-0.89); Glasgow AH score 0.77 (0.70-0.84); and age-bilirubin-international normalized ratio-creatinine (ABIC) score 0.82 (0.75-0.88). The ABIC score allowed an accurate stratification into three different risk subgroups with 13%, 50%, and 81% mortality rate at 90 days (P<0.001). CONCLUSIONS: The amount of alcohol consumption has a negative impact on short-term mortality among Mexicans with AH. The ABIC score is useful and comparable with MELD score for the prognostic stratification of these patients. PMID- 21556042 TI - The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature. AB - OBJECTIVE: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. METHODS AND RESULTS: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. CONCLUSION: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA. PMID- 21556043 TI - Caenorhabditis elegans as a model for obesity research. AB - Caenorhabditis elegans (C. elegans) is a small nematode that conserves 65% of the genes associated with human disease, has a 21-day lifespan, reproductive cycles of 3 days, large brood sizes, lives in an agar dish and does not require committee approvals for experimentation. Research using C. elegans is encouraged and a Caenorhabditis Genetics Center (CGC, Minnesota) is funded by the National Institutes of Health-National Center for Research Resources. Many genetically manipulated strains of C. elegans are available at nominal cost from the CGC. Studies using the C. elegans model have explored insulin signaling, response to dietary glucose, the influence of serotonin on obesity, satiety, feeding and hypoxia-associated illnesses. C. elegans has also been used as a model to evaluate potential obesity therapeutics, explore the mechanisms behind single gene mutations related to obesity and to define the mechanistic details of fat metabolism. Obesity now affects a third of the US population and is becoming a progressively more expensive public health problem. Faster and less expensive methods to reach more effective treatments are clearly needed. We present this review hoping to stimulate interest in using the C. elegans model as a vehicle to advance the understanding and future treatment of obesity. PMID- 21556044 TI - Diet-induced obesity affects expression of adiponutrin/PNPLA3 and adipose triglyceride lipase, two members of the same family. AB - BACKGROUND: Adiponutrin/PNPLA3 and adipose triglyceride lipase (ATGL) are proteins highly expressed in adipose tissue which have apparently different roles (lipogenic/lipolytic). Gene expression of both proteins and their nutritional regulation have been described to be altered in genetically obese animals. METHODS: We studied adiponutrin and ATGL expression in 6-month-old rats made obese by cafeteria diet feeding, submitted to different feeding conditions (feeding/fasting/re-feeding), compared with normoweight animals. Adiponutrin and ATGL mRNA levels were determined in white adipose tissue depots (subcutaneous and visceral) and in interscapular brown adipose tissue, and ATGL protein levels in selected depots. In addition, basal adiponutrin and ATGL expression levels were compared between 6- and 3-month-old animals. RESULTS: Obesity decreased adiponutrin and ATGL expression in different adipose depots. For adiponutrin, a tendency to lower mRNA levels was observed in the white adipose depots studied in obese animals, although the decrease was only significant in the subcutaneous depot. For ATGL, a generalized and significant lower expression was found in white and brown adipose tissue of cafeteria-obese rats. When considering nutritional regulation, according to a lipogenic role, adiponutrin mRNA expression decreased with fasting and was recovered by re-feeding in normoweight animals; this regulation was lost in obese rats. Expression of the lipolytic ATGL (mRNA and protein levels) was increased by fasting in normoweight animals in the mesenteric adipose depot, while no change was evident in obese rats. Moreover, adiponutrin and ATGL nutritional regulation was affected by age, and we report a downregulation of adiponutrin mRNA basal levels with age in internal adipose depots. CONCLUSIONS: Cafeteria diet-induced obesity and age alter adiponutrin and ATGL expression and their regulation by feeding conditions. These results reinforce the importance of a proper expression and regulation of both proteins for body weight maintenance and their role in energy metabolism. PMID- 21556045 TI - A bi-directional relationship between obesity and health-related quality of life: evidence from the longitudinal AusDiab study. AB - OBJECTIVE: To assess the prospective relationship between obesity and health related quality of life, including a novel assessment of the impact of health related quality of life on weight gain. DESIGN AND SETTING: Longitudinal, national, population-based Australian Diabetes, Obesity and Lifestyle (AusDiab) study, with surveys conducted in 1999/2000 and 2004/2005. PARTICIPANTS: A total of 5985 men and women aged >= 25 years at study entry. MAIN OUTCOME MEASURE(S): At both time points, height, weight and waist circumference were measured and self-report data on health-related quality of life from the SF-36 questionnaire were obtained. Cross-sectional and bi-directional, prospective associations between obesity categories and health-related quality of life were assessed. RESULTS: Higher body mass index (BMI) at baseline was associated with deterioration in health-related quality of life over 5 years for seven of the eight health-related quality of life domains in women (all P <= 0.01, with the exception of mental health, P>0.05), and six out of eight in men (all P<0.05, with the exception of role-emotional, P=0.055, and mental health, P>0.05). Each of the quality-of-life domains related to mental health as well as the mental component summary were inversely associated with BMI change (all P<0.0001 for women and P <= 0.01 for men), with the exception of vitality, which was significant in women only (P=0.008). For the physical domains, change in BMI was inversely associated with baseline general health in women only (P=0.023). CONCLUSIONS: Obesity was associated with a deterioration in health-related quality of life (including both physical and mental health domains) in this cohort of Australian adults followed over 5 years. Health-related quality of life was also a predictor of weight gain over 5 years, indicating a bi-directional association between obesity and health-related quality of life. The identification of those with poor health-related quality of life may be important in assessing the risk of future weight gain, and a focus on health-related quality of life may be beneficial in weight management strategies. PMID- 21556046 TI - Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice. AB - AIM: Angiotensin-converting enzyme (ACE) inhibition can reduce the body weight of mice maintained on a high-fat diet. The current study examined the effect of the ACE inhibitor, captopril (CAP), on the reversal of diet-induced obesity (DIO), insulin resistance and inflammation in mice. MATERIALS AND METHODS: DIO was produced in C57BL/6J male mice (n=30) by maintaining animals on a high-fat diet (w/w 21% fat) for 12 weeks. During the subsequent 12-week treatment period, the animals were allowed access to the high-fat diet and either water containing CAP (0.05 mg ml(-1)) or plain tap water (CON, control). RESULTS: From the first week of treatment, food intake and body weight decreased in CAP-treated mice compared with CON mice. Both peripheral insulin sensitivity and hepatic insulin sensitivity were improved in CAP-treated mice compared with CON mice. CAP-treated mice had decreased absolute and relative liver and epididymal fat weights compared with CON mice. CAP-treated mice had higher plasma adiponectin and lower plasma leptin levels than CON mice. Relative to CON mice, CAP-treated mice had reduced adipose and skeletal muscle monocyte chemoattractant protein 1 (MCP-1), adipose interleukin-6 (IL-6), toll-like receptor 4 (TLR4) and uncoupling protein 2 (UCP2) mRNA expressions. Furthermore, CAP-treated mice had increased peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), long chain acyl-CoA dehydrogenase (LCAD), hormone sensitive lipase (HSL) and decreased lipoprotein lipase (LPL) mRNA expressions in the liver. CONCLUSION: The results of the current study indicate that in mice with DIO, CAP treatment reduced food intake and body weight, improved insulin sensitivity and decreased the mRNA expression of markers of inflammation. Thus, CAP may be a viable treatment for obesity, insulin resistance and inflammation. PMID- 21556047 TI - Modulating F-actin organization induces organ growth by affecting the Hippo pathway. AB - The Hippo tumour suppressor pathway is a conserved signalling pathway that controls organ size. The core of the Hpo pathway is a kinase cascade, which in Drosophila involves the Hpo and Warts kinases that negatively regulate the activity of the transcriptional coactivator Yorkie. Although several additional components of the Hippo pathway have been discovered, the inputs that regulate Hippo signalling are not fully understood. Here, we report that induction of extra F-actin formation, by loss of Capping proteins A or B, or caused by overexpression of an activated version of the formin Diaphanous, induced strong overgrowth in Drosophila imaginal discs through modulating the activity of the Hippo pathway. Importantly, loss of Capping proteins and Diaphanous overexpression did not significantly affect cell polarity and other signalling pathways, including Hedgehog and Decapentaplegic signalling. The interaction between F-actin and Hpo signalling is evolutionarily conserved, as the activity of the mammalian Yorkie-orthologue Yap is modulated by changes in F-actin. Thus, regulators of F-actin, and in particular Capping proteins, are essential for proper growth control by affecting Hippo signalling. PMID- 21556048 TI - Skeletal myosin light chain kinase regulates skeletal myogenesis by phosphorylation of MEF2C. AB - The MEF2 factors regulate transcription during cardiac and skeletal myogenesis. MEF2 factors establish skeletal muscle commitment by amplifying and synergizing with MyoD. While phosphorylation is known to regulate MEF2 function, lineage specific regulation is unknown. Here, we show that phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis. A phosphorylation-deficient MEF2C mutant (MEFT80A) enhanced cardiac, but not skeletal myogenesis in P19 stem cells. Further, MEFT80A was deficient in recruitment of p300 to skeletal but not cardiac muscle promoters. In gain-of-function studies, skMLCK upregulated myogenic regulatory factor (MRF) expression, leading to enhanced skeletal myogenesis in P19 cells and more efficient myogenic conversion. In loss-of-function studies, MLCK was essential for efficient MRF expression and subsequent myogenesis in embryonic stem (ES) and P19 cells as well as for proper activation of quiescent satellite cells. Thus, skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters. This work identifies the first kinase that regulates MyoD and Myf5 expression in ES or satellite cells. PMID- 21556049 TI - Box C/D snoRNP catalysed methylation is aided by additional pre-rRNA base pairing. AB - 2'-O-methylation of eukaryotic ribosomal RNA (r)RNA, essential for ribosome function, is catalysed by box C/D small nucleolar (sno)RNPs. The RNA components of these complexes (snoRNAs) contain one or two guide sequences, which, through base-pairing, select the rRNA modification site. Adjacent to the guide sequences are protein-binding sites (the C/D or C'/D' motifs). Analysis of >2000 yeast box C/D snoRNAs identified additional conserved sequences in many snoRNAs that are complementary to regions adjacent to the rRNA methylation site. This 'extra base pairing' was also found in many human box C/D snoRNAs and can stimulate methylation by up to five-fold. Sequence analysis, combined with RNA-protein crosslinking in Saccharomyces cerevisiae, identified highly divergent box C'/D' motifs that are bound by snoRNP proteins. In vivo rRNA methylation assays showed these to be active. Our data suggest roles for non-catalytic subunits (Nop56 and Nop58) in rRNA binding and support an asymmetric model for box C/D snoRNP organization. The study provides novel insights into the extent of the snoRNA rRNA interactions required for efficient methylation and the structural organization of the snoRNPs. PMID- 21556050 TI - eIF2A mediates translation of hepatitis C viral mRNA under stress conditions. AB - Translation of most mRNAs is suppressed under stress conditions. Phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2), which delivers initiator tRNA (Met-tRNA(i)) to the P site of the 40S ribosomal subunit, is responsible for such translational suppression. However, translation of hepatitis C viral (HCV) mRNA is refractory to the inhibitory effects of eIF2alpha phosphorylation, which prevents translation by disrupting formation of the eIF2 GTP-Met-tRNA(i) ternary complex. Here, we report that eIF2A, an alternative initiator tRNA-binding protein, has a key role in the translation of HCV mRNA during HCV infection, in turn promoting eIF2alpha phosphorylation by activating the eIF2alpha kinase PKR. Direct interaction of eIF2A with the IIId domain of the HCV internal ribosome entry site (IRES) is required for eIF2A-dependent translation. These data indicate that stress-independent translation of HCV mRNA occurs by recruitment of eIF2A to the HCV IRES via direct interaction with the IIId domain and subsequent loading of Met-tRNA(i) to the P site of the 40S ribosomal subunit. PMID- 21556051 TI - Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth. AB - The UBE2C oncogene is overexpressed in many types of solid tumours including the lethal castration-resistant prostate cancer (CRPC). The underlying mechanisms causing UBE2C gene overexpression in CRPC are not fully understood. Here, we show that CRPC-specific enhancers drive UBE2C overexpression in both AR-negative and positive CRPC cells. We further show that co-activator MED1 recruitment to the UBE2C enhancers is required for long-range UBE2C enhancer/promoter interactions. Importantly, we find that the molecular mechanism underlying MED1-mediated chromatin looping involves PI3K/AKT phosphorylated MED1-mediated recruitment of FoxA1, RNA polymerase II and TATA binding protein and their subsequent interactions at the UBE2C locus. MED1 phosphorylation leads to UBE2C locus looping, UBE2C gene expression and cell growth. Our results not only define a causal role of a post-translational modification (phosphorylation) of a co activator (MED1) in forming or sustaining an active chromatin structure, but also suggest that development of specific therapies for CRPC should take account of targeting phosphorylated MED1. PMID- 21556052 TI - A cell-penetrating peptide suppresses inflammation by inhibiting NF-kappaB signaling. AB - Nuclear factor-kappaB (NF-kappaB) is a central regulator of immune response and a potential target for developing anti-inflammatory agents. Mechanistic studies suggest that compounds that directly inhibit NF-kappaB DNA binding may block inflammation and the associated tissue damage. Thus, we attempted to discover peptides that could interfere with NF-kappaB signaling based on a highly conserved DNA-binding domain found in all NF-kappaB members. One such small peptide, designated as anti-inflammatory peptide-6 (AIP6), was characterized in the current study. AIP6 directly interacted with p65 and displayed an intrinsic cell-penetrating property. This peptide demonstrated significant anti inflammatory effects in vitro and in vivo. In vitro, AIP6 inhibited the DNA binding and transcriptional activities of the p65 NF-kappaB subunit as well as the production of inflammatory mediators in macrophages upon stimulation. Local administration of AIP6 significantly inhibited inflammation induced by zymosan in mice. Collectively, our results suggest that AIP6 is a promising lead peptide for the development of specific NF-kappaB inhibitors as potential anti-inflammatory agents. PMID- 21556053 TI - miRNA-mediated silencing in hepatocytes can increase adaptive immune responses to adenovirus vector-delivered transgenic antigens. AB - Adenovirus vectors based on human serotype 5 can induce potent CD8 T cell responses to vector-encoded transgenic antigens. However, the individual contribution of different cell types expressing antigen upon adenovirus vector injection to the generation of antigen-directed adaptive immune responses is poorly understood so far. We investigated the role of hepatocytes, skeletal muscle, and hematopoietic cells for the induction of cellular and humoral immune responses by miRNA-mediated tissue-specific silencing of antigen expression. Using hepatitis B small surface antigen (HBsAg) as the vector-encoded transgene we show that adenovirus vector dissemination from an intramuscular (i.m.) injection site into the liver followed by HBsAg expression in hepatocytes can limit early priming of CD8 T cells and the generation of anti-HBsAg antibody responses. However, hepatocyte-specific miRNA122a-mediated silencing of HBsAg expression overcame these limitations. Early clonal expansion of K(b)/S(190-197) specific CD8 T cells was significantly enhanced and improved polyfunctionality of CD8 T cells was found. Furthermore, miRNA122a-mediated antigen silencing induced significantly higher anti-HBsAg antibody titers allowing an up to 100-fold vector dose reduction. These results indicate that miRNA-mediated regulation of antigen expression in the context of adenovirus vectors can significantly improve transgene product-directed immune responses. This finding could be of interest for future adenovirus vaccine vector development. PMID- 21556054 TI - Engineering biosynthetic excitable tissues from unexcitable cells for electrophysiological and cell therapy studies. AB - Patch-clamp recordings in single-cell expression systems have been traditionally used to study the function of ion channels. However, this experimental setting does not enable assessment of tissue-level function such as action potential (AP) conduction. Here we introduce a biosynthetic system that permits studies of both channel activity in single cells and electrical conduction in multicellular networks. We convert unexcitable somatic cells into an autonomous source of electrically excitable and conducting cells by stably expressing only three membrane channels. The specific roles that these expressed channels have on AP shape and conduction are revealed by different pharmacological and pacing protocols. Furthermore, we demonstrate that biosynthetic excitable cells and tissues can repair large conduction defects within primary 2- and 3-dimensional cardiac cell cultures. This approach enables novel studies of ion channel function in a reproducible tissue-level setting and may stimulate the development of new cell-based therapies for excitable tissue repair. PMID- 21556055 TI - Photosynthetic growth despite a broken Q-cycle. AB - Central in respiration or photosynthesis, the cytochrome bc(1) and b(6)f complexes are regarded as functionally similar quinol oxidoreductases. They both catalyse a redox loop, the Q-cycle, which couples electron and proton transfer. This loop involves a bifurcated electron transfer step considered as being mechanistically mandatory, making the Q-cycle indispensable for growth. Attempts to falsify this paradigm in the case of cytochrome bc(1) have failed. The rapid proteolytic degradation of b(6)f complexes bearing mutations aimed at hindering the Q-cycle has precluded so far the experimental assessment of this model in the photosynthetic chain. Here we combine mutations in Chlamydomonas that inactivate the redox loop but preserve high accumulation levels of b(6)f complexes. The oxidoreductase activity of these crippled complexes is sufficient to sustain photosynthetic growth, which demonstrates that the Q-cycle is dispensable for oxygenic photosynthesis. PMID- 21556056 TI - Parallel evolution of the make-accumulate-consume strategy in Saccharomyces and Dekkera yeasts. AB - Saccharomyces yeasts degrade sugars to two-carbon components, in particular ethanol, even in the presence of excess oxygen. This characteristic is called the Crabtree effect and is the background for the 'make-accumulate-consume' life strategy, which in natural habitats helps Saccharomyces yeasts to out-compete other microorganisms. A global promoter rewiring in the Saccharomyces cerevisiae lineage, which occurred around 100 mya, was one of the main molecular events providing the background for evolution of this strategy. Here we show that the Dekkera bruxellensis lineage, which separated from the Saccharomyces yeasts more than 200 mya, also efficiently makes, accumulates and consumes ethanol and acetic acid. Analysis of promoter sequences indicates that both lineages independently underwent a massive loss of a specific cis-regulatory element from dozens of genes associated with respiration, and we show that also in D. bruxellensis this promoter rewiring contributes to the observed Crabtree effect. PMID- 21556057 TI - Two splice variants of the IDD14 transcription factor competitively form nonfunctional heterodimers which may regulate starch metabolism. AB - Alternative splicing of primary gene transcripts provides eukaryotic cells, with a critical scheme for enriching transcriptome and proteome diversity. Here we report that alternative splicing of the Arabidopsis INDERMINATE DOMAIN 14 (IDD14) transcription factor gene generates a competitive inhibitor in regulating starch metabolism. An alternatively spliced IDD14 form (IDD14beta), which is produced predominantly under cold conditions, lacks functional DNA-binding domain but is able to form heterodimers with the functional IDD14 form (IDD14alpha). IDD14alpha IDD14beta heterodimers have reduced binding activity to the promoter of Qua-Quine Starch (QQS) gene that regulates starch accumulation. Transgenic Arabidopsis plants overproducing IDD14alpha (35S:IDD14alpha) exhibited retarded growth with pale green leaves as appeared on QQS-overexpressing plants. Notably, IDD14beta overproduction rescued the 35S:IDD14alpha phenotypes. We propose that alternative splicing of the IDD14 gene generates a self-controlled regulatory loop that may modulate starch accumulation in response to cold. PMID- 21556058 TI - Mutual adaptation of a membrane protein and its lipid bilayer during conformational changes. AB - The structural elucidation of membrane proteins continues to gather pace, but we know little about their molecular interactions with the lipid environment or how they interact with the surrounding bilayer. Here, with the aid of low-resolution X-ray crystallography, we present direct structural information on membrane interfaces as delineated by lipid phosphate groups surrounding the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) in its phosphorylated and dephosphorylated Ca(2+)-free forms. The protein-lipid interactions are further analysed using molecular dynamics simulations. We find that SERCA adapts to membranes of different hydrophobic thicknesses by inducing local deformations in the lipid bilayers and by undergoing small rearrangements of the amino-acid side chains and helix tilts. These mutually adaptive interactions allow smooth transitions through large conformational changes associated with the transport cycle of SERCA, a strategy that may be of general nature for many membrane proteins. PMID- 21556059 TI - Revealing the molecular structure of single-molecule junctions in different conductance states by fishing-mode tip-enhanced Raman spectroscopy. AB - The conductance of single-molecule junctions may be governed by the structure of the molecule in the gap or by the way it bonds with the leads, and the information contained in a Raman spectrum is ideal for examining both. Here we demonstrate that molecule-to-surface bonding may be characterized during electron transport by 'fishing-mode' tip-enhanced Raman spectroscopy (FM-TERS). This technique allows mutually verifiable single-molecule conductance and Raman signals with single-molecule contributions to be acquired simultaneously at room temperature. Density functional theory calculations reveal that the most significant spectral change seen for a gold-4,4'-bipyridine-gold junction results from the deformation of the pyridine ring in contact with the drain electrode at high voltage, and these calculations suggest that a stronger bonding interaction between the molecule and the drain may account for the nonlinear dependence of conductance on bias voltage. FM-TERS will lead to a better understanding of electron-transport processes in molecular junctions. PMID- 21556060 TI - Optogenetic analysis of synaptic transmission in the central nervous system of the nematode Caenorhabditis elegans. AB - A reliable method for recording evoked synaptic events in identified neurons in Caenorhabditis elegans would greatly accelerate our understanding of its nervous system at the molecular, cellular and network levels. Here we describe a method for recording synaptic currents and potentials from identified neurons in nearly intact worms. Dissection and exposure of postsynaptic neurons is facilitated by microfabricated agar substrates, and ChannelRhodopsin-2 is used to stimulate presynaptic neurons. We used the method to analyse functional connectivity between a polymodal nociceptor and a command neuron that initiates a stochastic escape behaviour. We find that escape probability mirrors the time course of synaptic current in the command neuron. Moreover, synaptic input increases smoothly as stimulus strength is increased, suggesting that the overall input output function of the connection is graded. We propose a model in which the energetic cost of escape behaviours in C. elegans is tuned to the intensity of the threat. PMID- 21556061 TI - alpha-Mannosidase 2C1 attenuates PTEN function in prostate cancer cells. AB - PTEN dephosphorylates the 3-position phosphate of phosphatidylinositol 3,4,5 triphosphate (PIP(3)), thereby inhibiting AKT activation. Although attenuation of PTEN function has a major role in tumourigenesis, the underlying mechanisms remain unclear. Here we show that alpha-mannosidase 2C1 (MAN2C1) inhibits PTEN function in prostate cancer (PC) cells and is associated with a reduction in PTEN function in primary PC. MAN2C1 activates AKT and promotes the formation of PTEN positive DU145 cell-derived xenograft tumours by imparing endogenous PTEN function. In 659 PC patients who were examined, ~60% of tumours were PTEN positive with elevated AKT activation. Of these, 80% display MAN2C1 overexpression that co-localizes with PTEN. Increases in MAN2C1 were detected only in PTEN-positive prostatic intraepithelial neoplasia and carcinomas, and showed a significant association with PC recurrence only in patients with PTEN positive PCs. Mechanistically, MAN2C1 binds PTEN thereby inhibiting its PIP(3) phosphatase activity. These findings show that MAN2C1 function as a PTEN-negative regulator in PC cells. PMID- 21556062 TI - Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. AB - Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by a loss of the dystrophin protein. Control of dystrophin mRNA splicing to convert severe DMD to a milder phenotype is attracting much attention. Here we report a dystrophinopathy patient who has a point mutation in exon 31 of the dystrophin gene. Although the mutation generates a stop codon, a small amount of internally deleted, but functional, dystrophin protein is produced in the patient cells. An analysis of the mRNA reveals that the mutation promotes exon skipping and restores the open reading frame of dystrophin. Presumably, the mutation disrupts an exonic splicing enhancer and creates an exonic splicing silencer. Therefore, we searched for small chemicals that enhance exon skipping, and found that TG003 promotes the skipping of exon 31 in the endogenous dystrophin gene in a dose dependent manner and increases the production of the dystrophin protein in the patient's cells. PMID- 21556063 TI - Large-scale single-chirality separation of single-wall carbon nanotubes by simple gel chromatography. AB - Monostructured single-wall carbon nanotubes (SWCNTs) are important in both scientific research and electronic and biomedical applications; however, the bulk separation of SWCNTs into populations of single-chirality nanotubes remains challenging. Here we report a simple and effective method for the large-scale chirality separation of SWCNTs using a single-surfactant multicolumn gel chromatography method utilizing one surfactant and a series of vertically connected gel columns. This method is based on the structure-dependent interaction strength of SWCNTs with an allyl dextran-based gel. Overloading an SWCNT dispersion on the top column results in the adsorption sites of the column becoming fully occupied by the nanotubes that exhibit the strongest interaction with the gel. The unbound nanotubes flow through to the next column, and the nanotubes with the second strongest interaction with the gel are adsorbed in this stage. In this manner, 13 different (n, m) species were separated. Metallic SWCNTs were finally collected as unbound nanotubes because they exhibited the lowest interaction with the gel. PMID- 21556064 TI - An evolutionarily conserved three-dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and coregulation. AB - Developmental gene clusters are paradigms for the study of gene regulation; however, the mechanisms that mediate phenomena such as coregulation and enhancer sharing remain largely elusive. Here we address this issue by analysing the vertebrate Irx clusters. We first present a deep enhancer screen of a 2-Mbp span covering the IrxA cluster. Using chromosome conformation capture, we show that enhancer sharing is widespread within the cluster, explaining its evolutionarily conserved organization. We also identify a three-dimensional architecture, probably formed through interactions with CCCTC-binding factor, which is present within both Irx clusters of mouse, Xenopus and zebrafish. This architecture brings the promoters of the first two genes together in the same chromatin landscape. We propose that this unique and evolutionarily conserved genomic architecture of the vertebrate Irx clusters is essential for the coregulation of the first two genes and simultaneously maintains the third gene in a partially independent regulatory landscape. PMID- 21556065 TI - Engineering microbial biofuel tolerance and export using efflux pumps. AB - Many compounds being considered as candidates for advanced biofuels are toxic to microorganisms. This introduces an undesirable trade-off when engineering metabolic pathways for biofuel production because the engineered microbes must balance production against survival. Cellular export systems, such as efflux pumps, provide a direct mechanism for reducing biofuel toxicity. To identify novel biofuel pumps, we used bioinformatics to generate a list of all efflux pumps from sequenced bacterial genomes and prioritized a subset of targets for cloning. The resulting library of 43 pumps was heterologously expressed in Escherichia coli, where we tested it against seven representative biofuels. By using a competitive growth assay, we efficiently distinguished pumps that improved survival. For two of the fuels (n-butanol and isopentanol), none of the pumps improved tolerance. For all other fuels, we identified pumps that restored growth in the presence of biofuel. We then tested a beneficial pump directly in a production strain and demonstrated that it improved biofuel yields. Our findings introduce new tools for engineering production strains and utilize the increasingly large database of sequenced genomes. PMID- 21556067 TI - [Prestige and prioritization]. PMID- 21556066 TI - Stimulus-dependent dynamics of p53 in single cells. AB - Many biological networks respond to various inputs through a common signaling molecule that triggers distinct cellular outcomes. One potential mechanism for achieving specific input-output relationships is to trigger distinct dynamical patterns in response to different stimuli. Here we focused on the dynamics of p53, a tumor suppressor activated in response to cellular stress. We quantified the dynamics of p53 in individual cells in response to UV and observed a single pulse that increases in amplitude and duration in proportion to the UV dose. This graded response contrasts with the previously described series of fixed pulses in response to gamma-radiation. We further found that while gamma-triggered p53 pulses are excitable, the p53 response to UV is not excitable and depends on continuous signaling from the input-sensing kinases. Using mathematical modeling and experiments, we identified feedback loops that contribute to specific features of the stimulus-dependent dynamics of p53, including excitability and input-duration dependency. Our study shows that different stresses elicit different temporal profiles of p53, suggesting that modulation of p53 dynamics might be used to achieve specificity in this network. PMID- 21556068 TI - [Clarification about pregabalin and the Norwegian Prescription Database]. PMID- 21556070 TI - [Don't withdraw all blood platelet inhibitors]. PMID- 21556071 TI - [More expenses in humanitarian work]. PMID- 21556072 TI - [Whiplash--professorial arrogance]. PMID- 21556073 TI - [Chlamydia infections in South Trondelag--treatment and follow-up]. PMID- 21556076 TI - [Graded exercise therapy can have harmful effects]. PMID- 21556077 TI - [Elderly pilots, professional drivers--and physicians]. PMID- 21556078 TI - [Diabetic foot team and incidence of amputations]. PMID- 21556079 TI - [More physicians should learn leadership]. PMID- 21556080 TI - [Can pre-eclampsia be predicted?]. PMID- 21556081 TI - [Challenges of the internship]. PMID- 21556084 TI - [Patients with acute cerebral infarction admitted to stroke unit]. AB - BACKGROUND: Treatment of acute cerebral infarction has greatly improved over the last 15 years. The purpose of this article is to describe patients with acute cerebral infarction admitted to a stroke unit from a geographically well defined population between 2007 and 2009. MATERIAL AND METHOD: All patients were included aged over 15 years with acute cerebral infarction living in a well defined geographical area and admitted to Haukeland University Hospital between August 2007 and October 2009. Risk factors, neurological status, treatment, complications, results of evaluation, and outcome were registered in a stroke database (Bergen Stroke Registry). Data on mortality as of November 2009 were provided by the official population registry. RESULTS: In total, 553 patients with acute cerebral infarction were included: 260 (47%) females and 293 (53%) men. The mean age was 74.2 years. The incidence of patients admitted with acute cerebral infarction was 105 per 100,000 citizens per year. Thrombolysis was administered to 15%. Duplex sonography of neck vessels disclosed plaques in 68%. Atrial fibrillation was known before admission in 20%. Evaluation disclosed atrial fibrillation in another 12%. Recurrence of cerebral infarction occurred in 1% during the hospital stay. Estimated survival after one year was 82%. CONCLUSION: The incidence of acute cerebral infarction in Bergen is low. Systematic evaluation discloses risk factors with therapeutic consequences in many patients. PMID- 21556085 TI - [Treatment of cerebrovascular disease in a comprehensive stroke unit]. AB - BACKGROUND: Development of stroke units during the last decade has changed management of patients with stroke. The aim of this study is to assess unselected patients admitted to an acute stroke unit with respect to daily functioning (neurological deficits), treatment and 7-day outcome. MATERIAL AND METHODS: All patients with suspected neurovascular disease were admitted to the stroke unit as emergencies. Patients with confirmed cerebrovascular disease were prospectively included in the Bergen Stroke Study in the period 1 February 2006-30 April 2009. Patients who had other diagnoses were not included, but their diagnoses were prospectively recorded in a 3 month-period. RESULTS: 49.8% of the patients had other diagnoses than acute stroke. Of 1101 patients with neurovascular disease; 10% had transient ischemic attacks, 79% had ischemic and 10% had hemorrhagic stroke. On admission, 72% of the patients had none or minor neurological deficits. After one week 63% of the patients were independent, 25% needed long term rehabilitation and 10% were bedridden. INTERPRETATION: Most patients in our study had mild deficits and first of all need an exact diagnostic work-up, acute and prophylactic treatment. Rehabilitation is important for a minority of patients. PMID- 21556086 TI - [Evaluation of the compulsory practice period for doctors in Norwegian hospitals]. AB - BACKGROUND: The Norwegian Internship Council has uncovered weaknesses associated with the compulsory practice period in hospitals for doctors, both on a national basis and for North Trondelag County. MATERIAL AND METHODS: In 2007 and 2008, 79% (859) of all interns in Norwegian hospitals participated in the Council's national evaluation of the practice period. We compared the results from interns serving at hospitals in Levanger and Namsos (North Trondelag) (n = 39) with those from interns serving at the other hospitals in Norway (n = 820). RESULTS: At the surgical and medical departments in Levanger, the training in clinical procedures and acute medical conditions (simulator training) was similar or better than that in the other hospitals in Norway, but the guidance given to candidates in these departments was neither considered to be especially useful (12% and 17%) nor did it focus on problems related to ethics (0-8%). In general the guidance was perceived as more useful and systematic in psychiatric wards than in somatic ones. Fewer candidates in Namsos had experience with patient rounds (69%) and writing of case reports (79%) than those in hospitals in the rest of the country, and no interns in psychiatry reported that they had received thorough training in cooperation with the primary health services or in psychopharmacology. INTERPRETATION: National data from the Internship Council conceal important variations between hospitals, and to be useful for local improvement work they have to be reanalysed. The identified weaknesses for interns in North Trondelag led to implementation of new routines for guidance, training in simulation and law before start of the practice period. PMID- 21556087 TI - [Glucose transporter protein type 1 (GLUT-1) deficiency syndrome]. AB - BACKGROUND: Glucose is the brain's main source of energy. To pass the blood-brain barrier, glucose transporter protein type 1 (GLUT-1) is essential. Mutations in the SLC2A1 gene which codes for GLUT-1 may therefore compromise the supply of glucose to the brain. The aim of this review is to describe the clinical consequences of such mutations, with special emphasis on GLUT-1 encephalopathy. MATERIAL AND METHODS: This review is based on a non-systematic literature search in PubMed and the authors' experience within the field. RESULTS: Epileptic or epilepsy-like are usually the first symptom in children with the GLUT-1 deficiency syndrome. Later on these children suffer delayed psychomotor development, microcephaly, ataxia, spasticity or movement disorders. EEG abnormalities may develop. GLUT-1 deficiency syndrome should be suspected in children with epilepsy-like seizures and delayed development combined with a low content of glucose in spinal fluid. The diagnosis is confirmed by genetic testing. Treatment is a ketogenic diet, as ketone bodies pass the blood-brain barrier using other transport proteins than GLUT-1. INTERPRETATION: GLUT-1 deficiency syndrome is a rare metabolic encephalopathy which is not well known and probably underdiagnosed. An early diagnosis and early start of a ketogenic diet may give these children a normal or nearly normal life. PMID- 21556088 TI - [Development of new therapies for multiple sclerosis]. AB - BACKGROUND: Current first line treatment for multiple sclerosis is only moderately effective and is associated with frequent and disturbing side effects. We here describe opportunities and challenges related to drugs under development. MATERIAL AND METHODS: Non-systematic search in PubMed and congress abstracts. RESULTS AND INTERPRETATION: Monoclonal antibodies (e.g. natalizumab, alemtuzumab, rituximnab and dacklizumab) and oral agents (e.g. fingolimod and cladribine) target molecules or cells which are important in the immunopathogenesis of multiple sclerosis. These agents seem to have a considerable effect on relapsing remitting multiple sclerosis, but may also be associated with serious side effects. Natalizumab is licensed as second line treatment for relapsing-remitting multiple sclerosis, and also as first line treatment in especially serious cases. Cladribine and fingolimod may be available in Norway in 2011. INTERPRETATION: Treatment of exacerbations in multiple sclerosis is changing. Indication for the drugs under development is not yet clear. PMID- 21556089 TI - [Use of Saint Johns wort against mild depression]. PMID- 21556090 TI - [Hypotension and oxygen saturation fall in a woman during sentinel lymph node biopsy]. PMID- 21556091 TI - [Dangerous blue?]. PMID- 21556092 TI - [Naltrexone--high expectations to low dosages]. PMID- 21556095 TI - Generation of high-energy vacuum UV femtosecond pulses by multiple-beam cascaded four-wave mixing in a transparent solid. AB - The generation of ultrashort vacuum UV (VUV) pulses by nondegenerate cascaded four-wave mixing of femtosecond pulses in a thin slide of a large band-gap transparent solid is numerically demonstrated. Using a novel noncollinear multiple-beam configuration, cascaded four-wave mixing of amplified 30 fs Ti:sapphire laser pulses at 800 nm, and their second harmonic in lithium fluoride results in the generation of VUV radiation down to 134 nm with energies in the MUJ range and durations comparable to those of the pump pulses. The proposed geometry is advantageous in large dispersion scenarios, namely for generating radiation close to absorption bands. Hence these results set this technique as a promising way to efficiently generate ultrashort VUV radiation in solids for several applications in science and technology. PMID- 21556096 TI - Chalcogenide glass microlenses by inkjet printing. AB - We demonstrate micrometer scale mid-IR lenses for integrated optics, using solution-based inkjet printing techniques and subsequent processing. Arsenic sulfide spherical microlenses with diameters of 10-350 MUm and focal lengths of 10-700 MUm have been fabricated. The baking conditions can be used to tune the precise focal length. PMID- 21556097 TI - 1.4 ps pedestal-free low timing jitter 10 GHz pulse source using commercial cascaded LiNbO3 modulators and fiber-based compressor. AB - A stable 10 GHz pedestal-free short pulse generation scheme consisting of cascaded commercial LiNbO(3) modulators has been proposed and successfully demonstrated experimentally. Fiber-based pulse compression and reshaping stages have been utilized to obtain a 1.38 ps optical pulse train with very little pedestal and 132 fs timing jitter. Excellent performance of multiplexing from 10 Gbits/s to 160 Gbits/s using this method indicates good potential for application in ultrahigh-speed optical time-division-multiplexing systems. PMID- 21556098 TI - Material removal in magnetorheological finishing of optics. AB - A concept of material removal based on the principle of conservation of particles momentum in a binary suspension is applied to analyze material removal in magnetorheological finishing and magnetorheological jet processes widely used in precision optics fabrication. According to this concept, a load for surface indentation by abrasive particles is provided at their interaction near the wall with heavier basic (magnetic) particles, which fluctuate (due to collision) in the shear flow of concentrated suspension. The model is in good qualitative and quantitative agreement with experimental results. PMID- 21556099 TI - All-optical analog-to-digital conversion scheme based on Sagnac loop and balanced receivers. AB - An all-optical analog-to-digital conversion scheme based on a Sagnac loop and balanced receivers is proposed and experimentally demonstrated. Adjustable phase shift about the transfer function of the Sagnac loop is obtained by using the multiwavelength optical pulses to realize the phase-shift optical quantization. Benefit from the complementary outputs at the transmitted and reflected ports of the Sagnac loop and balanced receiver can be used to obtain the quantized output binary signal for the encoding operation. A proof-of-concept experiment is implemented using a wavelength tunable continuous-wave laser diode. Using 16 different wavelengths, the 16 quantization levels are demonstrated and an effective number of bits (ENOB) of 4 bits is obtained. PMID- 21556100 TI - Characterization and optimization of Yb-doped photonic-crystal fiber rod amplifiers using spatially resolved spectral interferometry. AB - Spatially resolved spectral interferometry is used to measure the mode content of a Yb-doped photonic-crystal fiber rod amplifier with a 2300 MUm(2) mode area. The technique, known as S(2) imaging, was adapted for the short fiber amplifier at full power and revealed a small amount of a copolarized LP(11) mode. Simulations illustrate the potential for weak mode suppression in this fiber and agree qualitatively with the measurements of S(2) and M(2). Higher-order-mode content depends on the alignment of the input signal at injection and ranged from -18 dB for optimized alignment to -13 dB when the injection alignment was offset along the LP(11) axis by 30% of the 55 MUm mode-field diameter. PMID- 21556101 TI - Quantitative phase retrieval of complex-valued specimens based on noninterferometric imaging. AB - In recent years, the interferometric imaging method has been applied to analyze the structure of various specimens, such as crystals and biological tissues. However, the interferometric imaging method may require a relatively complex optical recording system, such as a reference wave and temporal coherence. In this paper, we propose a method based on noninterferometric imaging for quantitative phase retrieval of complex-valued specimens. A strategy using different focal lengths in the lens function is developed, and a series of diffraction intensity maps is recorded. Numerical simulation results are presented to demonstrate the feasibility and effectiveness of the proposed method. PMID- 21556102 TI - Design and optimization of broadband and polarization-insensitive dual-core photonic crystal fiber coupler. AB - In this paper, we propose a novel (to our knowledge) broadband and polarization insensitive dual-core photonic crystal fiber (PCF) coupler through the introduction of an elliptical-shaped central air hole to offset the slight birefringence arising from the dual core. With a full vectorial finite element method and anisotropic perfectly matched layers as the external boundaries, the impact of several fiber parameters on the coupling characteristics of dual-core PCF is investigated in detail. Through optimizing the main fiber parameters, including core diameter, size and ellipticity of the central air hole, and refractive index difference, broadband and polarization-insensitive characteristics are achieved in the wavelength range from 0.8 to 1.7 MUm. The variation of the coupling ratio is stabilized at 50+/-1%, and the coupling ratio difference between x polarization and y polarization is less than 2% over the wavelength range. This dual-core PCF makes it easier to develop a 3 dB coupler over a wide wavelength for passive optical networks and large optical systems. PMID- 21556103 TI - Misalignment aberrations calibration in testing of high-numerical-aperture spherical surfaces. AB - The calibration of misalignment aberrations is a key issue in the testing of high numerical-aperture spherical surfaces, and it is hard to separate the high-order aberrations introduced by misalignment from the measured data. The traditional calibration method is still applicable in the case of only wavefront tilt, but no longer effective in the existence of defocus. A calibration technique based on the wavefront difference is proposed to calibrate the misalignment aberrations in the presence of wavefront defocus, and it can be carried out without foreknowledge of the spherical surface under test. With the wavefront difference method, the calibration needs two separate measurements to separate the high order aberrations. Both the computer simulation and experiments with the ZYGO interferometer have been carried out to validate the proposed calibration technique, with the accuracies better than 0.0005lambda RMS and 0.0010lambda RMS achieved, respectively. The proposed calibration method provides a feasible way to lower the requirement on the adjustment in the measurement, while retaining good accuracy. PMID- 21556104 TI - Surface-plasmon-resonance-based fiber-optic refractive index sensor: sensitivity enhancement. AB - We have experimentally studied the surface plasmon resonance (SPR)-based fiber optic refractive index sensor incorporating a high-index dielectric layer using the wavelength interrogation method. Silver and gold have been used as SPR active metals followed by a high-index dielectric layer of silicon. Experimental results predict a redshift in the resonance wavelength with the increase in the refractive index of the sensing layer for a given thickness of the silicon layer. Further, as the thickness of the silicon layer increases, the sensitivity of the sensor increases. The upper limit of the silicon film thickness for the enhancement of the sensitivity has been found to be around 10 nm. The experimental results obtained on sensitivity match qualitatively with the theoretical results obtained using the N-layer model and the ray approach. The increase in sensitivity is due to the increase in the electric field intensity at the silicon-sensing-region interface. In addition to an increase in sensitivity, the silicon layer can be used to tune the resonance wavelength and can protect the metal layer from oxidation and hence can improve the durability of the probe. PMID- 21556105 TI - Light absorption from particulate impurities in snow and ice determined by spectrophotometric analysis of filters. AB - Light absorption by particulate impurities in snow and ice can affect the surface albedo and is important for the climate. The absorption properties of these particles can be determined by collecting and melting snow samples and extracting the particulate material by filtration of the meltwater. This paper describes the optical design and testing of a new instrument to measure the absorption spectrum from 400 to 750 nm wavelength of the particles collected on filters using an "integrating-sandwich" configuration. The measured absorption is shown to be unaffected by scattering of light from the deposited particulates. A set of calibration standards is used to derive an upper limit for the concentration of black carbon (BC) in the snow. The wavelength dependence of the absorption spectra from 450 to 600 nm is used to calculate an absorption Angstrom exponent for the aerosol. This exponent is used to estimate the actual BC concentration in the snow samples as well as the relative contributions of BC and non-BC constituents to the absorption of solar radiation integrated over the wavelength band 300 to 750 nm. PMID- 21556106 TI - Band-edge oscillations of the diffraction spectrum of a volume hologram investigated by the air-doping model. AB - Oscillation exists at the high-frequency band edge in the diffraction spectrum of a volume hologram. An air-doping model of a volume hologram is proposed to explain the phenomenon. The numerical results show good agreement with the experimental results, which cannot be explained by the conventional models. The results show that the position of air impurity is the key factor to control the number and width of the oscillations. The present work gives a new approach to generate and control the defect mode in a holographic photonic crystal. PMID- 21556107 TI - Feasibility study on 1.6 MUm continuous-wave modulation laser absorption spectrometer system for measurement of global CO2 concentration from a satellite. AB - A feasibility study is carried out on a 1.6 MUm continuous-wave modulation laser absorption spectrometer system for measurement of global CO(2)concentration from a satellite. The studies are performed for wavelength selection and both systematic and random error analyses. The systematic error in the differential absorption optical depth (DAOD) is mainly caused by the temperature estimation error, surface pressure estimation error, altitude estimation error, and ON wavelength instability. The systematic errors caused by unwanted backscattering from background aerosols and dust aerosols can be reduced to less than 0.26% by using a modulation frequency of around 200 kHz, when backscatter coefficients of these unwanted backscattering have a simple profile on altitude. The influence of backscattering from cirrus clouds is much larger than that of dust aerosols. The transmission power required to reduce the random error in the DAOD to 0.26% is determined by the signal-to-noise ratio and the carrier-to-noise ratio calculations. For a satellite altitude of 400 km and receiving aperture diameter of 1 m, the required transmission power is approximately 18 W and 70 W when albedo is 0.31 and 0.08, respectively; the total measurement time in this case is 4 s, which corresponds to a horizontal resolution of 28 km. PMID- 21556108 TI - Vertical profiles of microphysical particle properties derived from inversion with two-dimensional regularization of multiwavelength Raman lidar data: experiment. AB - Inversion with two-dimensional (2-D) regularization is a new methodology that can be used for the retrieval of profiles of microphysical properties, e.g., effective radius and complex refractive index of atmospheric particles from complete (or sections) of profiles of optical particle properties. The optical profiles are acquired with multiwavelength Raman lidar. Previous simulations with synthetic data have shown advantages in terms of retrieval accuracy compared to our so-called classical one-dimensional (1-D) regularization, which is a method mostly used in the European Aerosol Research Lidar Network (EARLINET). The 1-D regularization suffers from flaws such as retrieval accuracy, speed, and ability for error analysis. In this contribution, we test for the first time the performance of the new 2-D regularization algorithm on the basis of experimental data. We measured with lidar an aged biomass-burning plume over West/Central Europe. For comparison, we use particle in situ data taken in the smoke plume during research aircraft flights upwind of the lidar. We find good agreement for effective radius and volume, surface-area, and number concentrations. The retrieved complex refractive index on average is lower than what we find from the in situ observations. Accordingly, the single-scattering albedo that we obtain from the inversion is higher than what we obtain from the aircraft data. In view of the difficult measurement situation, i.e., the large spatial and temporal distances between aircraft and lidar measurements, this test of our new inversion methodology is satisfactory. PMID- 21556109 TI - Analysis of static and time-varying polarization errors in the multiangle spectropolarimetric imager. AB - Multiangle Spectropolarimetric Imager (MSPI) sensitivity to static and time varying polarization errors is examined. For a system without noise, static polarization errors are accurately represented by the calibration coefficients, and therefore do not impede correct mapping of measured to input Stokes vectors. But noise is invariably introduced during the detection process, and static polarization errors reduce the system's signal-to-noise ratio (SNR) by increasing noise sensitivity. Noise sensitivity is minimized by minimizing the condition number of the system data reduction matrix [Appl. Opt.41, 619 (2002)]. The sensitivity of condition numbers to static polarization errors is presented. The condition number of the nominal MSPI data reduction matrix is approximately 1.1 or less for all fields. The increase in the condition number above 1 results primarily from a quarter wave plate and mirror coating retardance magnitude errors. Sensitivity of the degree of linear polarization (DoLP) error with respect to time-varying diattenuation and retardance error was used to set a time varying diattenuation magnitude tolerance of 0.005 and a time-varying retardance magnitude tolerance of +/-0.2 degrees . A Monte Carlo simulation of the calibration and measurements using anticipated static and time-varying errors indicates that MSPI has a probability of 0.9 of meeting its 0.005 DoLP uncertainty requirement. PMID- 21556110 TI - Single-camera motion measurement and monitoring for magnetic resonance applications. AB - An optically based rigid-body six-degrees of freedom (DOF) measurement system optimized for prospective (real-time) motion correction in magnetic resonance imaging (MRI) applications is described. By optimizing system capabilities to the specific applications requirements, the six-DOF measurement is accomplished using a single camera and simple three-disc fiducial at rates of 50 Hz. The algorithm utilizes successive approximation to solve the three point pose problem for angles close to the origin. Convergence to submicroradian levels occurs within 20 iterations for angles in an approximate half-radian (29 degrees ) arc centered on the origin. The overall absolute accuracy of the instrument is 10-100 MUm for translational and <100 MUrad (0.005 degrees ) for rotational motions. Results for head nodding and speech tasks are presented for subjects in the MR scanner, and the instrument results are compared to standard prospective acquisition correction. PMID- 21556111 TI - Atmospheric CO2 measurements with a 2 MUm airborne laser absorption spectrometer employing coherent detection. AB - We report airborne measurements of CO(2) column abundance conducted during two 2009 campaigns using a 2.05 MUm laser absorption spectrometer. The two flight campaigns took place in the California Mojave desert and in Oklahoma. The integrated path differential absorption (IPDA) method is used for the CO(2) column mixing ratio retrievals. This instrument and the data analysis methodology provide insight into the capabilities of the IPDA method for both airborne measurements and future global-scale CO(2) measurements from low Earth orbit pertinent to the NASA Active Sensing of CO(2) Emissions over Nights, Days, and Seasons mission. The use of a favorable absorption line in the CO(2) 2 MUm band allows the on-line frequency to be displaced two (surface pressure) half-widths from line center, providing high sensitivity to the lower tropospheric CO(2). The measurement repeatability and measurement precision are in good agreement with predicted estimates. We also report comparisons with airborne in situ measurements conducted during the Oklahoma campaign. PMID- 21556112 TI - Field demonstration of a scanning lidar and detection algorithm for spatially mapping honeybees for biological detection of land mines. AB - A biological detection scheme based on the natural foraging behavior of conditioned honeybees for detecting chemical vapor plumes associated with unexploded ordnance devices utilizes a scanning lidar instrument to provide spatial mapping of honeybee densities. The scanning light detection and ranging (lidar) instrument uses a frequency doubled Nd:YAG microchip laser to send out a series of pulses at a pulse repetition rate of 6.853 kHz. The scattered light is monitored to produce a discrete time series for each range. This discrete time series is then processed using an efficient algorithm that is able to isolate and identify the return signal from a honeybee in a cluttered environment, producing spatially mapped honeybee densities. Two field experiments were performed with the scanning lidar instrument that demonstrate good correlation between the honeybee density maps and the target locations. PMID- 21556113 TI - Visible and infrared extinction of atmospheric aerosol in the marine and coastal environment. AB - The microphysical model Marine Aerosol Extinction Profiles (MaexPro) for surface layer marine and coastal atmospheric aerosols, which is based on long-term observations of size distributions for 0.01-100 MUm particles, is presented. The fundamental feature of the model is a parameterization of amplitudes and widths for aerosol modes of the aerosol size distribution function (ASDF) as functions of fetch and wind speed. The shape of the ASDF and its dependence on meteorological parameters, altitudes above the sea level (H), fetch (X), wind speed (U), and relative humidity is investigated. The model is primarily to characterize aerosols for the near-surface layer (within 25 m). The model is also applicable to higher altitudes within the atmospheric boundary layer, where the change in the vertical profile of aerosol is not very large. In this case, it is only valid for "clean" marine environments, in the absence of air pollution or any other major sources of continental aerosols, such desert dust or smoke from biomass burning. The spectral profiles of the aerosol extinction coefficients calculated by MaexPro are in good agreement with observational data and the numerical results obtained by the well-known Navy Aerosol Model and Advanced Navy Aerosol Model codes. Moreover, MaexPro was found to be an accurate and reliable instrument for investigation of the optical properties of atmospheric aerosols. PMID- 21556114 TI - Color image hiding based on the phase retrieval technique and Arnold transform. AB - A new (to our knowledge) method is proposed in this paper for color image hiding and extracting using the phase retrieval algorithm in the fractional Fourier transform (FRFT) domain and Arnold transform (ART). Based on a cascaded phase iterative FRFT algorithm, the three channels (R, G, and B) of the secret color image permuted by ART are encrypted. Then the encoded information is embedded in the blue channel (B channel) of the enlarged color host image. Using the security enhanced encryption method, not only the random phase mask and the wavelength but also the transform parameters of ART and FRFT are provided as additional keys for decryption. It is shown that the security of information hiding will be enhanced. Computer simulations are performed to show the hiding capacity of the proposed system. Numerical results are presented to verify the validity and efficiency of the proposed method. PMID- 21556115 TI - Optimization of the tartrate-resistant acid phosphatase detection by histochemical method. AB - According to the new KDIGO (Kidney Disease Improving Global Outcomes) guidelines, the term of renal osteodystrophy, should be used exclusively in reference to the invasive diagnosis of bone abnormalities. Due to the low sensitivity and specificity of biochemical serum markers of bone remodelling,the performance of bone biopsies is highly stimulated in dialysis patients and after kidney transplantation. The tartrate-resistant acid phosphatase (TRACP) is an iso-enzyme of the group of acid phosphatases, which is highly expressed by activated osteoclasts and macrophages. TRACP in osteoclasts is in intracytoplasmic vesicles that transport the products of bone matrix degradation. Being present in activated osteoclasts, the identification of this enzyme by histochemistry in undecalcified bone biopsies is an excellent method to quantify the resorption of bone. Since it is an enzymatic histochemical method for a thermolabile enzyme, the temperature at which it is performed is particularly relevant. This study aimed to determine the optimal temperature for identification of TRACP in activated osteoclasts in undecalcified bone biopsies embedded in methylmethacrylate. We selected 10 cases of undecalcified bone biopsies from hemodialysis patients with the diagnosis of secondary hyperparathyroidism. Sections of 5 μm were stained to identify TRACP at different incubation temperatures (37º, 45º, 60º, 70º and 80ºC) for 30 minutes. Activated osteoclasts stained red and trabecular bone (mineralized bone) was contrasted with toluidine blue. This approach also increased the visibility of the trabecular bone resorption areas (Howship lacunae). Unlike what is suggested in the literature and in several international protocols, we found that the best results were obtained with temperatures between 60ºC and 70ºC. For technical reasons and according to the results of the present study, we recommended that, for an incubation time of 30 minutes, the reaction should be carried out at 60ºC. As active osteoclasts are usually scarce in a bone section, the standardization of the histochemistry method is of great relevance, to optimize the identification of these cells and increase the accuracy of the histomosphometric results. Our results, allowing an increase in osteoclasts contrast, also support the use of semi-automatic histomorphometric measurements. PMID- 21556116 TI - The expression of Sirtuins 1 and 4 in peripheral blood leukocytes from patients with type 2 diabetes. AB - This study was designed to investigate the relationship between SIRTs 1 and 4 in peripheral blood leukocytes (PBLs) and human type 2 diabetes mellitus (T2DM). SIRTs 1 and 4 have been confirmed to be associated with homeostasis of glucose/lipid metabolism, but their roles in T2DM are still poorly understood. Peripheral blood and biochemical data were collected from 52 healthy individuals (normal control group, NC group) and 113 cases of T2DM patients. Immunocytochemical staining was used to detect SIRT1 and SIRT4 and reverse transcription polymerase chain reaction (RT-PCR) was used to detect SIRT1 or SIRT4 mRNA levels in PBLs. Immunocytochemical staining showed that SIRT1 is expressed in both nucleus and cytoplasm, and SIRT4 in the cytoplasm of granulocytes and monocytes. No SIRT1 or SIRT4 was found in lymphocytes. RT-PCR showed that SIRT1 and SIRT4 mRNA levels in T2DM group were lower than those in NC group (P<0.01). Correlation analysis showed that there is a negative correlation between SIRTs 1 and 4 and fasting plasma glucose (FPG) (P<0.05) (r= -0.161 and 0.156), a positive correlation between SIRT4 mRNA levels and triglyceride (TG)/lipoprotein a (LPa) levels (P<0.05), and a negative correlation between SIRT4 mRNA levels and high density lipoprotein cholesterol (HDL) (P<0.05). SIRTs 1 and 4 may have a role in the pathogenesis of T2DM and their expression in granulocytes and monocytes may indirectly reflect the homeostasis of glucose/lipid metabolism in T2DM. PMID- 21556117 TI - Maturation of neurotransmission in the developing rat cochlea: immunohistochemical evidence from differential expression of synaptophysin and synaptobrevin 2. AB - Synaptophysin and synaptobrevin 2 associate closely with packaging and storage of synaptic vesicles and transmitter release, and both play important roles in the development of rat cochlea. We examined the differential expression of synaptophysin and synaptobrevin 2 in the developing Sprague-Dawley rat cochlea, and investigated the relationship between their expression and auditory development. The expression of synaptophysin and synaptobrevin 2 was not observed in Kolliker’s and Corti’s organ at postnatal 1 day (P1) and P5, and the top turn of the cochlea at P10. Expression was detected in the outer spiral bundle (OSB), the inner spiral bundle (ISB), and the medial wall of the Deiters’ cell of the cochlea at P14, and P28, and in the middle or the basal turn of Corti’s organ at P10. Synaptobrevin 2 was expressed in the top of the inner hair cells (IHCs) in Corti’s organ of both P14 and P28 rats. All spiral ganglion neurons (SGNs) were stained at all ages examined. The localization of synaptophysin and synaptobrevin 2 in the cochlea was closely associated with the distribution of nerve fibers and neural activity (the docking and release of synaptic vesicles). Synaptophysin and synaptobrevin 2 were expressed in a dynamic manner during the development of rat cochlea. Their expression differences during the development were in favor of the configuration course constructed between nerve endings and target cells. It also played a key role in the formation of the correct coding of auditory information during auditory system development. PMID- 21556118 TI - Subcellular localization and distribution of the reduced folate carrier in normal rat tissues. AB - The reduced folate carrier (Rfc1; Slc19a1) mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) play an essential role in physiological folate homeostasis and MTX cancer chemotherapy. As no systematic reports are as yet available correlating Rfc1 gene expression and protein levels in all tissues crucial for folate and antifolate uptake, storage or elimination, we investigated gene and protein expression of rat Rfc1 (rRfc1) in selected tissues. This included the generation of a specific anti-rRfc1 antibody. Rabbits were immunised with isolated rRfc1 peptides producing specific anti-rRfc1 antiserum targeted to the intracellular C-terminus of the carrier. Using RT-PCR analysis, high rRfc1 transcript levels were detected in colon, kidney, brain, thymus, and spleen. Moderate rRfc1 gene expression was observed in small intestine, liver, bone marrow, lung, and testes whereas transcript levels were negligible in heart, skeletal muscle or leukocytes. Immunohistochemical analyses revealed strong carrier expression in the apical membrane of tunica mucosa epithelial cells of small intestine and colon, in the brush-border membrane of choroid plexus epithelial cells or in endothelial cells of small vessels in brain and heart. Additionally, high rRfc1 protein levels were localized in the basolateral membrane of renal tubular epithelial cells, in the plasma membrane of periportal hepatocytes, and sertoli cells of the testes. Taken together, our results demonstrated that rRfc1 is expressed almost ubiquitously but to very different levels. The predominant tissue distribution supports the essential role of Rfc1 in physiological folate homeostasis. Moreover, our results may contribute to understand antifolate pharmacokinetics and selected organ toxicity associated with MTX chemotherapy. PMID- 21556119 TI - Establishment and biological characteristics of a Jingning chicken embryonic fibroblast bank. AB - Using tissue explantation and cryopreservation biotechniques, a Jingning chicken embryonic fibroblast bank was successfully established, which includes 43 embryo samples and a stock of 178 cryovials, each one containing 3.0×106 cells. Most of the cells were apparently fibroblasts in their morphology, and the population doubling time (PDT) was about 48 h. The total chromosome number of a diploid cell was 78. According to karyotyping and G-banding, the diploid rate in the cell bank was 97.62±2.12%. The cells were tested for microbial contamination and found free of infections from bacteria, fungi, viruses and mycoplasms. There was no cross-contamination from other cell lines as revealed by lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) isoenzyme polymorphisms. Six fluorescent proteins were transfected into the Jingning chicken embryonic fibroblasts, and the transfection efficiencies of these genes were between 10.1 and 41.9%. All the tests showed that the quality of the cell line conforms to the quality criteria of the ATCC (American type culture collection). This work succeeded not only in preserving the genetic resources of Jingning chicken, but it also established a new protocol to preserve endangered animal breeds. PMID- 21556120 TI - Altered alkaline phosphatase activity in obese Zucker rats liver respect to lean Zucker and Wistar rats discussed in terms of all putative roles ascribed to the enzyme. AB - Biliary complications often lead to acute and chronic liver injury after orthotopic liver transplantation (OLT). Bile composition and secretion depend on the integrated action of all the components of the biliary tree, starting from hepatocytes. Fatty livers are often discarded as grafts for OLT, since they are extremely vulnerable to conventional cold storage (CS). However, the insufficiency of donors has stimulated research to improve the usage of such marginal organs as well as grafts. Our group has recently developed a machine perfusion system at subnormothermic temperature (20°C; MP20) that allows a marked improvement in preservation of fatty and even of normal rat livers as compared with CS. We sought to evaluate the response of the biliary tree of fatty liver to MP20, and a suitable marker was essential to this purpose. Alkaline phosphatase (AlkP, EC 3.1.3.1), frequently used as marker of membrane transport in hepatocytes and bile ducts, was our first choice. Since no histochemical data were available on AlkP distribution and activity in fatty liver, we have first settled to investigate AlkP activity in the steatotic liver of fatty Zucker rats (fa/fa), using as controls lean Zucker (fa/+) and normal Wistar rats. The AlkP reaction in Wistar rats was in accordance with the existing data and, in particular, was present in bile canaliculi of hepatocytes in the periportal region and midzone, in the canals of Hering and in small bile ducts but not in large bile ducts. In lean ZR liver the AlkP reaction in Hering canals and small bile ducts was similar to Wistar rat liver but hepatocytes had lower canalicular activity and besides presented moderate basolateral reaction. The difference between lean Zucker and Wistar rats, both phenotypically normal animals, could be related to the fact that lean Zucker rats are genotypically heterozygous for a recessive mutated allele. In fatty liver, the activity in ductules and small bile ducts was unchanged, but most hepatocytes were devoid of AlkP activity with the exception of clusters of macrosteatotic hepatocytes in the mid-zone, where the reaction was intense in basolateral domains and in distorted canaliculi, a typical pattern of cholestasis. The interpretation of these data was hindered by the fact that the physiological role of AlkP is still under debate. In the present study, the various functions proposed for the role of the enzyme in bile canaliculi and in cholangiocytes are reviewed. Independently of the AlkP role, our data suggest that AlkP does not seem to be a reliable marker to study the initial step of bile production during OLT of fatty livers, but may still be used to investigate the behaviour of bile ductules and small bile ducts. PMID- 21556121 TI - Evidence that muscle cells do not express the histidine-rich glycoprotein associated with AMP deaminase but can internalise the plasma protein. AB - Histidine-rich glycoprotein (HRG) is synthesized by liver and is present at relatively high concentration in the plasma of vertebrates. We have previously described the association of a HRG-like molecule to purified rabbit skeletal muscle AMP deaminase (AMPD). We also provided the first evidence for the presence of a HRG-like protein in human skeletal muscle where a positive correlation between HRG content and total determined AMPD activity has been shown. In the present paper we investigate the origin of skeletal muscle HRG. The screening of a human skeletal muscle cDNA expression library using an anti-HRG antibody failed to reveal any positive clone. The RT-PCR analysis, performed on human skeletal muscle RNA as well as on RNA from the rhabdomyosarcoma (RD) cell line, failed to show any mRNA specific for the plasma HRG or for the putative muscle variant. When the RD cells were incubated with human plasma HRG, a time-dependent increase of the HRG immunoreactivity was detected both at the plasma membrane level and intracellularly. The internalisation of HRG was inhibited by the addition of heparin. The above data strongly suggest that skeletal muscle cells do not synthesize the muscle variant of HRG but instead can actively internalise it from plasma. PMID- 21556122 TI - MAGE-A3/4 and NY-ESO-1 antigens expression in metastatic esophageal squamous cell carcinoma. AB - In the present study we analyzed immunohistochemical expression of MAGE-A 3/4 and NY-ESO-1 in 55 samples of esophageal squamous cell carcinomas (ESCC) and their respective lymph node metastases. To our knowledge this is the first study to assess and compare the expression of these antigens in ESCC lymph node metastases. Fifty (90.9%) primary ESCC were positive for MAGE-A 3/4 and 53 (96.6%) were positive for NY-ESO-1. MAGE-A 3/4 was expressed in all lymph node metastases and the intensity of expression was high in a majority of cases. NY ESO-1 was negative in 2 (7.1%) lymph nodes metastases, while the reaction was predominantly moderate in the positive group. In primary tumors MAGE-A 3/4 showed a significantly higher intensity of expression compared to NY-ESO-1 (P=0.047), while in lymph node metastases the intensity of expression was not significantly different (P=0.387). Primary tumors with and without lymph node metastases showed no significant differences in MAGE-A 3/4 (P=0.672) and NY-ESO-1 (P=0.444) expression. Intensity of MAGE-A 3/4 (P=0.461) and NY-ESO-1 (P=0.414) expression in primary tumors was not significantly different compared to the expression in their respective lymph nodes metastases. Expression of MAGE-A 3/4 in primary tumors showed significant positive correlation with primary tumor expression of NY-ESO-1 (P=0.021) but no significant correlation with the expression of MAGE-A 3/4 in lymph node metastases (P=0.056). Expression of NY-ESO-1 in primary tumors showed significant positive correlation with the expression of NY-ESO-1 in lymph node metastases (P=0.001) and significant negative correlation with patients’ age (P<0.001). Expression of MAGE-A 3/4 and NY-ESO-1 in primary tumors and lymph node metastases showed no significant correlation with prognostic parameters such as tumor grade and TNM stage (P>0.05). We have shown different levels of MAGE-A 3/4 and NY-ESO-1 expression in almost all specimens of primary tumor and lymph node metastases, suggesting that ESCC may be possible target of immunotherapy and anti-tumor vaccination. High levels of expression in lymph node metastases indicate possible clinical benefit of postoperative vaccine with MAGE-A3 and NY-ESO-1 in advanced stage of disease. PMID- 21556123 TI - Co-overexpression of bcl-2 and c-myc in uterine cervix carcinomas and premalignant lesions. AB - To establish the role of co-overexpression of bcl-2 and c-myc protooncogenes in uterine cervix carcinogenesis, we examined 138 tissue samples of low grade cervical squamous intraepithelial lesions (SIL), high grade SIL, portio vaginalis uteri (PVU) carcinoma in situ and PVU carcinoma invasive, stage IA-IIA (study group) and 36 samples without SIL or malignancy (control group). The expression of bcl-2 and c-myc was detected immunohistochemically using a monoclonal antibody. Fisher’s exact test (P<0.05) was used to assess statistical significance. Overexpression of bcl-2 was found to increase in direct relation to the grade of the cervical lesions. High sensitivity was of great diagnostic significance for the detection of these types of changes in the uterine cervix. On the basis of high predictive values it can be said that in patients with bcl-2 overexpression there is a great possibility that they have premalignant or malignant changes in the uterine cervix. Co-overexpression of bcl-2 and c-myc oncogenes was found only in patients with PVU invasive carcinoma (6/26-23.0%). Statistically significant difference was not found in the frequency of co overexpression in patients with PVU invasive carcinoma in relation to the control group (Fisher’s test; P=0.064). The method's sensitivity of determining these oncogenes with the aim of detecting PVU invasive carcinoma was 23%, while specificity was 72.2%. On the basis of high predictive values (100%), speaking in statistical terms, it can be concluded that all patients with co-overexpression of bcl-2 and c-myc oncogenes will have PVU invasive carcinoma. We confirmed in our research that co-overexpression of bcl-2 and c-myc oncogenes was increased only in PVU invasive carcinoma. However, a more extensive series of samples and additional tests are required to establish the prognostic significance of bcl-2 and c-myc co-overexpression in cervical carcinogenesis. PMID- 21556124 TI - Significance and relationship between DJ-1 gene and surviving gene expression in laryngeal carcinoma. AB - This study aimed at exploring the correlation between DJ-1 gene and survivin gene in laryngeal squamous cell carcinoma by analyzing their gene expression levels and their relationship with clinicopathologic parameters. The expression of DJ-1 gene and survivin gene in 82 laryngeal carcinoma tissues from patients and 82 negative surgical margin tissue samples were detected by immunohistochemistry, respectively. The correlation of their expression levels and patients’ clinical parameters were then analyzed by Pearson correlation analysis. The positive detection rates of DJ-1 and survivin in laryngeal carcinoma tissues were 71.95% and 60.98%, which were higher than those of the normal control that were 29.27% and 0.00%, respectively (P<0.01). The positive detection rates of DJ-1 and survivin were found associated with tumor stages (P<0.05), but not with lymph node metastasis. The DJ-1 gene expression level was related to cell differentiation (P<0.05). Finally, a positive correlation between DJ-1 and survivin gene expression in laryngeal carcinoma was found. The overall survival rate of patients was 51.2%, and disease-free survival (DFS) was 39.0%. DFS in DJ 1 negative-expression group was 87.0%, and 20.3% in DJ-1 positive-expression group. The negative expression of DJ-1 was associated with a shorter mean patient DFS time (44.643±1.417 months), whereas positive expression of DJ-1 was associated with a longer mean DSF time (25.943±1.297 months). DJ-1 and survivin play a vital role in the occurrence and development of laryngeal carcinoma. DJ-1 may promote the carcinogenesis of laryngeal cells by up regulating the survivin gene expression. PMID- 21556128 TI - Digestive oncologist in the gastroenterology training curriculum. AB - Until the late 1980s, gastroenterology (GE) was considered a subspecialty of Internal Medicine. Today, GE also incorporates Hepatology. However, Digestive Oncology training is poorly defined in the Hepatogastroenterology (HGE) curriculum. Therefore, a Digestive Oncology curriculum should be developed and this document might be a starting point for such a curriculum. HGE-specialists are increasingly resisting the paradigm in which they play only a diagnostic and technical role in the management of digestive tumors. We suggest minimum end points in the standard HGE-curriculum for oncology, and recommend a focus year in the Netherlands for Digestive Oncology in the HGE-curriculum. To produce well trained digestive oncologists, an advanced Digestive Oncology training program with specific qualifications in Digestive Oncology (2 years) has been developed. The schedule in Belgium includes a period of at least 6 mo to be spent in a medical oncology department. The goal of these programs remains the production of well-trained digestive oncologists. HGE specialists are part of the multidisciplinary oncological teams, and some have been administering chemotherapy in their countries for years. In this article, we provide a road map for the organization of a proper training in Digestive Oncology. We hope that the World Gastroenterology Organisation and other (inter)national societies will support the necessary certifications for this specific training in the HGE curriculum. PMID- 21556129 TI - The role of degree distribution in shaping the dynamics in networks of sparsely connected spiking neurons. AB - Neuronal network models often assume a fixed probability of connection between neurons. This assumption leads to random networks with binomial in-degree and out degree distributions which are relatively narrow. Here I study the effect of broad degree distributions on network dynamics by interpolating between a binomial and a truncated power-law distribution for the in-degree and out-degree independently. This is done both for an inhibitory network (I network) as well as for the recurrent excitatory connections in a network of excitatory and inhibitory neurons (EI network). In both cases increasing the width of the in degree distribution affects the global state of the network by driving transitions between asynchronous behavior and oscillations. This effect is reproduced in a simplified rate model which includes the heterogeneity in neuronal input due to the in-degree of cells. On the other hand, broadening the out-degree distribution is shown to increase the fraction of common inputs to pairs of neurons. This leads to increases in the amplitude of the cross correlation (CC) of synaptic currents. In the case of the I network, despite strong oscillatory CCs in the currents, CCs of the membrane potential are low due to filtering and reset effects, leading to very weak CCs of the spike-count. In the asynchronous regime of the EI network, broadening the out-degree increases the amplitude of CCs in the recurrent excitatory currents, while CC of the total current is essentially unaffected as are pairwise spiking correlations. This is due to a dynamic balance between excitatory and inhibitory synaptic currents. In the oscillatory regime, changes in the out-degree can have a large effect on spiking correlations and even on the qualitative dynamical state of the network. PMID- 21556130 TI - Characterization of a human cell line stably over-expressing the candidate oncogene, dual specificity phosphatase 12. AB - BACKGROUND: Analysis of chromosomal rearrangements within primary tumors has been influential in the identification of novel oncogenes. Identification of the "driver" gene(s) within cancer-derived amplicons is, however, hampered by the fact that most amplicons contain many gene products. Amplification of 1q21-1q23 is strongly associated with liposarcomas and microarray-based comparative genomic hybridization narrowed down the likely candidate oncogenes to two: the activating transcription factor 6 (atf6) and the dual specificity phosphatase 12 (dusp12). While atf6 is an established transcriptional regulator of the unfolded protein response, the potential role of dusp12 in cancer remains uncharacterized. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the oncogenic potential of dusp12, we established stable cell lines that ectopically over-express dusp12 in isolation and determined whether this cell line acquired properties frequently associated with transformed cells. Here, we demonstrate that cells over-expressing dusp12 display increased cell motility and resistance to apoptosis. Additionally, over expression of dusp12 promoted increased expression of the c-met proto-oncogene and the collagen and laminin receptor intergrin alpha 1 (itga1) which is implicated in metastasis. SIGNIFICANCE: Collectively, these results suggest that dusp12 is oncologically relevant and exposes a potential association between dusp12 and established oncogenes that could be therapeutically targeted. PMID- 21556131 TI - Disentangling the roles of approach, activation and valence in instrumental and pavlovian responding. AB - Hard-wired, Pavlovian, responses elicited by predictions of rewards and punishments exert significant benevolent and malevolent influences over instrumentally-appropriate actions. These influences come in two main groups, defined along anatomical, pharmacological, behavioural and functional lines. Investigations of the influences have so far concentrated on the groups as a whole; here we take the critical step of looking inside each group, using a detailed reinforcement learning model to distinguish effects to do with value, specific actions, and general activation or inhibition. We show a high degree of sophistication in Pavlovian influences, with appetitive Pavlovian stimuli specifically promoting approach and inhibiting withdrawal, and aversive Pavlovian stimuli promoting withdrawal and inhibiting approach. These influences account for differences in the instrumental performance of approach and withdrawal behaviours. Finally, although losses are as informative as gains, we find that subjects neglect losses in their instrumental learning. Our findings argue for a view of the Pavlovian system as a constraint or prior, facilitating learning by alleviating computational costs that come with increased flexibility. PMID- 21556132 TI - Using functional annotation for the empirical determination of Bayes Factors for genome-wide association study analysis. AB - A genome wide association study (GWAS) typically results in a few highly significant 'hits' and a much larger set of suggestive signals ('near-hits'). The latter group are expected to be a mixture of true and false associations. One promising strategy to help separate these is to use functional annotations for prioritisation of variants for follow-up. A key task is to determine which annotations might prove most valuable. We address this question by examining the functional annotations of previously published GWAS hits. We explore three annotation categories: non-synonymous SNPs (nsSNPs), promoter SNPs and cis expression quantitative trait loci (eQTLs) in open chromatin regions. We demonstrate that GWAS hit SNPs are enriched for these three functional categories, and that it would be appropriate to provide a higher weighting for such SNPs when performing Bayesian association analyses. For GWAS studies, our analyses suggest the use of a Bayes Factor of about 4 for cis eQTL SNPs within regions of open chromatin, 3 for nsSNPs and 2 for promoter SNPs. PMID- 21556133 TI - Experience-independent development of the hamster circadian visual system. AB - Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduction of a light-dark cycle. In adulthood, previously-occluded eyes were challenged with visual stimuli. Whereas image formation and motion-detection were markedly impaired by monocular occlusion, neither entrainment to a light-dark cycle, nor phase-resetting responses to shifts in the light-dark cycle were affected by prior monocular deprivation. Cholera toxin-b subunit fluorescent tract-tracing revealed that in monocularly deprived hamsters the density of fibers projecting from the retina to the suprachiasmatic nucleus (SCN) was comparable regardless of whether such fibers originated from occluded or exposed eyes. In addition, long-term monocular deprivation did not attenuate light-induced c-Fos expression in the SCN. Thus, in contrast to the thalamocortical projections of the primary visual system, retinohypothalamic projections terminating in the SCN develop into normal adult patterns and mediate circadian responses to light largely independent of light experience during development. The data identify a categorical difference in the requirement for light input during postnatal development between circadian and non-circadian visual systems. PMID- 21556134 TI - Solving the puzzle of metastasis: the evolution of cell migration in neoplasms. AB - BACKGROUND: Metastasis represents one of the most clinically important transitions in neoplastic progression. The evolution of metastasis is a puzzle because a metastatic clone is at a disadvantage in competition for space and resources with non-metastatic clones in the primary tumor. Metastatic clones waste some of their reproductive potential on emigrating cells with little chance of establishing metastases. We suggest that resource heterogeneity within primary tumors selects for cell migration, and that cell emigration is a by-product of that selection. METHODS AND FINDINGS: We developed an agent-based model to simulate the evolution of neoplastic cell migration. We simulated the essential dynamics of neoangiogenesis and blood vessel occlusion that lead to resource heterogeneity in neoplasms. We observed the probability and speed of cell migration that evolves with changes in parameters that control the degree of spatial and temporal resource heterogeneity. Across a broad range of realistic parameter values, increasing degrees of spatial and temporal heterogeneity select for the evolution of increased cell migration and emigration. CONCLUSIONS: We showed that variability in resources within a neoplasm (e.g. oxygen and nutrients provided by angiogenesis) is sufficient to select for cells with high motility. These cells are also more likely to emigrate from the tumor, which is the first step in metastasis and the key to the puzzle of metastasis. Thus, we have identified a novel potential solution to the puzzle of metastasis. PMID- 21556135 TI - Interspecies somatic cell nuclear transfer is dependent on compatible mitochondrial DNA and reprogramming factors. AB - Interspecies somatic cell nuclear transfer (iSCNT) involves the transfer of a nucleus or cell from one species into the cytoplasm of an enucleated oocyte from another. Once activated, reconstructed oocytes can be cultured in vitro to blastocyst, the final stage of preimplantation development. However, they often arrest during the early stages of preimplantation development; fail to reprogramme the somatic nucleus; and eliminate the accompanying donor cell's mitochondrial DNA (mtDNA) in favour of the recipient oocyte's genetically more divergent population. This last point has consequences for the production of ATP by the electron transfer chain, which is encoded by nuclear and mtDNA. Using a murine-porcine interspecies model, we investigated the importance of nuclear cytoplasmic compatibility on successful development. Initially, we transferred murine fetal fibroblasts into enucleated porcine oocytes, which resulted in extremely low blastocyst rates (0.48%); and failure to replicate nuclear DNA and express Oct-4, the key marker of reprogramming. Using allele specific-PCR, we detected peak levels of murine mtDNA at 0.14+/-0.055% of total mtDNA at the 2 cell embryo stage and then at ever-decreasing levels to the blastocyst stage (<0.001%). Furthermore, these embryos had an overall mtDNA profile similar to porcine embryos. We then depleted porcine oocytes of their mtDNA using 10 uM 2',3'-dideoxycytidine and transferred murine somatic cells along with murine embryonic stem cell extract, which expressed key pluripotent genes associated with reprogramming and contained mitochondria, into these oocytes. Blastocyst rates increased significantly (3.38%) compared to embryos generated from non supplemented oocytes (P<0.01). They also had significantly more murine mtDNA at the 2-cell stage than the non-supplemented embryos, which was maintained throughout early preimplantation development. At later stages, these embryos possessed 49.99+/-2.97% murine mtDNA. They also exhibited an mtDNA profile similar to murine preimplantation embryos. Overall, these data demonstrate that the addition of species compatible mtDNA and reprogramming factors improves developmental outcomes for iSCNT embryos. PMID- 21556136 TI - The rate of NF-kappaB nuclear translocation is regulated by PKA and A kinase interacting protein 1. AB - The mechanism of PKAc-dependent NF-kappaB activation and subsequent translocation into the nucleus is not well defined. Previously, we showed that A kinase interacting protein 1 (AKIP1) was important for binding and retaining PKAc in the nucleus. Since then, other groups have demonstrated that AKIP1 binds the p65 subunit of NF-kappaB and regulates its transcriptional activity through the phosphorylation at Ser 276 by PKAc. However, little is known about the formation and activation of the PKAc/AKIP1/p65 complex and the rate at which it enters the nucleus. Initially, we found that the AKIP1 isoform (AKIP 1A) simultaneously binds PKAc and p65 in resting and serum starved cells. Using peptide arrays, we refined the region of AKIP 1A binding on PKAc and mapped the non-overlapping regions on AKIP 1A where PKAc and p65 bind. A peptide to the amino-terminus of PKAc (CAT 1-29) was generated to specifically disrupt the interaction between AKIP 1A and PKAc to study nuclear import of the complex. The rate of p65 nuclear translocation was monitored in the presence or absence of overexpressed AKIP 1A and/or (CAT 1-29). Enhanced nuclear translocation of p65 was observed in the presence of overexpressed AKIP1 and/or CAT 1-29 in cells stimulated with TNFalpha, and this correlated with decreased phosphorylation of serine 276. To determine whether PKAc phosphorylation of p65 in the cytosol regulated nuclear translocation, serine 276 was mutated to alanine or aspartic acid. Accelerated nuclear accumulation of p65 was observed in the alanine mutant, while the aspartic acid mutation displayed slowed nuclear translocation kinetics. In addition, enhanced nuclear translocation of p65 was observed when PKAc was knocked-down by siRNA. Taken together, these results suggest that AKIP 1A acts to scaffold PKAc to NF-kappaB in the cytosol by protecting the phosphorylation site and thereby regulating the rate of nuclear translocation of p65. PMID- 21556137 TI - Citizen science reveals unexpected continental-scale evolutionary change in a model organism. AB - Organisms provide some of the most sensitive indicators of climate change and evolutionary responses are becoming apparent in species with short generation times. Large datasets on genetic polymorphism that can provide an historical benchmark against which to test for recent evolutionary responses are very rare, but an exception is found in the brown-lipped banded snail (Cepaea nemoralis). This species is sensitive to its thermal environment and exhibits several polymorphisms of shell colour and banding pattern affecting shell albedo in the majority of populations within its native range in Europe. We tested for evolutionary changes in shell albedo that might have been driven by the warming of the climate in Europe over the last half century by compiling an historical dataset for 6,515 native populations of C. nemoralis and comparing this with new data on nearly 3,000 populations. The new data were sampled mainly in 2009 through the Evolution MegaLab, a citizen science project that engaged thousands of volunteers in 15 countries throughout Europe in the biggest such exercise ever undertaken. A known geographic cline in the frequency of the colour phenotype with the highest albedo (yellow) was shown to have persisted and a difference in colour frequency between woodland and more open habitats was confirmed, but there was no general increase in the frequency of yellow shells. This may have been because snails adapted to a warming climate through behavioural thermoregulation. By contrast, we detected an unexpected decrease in the frequency of Unbanded shells and an increase in the Mid-banded morph. Neither of these evolutionary changes appears to be a direct response to climate change, indicating that the influence of other selective agents, possibly related to changing predation pressure and habitat change with effects on micro-climate. PMID- 21556138 TI - Representative proteomes: a stable, scalable and unbiased proteome set for sequence analysis and functional annotation. AB - The accelerating growth in the number of protein sequences taxes both the computational and manual resources needed to analyze them. One approach to dealing with this problem is to minimize the number of proteins subjected to such analysis in a way that minimizes loss of information. To this end we have developed a set of Representative Proteomes (RPs), each selected from a Representative Proteome Group (RPG) containing similar proteomes calculated based on co-membership in UniRef50 clusters. A Representative Proteome is the proteome that can best represent all the proteomes in its group in terms of the majority of the sequence space and information. RPs at 75%, 55%, 35% and 15% co-membership threshold (CMT) are provided to allow users to decrease or increase the granularity of the sequence space based on their requirements. We find that a CMT of 55% (RP55) most closely follows standard taxonomic classifications. Further analysis of this set reveals that sequence space is reduced by more than 80% relative to UniProtKB, while retaining both sequence diversity (over 95% of InterPro domains) and annotation information (93% of experimentally characterized proteins). All sets can be browsed and are available for sequence similarity searches and download at http://www.proteininformationresource.org/rps, while the set of 637 RPs determined using a 55% CMT are also available for text searches. Potential applications include sequence similarity searches, protein classification and targeted protein annotation and characterization. PMID- 21556139 TI - Agreeable smellers and sensitive neurotics--correlations among personality traits and sensory thresholds. AB - Correlations between personality traits and a wide range of sensory thresholds were examined. Participants (N = 124) completed a personality inventory (NEO-FFI) and underwent assessment of olfactory, trigeminal, tactile and gustatory detection thresholds, as well as examination of trigeminal and tactile pain thresholds. Significantly enhanced odor sensitivity in socially agreeable people, significantly enhanced trigeminal sensitivity in neurotic subjects, and a tendency for enhanced pain tolerance in highly conscientious participants was revealed. It is postulated that varied sensory processing may influence an individual's perception of the environment; particularly their perception of socially relevant or potentially dangerous stimuli and thus, varied with personality. PMID- 21556140 TI - Between-monitor differences in step counts are related to body size: implications for objective physical activity measurement. AB - BACKGROUND: The quantification of the relationships between walking and health requires that walking is measured accurately. We correlated different measures of step accumulation to body size, overall physical activity level, and glucose regulation. METHODS: Participants were 25 men and 25 women American Indians without diabetes (Age: 20-34 years) in Phoenix, Arizona, USA. We assessed steps/day during 7 days of free living, simultaneously with three different monitors (Accusplit-AX120, MTI-ActiGraph, and Dynastream-AMP). We assessed total physical activity during free-living with doubly labeled water combined with resting metabolic rate measured by expired gas indirect calorimetry. Glucose tolerance was determined during an oral glucose tolerance test. FINDINGS: Based on observed counts in the laboratory, the AMP was the most accurate device, followed by the MTI and the AX120, respectively. The estimated energy cost of 1000 steps per day was lower in the AX120 than the MTI or AMP. The correlation between AX120-assessed steps/day and waist circumference was significantly higher than the correlation between AMP steps and waist circumference. The difference in steps per day between the AX120 and both the AMP and the MTI were significantly related to waist circumference. INTERPRETATION: Between-monitor differences in step counts influence the observed relationship between walking and obesity related traits. PMID- 21556141 TI - Tg2576 cortical neurons that express human Ab are susceptible to extracellular Abeta-induced, K+ efflux dependent neurodegeneration. AB - BACKGROUND: One of the key pathological features of AD is the formation of insoluble amyloid plaques. The major constituent of these extracellular plaques is the beta-amyloid peptide (Abeta), although Abeta is also found to accumulate intraneuronally in AD. Due to the slowly progressive nature of the disease, it is likely that neurons are exposed to sublethal concentrations of both intracellular and extracellular Abeta for extended periods of time. RESULTS: In this study, we report that daily exposure to a sublethal concentration of Abeta(1-40) (1 uM) for six days induces substantial apoptosis of cortical neurons cultured from Tg2576 mice (which express substantial but sublethal levels of intracellular Abeta). Notably, untreated Tg2576 neurons of similar age did not display any signs of apoptosis, indicating that the level of intracellular Abeta present in these neurons was not the cause of toxicity. Furthermore, wildtype neurons did not become apoptotic under the same chronic Abeta(1-40) treatment. We found that this apoptosis was linked to Tg2576 neurons being unable to maintain K(+) homeostasis following Abeta treatment. Furthermore, blocking K(+) efflux protected Tg2576 neurons from Abeta-induced neurotoxicity. Interestingly, chronic exposure to 1 uM Abeta(1-40) caused the generation of axonal swellings in Tg2576 neurons that contained dense concentrations of hyperphosphorylated tau. These were not observed in wildtype neurons under the same treatment conditions. CONCLUSIONS: Our data suggest that when neurons are chronically exposed to sublethal levels of both intra- and extra-cellular Abeta, this causes a K(+)-dependent neurodegeneration that has pathological characteristics similar to AD. PMID- 21556142 TI - T cell responses to the RTS,S/AS01(E) and RTS,S/AS02(D) malaria candidate vaccines administered according to different schedules to Ghanaian children. AB - BACKGROUND: The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01(E) or the oil-in-water based adjuvant AS02(D) induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults. METHODS: This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2- and 0,1,7-month) of RTS,S/AS01(E) and RTS,S/AS02(D) in children aged 5-17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites. RESULTS: Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01(E) induced CSP specific CD4 T cells producing IL-2, TNF-alpha, and IFN-gamma. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1- or 0,1,2 month schedule. RTS,S/AS01(E) induced higher CD4 T cell responses as compared to RTS,S/AS02(D) when given on a 0,1,7-month schedule. CONCLUSIONS: These findings support further Phase III evaluation of RTS,S/AS01(E). The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00360230. PMID- 21556143 TI - Frequency of aneuploidy related to age in porcine oocytes. AB - It is generally accepted that mammalian oocytes are frequently suffering from chromosome segregation errors during meiosis I, which have severe consequences, including pregnancy loss, developmental disorders and mental retardation. In a search for physiologically more relevant model than rodent oocytes to study this phenomenon, we have employed comparative genomic hybridization (CGH), combined with whole genome amplification (WGA), to study the frequency of aneuploidy in porcine oocytes, including rare cells obtained from aged animals. Using this method, we were able to analyze segregation pattern of each individual chromosome during meiosis I. In contrast to the previous reports where conventional methods, such as chromosome spreads or FISH, were used to estimate frequency of aneuploidy, our results presented here show, that the frequency of this phenomenon was overestimated in porcine oocytes. Surprisingly, despite the results from human and mouse showing an increase in the frequency of aneuploidy with advanced maternal age, our results obtained by the most accurate method currently available for scoring the aneuploidy in oocytes indicated no increase in the frequency of aneuploidy even in oocytes from animals, whose age was close to the life expectancy of the breed. PMID- 21556144 TI - Region-specific expression of mitochondrial complex I genes during murine brain development. AB - Mutations in the nuclear encoded subunits of mitochondrial complex I (NADH:ubiquinone oxidoreductase) may cause circumscribed cerebral lesions ranging from degeneration of the striatal and brainstem gray matter (Leigh syndrome) to leukodystrophy. We hypothesized that such pattern of regional pathology might be due to local differences in the dependence on complex I function. Using in situ hybridization we investigated the relative expression of 33 nuclear encoded complex I subunits in different brain regions of the mouse at E11.5, E17.5, P1, P11, P28 and adult (12 weeks). With respect to timing and relative intensity of complex I gene expression we found a highly variant pattern in different regions during development. High average expression levels were detected in periods of intense neurogenesis. In cerebellar Purkinje and in hippocampal CA1/CA3 pyramidal neurons we found a second even higher peak during the period of synaptogenesis and maturation. The extraordinary dependence of these structures on complex I gene expression during synaptogenesis is in accord with our recent findings that gamma oscillations--known to be associated with higher cognitive functions of the mammalian brain--strongly depend on the complex I activity. However, with the exception of the mesencephalon, we detected only average complex I expression levels in the striatum and basal ganglia, which does not explain the exquisite vulnerability of these structures in mitochondrial disorders. PMID- 21556145 TI - Ribosome-dependent ATPase interacts with conserved membrane protein in Escherichia coli to modulate protein synthesis and oxidative phosphorylation. AB - Elongation factor RbbA is required for ATP-dependent deacyl-tRNA release presumably after each peptide bond formation; however, there is no information about the cellular role. Proteomic analysis in Escherichia coli revealed that RbbA reciprocally co-purified with a conserved inner membrane protein of unknown function, YhjD. Both proteins are also physically associated with the 30S ribosome and with members of the lipopolysaccharide transport machinery. Genome wide genetic screens of rbbA and yhjD deletion mutants revealed aggravating genetic interactions with mutants deficient in the electron transport chain. Cells lacking both rbbA and yhjD exhibited reduced cell division, respiration and global protein synthesis as well as increased sensitivity to antibiotics targeting the ETC and the accuracy of protein synthesis. Our results suggest that RbbA appears to function together with YhjD as part of a regulatory network that impacts bacterial oxidative phosphorylation and translation efficiency. PMID- 21556146 TI - Targeting protein-protein interactions for parasite control. AB - Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs) offer a realm of unexplored potential drug targets and are thought to be the next generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific orthologous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank). EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite) and B. malayi (H. sapiens parasite), which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly applicable. PMID- 21556147 TI - SDF1-induced antagonism of axonal repulsion requires multiple G-protein coupled signaling components that work in parallel. AB - SDF1 reduces the responsiveness of axonal growth cones to repellent guidance cues in a pertussis-toxin-sensitive, cAMP-dependent manner. Here, we show that SDF1's antirepellent effect can be blocked in embryonic chick dorsal root ganglia (DRGs) by expression of peptides or proteins inhibiting either Galpha(i), Galpha(q), or Gbetagamma. SDF1 antirepellent activity is also blocked by pharmacological inhibition of PLC, a common effector protein for Galpha(q). We also show that SDF1 antirepellent activity can be mimicked by overexpression of constitutively active Galpha(i), Galpha(q), or Galpha(s). These results suggest a model in which multiple G protein components cooperate to produce the cAMP levels required for SDF1 antirepellent activity. PMID- 21556148 TI - Amyloid precursor protein is trafficked and secreted via synaptic vesicles. AB - A large body of evidence has implicated amyloid precursor protein (APP) and its proteolytic derivatives as key players in the physiological context of neuronal synaptogenesis and synapse maintenance, as well as in the pathology of Alzheimer's Disease (AD). Although APP processing and release are known to occur in response to neuronal stimulation, the exact mechanism by which APP reaches the neuronal surface is unclear. We now demonstrate that a small but relevant number of synaptic vesicles contain APP, which can be released during neuronal activity, and most likely represent the major exocytic pathway of APP. This novel finding leads us to propose a revised model of presynaptic APP trafficking that reconciles existing knowledge on APP with our present understanding of vesicular release and recycling. PMID- 21556149 TI - Bonobos extract meaning from call sequences. AB - Studies on language-trained bonobos have revealed their remarkable abilities in representational and communication tasks. Surprisingly, however, corresponding research into their natural communication has largely been neglected. We address this issue with a first playback study on the natural vocal behaviour of bonobos. Bonobos produce five acoustically distinct call types when finding food, which they regularly mix together into longer call sequences. We found that individual call types were relatively poor indicators of food quality, while context specificity was much greater at the call sequence level. We therefore investigated whether receivers could extract meaning about the quality of food encountered by the caller by integrating across different call sequences. We first trained four captive individuals to find two types of foods, kiwi (preferred) and apples (less preferred) at two different locations. We then conducted naturalistic playback experiments during which we broadcasted sequences of four calls, originally produced by a familiar individual responding to either kiwi or apples. All sequences contained the same number of calls but varied in the composition of call types. Following playbacks, we found that subjects devoted significantly more search effort to the field indicated by the call sequence. Rather than attending to individual calls, bonobos attended to the entire sequences to make inferences about the food encountered by a caller. These results provide the first empirical evidence that bonobos are able to extract information about external events by attending to vocal sequences of other individuals and highlight the importance of call combinations in their natural communication system. PMID- 21556150 TI - Lateralization in the invertebrate brain: left-right asymmetry of olfaction in bumble bee, Bombus terrestris. AB - Brain and behavioural lateralization at the population level has been recently hypothesized to have evolved under social selective pressures as a strategy to optimize coordination among asymmetrical individuals. Evidence for this hypothesis have been collected in Hymenoptera: eusocial honey bees showed olfactory lateralization at the population level, whereas solitary mason bees only showed individual-level olfactory lateralization. Here we investigated lateralization of odour detection and learning in the bumble bee, Bombus terrestris L., an annual eusocial species of Hymenoptera. By training bumble bees on the proboscis extension reflex paradigm with only one antenna in use, we provided the very first evidence of asymmetrical performance favouring the right antenna in responding to learned odours in this species. Electroantennographic responses did not reveal significant antennal asymmetries in odour detection, whereas morphological counting of olfactory sensilla showed a predominance in the number of olfactory sensilla trichodea type A in the right antenna. The occurrence of a population level asymmetry in olfactory learning of bumble bee provides new information on the relationship between social behaviour and the evolution of population-level asymmetries in animals. PMID- 21556151 TI - Monitoring influenza activity in the United States: a comparison of traditional surveillance systems with Google Flu Trends. AB - BACKGROUND: Google Flu Trends was developed to estimate US influenza-like illness (ILI) rates from internet searches; however ILI does not necessarily correlate with actual influenza virus infections. METHODS AND FINDINGS: Influenza activity data from 2003-04 through 2007-08 were obtained from three US surveillance systems: Google Flu Trends, CDC Outpatient ILI Surveillance Network (CDC ILI Surveillance), and US Influenza Virologic Surveillance System (CDC Virus Surveillance). Pearson's correlation coefficients with 95% confidence intervals (95% CI) were calculated to compare surveillance data. An analysis was performed to investigate outlier observations and determine the extent to which they affected the correlations between surveillance data. Pearson's correlation coefficient describing Google Flu Trends and CDC Virus Surveillance over the study period was 0.72 (95% CI: 0.64, 0.79). The correlation between CDC ILI Surveillance and CDC Virus Surveillance over the same period was 0.85 (95% CI: 0.81, 0.89). Most of the outlier observations in both comparisons were from the 2003-04 influenza season. Exclusion of the outlier observations did not substantially improve the correlation between Google Flu Trends and CDC Virus Surveillance (0.82; 95% CI: 0.76, 0.87) or CDC ILI Surveillance and CDC Virus Surveillance (0.86; 95%CI: 0.82, 0.90). CONCLUSIONS: This analysis demonstrates that while Google Flu Trends is highly correlated with rates of ILI, it has a lower correlation with surveillance for laboratory-confirmed influenza. Most of the outlier observations occurred during the 2003-04 influenza season that was characterized by early and intense influenza activity, which potentially altered health care seeking behavior, physician testing practices, and internet search behavior. PMID- 21556152 TI - Predictors of the uptake of A (H1N1) influenza vaccine: findings from a population-based longitudinal study in Tokyo. AB - BACKGROUND: Overall pandemic A (H1N1) influenza vaccination rates remain low across all nations, including Japan. To increase the rates, it is important to understand the motives and barriers for the acceptance of the vaccine. We conducted this study to determine potential predictors of the uptake of A (H1N1) influenza vaccine in a cohort of Japanese general population. METHODOLOGY/PRINCIPAL FINDINGS: By using self-administered questionnaires, this population-based longitudinal study was conducted from October 2009 to April 2010 among 428 adults aged 18-65 years randomly selected from each household residing in four wards and one city in Tokyo. Multiple logistic regression analyses were performed. Of total, 38.1% of participants received seasonal influenza vaccine during the preceding season, 57.0% had willingness to accept A (H1N1) influenza vaccine at baseline, and 12.1% had received A (H1N1) influenza vaccine by the time of follow-up. After adjustment for potential confounding variables, people who had been vaccinated were significantly more likely to be living with an underlying disease (p = 0.001), to perceive high susceptibility to influenza (p = 0.03), to have willingness to pay even if the vaccine costs >= US$44 (p = 0.04), to have received seasonal influenza vaccine during the preceding season (p<0.001), and to have willingness to accept A (H1N1) influenza vaccine at baseline (p<0.001) compared to those who had not been vaccinated. CONCLUSIONS/SIGNIFICANCE: While studies have reported high rates of willingness to receive A (H1N1) influenza vaccine, these rates may not transpire in the actual practices. The uptake of the vaccine may be determined by several potential factors such as perceived susceptibility to influenza and sensitivity to vaccination cost in general population. PMID- 21556153 TI - Super-aggregations of krill and humpback whales in Wilhelmina Bay, Antarctic Peninsula. AB - Ecological relationships of krill and whales have not been explored in the Western Antarctic Peninsula (WAP), and have only rarely been studied elsewhere in the Southern Ocean. In the austral autumn we observed an extremely high density (5.1 whales per km(2)) of humpback whales (Megaptera novaeangliae) feeding on a super-aggregation of Antarctic krill (Euphausia superba) in Wilhelmina Bay. The krill biomass was approximately 2 million tons, distributed over an area of 100 km(2) at densities of up to 2000 individuals m(-3); reports of such 'super aggregations' of krill have been absent in the scientific literature for >20 years. Retentive circulation patterns in the Bay entrained phytoplankton and meso zooplankton that were grazed by the krill. Tagged whales rested during daylight hours and fed intensively throughout the night as krill migrated toward the surface. We infer that the previously unstudied WAP embayments are important foraging areas for whales during autumn and, furthermore, that meso-scale variation in the distribution of whales and their prey are important features of this system. Recent decreases in the abundance of Antarctic krill around the WAP have been linked to reductions in sea ice, mediated by rapid climate change in this area. At the same time, baleen whale populations in the Southern Ocean, which feed primarily on krill, are recovering from past exploitation. Consideration of these features and the effects of climate change on krill dynamics are critical to managing both krill harvests and the recovery of baleen whales in the Southern Ocean. PMID- 21556154 TI - Anodal stimulation - the intrigue continues. PMID- 21556155 TI - Anodal stimulation: an underrecognized cause of nonresponders to cardiac resynchronization therapy. AB - OBJECTIVE: The purpose of this study was to determine if anodal stimulation accounts for failure to benefit from cardiac resynchronization therapy (CRT) in some patients. BACKGROUND: Approximately 30-40% of patients with moderate to severe heart failure do not have symptomatic nor echocardiographic improvement in cardiac function following CRT. Modern CRT devices allow the option of programming left ventricular (LV) lead pacing as LV tip to right ventricular (RV) lead coil to potentially improve pacing thresholds. However, anodal stimulation can result in unintentional RV pacing (anode) instead of LV pacing (cathode). METHODS: Patients enrolled in our center's CRT registry had an echocardiogram, 6 minute walk (6MW), and Minnesota Living with HF Questionnaire (MLHFQ) pre-implant and 6 months after CRT. Electrocardiograms (12 lead) during RV, LV, and biventricular (BiV) pacing were obtained at the end of the implant in 102 patients. Anodal stimulation was defined as LV pacing QRS morphology on EKG being identical to RV pacing or consistent with fusion with RV and LV electrode capture. LV end systolic volume (LVESV) was measured by echo biplane Simpson's method and CRT responder was defined as 15% or greater reduction in LVESV. RESULTS: Of the 102 patients, 46 (45.1%) had the final LV lead pacing configuration programmed LV (tip or ring) to RV (coil or ring). 3 of the 46 subjects (6.5%) had EKG findings consistent with anodal stimulation, not corrected intraoperatively. All anodal stimulation patients were nonresponders to CRT by echo criteria (reduction in LVESV 13.3 +/- 0.6%, increase in EF 5.0 +/- 1.4%) compared to 46% responders for those without anodal stimulation, (change in LVESV 18.7 +/- 25.6%, EF 7.6 +/-10.9%). None of the anodal stimulation patients were responders for the 6 minute walk, compared to 32 of 66 (48%) of those without anodal stimulation. CONCLUSION: Anodal stimulation is a potential underrecognized and ameliorable cause of poor response to CRT. PMID- 21556156 TI - Increased p wave dispersion in elite athletes. AB - BACKGROUND: Few studies have been performed on P wave indices in athletes. The aim of this study was to determine the behaviour of maximum P wave duration (Pmax), minimum P wave duration (Pmin) and P wave dispersion (PWD) in young high performance athletes, as well as the relationship of PWD with training history, heart rate (HR) and echocardiographic parameters. METHODS: We performed a cross sectional observational study in 38 athletes of high performance in sports: water polo, distance running and weight lifting compared with 34 sedentary controls. RESULTS: The average age in both groups was 20.6 years. Note that PWD was increased in athletes (57 +/- 14 ms vs. 40 +/- 12 ms, p <0.001) while Pmin was significantly lower (57 +/- 13 ms vs. 72 +/- 13 ms, p <0.001), and there was no difference when comparing Pmax (114 +/- 9 ms vs. 117 +/- 14 ms, p> 0.05). The correlation between the duration of training (r = 0.511) and resting HR (r = 0.461) with PWD was significant (p <0.01). CONCLUSIONS: PWD is increased in young athletes of high performance and was positively correlated with duration of training and baseline HR. The increase in PWD was secondary to a significant decrease in Pmin. PMID- 21556157 TI - Ablation of Premature Ventricular Complexes Triggering Ventricular Fibrillation in a Patient with Long QT Syndrome. AB - We describe the case of a patient with long QT syndrome and recurrent ventricular fibrillation, triggered by premature ventricular complexes (PVCs) with a left bundle branch block pattern and inferior axis of the QRS. Activation mapping demonstrated the origin of the PVCs to be in the right ventricular outflow tract. Ventricular fibrillation (VF) was successfully treated by catheter ablation of the triggering PVCs and there has been no recurrence of VF during a follow-up period of 14 months. PMID- 21556158 TI - Suppression of frequent ventricular ectopy in a patient with hypertrophic heart disease with ranolazine: a case report. AB - BACKGROUND: Pro-arrhythmic concerns with most anti-arrhythmic agents in patients with significant left ventricular hypertrophy (LVH) limits options when anti arrhythmic therapy is indicated. Ranolazine, an anti-anginal agent which inhibits late Na+ currents, indirectly causes a decrease in diastolic cardiomyocyte Ca++ levels producing an energy sparing effect. Ranolazine also inhibits triggered activity in animal studies and has anti-arrhythmic properties in patients with ischemic heart disease. Here we report the dramatic anti-arrhythmic effects of ranolazine in a patient with frequent ventricular and supraventricular ectopy in the setting of hypertrophic heart disease without significant coronary artery disease. METHODS: A 72 year old hypertensive patient with palpitations and significant exercise intolerance due to dyspnea was evaluated with echocardiography, thallium stress testing and cardiac catheterization. Holter monitor data prior to, and after institution of ranolazine 1000 mg twice daily was compared. Patient tolerance and sense of well being after ranolazine was assessed. RESULTS: Significant LVH was noted and obstructive coronary artery disease was ruled out by cardiac catheterization. Within two hours of the initial dose of ranolazine a marked decrease in ventricular ectopy was observed. Ventricular ectopy on Holter monitor decreased approximately 12 fold (23.8% of beats to1.9%) while supraventricular ectopy decreased approximately 7 fold (5.3% of beats to 0.8%). The decrease in ectopy was associated with an improved sense of well being. CONCLUSION: Ranolazine had rapid onset, potent anti-arrhythmic properties in the absence of obstructive coronary artery disease in a patient with LVH and may be an ideal agent in patients where few anti-arrhythmic options exist. PMID- 21556159 TI - A Proposal For An Upgraded Microvolt T-wave Alternans Index With Consideration Of T-wave Amplitudes And The Rise In Heart Rate. PMID- 21556160 TI - Isolation of a new natural product and cytotoxic and antimicrobial activities of extracts from fungi of Indonesian marine habitats. AB - In the search for bioactive compounds, 11 fungal strains were isolated from Indonesian marine habitats. Ethyl acetate extracts of their culture broth were tested for cytotoxic activity against a urinary bladder carcinoma cell line and for antifungal and antibacterial activities against fish and human pathogenic bacteria as well as against plant and human pathogenic fungi. The crude extract of a sterile algicolous fungus (KT31), isolated from the red seaweed Kappaphycus alvarezii (Doty) Doty ex P.C. Silva exhibited potent cytotoxic activity with an IC50 value of 1.5 MUg/mL. Another fungal strain (KT29) displayed fungicidal properties against the plant pathogenic fungus Cladosporium cucumerinum Ell. et Arth. at 50 MUg/spot. 2-Carboxy-8-methoxy-naphthalene-1-ol (1) could be isolated as a new natural product. PMID- 21556161 TI - Antinociceptive and anti-inflammatory activity from algae of the genus Caulerpa. AB - Marine natural products have been the focus of discovery for new products of chemical and pharmacological interest. The aim of this study was to evaluate the antinociceptive activity of the methanolic (ME), acetate (AE), hexanic (HE) and chloroform (CE) extracts obtained from Caulerpa mexicana, and ME, CE and HE obtained from Caulerpa sertularioides. These marine algae are found all over the world, mainly in tropical regions. Models such as the writhing test, the hot plate test and formalin-induced nociception test were used to evaluate antinociceptive activity in laboratory mice. In the writhing test, all the extracts were administered orally at a concentration of 100 mg/kg, and induced high peripheral antinociceptive activity, with a reduction in the nociception induced by acetic acid above 65%. In the hot plate test, treatment with extracts from C. sertularioides (100 mg/kg, p.o.) did not significantly increase the latency of response, although the ME, AE and HE from C. mexicana showed activity in this model. This result suggests that these extracts exhibit antinociceptive activity. In the formalin test, it was observed that ME, AE and HE obtained from C. mexicana reduced the effects of formalin in both phases. On the other hand only CE from C. sertularioides induced significant inhibition of the nociceptive response in the first phase. To better assess the potential anti-inflammatory activity of the extracts, the carrageenan-induced peritonitis test was used to test Caulerpa spp. extracts on cell migration into the peritoneal cavity. In this assay, all extracts evaluated were able to significantly inhibit leukocyte migration into the peritoneal cavity in comparison with carrageenan. These data demonstrate that extracts from Caulerpa species elicit pronounced antinociceptive and anti-inflamatory activity against several nociception models. However, pharmacological and chemical studies are continuing in order to characterize the mechanism(s) responsible for the antinociceptive action and also to identify the active principles present in the Caulerpa species. PMID- 21556162 TI - Marine carotenoids: biological functions and commercial applications. AB - Carotenoids are the most common pigments in nature and are synthesized by all photosynthetic organisms and fungi. Carotenoids are considered key molecules for life. Light capture, photosynthesis photoprotection, excess light dissipation and quenching of singlet oxygen are among key biological functions of carotenoids relevant for life on earth. Biological properties of carotenoids allow for a wide range of commercial applications. Indeed, recent interest in the carotenoids has been mainly for their nutraceutical properties. A large number of scientific studies have confirmed the benefits of carotenoids to health and their use for this purpose is growing rapidly. In addition, carotenoids have traditionally been used in food and animal feed for their color properties. Carotenoids are also known to improve consumer perception of quality; an example is the addition of carotenoids to fish feed to impart color to farmed salmon. PMID- 21556163 TI - Cytotoxic and antimicrobial activity of pseudopterosins and seco-pseudopterosins isolated from the octocoral Pseudopterogorgia elisabethae of San Andres and Providencia Islands (Southwest Caribbean Sea). AB - To expand the potential of pseudopterosins and seco-pseudopterosins isolated from the octocoral Pseudopterogorgia elisabethae of San Andres and Providencia islands (southwest Caribbean Sea), we report the anti-microbial profile against four pathogenic microorganisms (Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa and Candida albicans) and report a more complete cytotoxic profile against five human cells lines (HeLa, PC-3, HCT116, MCF-7 and BJ) for the compounds PsG, PsP, PsQ, PsS, PsT, PsU, 3-O-acetyl-PsU, seco-PsJ, seco-PsK and IMNGD. For the cytotoxic profiles, all compounds evaluated showed moderate and non-selective activity against both tumor and normal cell lines, where PsQ and PsG were the most active compounds (GI50 values between 5.8 MUM to 12.0 MUM). With respect to their anti-microbial activity the compounds showed good and selective activity against the Gram-positive bacteria, while they did not show activity against the Gram-negative bacterium or yeast. PsU, PsQ, PsS, seco-PsK and PsG were the most active compounds (IC50 2.9-4.5 MUM) against S. aureus and PsG, PsU and seco-PsK showed good activity (IC50 3.1-3.8 MUM) against E. faecalis, comparable to the reference drug vancomycin (4.2 MUM). PMID- 21556164 TI - Dynamics of dissolved and particulate polyunsaturated aldehydes in mesocosms inoculated with different densities of the diatom Skeletonema marinoi. AB - A survey of the production of polyunsaturated aldehydes (PUA) of manipulated plankton communities is presented here. PUA are phytoplankton-derived metabolites that are proposed to play an important role in chemically mediated plankton interactions. Blooms of different intensities of the diatom Skeletonema marinoi were generated in eight mesocosms filled with water from the surrounding fjord by adding different amounts of a starting culture and nutrients. This set-up allowed us to follow PUA production of the plankton community over the entire induced bloom development, and to compare it with the natural levels of PUA. We found that S. marinoi is a major source for the particulate PUA 2,4-heptadienal and 2,4 octadienal (defined as PUA released upon wounding of the diatom cells) during the entire bloom development. Just before, and during, the decline of the induced diatom blooms, these PUA were also detected in up to 1 nM concentrations dissolved in the water. In addition, we detected high levels of the PUA 2,4 decadienal that was not produced by the diatom S. marinoi. Particulate decadienal correlated well with the cell counts of the prymnesiophyte Phaeocystis sp. that also developed in the fertilized mesocosms. Particulate decadienal levels were often even higher than those of diatom-derived PUA, indicating that PUA sources other than diatoms should be considered when it comes to the evaluation of the impact of these metabolites. PMID- 21556165 TI - Lobophorin C and D, new kijanimicin derivatives from a marine sponge-associated actinomycetal strain AZS17. AB - Marine sponge Hymeniacidon sp. was collected from coastal waters of the East China Sea to isolate symbiotic microorganisms. The resulting sponge-associated actinomycete, Streptomyces carnosus strain AZS17, was cultivated in a 20 L volume of medium for production of bioactive secondary metabolites. Bioassay-guided isolation and purification by varied chromatographic methods yielded two new compounds of kijanimicin derivatives, AS7-2 and AS9-12. Their structures were elucidated by spectroscopy and comparison with literatures. Results showed these two compounds were structurally similar to the previously reported compounds lobophorin A and B, yet differed in specific bond forms, stereochemistry and optical activities. The two novel compounds were named lobophorin C and D. In vitro cytotoxicity investigation by MTT assay indicated their selective activities. Lobophorin C displayed potent cytotoxic activity against the human liver cancer cell line 7402, while lobophorin D showed significant inhibitory effect on human breast cancer cells MDA-MB 435. PMID- 21556166 TI - Chemical screening method for the rapid identification of microbial sources of marine invertebrate-associated metabolites. AB - Marine invertebrates have proven to be a rich source of secondary metabolites. The growing recognition that marine microorganisms associated with invertebrate hosts are involved in the biosynthesis of secondary metabolites offers new alternatives for the discovery and development of marine natural products. However, the discovery of microorganisms producing secondary metabolites previously attributed to an invertebrate host poses a significant challenge. This study describes an efficient chemical screening method utilizing a 96-well plate based bacterial cultivation strategy to identify and isolate microbial producers of marine invertebrate-associated metabolites. PMID- 21556167 TI - An acetylenic alkaloid from the calcareous sponge Leucetta sp. AB - A new acetylenic alkaloid was isolated from the sponge Leucetta sp. The structure was established by analyzing spectroscopic data. The alkaloid showed cytotoxicity IC50 2.5 MUg/mL against NBT-T2 cells. PMID- 21556168 TI - Mycosporine-like amino acids: relevant secondary metabolites. Chemical and ecological aspects. AB - Taxonomically diverse marine, freshwater and terrestrial organisms have evolved the capacity to synthesize, accumulate and metabolize a variety of UV-absorbing substances called mycosporine-like amino acids (MAAs) as part of an overall strategy to diminish the direct and indirect damaging effects of environmental ultraviolet radiation (UVR). Whereas the enzymatic machinery to synthesize MAAs was probably inherited from cyanobacteria ancestors via the endosymbionts hypothesis, metazoans lack this biochemical pathway, but can acquire and metabolize these compounds by trophic transference, symbiotic or bacterial association. In this review we describe the structure and physicochemical properties of MAAs, including the recently discovered compounds and the modern methods used for their isolation and identification, updating previous reviews. On this basis, we review the metabolism and distribution of this unique class of metabolites among marine organism. PMID- 21556169 TI - Astaxanthin: a potential therapeutic agent in cardiovascular disease. AB - Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID- 21556170 TI - Preparation of calibration standards of N1-H paralytic shellfish toxin analogues by large-scale culture of cyanobacterium Anabaena circinalis (TA04). AB - Mouse bioassay is the official testing method to quantify paralytic shellfish toxins (PSTs) in bivalves. A number of alternative analytical methods have been reported. Some methods have been evaluated by a single laboratory validation. Among the different types of methods, chemical analyses are capable of identifying and quantifying the toxins, however a shortage of the necessary calibration standards hampers implementation of the chemical analyses in routine monitoring of PSTs in bivalves. In our present study, we studied preparation of major PST analogues as calibrants by large-scale cultivation of toxic freshwater cyanobacteria Anabaena circinalis TA04. The cells were steadily grown in 10 L bottle for 28 days. The primary N1-H toxins, C1/C2, were produced at a concentration of 1.3 +/- 0.1 MUmol/L. The intracellular and extracellular toxins occupied 80% and 20%, respectively. Over 220 MUmol of the toxins was obtained from approximately 200 L of the culture over six months, demonstrating that it is sufficient to prepare saxitoxin analogues. The toxins were chemically converted to six N1-H analogues. Preparation of the analogues was carried out at relatively high yields (50-90%). The results indicate that our preparation method is useful to produce N1-H toxins. In our present study, detailed conditions for preparation of one of the rare N1-H analogues, gonyautoxin-5, were investigated. PMID- 21556171 TI - Combined toxic exposures and human health: biomarkers of exposure and effect. AB - Procedures for risk assessment of chemical mixtures, combined and cumulative exposures are under development, but the scientific database needs considerable expansion. In particular, there is a lack of knowledge on how to monitor effects of complex exposures, and there are few reviews on biomonitoring complex exposures. In this review we summarize articles in which biomonitoring techniques have been developed and used. Most examples describe techniques for biomonitoring effects which may detect early changes induced by many chemical stressors and which have the potential to accelerate data gathering. Some emphasis is put on endocrine disrupters acting via epigenetic mechanisms and on carcinogens. Solid evidence shows that these groups of chemicals can interact and even produce synergistic effects. They may act during sensitive time windows and biomonitoring their effects in epidemiological studies is a challenging task. PMID- 21556172 TI - Recent contributions of air- and biomarkers to the control of secondhand smoke (SHS): a review. AB - Since the publication of the US Surgeon General Reports in 1996 and 2006 and the report of the California Environmental Protection Agency in 1999, many reports have appeared on the contribution of air and biomarkers to different facets of the secondhand smoke (SHS) issue, which are the targets of this review. These recent studies have allowed earlier epidemiological surveys to be biologically validated, and their plausibility demonstrated, quantified the levels of exposure to SHS before the bans in various environments, showed the deficiencies of mechanical control methods and of partial bans and the frequently correct implementation of the efficient total bans. More stringent regulation remains necessary in the public domain (workplaces, hospitality venues, transport sector, etc.) in many countries. Personal voluntary protection efforts against SHS are also needed in the private domain (homes, private cars). The effects of SHS on the cardiovascular, respiratory and neuropsychic systems, on pregnancy and fertility, on cancers and on SHS genotoxicity are confirmed through experimental human studies and through the relationship between markers and prevalence of disease or of markers of disease risk. PMID- 21556173 TI - Control of advanced cancer: the road to chronicity. AB - Despite the recent trend toward a slight decrease in age-adjusted cancer mortality in some countries, crude mortality rates will continue to increase, driven by the demographic shift towards an aged population. Small molecules (small molecules and biologics) are not only a new therapeutic acquisition, but the tools of a more fundamental transition: the transformation of cancer from a rapidly fatal disease into a chronic condition. Antibodies and cancer vaccines can be used for a long time, even beyond progressive disease, and in aged patients, usually unfit for more aggressive conventional treatments. However, this transition to chronicity will require novel developmental guidelines adequate to this kind of drugs, for which optimal dose is not usually the maximal tolerated dose, pharmacokinetics does not define treatment schedule, and tumor shrinkage is not a good correlate of survival. The ongoing cancer immunotherapy program (including several monoclonal antibodies and therapeutic vaccines) at the Centre of Molecular Immunology can illustrate the issues to be addressed, both biological and social, along the path to transform advanced cancer into a chronic non-communicable disease compatible with years of quality life. PMID- 21556174 TI - Mercury levels in an urban pregnant population in Durham County, North Carolina. AB - The adverse effects of prenatal mercury exposure, most commonly resulting from maternal fish consumption, have been detected at very low exposure levels. The omega-3 fatty acids found in fish, however, have been shown to support fetal brain and vision development. Using data from a prospective, cohort study of pregnant women from an inland area in the US South, we sought to understand the fish consumption habits and associated mercury levels across subpopulations. Over 30% of women had at least 1 MUg/L of mercury in their blood, and about 2% had blood mercury levels above the level of concern during pregnancy (>= 3.5 MUg/L). Mercury levels were higher among Asian/Pacific Islander, older, higher educated, and married women. Fish consumption from any source was reported by 2/3 of the women in our study, with older women more likely to consume fish. Despite eating more fish meals per week, lower income, lower educated women had lower blood mercury levels than higher income, higher educated women. This suggests the different demographic groups consume different types of fish. Encouraging increased fish consumption while minimizing mercury exposure requires careful crafting of a complex health message. PMID- 21556175 TI - Three potential sources of microfungi in a treated municipal water supply system in sub-tropical Australia. AB - Some microfungi are known to be opportunistic human pathogens, and there is a body of scientific opinion that one of their routes of infection may be water aerosols. Others have been implicated as causative agents of odours and off tastes in drinking water. This study was undertaken to investigate three potential sources of microfungi in a treated, oligotrophic municipal water supply system in sub-tropical Australia. Formation of the microfungal component of developing biofilm on hard surfaces in water storage reservoirs was also assessed. Inside and outside air samples were collected from two reservoirs using two types of Burkard air samplers. Biofilm and soft sediment samples were collected from the inner surfaces of asbestos cement water pipes and from pipe dead ends respectively. These were analysed for microfungal growth and sporulation using Calcofluor White stain and epifluorescent microscopy. Artificial coupons of glass, PVC and concrete were immersed in two reservoirs to assess microfungal biofilm formation. This was analysed periodically using Calcofluor White stain and epifluorescent microscopy, cultures of coupon swabs and scanning electron microscopy. Fungal spores were recovered from all air samples. The number of colonies and the genera were similar for both inside and outside air. Microfungal filaments and sporulating structures were recovered from most of the pipe inner surface biofilm and dead end sediment samples, but were sparser in the biofilm than in the sediment samples. No recognisable, vegetative filamentous fungi were found in the slowly developing biofilm on coupons. This study indicates that airborne spores are an important potential source of microfungi found in water storage reservoirs. It has also demonstrated conclusively that filamentous microfungi grow and sporulate on water pipe inner surfaces and in soft sediments within the water distribution system. PMID- 21556176 TI - Assessing the impacts of local knowledge and technology on climate change vulnerability in remote communities. AB - The introduction of new technologies into small remote communities can alter how individuals acquire knowledge about their surrounding environment. This is especially true when technologies that satisfy basic needs, such as freshwater use, create a distance (i.e., diminishing exposure) between individuals and their environment. However, such distancing can potentially be countered by the transfer of local knowledge between community members and from one generation to the next. The objective of this study is to simulate by way of agent-based modeling the tensions between technology-induced distancing and local knowledge that are exerted on community vulnerability to climate change. A model is developed that simulates how a collection of individual perceptions about changes to climatic-related variables manifest into community perceptions, how perceptions are influenced by the movement away from traditional resource use, and how the transmission of knowledge mitigates the potentially adverse effects of technology-induced distancing. The model is implemented utilizing climate and social data for two remote communities located on the Seward Peninsula in western Alaska. The agent-based model simulates a set of scenarios that depict different ways in which these communities may potentially engage with their natural resources, utilize knowledge transfer, and develop perceptions of how the local climate is different from previous years. A loosely-coupled pan-arctic climate model simulates changes monthly changes to climatic variables. The discrepancy between the perceptions derived from the agent-based model and the projections simulated by the climate model represent community vulnerability. The results demonstrate how demographics, the communication of knowledge and the types of 'knowledge-providers' influence community perception about changes to their local climate. PMID- 21556177 TI - Increase in metabolic syndrome-related hospitalizations in relation to environmental sources of persistent organic pollutants. AB - Evidence from cell studies indicates that persistent organic pollutants (POP) can induce insulin resistance, an essential component of the metabolic syndrome (MetS). We hypothesized that residential proximity to environmental sources of POP would be associated with the MetS in the population. The present study examined the association between residency in a zip code containing or abutting environmental sources of POP and MetS-related hospitalization rates. Hospitalization data were obtained from the New York Statewide Planning and Research Cooperative System. Relative risks (RR) were calculated as hospitalization rate ratios. Adjusted RR and their 95% confidence intervals (CI) were estimated by multivariable Poisson regression. A higher proportion of African Americans resided in POP zip codes compared to Caucasians (25.9% and 24.3%, respectively, p < 0.01). Residence in POP zip codes was associated with a statistically significant 39.2% increase in MetS-related hospitalization rates, adjusted for race, gender, and age (adjusted RR = 1.392, 95% CI: 1.032-1.879, p = 0.030). Increase in age was independently associated with higher MetS-related hospitalization rates (p for trend < 0.001). Our findings contribute to the body of evidence supporting the hypothesis of POP constituting an environmental risk factor for the MetS. Further studies investigating exposure to POP and insulin resistance are warranted. PMID- 21556178 TI - The influence of traffic noise on appreciation of the living quality of a neighborhood. AB - Traffic influences the quality of life in a neighborhood in many different ways. Today, in many patsy of the world the benefits of accessibility are taken for granted and traffic is perceived as having a negative impact on satisfaction with the neighborhood. Negative health effects are observed in a number of studies and these stimulate the negative feelings in the exposed population. The noise produced by traffic is one of the most important contributors to the appreciation of the quality of life. Thus, it is useful to define a number of indicators that allow monitoring the current impact of noise on the quality of life and predicting the effect of future developments. This work investigates and compares a set of indicators related to exposure at home and exposure during trips around the house. The latter require detailed modeling of the population's trip behavior. The validity of the indicators is checked by their ability to predict the outcome of a social survey and by outlining potential causal paths between them and the outcome variables considered: general satisfaction with the quality of life in the neighborhood, noise annoyance at home, and reported traffic density in the area. PMID- 21556179 TI - Measurement of community empowerment in three community programs in Rapla (Estonia). AB - Community empowerment approaches have been proven to be powerful tools for solving local health problems. However, the methods for measuring empowerment in the community remain unclear and open to dispute. This study aims to describe how a context-specific community empowerment measurement tool was developed and changes made to three health promotion programs in Rapla, Estonia. An empowerment expansion model was compiled and applied to three existing programs: Safe Community, Drug/HIV Prevention and Elderly Quality of Life. The consensus workshop method was used to create the measurement tool and collect data on the Organizational Domains of Community Empowerment (ODCE). The study demonstrated considerable increases in the ODCE among the community workgroup, which was initiated by community members and the municipality's decision-makers. The increase was within the workgroup, which had strong political and financial support on a national level but was not the community's priority. The program was initiated and implemented by the local community members, and continuous development still occurred, though at a reduced pace. The use of the empowerment expansion model has proven to be an applicable, relevant, simple and inexpensive tool for the evaluation of community empowerment. PMID- 21556180 TI - Geological carbon sequestration: a new approach for near-surface assurance monitoring. AB - There are two distinct objectives in monitoring geological carbon sequestration (GCS): Deep monitoring of the reservoir's integrity and plume movement and near surface monitoring (NSM) to ensure public health and the safety of the environment. However, the minimum detection limits of the current instrumentation for NSM is too high for detecting weak signals that are embedded in the background levels of the natural variations, and the data obtained represents point measurements in space and time. A new approach for NSM, based on gamma-ray spectroscopy induced by inelastic neutron scatterings (INS), offers novel and unique characteristics providing the following: (1) High sensitivity with a reducible error of measurement and detection limits, and, (2) temporal- and spatial-integration of carbon in soil that results from underground CO(2) seepage. Preliminary field results validated this approach showing carbon suppression of 14% in the first year and 7% in the second year. In addition the temporal behavior of the error propagation is presented and it is shown that for a signal at the level of the minimum detection level the error asymptotically approaches 47%. PMID- 21556181 TI - Subjects agree to participate in environmental health studies without fully comprehending the associated risk. AB - Recent advances in environmental health research have greatly improved our ability to measure and quantify how individuals are exposed. These advances, however, bring bioethical uncertainties and potential risks that individuals should be aware of before consenting to participate. This study assessed how well participants from two environmental health studies comprehended consent form material. After signing the consent form, participants were asked to complete a comprehension assessment tool. The tool measured whether participants could recognize or recall six elements of the consent form they had just reviewed. Additional data were collected to look for differences in comprehension by gender, age, race, and the time spent reading the original consent form. Seventy three participants completed a comprehension assessment tool. Scores ranged from 1.91 to 6.00 (mean = 4.66); only three people had perfect comprehension scores. Among the least comprehended material were questions on study-related risks. Overall, 53% of participants were not aware of two or more study-related risks. As environmental public health studies pose uncertainties and potential risks, researchers need to do more to assess participants' understanding before assuming that individuals have given their 'informed' consent. PMID- 21556182 TI - Socioeconomic differences in exposure to tobacco smoke pollution (TSP) in Bangladeshi households with children: findings from the International Tobacco Control (ITC) Bangladesh Survey. AB - This study assessed the pattern of exposure to tobacco smoke pollution (TSP; also known as, secondhand smoke) in Bangladeshi households with children and examined the variations in household smoking restrictions and perception of risk for children's exposure to TSP by socioeconomic status. We interviewed 1,947 respondents from Bangladeshi households with children from the first wave (2009) of the International Tobacco Control (ITC) Bangladesh Survey. 43.5% of the respondents had complete smoking restrictions at home and 39.7% were very or extremely concerned about TSP risk to children's health. Participants with lower level of education were significantly less likely to be concerned about the risk of TSP exposure to children's health and less likely to adopt complete smoking restrictions at home. Logistic regression revealed that the predictors of concern for TSP exposure risk were educational attainment of 1 to 8 years (OR = 1.94) or 9 years or more (OR = 4.07) and being a smoker (OR = 0.24). The predictors of having complete household smoking restrictions were: urban residence (OR = 1.64), attaining education of 9 years or more (OR = 1.94), being a smoker (OR = 0.40) and being concerned about TSP exposure risk to children (OR = 3.25). The findings show that a high proportion of adults with children at home smoke tobacco at home and their perceptions of risk about TSP exposure to children's health were low. These behaviours were more prevalent among rural smokers who were illiterate. There is a need for targeted intervention, customized for low educated public, on TSP risk to children's health and tobacco control policy with specific focus on smoke-free home. PMID- 21556183 TI - Long-term low-level arsenic exposure is associated with poorer neuropsychological functioning: a Project FRONTIER study. AB - Exposure to elements in groundwater (toxic or beneficial) is commonplace yet, outside of lead and mercury, little research has examined the impact of many commonly occurring environmental exposures on mental abilities during the aging process. Inorganic arsenic is a known neurotoxin that has both neurodevelopmental and neurocognitive consequences. The aim of this study was to examine the potential association between current and long-term arsenic exposure and detailed neuropsychological functioning in a sample of rural-dwelling adults and elders. Data were analyzed from 434 participants (133 men and 301 women) of Project FRONTIER, a community-based participatory research study of the epidemiology of health issues of rural-dwelling adults and elders. The results of the study showed that GIS-based groundwater arsenic exposure (current and long-term) was significantly related to poorer scores in language, visuospatial skills, and executive functioning. Additionally, long-term low-level exposure to arsenic was significantly correlated to poorer scores in global cognition, processing speed and immediate memory. The finding of a correlation between arsenic and the domains of executive functioning and memory is of critical importance as these are cognitive domains that reflect the earliest manifestations of Alzheimer's disease. Additional work is warranted given the population health implications associated with long-term low-level arsenic exposure. PMID- 21556185 TI - Clinical, radiological, and pathological investigation of asbestosis. AB - By the radiological examination, differential diagnosis of asbestosis from chronic interstitial pneumonia such as IPF/UIP is difficult. The pathological features of asbestosis show the peribronchiolar fibrosis which suggest that asbestos fibers cause the inflammation of bronchioli. Therefore, the criteria for pathological diagnosis of asbestosis in 2010, contain the finding of peribronchiolar fibrosis again. Chest CT scanning including HRCT for total of 38 cases clinically diagnosed asbestosis were reviewed by 3 radiologists and one pulmonologist. On the other hand, the histology of lung tissues obtained by surgery or autopsy were examined by 4 pulmonological pathologists. Furthermore, the content of asbestos bodies in the lung was counted by phase-contrast microscopy. Thirteen cases were definitely diagnosed of asbestosis in the image including HRCT and 17 cases were diagnosed by the histopathological examination showing lung fibrosis with peribronchiolar fibrosis. Only 10 cases were indicated asbestosis by both the radiological and histopathological examinations. The mean value of asbestos bodies for these cases, was 2,133,255 per gram of dry lung tissue. PMID- 21556184 TI - Life-long programming implications of exposure to tobacco smoking and nicotine before and soon after birth: evidence for altered lung development. AB - Tobacco smoking during pregnancy remains common, especially in indigenous communities, and likely contributes to respiratory illness in exposed offspring. It is now well established that components of tobacco smoke, notably nicotine, can affect multiple organs in the fetus and newborn, potentially with life-long consequences. Recent studies have shown that nicotine can permanently affect the developing lung such that its final structure and function are adversely affected; these changes can increase the risk of respiratory illness and accelerate the decline in lung function with age. In this review we discuss the impact of maternal smoking on the lungs and consider the evidence that smoking can have life-long, programming consequences for exposed offspring. Exposure to maternal tobacco smoking and nicotine intake during pregnancy and lactation changes the genetic program that controls the development and aging of the lungs of the offspring. Changes in the conducting airways and alveoli reduce lung function in exposed offspring, rendering the lungs more susceptible to obstructive lung disease and accelerating lung aging. Although it is generally accepted that prevention of maternal smoking during pregnancy and lactation is essential, current knowledge of the effects of nicotine on lung development does not support the use of nicotine replacement therapy in this group. PMID- 21556186 TI - Climate change and vector-borne diseases: an economic impact analysis of malaria in Africa. AB - A semi-parametric econometric model is used to study the relationship between malaria cases and climatic factors in 25 African countries. Results show that a marginal change in temperature and precipitation levels would lead to a significant change in the number of malaria cases for most countries by the end of the century. Consistent with the existing biophysical malaria model results, the projected effects of climate change are mixed. Our model projects that some countries will see an increase in malaria cases but others will see a decrease. We estimate projected malaria inpatient and outpatient treatment costs as a proportion of annual 2000 health expenditures per 1,000 people. We found that even under minimal climate change scenario, some countries may see their inpatient treatment cost of malaria increase more than 20%. PMID- 21556187 TI - Does the association between depressive symptomatology and physical activity depend on body image perception? A survey of students from seven universities in the UK. AB - This cross-sectional study assessed the association between depression and PA in university students of both genders and the role of body image perception as a potential effect modifier. Undergraduate students (N = 3706) from seven universities in the UK completed a self-administered questionnaire that assessed sociodemographic information; a range of health, health behaviour and health awareness related factors; the modified version of Beck's Depression Inventory (M BDI); educational achievement, and different levels of physical activity (PA), such as moderate PA (at least 5 days per week moderate exercise of at least 30 minutes), and vigorous PA (at least 3 days per week vigorous exercise of at least 20 minutes). Only 12.4% of the sample achieved the international recommended level for moderate PA, and 33.1% achieved the recommendations for vigorous PA. Both moderate and vigorous PA were inversely related to the M-BDI score. Physically active students, regardless of the type of PA, were significantly more likely to perceive their health as good, to have higher health awareness, to perform strengthening exercises, and to be males. The stratified analyses indicated that the association between depression and PA differed by body image. In students perceiving their body image as 'just right', moderate (>4th percentile) and high (>5th percentile) M-BDI scores were inversely related to vigorous PA. However, in students who perceived their body image as 'overweight', the inverse association was only significant in those with high M-BDI scores. We conclude that the positive effect of PA on depression could be down modulated by the negative impact of a 'distorted' body image on depression. The practical implications of these findings are that PA programmes targeting persons with depressive symptoms should include effective components to enhance body image perception. PMID- 21556188 TI - CCS activities being performed by the U.S. DOE. AB - The United States Department of Energy (DOE) is the lead federal agency for the development and deployment of carbon sequestration technologies. Its mission includes promoting scientific and technological innovations and transfer of knowledge for safe and permanent storage of CO(2) in the subsurface. To accomplish its mission, DOE is characterizing and classifying potential geologic storage reservoirs in basins throughout the U.S. and Canada, and developing best practices for project developers, to help ensure the safety of future geologic storage projects. DOE's Carbon Sequestration Program, Regional Carbon Sequestration Partnership (RCSP) Initiative, administered by the National Energy Technology Laboratory (NETL), is identifying, characterizing, and testing potential injection formations. The RCSP Initiative consists of collaborations among government, industry, universities, and international organizations. Through this collaborative effort, a series of integrated knowledge-based tools have been developed to help potential sequestration project developers. They are the Carbon Sequestration Atlas of the United States and Canada, National Carbon Sequestration Database and Geographic System (NATCARB), and best practice manuals for CCS including Depositional Reservoir Classification for CO(2); Public Outreach and Education for Carbon Storage Projects; Monitoring, Verification, and Accounting of CO(2)Stored in Deep Geologic Formation; Site Screening, Site Selection, and Initial Characterization of CO(2)Storage in Deep Geologic Formations. DOE's future research will help with refinement of these tools and additional best practice manuals (BPM) which focus on other technical aspects of project development. PMID- 21556189 TI - The effectiveness of tobacco marketing regulations on reducing smokers' exposure to advertising and promotion: findings from the International Tobacco Control (ITC) Four Country Survey. AB - Exposure to tobacco product marketing promotes the initiation, continuation, and reuptake of cigarette smoking and as a result the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) has called upon member Parties to enact comprehensive bans on tobacco advertising and promotion. This study examines the immediate and long term effectiveness of advertising restrictions enacted in different countries on exposure to different forms of product marketing, and examines differences in exposure across different socioeconomic status (SES) groups. Nationally representative data from the United Kingdom, Canada, Australia, and the United States, collected from adult smokers between 2002 and 2008 using the International Tobacco Control Four Country Survey (ITC 4), were used in this study (N = 21,615). In light of the specific marketing regulation changes that occurred during the course of this study period, changes in awareness of tobacco marketing via various channels were assessed for each country, and for different SES groups within countries. Tobacco marketing regulations, once implemented, were associated with significant reductions in smokers' reported awareness of pro-smoking cues, and the observed reductions were greatest immediately following the enactment of regulations. Changes in reported awareness were generally the same across different SES groups, although some exceptions were noted. While tobacco marketing regulations have been effective in reducing exposure to certain types of product marketing there still remain gaps, especially with regard to in-store marketing and price promotions. PMID- 21556190 TI - Neighbourhood environment correlates of physical activity: a study of eight Czech regional towns. AB - An adequate amount of physical activity (PA) is a key factor that is associated with good health. This study assessed socio-environmental factors associated with meeting the health recommendations for PA (achieving 10,000 steps per day). In total, 1,653 respondents randomly selected from across eight regional towns (each >90,000 inhabitants) in the Czech Republic participated in the study. The ANEWS questionnaire assessed the environment in neighbourhoods, and participants' weekly PA was objectively monitored (Yamax Digiwalker SW-700 pedometer). About 24% of participants were sufficiently active, 27% were highly active; 28% participants were overweight and 5% were obese. Although BMI was significantly inversely associated with the daily step counts achieved only in females, for both genders, BMI was generally not significantly associated with the criterion of achieving 10,000 steps per day during the week. Increased BMI in both genders was accompanied with a decline in participation in organized PA and with increasing age. As regards to the demographic/lifestyle factors, for females, more participation in organized PA was significantly positively correlated with the achieved daily step counts. In contrast, older age and higher BMI (for females) and smoking (for males) were significantly negatively correlated with the achieved daily step counts. In terms of the environmental aspects, pleasant environments were significantly positively correlated to daily step counts for both genders. Additionally, for males, better residencies (more family homes rather than apartment blocks) in the neighbourhood were significantly positively correlated with their daily step counts. For females, less accessibility of shops and non-sport facilities (depending on walking distance in minutes) were significantly negatively correlated to the achieved daily step counts. Individuals who lived in pleasant neighbourhoods, with better access to shops and who participated in organized PA (>= 2 times a week) tended to meet the recommendations for health-enhancing PA levels. The creation of physical activity friendly environments could be associated with enhancing people's achieved daily step counts and meeting the health criteria for PA. PMID- 21556191 TI - The role of food and nutrition system approaches in tackling hidden hunger. AB - One of the World's greatest challenges is to secure sufficient and healthy food for all, and to do so in an environmentally sustainable manner. This review explores the interrelationships of food, health, and environment, and their role in addressing chronic micronutrient deficiencies, also known as "hidden hunger", affecting over two billion people worldwide. While the complexity and underlying determinants of undernutrition have been well-understood for decades, the scaling of food and nutrition system approaches that combine sustainable agriculture aimed at improved diet diversity and livelihoods have been limited in their development and implementation. However, an integrated system approach to reduce hidden hunger could potentially serve as a sustainable opportunity. PMID- 21556192 TI - Field-scale spatial variation of saline-sodic soil and its relation with environmental factors in Western Songnen Plain of China. AB - The objectives of this study were to investigate the degree of spatial variability and variance structure of salinization parameters using classical and geostatistical method in Songnen Plain of China, which is one of largest saline sodic areas in the World, and to analyze the relationship between salinization parameters, including soil salinity content (SC), electrical conductivity (EC), sodium adsorption ratio (SAR), and pH, and seven environmental factors by Pearson and stepwise regression analysis. The environmental factors were ground elevation, surface ponding time, surface ponding depth, and soil moistures at four layers (0-10 cm, 10-30 cm, 30-60 cm, and 60-100 cm). The results indicated that SC, EC, and SAR showed great variations, whereas pH exhibited low variations. Four salinization parameters showed strongly spatial autocorrelation resulting from the compound impact of structural factors. The empirical semivariograms in the four parameters could be simulated by spherical and exponential models. The spatial distributions of SC, EC, SAR and pH showed similar patterns, with the coexistence of high salinity and sodicity in the areas with high ground elevation. By Pearson analysis, the soil salinization parameters showed a significant positive relationship with ground elevation, but a negative correlation with surface ponding time, surface ponding depth, and soil moistures. Both correlation and stepwise regression analysis showed that ground elevation is the most important environmental factor for spatial variation of soil sanilization. The results from this research can provide some useful information for explaining mechanism of salinization process and utilization of saline-sodic soils in the Western Songnen Plain. PMID- 21556193 TI - Smoking cessation in indigenous populations of Australia, New Zealand, Canada, and the United States: elements of effective interventions. AB - Indigenous people throughout the world suffer a higher burden of disease than their non-indigenous counterparts contributing to disproportionate rates of disability. A significant proportion of this disability can be attributed to the adverse effects of smoking. In this paper, we aimed to identify and discuss the key elements of individual-level smoking cessation interventions in indigenous people worldwide. An integrative review of published peer-reviewed literature was conducted. Literature on smoking cessation interventions in indigenous people was identified via search of electronic databases. Documents were selected for review if they were published in a peer-reviewed journal, written in English, published from 1990-2010, and documented an individual-level intervention to assist indigenous people to quit smoking. Studies that met inclusion criteria were limited to Australia, New Zealand, Canada, and the USA, despite seeking representation from other indigenous populations. Few interventions tailored for indigenous populations were identified and the level of detail included in evaluation reports was variable. Features associated with successful interventions were integrated, flexible, community-based approaches that addressed known barriers and facilitators to quitting smoking. More tailored and targeted approaches to smoking cessation interventions for indigenous populations are required. The complexity of achieving smoking cessation is underscored as is the need to collaboratively develop interventions that are acceptable and appropriate to local populations. PMID- 21556194 TI - Socioeconomic variation in the prevalence, introduction, retention, and removal of smoke-free policies among smokers: findings from the International Tobacco Control (ITC) Four Country Survey. AB - INTRODUCTION: Exposure to secondhand smoke causes premature death and disease in non-smokers and indoor smoke-free policies have become increasingly prevalent worldwide. Although socioeconomic disparities have been documented in tobacco use and cessation, the association between socioeconomic status (SES) and smoke-free policies is less well studied. METHODS: Data were obtained from the 2006 and 2007 Waves of the International Tobacco Control Four Country Survey (ITC-4), a prospective study of nationally representative samples of smokers in Canada, the United States, the United Kingdom, and Australia. Telephone interviews were administered to 8,245 current and former adult smokers from October 2006 to February 2007. Between September 2007 and February 2008, 5,866 respondents were re-interviewed. Self-reported education and annual household income were used to create SES tertiles. Outcomes included the presence, introduction, and removal of smoke-free policies in homes, worksites, bars, and restaurants. RESULTS: Smokers with high SES had increased odds of both having [OR: 1.54, 95% CI: 1.27-2.87] and introducing [OR: 1.49, 95% CI: 1.04-2.13] a total ban on smoking in the home compared to low SES smokers. Continuing smokers with high SES also had decreased odds of removing a total ban [OR: 0.44, 95% CI: 0.26-0.73]. No consistent association was observed between SES and the presence or introduction of bans in worksites, bars, or restaurants. CONCLUSIONS: The presence, introduction, and retention of smoke-free homes increases with increasing SES, but no consistent socioeconomic variation exists in the presence or introduction of total smoking bans in worksites, bars, or restaurants. Opportunities exist to reduce SES disparities in smoke-free homes, while the lack of socioeconomic differences in public workplace, bar, and restaurant smoke-free policies suggest these measures are now equitably distributed in these four countries. PMID- 21556195 TI - A model-based prioritisation exercise for the European water framework directive. AB - A model-based prioritisation exercise has been carried out for the Water Framework Directive (WFD) implementation. The approach considers two aspects: the hazard of a certain chemical and its exposure levels, and focuses on aquatic ecosystems, but also takes into account hazards due to secondary poisoning, bioaccumulation through the food chain and potential human health effects. A list provided by EU Member States, Stakeholders and Non-Governmental Organizations comprising 2,034 substances was evaluated according to hazard and exposure criteria. Then 78 substances classified as "of high concern" where analysed and ranked in terms of risk ratio (Predicted Environmental Concentration/Predicted No Effect Concentration). This exercise has been complemented by a monitoring-based prioritization exercise using data provided by Member States. The proposed approach constitutes the first step in setting the basis for an open modular screening tool that could be used for the next prioritization exercises foreseen by the WFD. PMID- 21556196 TI - Filamentous fungi in drinking water, particularly in relation to biofilm formation. AB - The presence of filamentous fungi in drinking water has become an area worthy of investigation with various studies now being published. The problems associated with fungi include blockage of water pipes, organoleptic deterioration, pathogenic fungi and mycotoxins. Fungal biofilm formation is a less developed field of study. This paper updates the topic and introduces novel methods on fungal biofilm analysis, particularly from work based in Brazil. Further recommendations for standard methodology are provided. PMID- 21556197 TI - Environmental implications of nanotechnology--an update. AB - Some engineers and scientists are either directly or indirectly involved with nanotechnology issues. Nanotechnology concerns dealing with environmental implications and regulatory compliance encompass practicing areas for these technical individuals. Areas of particular concern include current/proposed environmental regulations and procedures for quantifying both health risks and hazard risks. This article addresses both of these issues. PMID- 21556198 TI - A simple model of tetracycline antibiotic resistance in the aquatic environment (with application to the Poudre River). AB - Antibiotic resistance is a major concern, yet it is unclear what causes the relatively high densities of resistant bacteria in the anthropogenically impacted environment. There are various possible scenarios (hypotheses): (A) Input of resistant bacteria from wastewater and agricultural sources is significant, but they do not grow in the environment; (B) Input of resistant bacteria is negligible, but the resistant bacteria (exogenous or endogenous) grow due to the selection pressure of the antibiotic; (C) Exogenous bacteria transfer the resistance to the endogenous bacteria and those grow. This paper presents a simple mechanistic model of tetracycline resistance in the aquatic environment. It includes state variables for tetracyclines, susceptible and resistant bacteria, and particulate and dissolved organic matter in the water column and sediment bed. The antibiotic partitions between freely dissolved, dissolved organic matter (DOM)-bound and solids-bound phases, and decays. Bacteria growth is limited by DOM, inhibited by the antibiotic (susceptible bacteria only) and lower due to the metabolic cost of carrying the resistance (resistant bacteria only). Resistant bacteria can transfer resistance to the susceptible bacteria (conjugation) and lose the resistance (segregation). The model is applied to the Poudre River and can reproduce the major observed (literature data) patterns of antibiotic concentration and resistance. The model suggests observed densities of resistant bacteria in the sediment bed cannot be explained by input (scenario A), but require growth (scenarios B or C). PMID- 21556199 TI - Experiences of working with the tobacco issue in the context of health promoting hospitals and health services: a qualitative study. AB - The worldwide Health Promoting Hospital and Health Services (HPH) network was initiated by the World Health Organizations in the late 1980s. The goal of the network is to change the focus of health services from curing patients to also embrace disease prevention and health promotion. In Sweden the network started in 1996, and involves mainly hospitals and primary care. The network members collaborate in task forces, one of which is working on the tobacco issue. There is limited evidence on the value of working within an HPH organization. The aim of this study was to investigate the experiences of members of the Swedish HPH network tobacco task force. Focus group interviews with task force members were analyzed using implementation theory. Three themes, overall experiences of working with tobacco issues, experiences of working with "free from tobacco in connection with surgery", and experiences of work in the HPH tobacco task force, emerged from the interviews. The results show that working with the tobacco issue in the context of health-promoting hospitals and health services met with difficulties involving the following important factors: evidence, context, facilitation and adopter characteristics. Leadership, one contextual factor, at national and local level, seems to be crucial if the work is going to succeed. The tobacco task force of the HPH network is an important facilitator supporting the task. PMID- 21556200 TI - Hospital malnutrition: prevalence, identification and impact on patients and the healthcare system. AB - Malnutrition is a debilitating and highly prevalent condition in the acute hospital setting, with Australian and international studies reporting rates of approximately 40%. Malnutrition is associated with many adverse outcomes including depression of the immune system, impaired wound healing, muscle wasting, longer lengths of hospital stay, higher treatment costs and increased mortality. Referral rates for dietetic assessment and treatment of malnourished patients have proven to be suboptimal, thereby increasing the likelihood of developing such aforementioned complications. Nutrition risk screening using a validated tool is a simple technique to rapidly identify patients at risk of malnutrition, and provides a basis for prompt dietetic referrals. In Australia, nutrition screening upon hospital admission is not mandatory, which is of concern knowing that malnutrition remains under-reported and often poorly documented. Unidentified malnutrition not only heightens the risk of adverse complications for patients, but can potentially result in foregone reimbursements to the hospital through casemix-based funding schemes. It is strongly recommended that mandatory nutrition screening be widely adopted in line with published best practice guidelines to effectively target and reduce the incidence of hospital malnutrition. PMID- 21556201 TI - Smoking and socio-demographic determinant of cardiovascular diseases among males 45+ years in Indonesia. AB - The main objective of this study is to present the prevalence of Cardio Vascular Diseases (CVDs) defined as been diagnosed or having symptoms of Coronary Heart Disease, Arrhytmia, or Heart Failure. The main risk factor analyzed is smoking behavior. The data used for this study was from Basic Health Survey of 2007, a National baseline data collected every three years which consist of more than one million samples representing 33 provinces in Indonesia. Information on socio demographic characteristics, history of CVDs and smoking behavior were collected by highly-trained interviewers using a questionnaire which had been tested. A sub sample of the survey consisting of 100,009 males aged 45 years and over was analyzed. Crude and adjusted odds ratio (OR) were analyzed using logistic regressions to estimate the prevalence of CVDs by smoking behavior and socio demographic characteristics. Overall, 86.8% respondents reported that they had never been diagnosed as having CVDs or having any symptom of CVDs.; while 2.1% respondents reported that they had been diagnosed by a health professional (a doctor or a nurse) of having CVDs. The interviewers also identified three signs and symptoms of CVDs for all respondents if they reported of never been diagnosed CVDs. Among all respondents 2.3% had symptoms of coronary heart disease, 4.9% had symptoms of arrhytmia, and 3.9% had symptoms of heart failure. The prevalence of CVDs was significantly higher in former smokers (OR = 2.03), and duration of smoking for more than 20 years. The prevalence of CVDs was significantly higher among older groups. Old males who lived in Sulawesi island had higher probability of having CVDs (OR = 1.67). The lower prevalence of CVDs seemed to have associated with higher among Senior High School Graduate compared to those who Never Schooling (OR = 0.8). Since population of Indonesia is relatively young, the future of health care costs of Indonesia would be high due to high prevalence of smoking among males population. This finding suggests that Indonesia should ratify Framework Convention on Tobacco Control ans start impelementing measures to control tobacco uses in order to reduce public health and economic consequences of smoking in the future. PMID- 21556202 TI - Genotoxic effect of chronic exposure to DDT on lymphocytes, oral mucosa and breast cells of female rats. AB - The genotoxicity of some environmental contaminants may affect human health directly by damaging genetic material and thus plays an important role in cancer development. Xenoestrogens are one kind of environmental pollutants that may alter hormonal routes or directly affect DNA. The number of available biomarkers used to assess genetic risk and cancer is very extensive. The present study evaluated genotoxicity produced by the pesticide DDT on systemic and mammary gland cells obtained from adult female Wistar rats. Oral mucosa cells micronuclei were assessed; the comet assay in peripheral blood-isolated lymphocytes and mammary epithelial cells was also carried out. Additionally, oxidative stress was studied in mammary tissue through a lipid peroxidation assay. Our data showed an increase in lipid peroxidation, product of an increase in free oxygen radical levels, which leads to an oxidative stress status. Our results suggest that DDT is genotoxic, not only for lymphocytes but also to mammary epithelial cells. PMID- 21556203 TI - Prevalence and antimicrobial-resistance of Pseudomonas aeruginosa in swimming pools and hot tubs. AB - Pseudomonas aeruginosa is an important opportunistic pathogen in recreational waters and the primary cause of hot tub folliculitis and otitis externa. The aim of this surveillance study was to determine the background prevalence and antimicrobial resistance profile of P. aeruginosa in swimming pools and hot tubs. A convenience sample of 108 samples was obtained from three hot tubs and eight indoor swimming pools. Water and swab samples were processed using membrane filtration, followed by confirmation with polymerase chain reaction. Twenty-three samples (21%) were positive for P. aeruginosa, and 23 isolates underwent susceptibility testing using the microdilution method. Resistance was noted to several antibiotic agents, including amikacin (intermediate), aztreonam, ceftriaxone, gentamicin, imipenem, meropenem (intermediate), ticarcillin/clavulanic acid, tobramycin (intermediate), and trimethoprim/sulfamethoxazole. The results of this surveillance study indicate that 96% of P. aeruginosa isolates tested from swimming pools and hot tubs were multidrug resistant. These results may have important implications for cystic fibrosis patients and other immune-suppressed individuals, for whom infection with multidrug-resistant P. aeruginosa would have greater impact. Our results underlie the importance of rigorous facility maintenance, and provide prevalence data on the occurrence of antimicrobial resistant strains of this important recreational water-associated and nosocomial pathogen. PMID- 21556204 TI - Bottled water: United States consumers and their perceptions of water quality. AB - Consumption of bottled water is increasing worldwide. Prior research shows many consumers believe bottled water is convenient and has better taste than tap water, despite reports of a number of water quality incidents with bottled water. The authors explore the demographic and social factors associated with bottled water users in the U.S. and the relationship between bottled water use and perceptions of the quality of local water supply. They find that U.S. consumers are more likely to report bottled water as their primary drinking water source when they perceive that drinking water is not safe. Furthermore, those who give lower ratings to the quality of their ground water are more likely to regularly purchase bottle water for drinking and use bottle water as their primary drinking water source. PMID- 21556205 TI - The relationships between weather-related factors and daily outdoor physical activity counts on an urban greenway. AB - The purpose of this study was to examine relationships between weather and outdoor physical activity (PA). An online weather source was used to obtain daily max temperature [DMT], precipitation, and wind speed. An infra-red trail counter provided data on daily trail use along a greenway, over a 2-year period. Multiple regression analysis was used to examine associations between PA and weather, while controlling for day of the week and month of the year. The overall regression model explained 77.0% of the variance in daily PA (p < 0.001). DMT (b = 10.5), max temp-squared (b = -4.0), precipitation (b = -70.0), and max wind speed (b = 1.9) contributed significantly. CONCLUSION: Aggregated daily data can detect relationships between weather and outdoor PA. PMID- 21556206 TI - Early postnatal protein-calorie malnutrition and cognition: a review of human and animal studies. AB - Malnutrition continues to be recognized as the most common and serious form of children's dietary disease in the developing countries and is one of the principal factors affecting brain development. The purpose of this paper is to review human and animal studies relating malnutrition to cognitive development, focusing in correlational and interventional data, and to provide a discussion of possible mechanisms by which malnutrition affects cognition. PMID- 21556207 TI - Hazardous compounds in tobacco smoke. AB - Tobacco smoke is a toxic and carcinogenic mixture of more than 5,000 chemicals. The present article provides a list of 98 hazardous smoke components, based on an extensive literature search for known smoke components and their human health inhalation risks. An electronic database of smoke components containing more than 2,200 entries was generated. Emission levels in mainstream smoke have been found for 542 of the components and a human inhalation risk value for 98 components. As components with potential carcinogenic, cardiovascular and respiratory effects have been included, the three major smoke-related causes of death are all covered by the list. Given that the currently used Hoffmann list of hazardous smoke components is based on data from the 1990s and only includes carcinogens, it is recommended that the current list of 98 hazardous components is used for regulatory purposes instead. To enable risk assessment of components not covered by this list, thresholds of toxicological concern (TTC) have been established from the inhalation risk values found: 0.0018 MUg day(-1) for all risks, and 1.2 MUg day(-1) for all risks excluding carcinogenicity, the latter being similar to previously reported inhalation TTCs. PMID- 21556209 TI - Predictive characteristics of malignant pheochromocytoma. AB - PURPOSE: The prognosis of patients with malignant pheochromocytoma is poor, but the predictive factors are not well understood. We aimed to identify the clinical characteristics predictive of malignancy after initial surgical removal in patients with pheochromocytoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 152 patients diagnosed with pheochromocytoma, including 5 (3.3%) with metastasis at the time of the initial surgical excision and 12 (7.9%) who developed metastasis during follow-up. To determine the factors predictive of malignancy, we compared clinical, radiographical, and urinary chemical findings between patients with benign and malignant disease. Mean follow-up was 41.5 months (range, 0.9-298 months) after surgery. RESULTS: Malignant tumors were significantly larger than benign tumors (11.1+/-4.0 cm vs. 6.2+/-3.4 cm, p<0.001), and postoperative persistence of arterial hypertension was more frequent after removal of malignant than benign tumors (p=0.001). Among the 147 patients without metastatic disease at diagnosis, those who developed metastasis had significantly lower concentrations of urinary catecholamine metabolites per unit of tumor, including vanillylmandelic acid (1.2 vs. 3.7 mg/day/cm, p=0.049), epinephrine (4.5 vs. 168.9 ug/day/cm, p=0.008), and norepinephrine (13.1 vs. 121.8 mg/day/cm, p<0.001). The overall 5-year metastasis-free survival rate was 84.4% and was significantly higher in patients with smaller tumors (<=5.5 vs. >5.5 cm; 90.6% vs. 81.2%, p=0.025) and higher 24-hour secretion of vanillylmandelic acid (>2.1 vs. <=2.1 mg/day/cm; 94.9% vs. 70.9%, p=0.019). CONCLUSIONS: Large tumor size (>5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (<=2.1 mg/day/cm) were significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis free survival and mandating more rigorous follow-up after surgery. PMID- 21556208 TI - Radical cystectomy and orthotopic bladder substitution using ileum. AB - Over the past decade, continent urinary diversion, especially orthotopic bladder substitutions, has become increasingly popular following radical cystectomy for bladder cancer. The ultimate goal of orthotopic bladder substitution is to offer patients the best quality of life, similar to that of patients with native bladders. To achieve that purpose, surgeons should be familiar with the characteristics of good candidates for neobladders, the possible intraoperative and postoperative problems related to the surgery, and the solutions to these problems. Postoperative surveillance and instructions given to the patients also contribute to successful, functional results. Here, we reviewed the indications, pitfalls, and solutions for orthotopic bladder substitutions and the patients' quality of life after surgery. When performed properly, orthotopic continent diversion offers good quality of life with few long-term complications. Therefore, we believe it is the best option for the majority of patients requiring cystectomy. PMID- 21556210 TI - Relationship between the Glutathione-S-Transferase P1, M1, and T1 Genotypes and Prostate Cancer Risk in Korean Subjects. AB - PURPOSE: The glutathione-S-transferase (GST)P1, GSTM1, and GSTT1 genotypes have been associated with an increased risk of prostate, bladder, and lung cancers. The aim of this study was to investigate the association between the GSTP1, GSTM1, and GSTT1 genotypes and the risk of prostate cancer in Korean men. MATERIALS AND METHODS: The study group consisted of 166 patients with histologically confirmed prostate cancer. The control group consisted of 327 healthy, cancer-free individuals. The diagnosis of prostate cancer was made by transrectal ultrasound-guided biopsy. Patients with prostatic adenocarcinoma were divided into organ-confined (<=pT2) and non-organ-confined (>=pT3) subgroups. The histological grades were subdivided according to the Gleason score. The GSTP1, GSTM1, and GSTT1 genotypes were determined by using polymerase chain reaction based methods. The relationship among GSTP1, GSTM1, and GSTT1 polymorphisms and prostate cancer in a case-control study was investigated. RESULTS: The frequency of the GSTM1 null genotype in the prostate cancer group (54.2%) was higher than in the control group (odds ratio=1.53, 95% confidence interval=1.20-1.96). The comparison of the GSTP1, GSTM1, and GSTT1 genotypes and cancer prognostic factors, such as staging and grading, showed no statistical significance. CONCLUSIONS: An increased risk for prostate cancer may be associated with the GSTM1 null genotype in Korean men, but no association was found with the GSTT1 or GSTP1 genotypes. PMID- 21556211 TI - Cyclooxygenase-2 overexpression in chronic inflammation associated with benign prostatic hyperplasia: is it related to apoptosis and angiogenesis of prostate cancer? AB - PURPOSE: This study was performed to investigate the relationship between cyclooxygenase-2 (COX-2) expression and apoptosis/angiogenesis in inflammatory and noninflammatory benign prostatic hyperplasia (BPH) and prostate cancer (PC). MATERIALS AND METHODS: This study involved 64 BPH and 57 PC patients. The BPH histopathologies were classified by the presence of chronic inflammation as follows: noninflammatory BPH (NI-BPH; n=23) and inflammatory BPH (I-BPH; n=41). The association between the expression of COX-2, expression of Bcl-2, the apoptotic index (AI), expression of vascular endothelial growth factor (VEGF), and microvascular density (MVD) in the prostate was investigated. RESULTS: An overexpression of COX-2, Bcl-2, and VEGF was observed in cases of PC compared with cases of BPH. In PC, the AI was lower and MVD was higher than in BPH. In NI BPH, I-BPH, and PC, the overexpression of COX-2, Bcl-2, and VEGF gradually increased. The AI was high in I-BPH, but did not differ significantly between the NI-BPH and I-BPH groups or between the NI-BPH and PC groups. MVD was significantly high in PC, but no significant difference was found between NI-BPH and I-BPH. A significant correlation was shown between the overexpression of COX 2 and Bcl-2, and COX-2 and VEGF. However, the AI was not correlated with the overexpression of COX-2 or Bcl-2. MVD was correlated with the overexpression of COX-2 and VEGF. CONCLUSIONS: COX-2 overexpression in PC is correlated with a decrease in apoptosis and an increase in angiogenesis. Chronic inflammation in BPH causes an overexpression of COX-2, which induces the increased expression of Bcl-2 and VEGF. It is likely that chronic inflammation plays a role in the intermediate step of carcinogenesis in the prostate. PMID- 21556212 TI - Long-Term Follow-Up Results of Photoselective Vaporization of the Prostate with the 120 W Greenlight HPS Laser for Treatment of Benign Prostatic Hyperplasia. AB - PURPOSE: With the use of 12 months of follow-up data, this study was conducted to evaluate the efficacy of photoselective vaporization of the prostate (PVP) with the 120 W Greenlight high performance system (HPS) laser for the treatment of symptomatic benign prostatic hyperplasia. MATERIALS AND METHODS: Data were collected from 104 patients who were diagnosed with benign prostatic hyperplasia and who underwent PVP with the 120 W Greenlight HPS Laser. Postoperative parameters, including International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), and postvoid residual volume (PVR), were assessed and compared with preoperative baseline values. RESULTS: The mean age of the patients was 71.1+/-7.7. The baseline mean prostate-specific antigen level was 3.8+/-2.7 ng/ml, the mean prostate size was 43.9+/-20.6 g, the mean preoperative IPSS was 18.4+/-8.5, the mean QoL score was 4.1+/-1.0, the mean Qmax was 9.9+/-5.5 ml/sec, and the mean PVR was 89.6+/-207.1 ml. During surgery, the mean operation time was 21.8+/-11.3 minutes, the mean lasing time was 16.9+/ 10.5 minutes, and the mean total applied energy was 170,068+/-63,181 J. At 1 month, significant improvements were observed in total IPSS (11.5+/-6.7, p<0.05), voiding symptom score (6.1+/-5.4, p<0.05), and QoL score (2.2+/-1.5, p<0.05); however, there were no significant improvements in storage symptom score (4.8+/ 3.8, p=0.06), Qmax (12.6+/-10.2, p=0.06), and PVR (40.1+/-30.5, p=0.41). However, 3 months after surgery, all postoperative follow-up parameters showed significant improvements, and the 6- and 12-month data showed sustained improvement of postoperative follow-up parameters. CONCLUSIONS: Significant improvements were observed in subjective and objective voiding parameters, which were evident at 3 months after PVP and were sustained throughout a period of 12 months after PVP. PMID- 21556213 TI - Long-term effect of loxoprofen sodium on nocturia in patients with benign prostatic hyperplasia. AB - PURPOSE: We evaluated the long-term effects of loxoprofen on nocturia in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Between January 2006 and December 2008, 40 BPH patients with 2 or more episodes of nocturia received an alpha-blocker, 5-alpha reductase inhibitor, and a single dose of 60 mg of loxoprofen at night before sleep for 12 months (Group I). During the same period, 38 BPH patients selected as the control group received an alpha-blocker and 5-alpha reductase inhibitor (Group II). Patients were reevaluated after 3, 6, and 12 months of treatment by the number of nocturia episodes and side effects. RESULTS: After 3 months of treatment, the number of nocturia episodes decreased significantly compared with baseline in both group I and group II (1.9+/-0.7, 2.1+/-0.7, respectively, p<0.05). The degree of decrease in nocturia was significantly different between the groups (-1.5+/-0.9, -1.1+/-0.9, respectively, p=0.034). After 6 and 12 months, the number of nocturia episodes decreased significantly compared with baseline in both group I and group II (p<0.05), but the degree of decrease was not significantly different between the groups (p>0.05). After 6 and 12 months of treatment in group I, treatment-emergent adverse events, including 5 cases of gastric discomfort (12.5%), 3 cases of leg edema (7.5%), and 1 case of decreased urine volume (2.5%), occurred in 9 of the 40 (22.5%) patients. CONCLUSIONS: Loxoprofen can be an effective treatment for patients with nocturia secondary to BPH in the short term. Long-term use of loxoprofen is not recommended because of the side effects. PMID- 21556214 TI - Comparison of effectiveness of monopolar and bipolar transurethral resection of the prostate and open prostatectomy in large benign prostatic hyperplasia. AB - PURPOSE: Transurethral resection of the prostate (TURP) is still considered the gold standard in the treatment of benign prostatic hyperplasia (BPH). However, open prostatectomy is indicated for prostate glands over 75 ml. There have been few reports concerning the use of TURP for large prostate glands over 100 ml. Herein we compared the effectiveness of monopolar TURP, bipolar TURP, and open prostatectomy in prostate glands larger than 100 ml. MATERIALS AND METHODS: We reviewed the data of 48 patients with prostate glands larger than 100 ml. A total of 19, 17, and 12 patients underwent monopolar TURP (group A), bipolar TURP (group B), or open prostatectomy (group C), respectively. Preoperative International Prostate Symptom Score (IPSS), maximal flow rate (Qmax), prostate volume, resected tissue volume, resection velocity, and operative time were documented. Postoperative hemoglobin, serum sodium change, hospital stay, and postoperative 6-month IPSS and Qmax were evaluated. RESULTS: The prostate volumes did not differ significantly among the three groups. Operative time was similar in the two TURP groups, but open prostatectomy required a longer operative time. There was no significant difference in the resected prostate tissue or resection velocity between the two TURP groups. There was a marked decrease in postoperative serum sodium in the monopolar group compared with the other two groups. Among the groups, bipolar TURP required a shorter hospitalization. Postoperative IPSS, quality of life (QoL), and Qmax improved significantly in all groups. CONCLUSIONS: Even for large prostate glands, the results of this study suggest that bipolar TURP is an effective and safe operation owing to the significant improvements in voiding symptoms, shorter hospitalization, and fewer complications such as transurethral resection syndrome. PMID- 21556215 TI - Efficacy and safety of low-dose propiverine in patients with lower urinary tract symptoms/benign prostatic hyperplasia with storage symptoms: a prospective, randomized, single-blinded and multicenter clinical trial. AB - PURPOSE: The aim of this study was to evaluate whether low-dose anticholinergics combined with an alpha1-receptor antagonist would continue the effect of an alpha blocker, decrease the side effects of anticholinergics, and improve the symptoms of lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: Two hundred nine men with LUTS/BPH with storage symptoms (International Prostate Symptom Score [IPSS] >=12; storage symptoms >=4) were randomly assigned in a prospective, multicentered, and single-blind fashion to either the control group (alfuzosin 10 mg, once daily) or the combined group (alfuzosin 10 mg, once daily, and propiverine 10 mg, once daily) for 2 months. IPSS, maximal urinary flow rate (Qmax), and postvoid residual volume (PVR) were used to grade symptoms, side effects, and the impact on quality of life (QoL) at the start of the study and after 1 and 2 months. RESULTS: There were no significant differences in patient background, including age, prostate size, Qmax, and PVR, between the control group and the combined group. In the combined group, the IPSS total score and the IPSS storage symptom score were significantly improved compared with the control group. The IPSS voiding symptom score, QoL, Qmax, and PVR did not differ significantly. There were no serious side effects in either group. CONCLUSIONS: Management with an alpha1-receptor antagonist combined with a low-dose anticholinergic improved the total score and storage symptom score of the IPSS compared with alpha1-receptor antagonist only group without causing serious side effects. This initial combination medication can be considered an effective and safe treatment modality for LUTS/BPH patients with storage symptoms. PMID- 21556216 TI - Operative outcomes of robotic partial nephrectomy: a comparison with conventional laparoscopic partial nephrectomy. AB - PURPOSE: To determine the feasibility and safety of robotic partial nephrectomy (RPN), we compared the operative outcomes of patients who had undergone RPN with those of patients who had undergone laparoscopic partial nephrectomy (LPN). MATERIALS AND METHODS: Between February 2009 and June 2010, 13 patients underwent transperitoneal RPN (group 1) and 14 patients underwent transperitoneal LPN (group 2) by a single surgeon. The operative outcomes of the 2 groups were compared by using Mann-Whitney U and Fisher's exact tests. RESULTS: All cases were completed successfully without conversion to open surgery. The mean operative time was 153.2+/-22.3 and 117.5+/-32.0 minutes in groups 1 and 2, respectively (p=0.003). The mean robotic console time of group 1 was 101.2+/-21.5 minutes, and the mean laparoscopic time of group 2 was 86.8+/-32.3 minutes (p=0.139). The mean warm ischemic time was 35.3+/-8.5 minutes and 36.4+/-6.8 minutes in groups 1 and 2, respectively (p=0.823). The mean estimated blood loss was 283.6+/-113.5 ml and 264.1+/-163.7 ml (p=0.382), respectively. The mean length of hospital stay was 6.1 and 5.3 days (p=0.290), respectively. The mean tumor size was 2.7+/-1.2 cm and 2.0+/-1.2 cm (p=0.035), respectively. The surgical margins were negative in all cases. CONCLUSIONS: Although the operative time of RPN was longer than that of LPN, there were no significant differences in operative outcomes including robotic console time and laparoscopic time between the procedures. PMID- 21556217 TI - The Learning Curve for Flank Percutaneous Nephrolithotomy for Kidney Calculi: A Single Surgeon's Experience. AB - PURPOSE: Percutaneous nephrolithotomy (PCNL) is conventionally conducted in the prone position. However, the prone position increases anesthesia-related morbidity and position changes lengthen the operation time. We report perioperative outcomes and the learning curve for flank PCNL on the basis of a single surgeon's experience. MATERIALS AND METHODS: This study investigated 53 cases of flank PCNL performed for renal stones at our institution from April 2008 to September 2010. We compared mean operative time, stone-free rate, drop in hemoglobin level, length of hospital stay, complications, and need for additional procedures after the surgery. The 53 cases were divided into three groups by case number to compare therapeutic effect, stability, and the learning curve for flank position PCNL. RESULTS: The mean operation time for the 53 patients was 97.3+/ 43.1 minutes. The mean operation time gradually decreased as the surgeon accumulated experience. From the 36th case, the mean operation time showed a statistically significant decrease to 72.2+/-24.1 minutes (p=0.003). The overall stone-free rate was 64.2% for all procedures (range, 61.1-76.5%). There were no significant differences in the drop in hemoglobin level, stone-free rate, re treatment, hospital stay, or complication rate. There was no injury to the bowel or renal vessels, and no other major complications occurred. CONCLUSIONS: Flank PCNL can be used to remove renal stones effectively while overcoming the disadvantages of the existing prone position PCNL. After 36 cases, the learning curve showed acquisition of surgical competence. The clinical experience reported here suggests that flank PCNL is a safe and feasible technique. PMID- 21556218 TI - Efficacy of combination use of Beta-lactamase inhibitor with penicillin and fluoroquinolones for antibiotic prophylaxis in transrectal prostate biopsy. AB - PURPOSE: To investigate the efficacy of tazobactam/piperacillin (TAZ/PIPC) plus levofloxacin (LVFX) as a prophylactic administration in transrectal prostate biopsy (TPBX). MATERIALS AND METHODS: We investigated 201 consecutive patients who underwent TPBX in one Japanese hospital during the period of 2009-2010. The patients received TAZ/PIPC 4.5 g i.v. once just before and 3 hours after TPBX, plus oral LVFX 300 mg or 500 mg daily for 3 days. We examined the infectious adverse events and laboratory data (serum white blood cell [WBC] count and C reactive protein [CRP]) before and 1 day after TPBX. RESULTS: Only one patient (0.50%) in 201 cases had febrile complications after TPBX. Serum WBC and CRP did not rise significantly on the day after TPBX compared with before TPBX (p>0.05). There was no significant difference in the rise of serum WBC and CRP before and after TPBX in the comparison of LVFX 500 mg with LVFX 300 mg in the TAZ/PIPC plus LVFX regimen. CONCLUSIONS: TAZ/PIPC plus LVFX can be considered as a prophylactic regimen for preventing infectious complications in TPBX. PMID- 21556219 TI - Superficial dorsal vein rupture imitating penile fracture. AB - Dorsal vein rupture of the penis is a rare condition, and few cases have been reported in the literature. Herein we report a 41-year-old man who presented with mildly painful and acute swollen penis, which initially imitated a penile fracture but was surgically explored and shown to be a superficial dorsal vein rupture. PMID- 21556220 TI - Extensive systemic sarcoidosis with testicular involvement mimicking metastatic testicular cancer. AB - Sarcoidosis is an idiopathic, multisystem disease that rarely involves the genitourinary tract. Here we present an unusual case of testicular sarcoidosis with extensive lymphadenopathy that mimicked a metastatic testicular tumor. A 27 year-old male presented with a palpable right testicular mass accompanied by multiple palpable inguinal lymph nodes. The scrotal ultrasound showed a hypoechoic lesion at the inferior portion of the right testis. Extensive enlarged lymph nodes were noted in multiple areas on the abdominal computed tomography. Preoperative testicular tumor markers were within the normal range. Exploration of the right testis with a frozen section analysis of the right testicular mass and of a palpable right inguinal lymph node showed granulomatous inflammation. The testis was salvaged and the final pathological diagnosis was sarcoidosis. Treatment with high-dose corticosteroids resulted in complete resolution of the intratesticular mass and a significant decrease in the extent of the lymphadenopathy. PMID- 21556221 TI - Effect of phlorotannins isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibitory activity. AB - Inhibition of angiotensin I-converting enzyme (ACE) activity is the most common mechanism underlying the lowering of blood pressure. In the present study, five organic extracts of a marine brown seaweed Ecklonia cava were prepared by using ethanol, ethyl acetate, chloroform, hexane, and diethyl ether as solvents, which were then tested for their potential ACE inhibitory activities. Ethanol extract showed the strongest ACE inhibitory activity with an IC(50) value of 0.96 mg/ml. Five kinds of phlorotannins, phloroglucinol, triphlorethol-A, eckol, dieckol, and eckstolonol, were isolated from ethanol extract of E. cava, which exhibited potential ACE inhibition. Dieckol was the most potent ACE inhibitor and was found to be a non-competitive inhibitor against ACE according to Lineweaver-Burk plots. Dieckol had an inducible effect on the production of NO in EAhy926 cells without having cytotoxic effect. The results of this study indicate that E. cava could be a potential source of phlorotannins with ACE inhibitory activity for utilization in production of functional foods. PMID- 21556222 TI - Anti-inflammatory effect of the water fraction from hawthorn fruit on LPS stimulated RAW 264.7 cells. AB - The hawthorn fruit (Crataegus pinnatifida Bunge var. typica Schneider) is used as a traditional medicine in Korea. The objective of this study was to understand the mechanisms of the anti-inflammatory effects of the water fractionated portion of hawthorn fruit on a lipopolysaccharide (LPS)-stimulated RAW 264.7 cellular model. The level of nitric oxide (NO) production in the water fraction and LPS treated RAW 264.7 cells were determined with an ELISA. The cytotoxicity of the water fraction and LPS was measured with an MTT assay. Expression of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and interleukin 1beta (IL-1beta) mRNA were analyzed with a reverse transcription polymerase chain reaction (RT-PCR). The water fraction of hawthorn fruit was determined to be safe and significantly inhibited NO production in LPS-stimulated RAW 264.7 cells and suppressed COX-2, TNF-alpha, IL 1beta, and IL-6 expression. The observed anti-inflammatory effects of the water fraction of hawthorn fruit might be attributed to the down-regulation of COX-2, TNF-alpha, IL-1beta, and IL-6 expression in LPS-stimulated RAW 264.7 cells. PMID- 21556223 TI - Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus. AB - The objective of this study was to investigate the hypoglycemic effects of quercetin (QE) in animal models of diabetes mellitus (DM). A starch solution (1 g/kg) with and without QE (100 mg/kg) or acarbose (40 mg/kg) was orally administered to streptozotocin (STZ)-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calculated. To study the effects of chronic feeding of QE, five-week-old db/db mice were fed an AIN-93G diet, a diet containing QE at 0.08%, or a diet containing acarbose at 0.03% for 7 weeks after 1 week of adaptation. Plasma glucose and insulin, blood glycated hemoglobin, and maltase activity of the small intestine were measured. Oral administration of QE (100 mg/kg) or acarbose (40 mg/kg) to STZ-treated rats significantly decreased incremental plasma glucose levels 30-180 min after a single oral dose of starch and the area under the postprandial glucose response, compared with the control group. QE (0.08% of diet) or acarbose (0.03% of diet) offered to db/db mice significantly reduced both plasma glucose and blood glycated hemoglobin compared to controls without significant influence on plasma insulin. Small intestine maltase activities were significantly reduced by consumption of QE or acarbose. Thus, QE could be effective in controlling fasting and postprandial blood glucose levels in animal models of DM. PMID- 21556224 TI - Effect of paternal folate deficiency on placental folate content and folate receptor alpha expression in rats. AB - We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor alpha (FRalpha) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FRalpha (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FRalpha expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport. PMID- 21556225 TI - Energy and nutrient intake and food patterns among Turkish university students. AB - The goal of this study was to determine the nutritional value and nutrients provided by each meal and snack of consumed by university students. Subjects were randomly selected from volunteer students at five universities in Ankara. A sample of 400 students (167 female and 233 male) aged between 19 and 24 years participated in this study. A questionnaire designed to assess general characteristics, anthropometric measurements, and 24 hours dietary records was administered using face to face interviews. According to body mass index classifications, 69.5% of male students, and 77.7% of female students were found to be in the normal weight categories. Overweight categories were found to be 25.1% and 5.6% for males and females, respectively. Breakfast and lunch were the most frequently skipped meals, with a total of 47.7% of students skipping breakfast and 25.2% skipping lunch. The percentages of energy deficiency were found to be 78.4% in males, and 81.1% in females. Dinner was the main meal for consumption of energy and the other nutrients, except saturated fatty acids, for both genders. Also, dinner was the largest contributor of energy in both genders. Students ate more bread, cereals, and meat at dinner than during the other meals and snacks. Fruit was consumed more during snacks than at the other meals by all students. It was concluded that students need more nutritional information about healthy nutritional habits, adequate intake of nutrients, and ideal body weights. PMID- 21556226 TI - Lifestyle, dietary habits and consumption pattern of male university students according to the frequency of commercial beverage consumptions. AB - Because excessive consumption of sugar-sweetened beverages may reduce the quality of nutritional intake, this study examined the consumption patterns of commercial beverages, lifestyle, dietary habits, and perception of sweet taste. Participants were 407 male university students in Kyeonggido, Korea, and information was collected by self-administered questionnaire. Among them, 58 nonsmokers volunteered to participate in the taste test. Participants were divided into three groups according to the frequency of commercial beverage consumptions: 120 rare (< 1 serving/week), 227 moderate (1-3 servings/week) and 133 frequent (> 3 servings/week) consumption groups. More subjects from the rare consumption group chose water, tea, and soy milk, and more from the frequent consumption group chose carbonated soft drinks and coffee (P = 0.031) as their favorite drinks. Frequent consumption group consumed fruit juice, coffee, and sports and carbonated soft drinks significantly more often (P = 0.002, P = 0.000, P = 0.000, respectively), but not milk and tea. Frequent consumption group consumed beverages casually without a specific occasion (P = 0.000) than rare consumption group. Frequent drinking of commercial beverages was associated with frequent snacking (P = 0.002), meal skipping (P = 0.006), eating out (P = 0.003), eating delivered foods (P = 0.000), processed foods (P = 0.001), and sweets (P = 0.002), and drinking alcoholic beverages (P = 0.029). Frequent consumption group tended to have a higher threshold of sweet taste without reaching statistical significance. The results provide information for developing strategies for evidence-based nutrition education program focusing on reducing consumption of unnecessary sugar-sweetened commercial beverages. PMID- 21556227 TI - Relationship between 25-hydroxyvitamin D and metabolic syndrome among Jordanian adults. AB - Evidence of the association between 25-hydroxyvitamin D (25(OH)D) and metabolic syndrome (MeS) remains uncertain and incongruent. This study aimed to determine the association between 25(OH)D and MeS among Jordanian adults. A complex multistage sampling technique was used to select a national population-based household sample. The present report deals exclusively with adults aged > 18 years who had complete information on all components of MeS (n = 3,234). A structured questionnaire was used to collect all relevant information. Anthropometric, clinical, and laboratory measurements were obtained. MeS was defined according to the International Diabetes Federation (IDF) definition. Of the total, 42.0% had MeS and 31.7% had 25(OH)D < 30 ng/ml. In a stratified analysis, the prevalence of MeS did not differ significantly between subjects with low and normal 25(OH)D levels for men and women in all age groups. In the multivariate analysis, the odds of MeS were not significantly different between subjects with low and normal 25(OH)D levels (OR = 0.85, 95% CI: 0.70, 1.05, P value = 0.133). The association between 25(OH)D and MeS remained non-significant when 25(OH)D was analyzed as a continuous variable (OR = 1.004, 95% CI; 1.000, 1.008, P = 0.057) and when analyzed based on quartiles. None of the individual components of MeS were significantly associated with 25(OH)D level. This study does not provide evidence to support the association between 25(OH)D level and MeS or its individual components. Prospective studies are necessary to better determine the roles of 25(OH)D levels in the etiology of MeS. PMID- 21556228 TI - Study on the obesity and nutrition status of housewives in Seoul and Kyunggi area. AB - This study was conducted to evaluate the rate of obesity of 212 women (age 45-60 years) in Seoul and the Kyunggi area through analysis of BMI and the dietary life factors related to obesity using a survey on dietary habits, dietary assessment, and nutrient intake. The height of the underweight group was taller than normal. The height of the obese group was equal to that of the normal group, but the weight was 8.5 kg greater than the normal group. Women in the underweight group consumed meals irregularly, and only 33.4% ate breakfast. Additionally, the rate of overeating was low in the underweight group, and milk, dairy products (yogurt, etc.), fruit, and fruit juice were consumed more than once a day. It was found that 62.1% of the women in the obese group never ate out, and the rate of eating one serving of fruit, drinking one cup of fruit juice, and eating various kinds of foods was high. The average point of women's dietary life was 21.9 +/- 2.9, and 12.7% of all women responded that their dietary life was good. However, in the obese group, only 6.9% of the women reported that their dietary life was good. Evaluation of snacking habits revealed that the underweight group consumed a high level of carbonated drinks and ice cream, whereas for in the obese group, 24.1% of the women consumed milk and its products and 5.6% regularly consumed fast and fried foods. Evaluation of nutrient intake revealed that the consumption of energy, protein, vitamin A, vitamin B(1), B(2), B(6), niacin, vitamin C, and vitamin E was high in all of the groups, but the intake of folic acid in the underweight group was lower than the required level. Overall, 24.1% of the women in the obese group were found to have metabolic diseases, mostly hypertension (43%). In conclusion, a balanced diet to avoid excessive nutrient intake is needed to prevent obesity. PMID- 21556229 TI - Relationship between inflammation biomarkers, antioxidant vitamins, and bone mineral density in patients with metabolic syndrome. AB - Few studies have shown the correlation between metabolic syndrome and bone mineral density (BMD). The main pathogenic mechanisms of metabolic syndrome rely on chronic low-level inflammatory status and oxidative stress. There are few studies that examine the gender-specific effects of inflammation and antioxidants on BMD. In this study, we evaluated the relative contribution of these factors in patients with metabolic syndrome. We conducted a cross-sectional study of 67 men and 46 postmenopausal women with metabolic syndrome; metabolic syndrome was defined as having three or more metabolic syndrome risk factors. BMD, body fat mass, and lean body mass were evaluated. We also examined the levels of high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), adiponectin, vitamin E, and C in serum. Log-transformed hs-CRP levels were significantly higher in lumbar spine osteoporotic subjects than in normal subjects for women but not for men. There was no significant difference between the normal group and the osteoporotic group in other inflammatory markers. Stepwise regression analyses for BMD of the lumbar spine showed that lean body mass and vitamin E were significant determinants in men. Lean body mass and log-transformed hs-CRP were significant determinants in women Analysis for BMD of the femoral neck showed that lean body mass was a significant determinant for both men and women. There was no significant factor among the inflammatory markers or antioxidant vitamins affecting the femoral neck BMD for either gender. In conclusion, while hs-CRP is an independent predictor of the BMD of the lumbar spine in women, vitamin E showed profound effects on BMD in men but not women with metabolic syndrome. PMID- 21556230 TI - Ratio of fat to energy intake independently associated with the duration of diabetes and total cholesterol levels in type 2 diabetes. AB - The importance of dietary intake in the treatment of type 2 diabetes was emphasized. This study was performed to investigate the dietary intakes of Korean type 2 diabetes patients according to the treatment and duration of diabetes and to examine the relationships between their diet and serum lipid profiles. The subjects were 111 type 2 diabetic patients who were treated by medical nutrition therapy only, oral hypoglycemic agents (OHA), or insulin with medical nutrition therapy. Dietary intake was assessed by a registered dietitian using semi quantitative food frequency questionnaires. Comparisons according to treatment type were made using covariance analyses. General linear models identified the independent effects of the different treatments after covarying for age, duration of diabetes, and 2-way interactions. There were no significant differences in age and BMI but was in duration of diabetes according to treatment type in these subjects. Carbohydrate to energy ratio was higher in the OHA group (P < 0.05), whereas the fat to energy ratio was higher in the insulin group for males (P < 0.05). Carbohydrate (R(2) = 0.24, P = 0.005) and fat (R(2) = 0.26, P = 0.02) to energy ratios were independently associated with the duration of diabetes after covarying for age, sex, treatment, and 2-way interactions. The levels of triglyceride (TG; R(2) = 0.32, P = 0.02) and total cholesterol (TC) were associated independently with energy intake and the carbohydrate (R(2) = 0.15, P = 0.02) and fat (R(2) = 0.15, P = 0.01) to energy ratios, respectively. The concern that the independent association of dietary intake with either duration of diabetes or dietary factors affects blood lipid levels could suggest that specific dietary recommendations may work better for identifiable groups of diabetes patients. PMID- 21556231 TI - Service quality, satisfaction, and behavioral intention in home delivered meals program. AB - This study was conducted to evaluate recipients' perception of service quality, satisfaction, and behavioral intention in home delivered meals program in the US. Out of 398 questionnaires, 265 (66.6%) were collected, and 209 questionnaires (52.5%) were used for the statistical analysis. A Confirmatory Factor Analysis (CFA) with a maximum likelihood was first conducted to estimate the measurement model by verifying the underlying structure of constructs. The level of internal consistency in each construct was acceptable, with Cronbach's alpha estimates ranging from 0.7 to 0.94. All of the composite reliabilities of the constructs were over the cutoff value of 0.50, ensuring adequate internal consistency of multiple items for each construct. As a second step, a Meals-On-Wheels (MOW) recipient perception model was estimated. The model's fit as indicated by these indexes was satisfactory and path coefficients were analyzed. Two paths between (1) volunteer issues and behavioral intention and (2) responsiveness and behavioral intention were not significant. The path for predicting a positive relationship between food quality and satisfaction was supported. The results show that having high food quality may create recipient satisfaction. The findings suggest that food quality and responsiveness are significant predictors of positive satisfaction. Moreover, satisfied recipients have positive behavioral intention toward MOW programs. PMID- 21556232 TI - Factors influencing fast food consumption behaviors of middle-school students in Seoul: an application of theory of planned behaviors. AB - Fast food is popular among children and adolescents; however, its consumption has often been associated with negative impacts on nutrition and health. This study examined current fast food consumption status among middle school students and explored factors influencing fast food consumption by applying Theory of Planned Behavior. A total of 354 (52.5% boys) students were recruited from a middle school. The subjects completed a pre-tested questionnaire. The average monthly frequency of fast food consumption was 4.05 (4.25 for boys, 3.83 for girls). As expected, fast food consumption was considered to be a special event rather than part of an everyday diet, closely associated with meeting friends or celebrating, most likely with friends, special days. The Theory of Planned Behavior effectively explained fast food consumption behaviors with relatively high R(2) around 0.6. Multiple regression analyses showed that fast food consumption behavior was significantly related to behavioral intention (b = 0.61, P < 0.001) and perceived behavioral control (b = 0.19, P < 0.001). Further analysis showed that behavioral intention was significantly related to subjective norm (b = 0.15, P < 0.01) and perceived behavioral control (b = 0.56, P < 0.001). Attitude toward fast food consumption was not significantly associated with behavioral intention. Therefore, effective nutrition education programs on fast food consumption should include components to change the subjective norms of fast food consumption, especially among peers, and perceived behavioral control. Further studies should examine effective ways of changing subjective norms and possible alternatives to fast food consumption for students to alter perceived behavioral control. PMID- 21556233 TI - Validation of Pediatric Functional Assessment of Cancer Therapy Questionnaire (Version 2.0) in Brain Tumor Survivor Aged 13 Years and Older (Parent Form)(PedsFACT-BrS Parent of Adolescent). AB - OBJECTIVE: The aim of this study was to evaluate the reliability and validity of the Pediatric Functional Assessment of Cancer Therapy Questionnaire Brain Tumor Survivor (version 2.0) Aged 13 years and older (Parent Form) (pedsFACT-BrS parent of adolescent). METHODS: The pedsFACT-BrS parent of adolescent was translated and cross-culturally adapted into Korean, following standard Functional Assessment of Chronic Illness Therapy (FACIT) methodology. The psychometric properties of the pedsFACT-BrS parent of adolescent were evaluated in 170 brain tumor patient's mothers (mean age=43.38 years). Pretesting was performed in 30 mothers, and the results indicated good symptom coverage and overall comprehensibility. The participants also completed the Child Health Questionnaire Parent Form 50 (CHQ-PF 50), Neuroticism in Eysenck Personality Questionnaire, and Karnofsky score. RESULTS: In validating the pedsFACT-BrS parent of adolescent, we found high internal consistency, with Cronbach's alpha coefficients ranging from 0.76 to 0.94. The assessment of test-retest reliability using intraclass correlation coefficient revealed satisfactory values with ICCs ranging from 0.84 to 0.93. The pedsFACT-BrS for parent of adolescent also demonstrated good convergent and divergent validities when correlated with the Child Health Questionnaire Parent Form 50 (CHQ-PF-50) and the Neuroticism in Eysenck Personality Questionnaire. The pedsFACT-BrS parent of adolescent showed good clinical validity, and effectively differentiated between clinically distinct patient groups according to the type of treatment, tumor location, shunt, and Karnofsky score of parent proxy report. CONCLUSION: We confirmed that this reliable and valid instrument can be used to properly evaluate the quality of life of Korean adolescent brain tumor patients by their parents' proxy report. PMID- 21556234 TI - Angio-SealTM EvolutionTM versus Manual Compression for Common Femoral Artery Puncture in Neurovascular Diagnostic Angiography : A Prospective, Non-Randomized Study. AB - OBJECTIVE: This prospective, non-randomized study compared the safety and efficacy of the Angio-SealTM EvolutionTM to that of manual compression for common femoral artery punctures in neurovascular diagnostic angiography. METHODS: From June 2009 to September 2009, we performed 169 diagnostic trans-femoral cerebral angiographies, using either the Angio-SealTM EvolutionTM or manual compression to achieve hemostasis. We included 60 patients in this study, 30 in each group. We defined minor complications as those requiring no further treatment such as hematoma size less than 6 cm and bruise size less than 25 cm. Major complications were those requiring surgery of the femoral artery pseudoaneurysm and/or the second line increase of hospital stay even without further treatment. RESULTS: Mean time to hemostasis was 0.42+/-0.04 minutes for the angioseal and 15.83+/ 1.63 minutes for manual compression (p<0.001). Overall complication rate did not differ between the 2 groups. After the patients were fully mobile, at 24 hours, the rate of onset of new complication differed significantly between the 2 groups (p=0.032). In the angioseal group, 5 (16.7%) of the 30 patients experienced the onset of a new complication after 24 hours, including 3 (60.0%) of the 5 who experienced major complications. CONCLUSION: The Angio-SealTM EvolutionTM is effective at decreasing mean time to hemostasis, like other closing devices. However, it may not be effective at producing early ambulation and discharge, compared to manual compression, because delayed complications may occur significantly after 24 hours. PMID- 21556235 TI - Safety and efficacy of transluminal balloon angioplasty using a compliant balloon for severe cerebral vasospasm after an aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Vasospasm of cerebral vessels remains a major source of morbidity and mortality after an aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to evaluate the safety and efficacy of transluminal balloon angioplasty (TBA) for SAH-induced vasospasm. METHODS: Eleven patients with an angiographically confirmed significant vasospasm (>50% vessel narrowing and clinical deterioration) were studied. A total of 54 vessel segments with significant vasospasm were treated by TBA. Digital subtraction angiography was used to confirm the presence of vasospasm, and TBA was performed to dilate vasospastic arteries. Medical and angiographic reports were reviewed to determine technical efficacy and for procedural complications. RESULTS: TBA using Hyper Glide or Hyper-Form balloons (MicroTherapeutics, Irvine, CA) was successfully accomplished in 88.9% vasospastic segments (48 of 54), namely, in the distal internal carotid artery (100%, n=7), the middle cerebral artery (100%), including the M1 (n=10), M2 (n=10), and M3 segments (n=4), in the vertebral artery (100%, n=2), basilar artery (100%, n=1), and in the anterior cerebral artery (ACA), including the A1 (66%), A2 (66%), and A3 segments (100%). Vessel diameters significantly increased after TBA. There were no cases of vessel rupture or thromboembolic complications. GCS at one day after TBA showed an improvement in all patients except one. CONCLUSION: This study suggests that TBA using Hyper Glide or Hyper-Form balloons is a safe and effective treatment for subarachnoid hemorrhage-induced cerebral vasospasm. PMID- 21556236 TI - Paraspinal Muscle Sparing versus Percutaneous Screw Fixation : A Prospective and Comparative Study for the Treatment of L5-S1 Spondylolisthesis. AB - OBJECTIVE: Both the paraspinal muscle sparing approach and percutaneous screw fixation are less traumatic procedures in comparison with the conventional midline approach. These techniques have been used with the goal of reducing muscle injury. The purpose of this study was to evaluate and to compare the safety and efficacy of the paraspinal muscle sparing technique and percutaneous screw fixation for the treatment of L5-S1 spondylolisthesis. METHODS: Twenty patients who had undergone posterior lumbar interbody fusion (PLIF) at the L5-S1 segment for spondylolisthesis were prospectively studied. They were divided into two groups by screw fixation technique (Group I : paraspinal muscle sparing approach and Group II: percutaneous screw fixation). Clinical outcomes were assessed by Low Back Outcome Score (LBOS) and Visual Analogue Scale (VAS) for back and leg pain at different times after surgery. In addition, modified MacNab's grading criteria were used to assess subjective patients' outcomes 6 months after surgery. Postoperative midline surgical scarring, intraoperative blood loss, mean operation time, and procedure-related complications were analyzed. RESULTS: Excellent or good results were observed in all patients in both groups 6 months after surgery. Patients in both groups showed marked improvement in terms of LBOSs all over time intervals. Postoperative midline surgical scarring and intraoperative blood loss were lower in Group II compared to Group I although these differences were not statistically significant. Low back pain (LBP) and leg pain in both groups also showed significant improvement when compared to preoperative scores. However, at 7 days and 1 month after surgery, patients in Group II had significantly better LBP scores compared to Group I. CONCLUSION: In terms of LBP during the early postoperative period, patients who underwent percutaneous screw fixation showed better results compared to ones who underwent screw fixation via the paraspinal muscle sparing approach. Our results indicate that the percutaneous screw fixation procedure is the preferable minimally invasive technique for reducing LBP associated with L5-S1 spondylolisthesis. PMID- 21556237 TI - Resolution of isolated unilateral hypoglossal nerve palsy following microvascular decompression of the intracranial vertebral artery. AB - Isolated hypoglossal nerve paresis due to mechanical compression from a vascular lesion is very rare. We present a case of a 32-year-old man who presented with spontaneous abrupt-onset dysarthria, swallowing difficulty and left-sided tongue atrophy. Brain computed tomographic angiography and magnetic resonance imaging of the brainstem demonstrated an abnormal course of the left vertebral artery compressing the medulla oblongata at the exit zone of the hypoglossal rootlets that was relieved by microvascular decompression of the offending intracranial vertebral artery. This case supports the hypothesis that hypoglossal nerve palsy can be due to nerve stretching and compression by a pulsating normal vertebral artery. Microvascular decompression of the intracranial nerve and careful evaluation of the imaging studies can resolve unexpected isolated hypoglossal nerve palsy. PMID- 21556238 TI - Intraparenchymal myeloid sarcoma and subsequent spinal myeloid sarcoma for acute myeloblastic leukemia. AB - Myeloid sarcoma is a solid, extramedullary tumor composed of leukemic myeloblasts or immature myeloid cells. Intraparenchymal myeloid sarcoma without the involvement of the skull or meninges is extremely rare. Here, we present the case of a 49-year-old man who developed intraparenchymal myeloid sarcoma on the left cerebellum after allogeneic bone marrow transplantation (BMT). He received radiotherapy after complete removal of intraparenchymal myeloid sarcoma, but he was diagnosed spinal myeloid sarcoma three month later. Nine months after the operation, new intracranial and spinal myeloid sarcoma were diagnosed and the patient's condition had been worsened rapidly. Although the spinal myeloid sarcoma was not histologically diagnosed, this report provides valuable insights into the clinical course of progression of intraparenchymal myeloid sarcoma. PMID- 21556239 TI - Fatal subdural empyema following pyogenic meningitis. AB - Subdural empyema is a rare form of intracranial sepsis associated with high morbidity and mortality. The most frequent cause is extension of paranasal sinusitis through emissary veins or of mastoiditis through the mucosa, bone, and dura mater. Development of subdural empyema after pyogenic meningitis is known to be very unusual in adults. We report a rare case of fatal subdural empyema, an unusual complication of pyogenic meningitis. Our bitter experience suggests that subdural empyema should be borne in mind in patient with pyogenic meningitis who exhibit neurological deterioration. PMID- 21556240 TI - Congenital cleft of anterior arch and partial aplasia of the posterior arch of the c1. AB - Congenital anomalies in arches of the atlas are rare, and are usually discovered incidentally. However, a very rare subgroup of patients with unique radiographic features is predisposed to transient quadriparesis after minor cervical or head trauma. A 46-year-old male presented with a 2-month history of tremor and hyperesthesia of the lower extremities after experiencing a minor head trauma. He said that he had been quadriplegic for about 2 weeks after that trauma. Radiographs of his cervical spine revealed bilateral bony defects of the lateral aspects of the posterior arch of C1 and a midline cleft within the anterior arch of the atlas. A magnetic resonance imaging revealed an increased cord signal at the C2 level on the T2-weighted sagittal image. A posterior, suboccipital midline approach for excision of the remnant posterior tubercle was performed. The patient showed significant improvement of his motor and sensory functions. Since major neurologic deficits can be produced by a minor trauma, it is crucial to recognize this anomaly. PMID- 21556241 TI - Gas-Filled Intradural Cyst within the Cauda Equine. AB - A case of radicular pain that resulted from a gas-filled intradural cyst in an 80 year-old male is described. Temporary improvement of radicular pain was observed after CT-guided aspiration. However, recurrent radicular pain led to surgical treatment. In this report, the authors document the radiologic and intraoperative features of a gas-filled intradural cyst that migrated into the nerve root, and propose an optimal treatment plan based on a review of the literature. PMID- 21556242 TI - Occlusion of the Internal Carotid Artery due to Intracranial Fungal Infection. AB - In recent years the immunocompromised population has increased rapidly to include people with acquired immune deficiency syndrome (AIDS), drug abusers, and transplant patients. Accordingly, the incidence of intracranial fungal infection has increased. Our institution experienced 2 cases of internal carotid artery (ICA) occlusion due to invasion of the cavernous sinus by an intracranial fungal infection. The first case was a 60-year-old man who presented with headache, eye pain, conjunctival injection, right-sided diplopia, and blurred vision. Infected tissues within the frontal and ethmoid sinuses were removed via bifrontal craniotomy and endoscopic sinus surgery through the Caldwell Luc approach. The second case was a 63-year-old woman who developed right-sided facial pain after a tooth extraction. The infection was not controlled despite continuous use of antifungal agents, resulting in death from sepsis. We believe that when intracranial fungal infection is suspected in a patient with orbital symptoms and a focal neurologic deficit, immediate angiographic investigation of possible ICA occlusion is warranted. Aggressive treatment with antifungal agents is the only way to improve prognosis. PMID- 21556243 TI - Disseminated cysticercosis. AB - Disseminated cysticercosis is a rare form of cysticercosis in which the cysticerci spread out through the whole body. We report the first case of a 39 year-old Mongolian with disseminated cysticercosis. He visited our hospital with generalized tonic-clonic seizure. After extensive investigation from brain computed tomography (CT), spine magnetic resonance imaging (MRI), whole body MRI and pathologic biopsy, he was diagnosed as having cysticercosis involving the brain, subcutaneous tissue, and skeletal muscles through the whole body. We treated him with the albendazole in which case the followed MRI showed that numbers of cystic lesions were copiously decreased. We report an unsual case of disseminated cysticercosis treated with medical therapy. PMID- 21556244 TI - Immediate spontaneous shape correction using expantile zigzag craniectomy in infantile scaphocephaly -is there an improvement in the developmental quotient following surgery?-. AB - There is still debate over which method of the surgery is the most appropriate for the treatment of scaphocephalic infants. In addition, change in psychomotor development following these procedures is a very complex issue that has not yet been resolved. In this paper, the authors describe a surgical technique for immediate spontaneous shape correction of infantile scaphocephaly. There were significant differences between pre- and postoperative cephalic index. We also describe an improvement in the developmental quotient following surgery. Therefore, this expantile zigzag craniectomy should be recommended to correct for isolated sagittal craniosynostosis in infants. PMID- 21556245 TI - Urine biomarkers of risk in the molecular etiology of breast cancer. AB - Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen-DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies. PMID- 21556246 TI - Expression of Estrogen Sulfotransferase 1E1 and Steroid Sulfatase in Breast Cancer: A Immunohistochemical Study. AB - It is known that the steroid sulfatase (STS) and the estrogen sulfotransferase (EST1E1) are commonly expressed in human breast carcinomas. STS and EST1E1 combined action could maintain the equilibrium between sulfated (inactive) and unconjugated (active) estrogens, which might have effects on development of hormone dependent breast cancer.We studied the expression of the STS and EST1E1 in 88 breast carcinomas and 57 adjacent non-malignant tissues by immunohistochemistry. The results were correlated with the tumor expression of estrogen receptor alpha (ER-alpha) and beta (ER-beta), progesterone receptor A (PR-A) and B (PR-B) and the proliferation marker CDC47, the tumoral type and stage and the age at surgery.STS expression was higher in carcinoma specimens than in adjacent normal tissues, although not to a significant level (p = 0.064) and it was positively associated with CDC47 expression (p < 0.05). These observations support the hypothesis that STS is overexpressed in breast cancer and associated with a worse prognosis.EST1E1 was observed for the first time in the nuclei of epithelial and tumoral cells. Tumor expression of EST1E1 was positively correlated with ER-beta (p < 0.01) and PR-B (p < 0.05), two steroid receptors already associated with an improve prognosis for breast cancer.Controlling the STS overexpression in carcinomas could be a way to inhibit cancer growth. The significance of the association between EST1E1 and ER-beta or PR-B should be further studied since these two receptors are transcription activators and may regulate the expression of protective enzymes like EST1E1. PMID- 21556247 TI - Effects of celecoxib and ly117018 combination on human breast cancer cells in vitro. AB - Activation and signalling of estrogen receptor (ER) and COX-2 represent two important pathways in breast cancer cell regulation. Activation of either pathway is associated with breast cancer cell proliferation and eventually malignant progression. Raloxifene analogue, Ly117018, a selective estrogen receptor modulator and celecoxib, a specific COX-2 inhibitor have been shown to inhibit breast cancer cell proliferation when used alone in vitro and in vivo. In this study, the combined drug effects on hormone-dependent MCF-7 and hormone independent MDA-MB-435 cells in vitro were evaluated. Cell proliferation assays excluded drug antagonism and revealed a moderate synergistic growth inhibitory activity of Ly117018 and celecoxib on both cell lines when combined in specific concentrations. Growth inhibition of either compound was not associated with cell cycle arrest. In MCF-7 cells, western blot analysis revealed a decreased phosphorylation of the AKT protein by either agent alone or in combination. In MDA-MB-435 cells, celecoxib alone induced an increase in AKT phosphorylation relative to total AKT protein; this effect was decreased in the presence of Ly117018. These results indicate that these two drugs are non-antagonistic; and when combined in specific concentrations, moderate synergistic antiproliferative activity of celecoxib and Ly117018 were observed in hormone-dependent MCF-7 and hormone-independent MDA-MB-435 cells associated with changes in cell cycle distribution and regulation of AKT protein and phosphorylation. These findings further support a central role of the ER- and COX-2 pathways in human breast cancer cells. PMID- 21556248 TI - Quality of life and neutropenia in patients with early stage breast cancer: a randomized pilot study comparing additional treatment with mistletoe extract to chemotherapy alone. AB - BACKGROUND: Chemotherapy for breast cancer often deteriorates quality of life, augments fatigue, and induces neutropenia. Mistletoe preparations are frequently used by cancer patients in Central Europe. Physicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy. Mistletoe preparations also have immunostimulant properties and might therefore have protective effects against chemotherapy-induced neutropenia. PATIENTS AND METHODS: We conducted a prospective randomized open label pilot study with 95 patients randomized into three groups. Two groups received Iscador(r) M special (IMS) or a different mistletoe preparation, respectively, additionally to chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluoro-uracil (CAF). A control group received CAF with no additional therapy. Here we report the comparison IMS (n = 30) vs. control (n = 31). Quality of life including fatigue was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Neutropenia was defined as neutrophil counts <1,000/MUl and assessed at baseline and one day before each CAF cycle. RESULTS: In the descriptive analysis all 15 scores of the EORTC-QLQ-C30 showed better quality of life in the IMS group compared to the control group. In 12 scores the differences were significant (p < 0.02) and nine scores showed a clinically relevant and significant difference of at least 5 points. Neutropenia occurred in 3/30 IMS patients and in 8/31 control patients (p = 0.182). CONCLUSIONS: This pilot study showed an improvement of quality of life by treating breast cancer patients with IMS additionally to CAF. CAF-induced neutropenia showed a trend to lower frequency in the IMS group. PMID- 21556249 TI - Growth factor receptors and apoptosis regulators: signaling pathways, prognosis, chemosensitivity and treatment outcomes of breast cancer. AB - Biomarkers of breast cancer are necessary for prognosis and prediction to chemotherapy. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancers are growth factor receptors, steroid receptors, Ki-67, cyclins, urokinase plasminogen activator, p53, p21, pro- and anti-apoptotic factors, BRCA1 and BRCA2. But currently, the predictive markers are Estrogen and Progesterone receptors responding to endocrine therapy, and HER-2 responding to herceptin. But there are numerous breast cancer cases, where tamoxifen is ineffective even after estrogen receptor positivity. This lead to search of new prognostic and predictive markers and the number of potential markers is constantly increasing due to proteomics and genomics studies. However, most biomarkers individually have poor sensitivity or specificity, or other clinical value. It can be resolved by studying various biomarkers simultaneously, which will help in better prognosis and increasing sensitivity for chemotherapeutic agents. This review is focusing on growth factor receptors, apoptosis markers, signaling cascades, and their correlation with other associated biomarkers in breast cancers. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors. Rigorous comparison of these existing as well as emerging markers with current treatment selection is likely to see an escalation in an era of personalized medicines to ensure the breast cancer patients receive optimal treatment. This will also solve the treatment modalities and complications related to chemotherapeutic regimens. PMID- 21556250 TI - VEGF 936C > T Polymorphism and Association of BI-RADS Score in Women with Suspected Breast Cancer. AB - PURPOSE: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumors. A 936C > T polymorphism in the VEGF gene has been associated with reduced VEGF plasma levels. Purpose of the present study was to analyze the potential association between VEGF genotype and radiological appearance of breast lesions by mammography. MATERIALS AND METHODS: Fifty two women with 54 suspected breast lesions were analyzed by the use of mammography with the standard breast imaging reporting and data systems (BI-RADS). Germline VEGF genotype was determined in all subjects by allele-specific digestion of amplification products. An open biopsy was performed on all lesions. RESULTS: VEGF CC, CT and TT genotypes were found in 41 (79%), 9 (17%) and 2 (4%) patients. By mammography 26, 16 and 12 suspected breast lesions were classified as BI-RADS scores 3, 4 and 5, respectively. Both carriers of the TT genotype were classified as BI-RADS 5, whereas among CT or CC carriers, BI-RADS scores 3, 4 and 5 were found in 26, 16 and 10 subjects (P < 0.026). CONCLUSION: The VEGF 936C > T polymorphism seems to be associated with a high BI-RADS score in women with suspicious breast lesions. PMID- 21556251 TI - Characterization of a Test for Invasive Breast Cancer Using X-ray Diffraction of Hair-Results of a Clinical Trial. AB - OBJECTIVE: To assess the performance of a test for breast cancer utilizing synchrotron x-ray diffraction analysis of scalp hair from women undergoing diagnostic radiology assessment. DESIGN AND SETTING: A double-blinded clinical trial of women who attended diagnostic radiology clinics in Australia. PATIENTS: 1796 women referred for diagnostic radiology, with no previous history of cancer. MAIN OUTCOME MEASURES: Sensitivity, specificity and accuracy of the hair test analysis compared to the gold standard of imaging followed by biopsy where indicated. RESULTS: The hair-based assay had an overall accuracy of >77% and a negative predictive value of 99%. For all women, the sensitivity of both mammography and X-ray diffraction alone was 64%, but when used together the sensitivity rose to 86%. The sensitivity of the hair test for women under the age of 70 was 74%. CONCLUSION: In this large population trial the association between the presence of breast cancer and an altered hair fibre X-ray diffraction pattern previously reported has been confirmed. It appears that mammography and X-ray diffraction of hair detect different populations of breast cancers, and are synergistic when used together. PMID- 21556252 TI - Orbital metastasis of breast carcinoma. AB - We report a case of orbital metastasis in a previously diagnosed metastatic breast cancer in a 46-year old woman presenting with diplopia and proptosis of her left eye bulb. An orbital computed-tomography (CT) and a magnetic resonance imaging (MRI) both revealed an intra-orbital extra-bulbar mass of 1.5 * 3 cm in size, in the left orbit. The patient had been diagnosed with stage IV breast cancer 4 years before. She had received chemotherapy with docetaxel and was on hormone therapy at the time of presentation of her eye symptoms. Current treatment included systemic combination therapy with docetaxel and capecitabine as well as local irradiation with stereotactic radiosurgery (cyberknife). There was a gradual improvement of local symptoms and signs. The metastatic involvement of the orbit in malignant tumors is a rarely diagnosed condition. Breast cancer accounts for the majority of these cases. The appearance of eye symptoms in patients with a history of cancer should always be investigated with a consideration of ocular metastatic disease. PMID- 21556253 TI - Pros & cons. PMID- 21556254 TI - Identification of mono- or poly-specific monoclonal antibody to Porphyromonas gingivalis heat-shock protein 60. AB - PURPOSE: The aim of this study was to define the immunoreactive specificity of Porphyromonas gingivalis (P. gingivalis) heat shock protein (HSP) 60 in periodontitis and atherosclerosis. METHODS: In an attempt to define the cross reactive bacterial heat-shock protein with human self-antigen at molecular level, we have introduced a novel strategy for cloning hybridoma producing anti-P. gingivalis HSP 60 which is polyreactive to bacterial HSPs or to the human homolog. RESULTS: Five cross-reactive clones were obtained which recognized the #19 peptide (TLVVNRLRGSLKICAVKAPG) among 37 synthetic peptides (20-mer, 5 amino acids overlapping) spanning the whole molecule of P. gingivalis HSP 60. We have also established three anti-P. gingivalis HSP 60 monoclonal antibodies demonstrating mono-specificity. These clones recognized the #29 peptide (TVPGGGTTYIRAIAALEGLK). CONCLUSIONS: Peptide #19 and #29 of P. gingivalis HSP 60 might be important immunoreactive epitopes in the immunopathogenic mechanism of bacterial antigen-triggered autoimmune diseases. PMID- 21556255 TI - Labial and lingual/palatal bone thickness of maxillary and mandibular anteriors in human cadavers in Koreans. AB - PURPOSE: The aim of this study is to evaluate the buccal and lingual bone thickness in the anterior teeth and the relationship between bone thickness and the tissue biotype. METHODS: Three male and two female human cadaver heads (mean age, 55.4 years) were used in this study. First, the biotype of periodontium was evaluated and categorized into a thick or a thin group. Next, full thickness reflections of the mandible and the maxilla to expose the underlying bone for accurate measurements in the anterior regions were performed. After the removal of the half of the alveolar bone, the probe with a stopper was used to measure the thickness of bone plate at the alveolar crest (AC), 3 mm apical to the alveolar crest (AC-3), 6 mm apical to the alveolar crest (AC-6), and 9 mm apical to the alveolar crest (AC-9). RESULTS: Four of them had a thick biotype. There was no penetration or dehiscence. The thickness of the buccal plates at the alveolar crest were 0.97+/-0.18 mm, 0.78+/-0.21 mm, and 0.95+/-0.35 mm in the maxillary central incisors, lateral incisors, and canines, respectively. The thickness of the labial plates at the alveolar crest were 0.86+/-0.59 mm, 0.88+/ 0.70 mm, and 1.17+/-0.70 mm in the mandibular central incisors, lateral incisors and canines, respectively. CONCLUSIONS: The thickness of the labial plate in the maxillary anteriors is very thin that great caution is needed for placing an implant. The present study showed the bone thickness of maxillary and mandibular anteriors at different positions. Therefore, these data can be useful for the understanding of the bone thickness of the anteriors and a successful implant placement. PMID- 21556256 TI - Initial adhesion of bone marrow stromal cells to various bone graft substitutes. AB - PURPOSE: The aim of this study is to determine whether certain biomaterials have the potential to support cell attachment. After seeding bone marrow stromal cells onto the biomaterials, we investigated their responses to each material in vitro. METHODS: Rat bone marrow derived stromal cells were used. The biomaterials were deproteinized bovine bone mineral (DBBM), DBBM coated with fibronectin (FN), synthetic hydroxyapatite (HA), HA coated with FN, HA coated with beta-tricalcium phosphate (TCP), and pure beta-TCP. With confocal laser scanning microscopy, actin filaments and vinculin were observed after 6, 12, and 24 hours of cell seeding. The morphological features of cells on each biomaterial were observed using scanning electron microscopy at day 1 and 7. RESULTS: The cells on HA/FN and HA spread widely and showed better defined actin cytoskeletons than those on the other biomaterials. At the initial phase, FN seemed to have a favorable effect on cell adhesion. In DBBM, very few cells adhered to the surface. CONCLUSIONS: Within the limitations of this study, we can conclude that in contrast with DBBM not supporting cell attachment, HA provided a more favorable environment with respect to cell attachment. PMID- 21556257 TI - Effect of seeding using an avidin-biotin binding system on the attachment of periodontal ligament fibroblasts to nanohydroxyapatite scaffolds: three dimensional culture. AB - PURPOSE: For periodontal tissue engineering, it is a primary requisite and a challenge to select the optimum types of cells, properties of scaffold, and growth factor combination to reconstruct a specific tissue in its natural form and with the appropriate function. Owing to fundamental disadvantages associated with using a two-dimensional substrate, several methods of seeding cells into three-dimensional scaffolds have been reported and the authors have asserted its usefulness and effectiveness. In this study, we explore the cell attachment of periodontal ligament fibroblasts on nanohydroxyapatite (n-HA) scaffold using avidin biotin binding system (ABBS). METHODS: Human periodontal ligament fibroblasts were isolated from the health tooth extracted for the purpose of orthodontic procedure. HA nanoparticles were prepared and Ca(NO(3))(2)-4H(2)O and (OC(2)H(5))(3)P were selected as precursors of HA sol. The final scaffold was 8 mm in diameter and 3 mm in height disk with porosity value of 81.55%. 1*10(5) periodontal ligament fibroblasts were applied to each scaffold. The cells were seeded into scaffolds by static, agitating and ABBS seeding method. RESULTS: The number of periodontal ligament fibroblasts attached was greater for ABBS seeding method than for static or agitating method (P<0.05). No meaningful difference has been observed among seeding methods with scanning electron microscopy images. However, increased strength of cell attachment of ABBS could be deduced from the high affinity between avidin and biotin (Kd=10(-15) M). CONCLUSIONS: The high affinity ABBS enhances the ability of periodontal ligament fibroblasts to attach to three-dimensionally constructed n-HA scaffolds. PMID- 21556258 TI - Masticatory function following implants replacing a second molar. AB - PURPOSE: The aim of this study was to obtain objective and standardized information on masticatory function and patient satisfaction following second molar single implant therapy. METHODS: Twenty adult patients, who had restored second molar single implants more than 1 month before the study, were enrolled in this study. All patients received a chewing test using peanuts before and after insertion of the implant prosthesis, with a questionnaire and visual analogue scale (VAS) to evaluate the effect of second molar single implant therapy. RESULTS: This study obtained standardized information on the masticatory function objectively (e.g., P, R, X(50)) before (Pre-insertion) and after insertion (Post insertion) of the implant prosthesis. Masticatory performance (P) after insertion of the implant prosthesis significantly increased from 67.8+/-9.9 to 84.3+/-8.5% (P<0.0001). With the implant prosthesis, the P value increased by 24%. The masticatory efficiency index (R) of Post-insertion is higher than that of Pre insertion (P<0.0001). With the implant prosthesis, the R value increased by 29%. The median particle size (X(50)) of Post-insertion is lower than that of Pre insertion (P<0.0001). More than 90% of the patients were satisfied with the second molar single implant therapy from a functional point of view. CONCLUSIONS: These findings indicate that a second molar single implant can increase masticatory function. PMID- 21556259 TI - Cumulative survival rate of Astra Tech implants: a retrospective analysis. AB - PURPOSE: The aim of this study was to analyze the short-term predictability and reliability of Astra Tech implants according to the demographical distribution of patients and condition of implant sites and location of implants. METHODS: Among patients treated with Astra Tech implant (Astra Tech AB) in the Department of Periodontology at the Dental Hospital of Yonsei University of College of Dentisry and K Dental Clinic from May 2004 to March 2009, 195 implants in 98 patients which had been restored more than 6 months ago were reviewed in this study. Following data were reviewed from patient charts and implants success rate was examined: 1) patient type and implant location, 2) bone status at the implant site, 3) diameter and length of the placed implants, 4) presence or absence of bone augmentation and types of the augmentation. RESULTS: THE RESULTS FROM THIS STUDY ARE AS FOLLOWS: 1) most implants were placed in the molar area, especially 1st molar area of maxilla, 2) most implants were placed at D2 and D3 bone type, 3) most implants were placed in areas of B and C bone quantity, 4) autogenous and alloplastic bone graft and artificial membrane were used for placement of 74 implants. CONCLUSIONS: Short-term survival rate of Astra Tech implants was 100%. PMID- 21556260 TI - Comparative study on the results of non-surgical periodontal treatment according to the location of the affected site. AB - PURPOSE: The present study was performed to compare the treatment outcomes of non surgical periodontal treatment according to the distribution of attachment loss of a given patient. METHODS: Forty-five patients with moderate to severe periodontitis were divided in two subgroups; Group I patients with teeth manifesting attachment loss of >=6 mm at one or more sites on the buccal/labial aspect while maintaining an attachment level <=5 mm at the lingual/palatal aspect, Group II patients with teeth manifesting an attachment level >=6 mm at more than one site on the lingual/palatal aspect while maintaining an attachment level <=5 mm at the buccal/labial aspect. The probing pocket depth, probing attachment level, tooth mobility, and chewing discomfort were recorded at baseline and 6 months examinations following non-surgical periodontal therapy. RESULTS: The buccal/labial surfaces of teeth with moderate to severe periodontitis in Group I patients demonstrated a greater amount of pocket reduction, gain of attachment level, and tooth mobility reduction than the lingual/palatal aspects of teeth examined in Group II patients. CONCLUSIONS: Within the limits of the present study, the patients demonstrating attachment loss >=6 mm at buccal/labial surfaces responded better to the nonsurgical periodontal therapy than those demonstrating comparable attachment loss at lingual/palatal surfaces. PMID- 21556261 TI - Case series of maxillary sinus augmentation with biphasic calcium phosphate: a clinical and radiographic study. AB - PURPOSE: The aim of this study was to evaluate 3.5 years-cumulative survival rate of implants placed on augmented sinus using Osteon, a bone graft material, and to assess the height of the grafted material through radiographic evaluation. METHODS: Twenty patients were treated with maxillary sinus augmentation and 45 implant fixtures were installed simultaneously or after 6 months healing period. The height of the augmented sinus and the loss of marginal bone were measured by panoramic and intraoral radiographs immediately after augmentation and up to 42 months (mean, 19.4 months) subsequently. Changes in the height of the sinus graft material were calculated radiographically. RESULTS: The cumulative survival rate was 95.56% in all 45 implants. Additionally, normal healing process without any complication was observed in all patients. The original sinus height was mean 4.3 mm and the augmented sinus height was mean 13.4 mm after the surgery. The mean marginal bone loss till 42 months was 0.52+/-0.56 mm. The reduced height of Osteon was 0.83+/-0.38 mm and it did not show significant correlation with the follow up periods (P=0.102). There were no statistically significant differences in reduced height of Osteon according to the simultaneous/delayed implantation (P=0.299) and particle size of Osteon (P=0.644). CONCLUSIONS: It can be suggested that Osteon may have predictable result when it was used as a grafting material for sinus floor augmentation. PMID- 21556262 TI - The mandatory fortification of staple foods with folic acid: a current controversy in Germany. AB - INTRODUCTION: The mandatory fortification of staple foods with folic acid to prevent neural tube defects (NTDs) began in the USA in 1998. Since then, more than 50 countries around the world have followed suit. METHODS: Selective literature review including national study results. RESULTS AND DISCUSSION: Women of child-bearing age need sufficient body stores of folate before conception to prevent folate-sensitive NTDs, which make up 20% to 60% of all NTDs. Merely recommending folic acid supplementation before conception has been found to be an unsuitable strategy. Ingestion of folate-fortified food markedly increases folate intake, generally by about 50% of the recommended daily total intake. In Germany at present, debate surrounds the issue whether folate intake should be raised by mandatory folate supplementation, which will affect the entire population. Folate deficiency is associated with a higher risk of cancer and other diseases; on the other hand, there is concern that very high folic acid intake might promote the growth of pre-neoplastic lesions. There are no consistent study findings to support the latter hypothesis and the evidence for it is derived from research in animals whose folate metabolism differs from that in humans. About 800 pregnancies with NTD are diagnosed each year in Germany; in most cases, the pregnancy is terminated after positive prenatal screening. The incidence of NTDs in Germany is estimated at 12.36 per 10 000 births (a mean figure derived from registry data in Mainz and Saxony-Anhalt) and is thus much higher than the mean incidence across Europe, 7.88 per 10 000 births (EUROCAT data for 2004-2008). Mandatory folic acid fortification should be adopted, as it is a highly effective and inexpensive way to prevent NTDs. PMID- 21556263 TI - The German health care system in international comparison: the primary care physicians' perspective. AB - BACKGROUND: In 2009, the U.S. Commonwealth Fund conducted a survey of primary care physicians in a number of different countries to determine their views on aspects of their daily work and their perceptions of their countries' health care systems as a whole. A similar survey had been carried out in 2006. METHODS: From February to July 2009, the survey was carried out by interview in representative samples of primary care physicians, general practitioners, internists providing primary care, and pediatricians in 11 countries: Australia, Canada, France, Germany, Italy, the Netherlands, New Zealand, Norway, Sweden, the UK, and the USA. RESULTS: A total of 10 320 interviews were conducted. Only in the Netherlands and Norway did most respondents (60% and 56%, respectively) consider their health care system to be functioning well. Everywhere else, many of the respondents-in particular, 82% of the respondents in Germany-saw a fundamental need for change. 73% of the German physicians stated that recent changes in the health care system had brought about a decline in the quality of care. In all countries but Germany, the percentage of respondents sharing this opinion was 41% at the highest. Nevertheless, most of the German physicians had a positive opinion of the patient care that they themselves delivered. CONCLUSION: The 2009 survey, like its predecessor in 2006, revealed major differences in physicians' perceptions of their health care systems from one country to another. The German respondents' dissatisfaction with, and negative evaluation of, their health care system as a whole contrast with their positive views of their own patient care. PMID- 21556264 TI - Still shameful. PMID- 21556265 TI - Auditory perception disorder. PMID- 21556266 TI - Tests were not mentioned. PMID- 21556267 TI - Important cofactors. PMID- 21556268 TI - Professional politics. PMID- 21556269 TI - Interdisciplinary research. PMID- 21556271 TI - Understandable skepticism. PMID- 21556272 TI - Impulse control disorders: updated review of clinical characteristics and pharmacological management. AB - Impulse control disorders (ICDs) are characterized by urges and behaviors that are excessive and/or harmful to oneself or others and cause significant impairment in social and occupational functioning, as well as legal and financial difficulties. ICDs are relatively common psychiatric conditions, yet are poorly understood by the general public, clinicians, and individuals struggling with the disorder. Although ICD treatment research is limited, studies have shown ICDs may respond well to pharmacological treatment. This article presents a brief overview about the clinical characteristics of ICDs and pharmacological treatment options for individuals with ICDs. PMID- 21556273 TI - The Role of Attention-Deficit/hyperactivity Disorder in the Association between Verbal Ability and Conduct Disorder. AB - Although there is clear evidence that low verbal ability is a risk factor for conduct disorder (CD), some researchers have questioned whether this association is due to the common comorbidity between attention-deficit/hyperactivity disorder (ADHD) and CD. The present study examined the association among verbal ability, ADHD, and CD in a genetically informative sample in order to examine the role of genes and/or environmental influences shared in common with ADHD on the covariation between verbal ability and CD. Participants were 2744 adolescents from the Center for Antisocial Drug Dependence (CADD), and included 360 monozygotic (MZ) female twin pairs, 221 dizygotic (DZ) female twin pairs, 297 MZ male twin pairs, 220 DZ male twin pairs, and 274 opposite-sex DZ twin pairs. The Diagnostic Interview Schedule for Children (DISC-IV) was used to assess lifetime symptoms of ADHD and CD. Verbal ability was assessed via the Vocabulary subtest of the Wechsler Adult Intelligence Scale III (WAIS-III) for individuals over the age of 16 and the Vocabulary subtest of the Wechsler Intelligence Scale for Children III (WISC-III) for individuals under the age of 16. There was a small but significant negative covariance between verbal ability and CD and between verbal ability and ADHD. Results also suggest that the covariation between verbal ability and CD is due to influences shared in common with ADHD. PMID- 21556274 TI - Do Horizontal Saccadic Eye Movements Increase Interhemispheric Coherence? Investigation of a Hypothesized Neural Mechanism Underlying EMDR. AB - Series of horizontal saccadic eye movements (EMs) are known to improve episodic memory retrieval in healthy adults and to facilitate the processing of traumatic memories in eye movement desensitization and reprocessing (EMDR) therapy. Several authors have proposed that EMs achieve these effects by increasing the functional connectivity of the two brain hemispheres, but direct evidence for this proposal is lacking. The aim of this study was to investigate whether memory enhancement following bilateral EMs is associated with increased interhemispheric coherence in the electroencephalogram (EEG). Fourteen healthy young adults were asked to freely recall lists of studied neutral and emotional words after a series of bilateral EMs and a control procedure. Baseline EEG activity was recorded before and after the EM and control procedures. Phase and amplitude coherence between bilaterally homologous brain areas were calculated for six frequency bands and electrode pairs across the entire scalp. Behavioral analyses showed that participants recalled more emotional (but not neutral) words following the EM procedure than following the control procedure. However, the EEG analyses indicated no evidence that the EMs altered participants' interhemispheric coherence or that improvements in recall were correlated with such changes in coherence. These findings cast doubt on the interhemispheric interaction hypothesis, and therefore may have important implications for future research on the neurobiological mechanism underlying EMDR. PMID- 21556275 TI - Genome-wide expression analysis reveals diverse effects of acute nicotine exposure on neuronal function-related genes and pathways. AB - Previous human and animal studies demonstrate that acute nicotine exposure has complicated influences on the function of the nervous system, which may lead to long-lasting effects on the behavior and physiology of the subject. To determine the genes and pathways that might account for long-term changes after acute nicotine exposure, a pathway-focused oligoarray specifically designed for drug addiction research was used to assess acute nicotine effect on gene expression in the neuron-like SH-SY5Y cells. Our results showed that 295 genes involved in various biological functions were differentially regulated by 1 h of nicotine treatment. Among these genes, the expression changes of 221 were blocked by mecamylamine, indicating that the majority of nicotine-modulated genes were altered through the nicotinic acetylcholine receptors (nAChRs)-mediated signaling process. We further identified 14 biochemical pathways enriched among the nicotine-modulated genes, among which were those involved in neural development/synaptic plasticity, neuronal survival/death, immune response, or cellular metabolism. In the genes significantly regulated by nicotine but blocked by mecamylamine, 13 enriched pathways were detected. Nine of these pathways were shared with those enriched in the genes regulated by nicotine, including neuronal function-related pathways such as glucocorticoid receptor signaling, p38 MAPK signaling, PI3K/AKT signaling, and PTEN signaling, implying that nAChRs play important roles in the regulation of these biological processes. Together, our results not only provide insights into the mechanism underlying the acute response of neuronal cells to nicotine but also provide clues to how acute nicotine exposure exerts long-term effects on the nervous system. PMID- 21556276 TI - Association between 5-HTTLPR and Borderline Personality Disorder Traits among Youth. AB - This study provides the first genetic association examination of borderline personality disorder (BPD) traits in children and adolescents (ages 9-15) using two independent samples of youth recruited from the general community. We tested the a priori hypothesis that the serotonin transporter promoter gene (5-HTTLPR) would relate specifically to BPD traits in youth. This association was hypothesized based on prior genetic association research with BPD adults and theory positing that emotion dysregulation may be a core risk process contributing to BPD. Youth provided DNA via buccal cells. Both youth and a parent completed self-report measures assessing youth's BPD traits and depressive symptoms. Results from both Study 1 (N = 242) and an independent replication sample of Study 2 (N = 144) showed that carriers of the short allele of 5-HTTLPR exhibited the highest levels of BPD traits. This relation was observed even after controlling for the substantial co-occurrence between BPD traits and depressive symptoms. This specific association between 5-HTTLPR and BPD traits among youth supports previous genetic associations with adults diagnosed with BPD and provides preliminary support for a developmental extension of etiological risk for BPD among youth. PMID- 21556277 TI - Functional connectivity of brain structures correlates with treatment outcome in major depressive disorder. AB - Identifying biosignatures to assess the probability of response to an antidepressant for patients with major depressive disorder (MDD) is critically needed. Functional connectivity MRI (fcMRI) offers the promise to provide such a measure. Previous work with fcMRI demonstrated that the correlation in signal from one region to another is a measure of functional connectivity. In this pilot work, a baseline non-task fcMRI was acquired in 14 adults with MDD who were free of all medications. Participants were then treated for 8 weeks with an antidepressant and then clinically re-evaluated. Probabilistic anatomic regions of interest (ROI) were defined for 16 brain regions (eight for each hemisphere) previously identified as being important in mood disorders. These ROIs were used to determine mean time courses for each individual's baseline non-task fcMRI. The correlations in time courses between 16 brain regions were calculated. These calculated correlations were considered to signify measures of functional connectivity. The degree of connectivity for each participant was correlated with treatment outcome. Among 13 participants with 8 weeks follow-up data, connectivity measures in several regions, especially the subcallosal cortex, were highly correlated with treatment outcome. These connectivity measures could provide a means to evaluate how likely a patient is to respond to an antidepressant treatment. Further work using larger samples is required to confirm these findings and to assess if measures of functional connectivity can be used to predict differential outcomes between antidepressant treatments. PMID- 21556278 TI - A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor org25935. AB - Accumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc) as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol's effects within this system. PMID- 21556279 TI - Food cravings and the effects of left prefrontal repetitive transcranial magnetic stimulation using an improved sham condition. AB - This study examined whether a single session of repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex (PFC) would inhibit food cravings in healthy women who endorsed frequent food cravings. Ten participants viewed images of food and completed ratings for food cravings before and after receiving either real or sham rTMS over the left PFC (10 Hz, 100% resting motor threshold, 10 s-on, 20 s-off for 15 min; 3000 pulses). Sham-TMS was matched with real TMS with respect to perceived painfulness of the stimulation. Each participant received both real and sham rTMS in random order and were blind to the condition in a within-subject cross-over design. With an improved sham control condition, prefrontal rTMS inhibited food cravings no better than sham rTMS. The mild pain from the real and sham rTMS may distract or inhibit food craving, and the decreased craving may not be caused by the effect of rTMS itself. Further studies are needed to elucidate whether rTMS has any true effects on food craving and whether painful stimuli inhibit food or other cravings. A sham condition which matches the painfulness is important to understand the true effects of TMS on behaviors and diseases. PMID- 21556281 TI - Brief report: coronary heart disease: an unknown association to pathological gambling. AB - Pathological gamblers (PG), because of their high level of stress, depression, and alcohol or nicotine consumption may be overexposed to coronary heart disease (CHD). To test this association, we assessed pathological gambling (DSM-IV-TR criteria and South Oaks Gambling Screen scale) among 73 patients hospitalized in cardiology for CHD and 61 in-patients from the same department hospitalized for a non-coronary disorder. We found six cases of PG (8.2%) and one case of problem gambling in the CHD group versus no case in the non-coronary group (p = 0.01). Pathological gambling was not associated to a higher level of alcohol or nicotine consumption neither to a higher level of sensation-seeking. PMID- 21556280 TI - Anhedonia and substance dependence: clinical correlates and treatment options. AB - Anhedonia is a condition in which the capacity of experiencing pleasure is totally or partially lost, and it refers to both a state symptom in various psychiatric disorders and a personality trait. It has a putative neural substrate, originating in the dopaminergic mesolimbic and mesocortical reward circuit. Anhedonia frequently occurs in mood disorders, as a negative symptom in schizophrenia, and in substance use disorders. In particular, we focus our attention on the relationships occurring between anhedonia and substance use disorders, as highlighted by many studies. Several authors suggested that anhedonia is an important factor involved in relapse as well as in the transition from recreational use to excessive drug intake. In particular, anhedonia has been found to be a frequent feature in alcoholics and addicted patients during acute and chronic withdrawal as well as in cocaine, stimulant, and cannabis abusers. Furthermore, in subjects with a substance dependence disorder, there is a significant correlation between anhedonia, craving, intensity of withdrawal symptoms, and psychosocial and personality characteristics. Therefore treating anhedonia in detoxified alcohol-dependent subjects could be critical in terms of relapse prevention strategies, given its strong relationship with craving. PMID- 21556282 TI - Beyond the ubiquitous relapse curve: a data-informed approach. AB - Relapse to alcohol and other substances has generally been described by curves that resemble one another. However, these curves have been generated from the time to first use after a period of abstinence without regard to the movement of individuals into and out of drug use. Instead of measuring continuous abstinence, we considered post-treatment functioning as a more complicated phenomenon, describing how people move in and out of drinking states on a monthly basis over the course of a year. When we looked at time to first drink we observed the ubiquitous relapse curve. When we classified clients (N = 550) according to drinking state however, they frequently moved from one state to another with both abstinent and very heavy drinking states as being rather stable, and light or moderate drinking and heavy drinking being unstable. We found that clients with a family history of alcoholism were less likely to experience these unstable states. When we examined the distribution of cases crossed by the number of times clients switched states we found that a power function explained 83% of that relationship. Some of the remainder of the variance seems to be explained by the stable states of very heavy drinking and abstinence acting as attractors. PMID- 21556283 TI - Money Attitude, Self-esteem, and Compulsive Buying in a Population of Medical Students. AB - This study tried to determine the prevalence of compulsive buying (CB) and to identify among compulsive buyers a specific relation to money, a different buying style, and a lowered level of self-esteem. We included 203 medical students and diagnosed CB with the Mc Elroy criteria and a specific questionnaire. The money attitude was characterized by the Yamauchi and Templer's scale and self-esteem with the Rosenberg scale. 11% of the medical students presented compulsive buying (CB+). Sex ratio and mean ages were comparable in the CB+ and control groups. CB+ students drank less alcohol and smoked an equivalent number of cigarettes. Compulsive buyers had higher scores of distress (tendency to be hesitant, suspicious, and doubtful attitude toward situations involving money) and bargain missing (fear of missing a good opportunity to buy an item). They bought more often gifts for themselves, items they use less than expected and choose goods increasing their self-esteem. Their score of self-esteem was not different from the one from controls. PMID- 21556284 TI - Role of Thalamic Projection in NMDA Receptor-Induced Disruption of Cortical Slow Oscillation and Short-Term Plasticity. AB - NMDA receptor (NMDAR) antagonists, such as phencyclidine, ketamine, or dizocilpine (MK-801) are commonly used in psychiatric drug discovery in order to model several symptoms of schizophrenia, including psychosis and impairments in working memory. In spite of the widespread use of NMDAR antagonists in preclinical and clinical studies, our understanding of the mode of action of these drugs on brain circuits and neuronal networks is still limited. In the present study spontaneous local field potential (LFP), multi- (MUA) and single unit activity, and evoked potential, including paired-pulse facilitation (PPF) in response to electrical stimulation of the ipsilateral subiculum were carried out in the medial prefrontal cortex (mPFC) in urethane anesthetized rats. Systemic administration of MK-801 (0.05 mg/kg, i.v.) decreased overall MUA, with a diverse effect on single-unit activity, including increased, decreased, or unchanged firing, and in line with our previous findings shifted delta-frequency power of the LFP and disrupted PPF (Kiss et al., 2011). In order to provide further insight to the mechanisms of action of NMDAR antagonists, MK-801 was administered intracranially into the mPFC and mediodorsal nucleus of the thalamus (MD). Microinjections of MK-801, but not physiological saline, localized into the MD evoked changes in both LFP parameters and PPF similar to the effects of systemically administered MK-801. Local microinjection of MK-801 into the mPFC was without effect on these parameters. Our findings indicate that the primary site of the action of systemic administration of NMDAR antagonists is unlikely to be the cortex. We presume that multiple neuronal networks, involving thalamic nuclei contribute to disrupted behavior and cognition following NMDAR blockade. PMID- 21556285 TI - A targeted maximum likelihood estimator for two-stage designs. AB - We consider two-stage sampling designs, including so-called nested case control studies, where one takes a random sample from a target population and completes measurements on each subject in the first stage. The second stage involves drawing a subsample from the original sample, collecting additional data on the subsample. This data structure can be viewed as a missing data structure on the full-data structure collected in the second-stage of the study. Methods for analyzing two-stage designs include parametric maximum likelihood estimation and estimating equation methodology. We propose an inverse probability of censoring weighted targeted maximum likelihood estimator (IPCW-TMLE) in two-stage sampling designs and present simulation studies featuring this estimator. PMID- 21556286 TI - A complete graphical criterion for the adjustment formula in mediation analysis. AB - Various assumptions have been used in the literature to identify natural direct and indirect effects in mediation analysis. These effects are of interest because they allow for effect decomposition of a total effect into a direct and indirect effect even in the presence of interactions or non-linear models. In this paper, we consider the relation and interpretation of various identification assumptions in terms of causal diagrams interpreted as a set of non-parametric structural equations. We show that for such causal diagrams, two sets of assumptions for identification that have been described in the literature are in fact equivalent in the sense that if either set of assumptions holds for all models inducing a particular causal diagram, then the other set of assumptions will also hold for all models inducing that diagram. We moreover build on prior work concerning a complete graphical identification criterion for covariate adjustment for total effects to provide a complete graphical criterion for using covariate adjustment to identify natural direct and indirect effects. Finally, we show that this criterion is equivalent to the two sets of independence assumptions used previously for mediation analysis. PMID- 21556287 TI - Targeted maximum likelihood estimation of effect modification parameters in survival analysis. AB - The Cox proportional hazards model or its discrete time analogue, the logistic failure time model, posit highly restrictive parametric models and attempt to estimate parameters which are specific to the model proposed. These methods are typically implemented when assessing effect modification in survival analyses despite their flaws. The targeted maximum likelihood estimation (TMLE) methodology is more robust than the methods typically implemented and allows practitioners to estimate parameters that directly answer the question of interest. TMLE will be used in this paper to estimate two newly proposed parameters of interest that quantify effect modification in the time to event setting. These methods are then applied to the Tshepo study to assess if either gender or baseline CD4 level modify the effect of two cART therapies of interest, efavirenz (EFV) and nevirapine (NVP), on the progression of HIV. The results show that women tend to have more favorable outcomes using EFV while males tend to have more favorable outcomes with NVP. Furthermore, EFV tends to be favorable compared to NVP for individuals at high CD4 levels. PMID- 21556288 TI - Principal stratification--a goal or a tool? AB - Principal stratification has recently become a popular tool to address certain causal inference questions, particularly in dealing with post-randomization factors in randomized trials. Here, we analyze the conceptual basis for this framework and invite response to clarify the value of principal stratification in estimating causal effects of interest. PMID- 21556289 TI - Radiation-induced genomic instability. PMID- 21556290 TI - Missing value imputation in longitudinal measures of alcohol consumption. AB - Attrition in longitudinal studies can lead to biased results. The study is motivated by the unexpected observation that alcohol consumption decreased despite increased availability, which may be due to sample attrition of heavy drinkers. Several imputation methods have been proposed, but rarely compared in longitudinal studies of alcohol consumption. The imputation of consumption level measurements is computationally particularly challenging due to alcohol consumption being a semi-continuous variable (dichotomous drinking status and continuous volume among drinkers), and the non-normality of data in the continuous part. Data come from a longitudinal study in Denmark with four waves (2003-2006) and 1771 individuals at baseline. Five techniques for missing data are compared: Last value carried forward (LVCF) was used as a single, and Hotdeck, Heckman modelling, multivariate imputation by chained equations (MICE), and a Bayesian approach as multiple imputation methods. Predictive mean matching was used to account for non-normality, where instead of imputing regression estimates, "real" observed values from similar cases are imputed. Methods were also compared by means of a simulated dataset. The simulation showed that the Bayesian approach yielded the most unbiased estimates for imputation. The finding of no increase in consumption levels despite a higher availability remained unaltered. PMID- 21556291 TI - Update on Aurora Kinase Targeted Therapeutics in Oncology. AB - INTRODUCTION: Mammalian cells contain three distinct serine/threonine protein kinases with highly conserved catalytic domains, including aurora A and B kinases that are essential regulators of mitotic entry and progression. Overexpression of aurora A and/or B kinase is associated with high proliferation rates and poor prognosis, making them ideal targets for anti-cancer therapy. Disruption of mitotic machinery is a proven anti-cancer strategy employed by multiple chemotherapeutic agents. Numerous small molecule inhibitors of the aurora kinases have been discovered and tested in vivo and in vitro, with a few currently in phase II testing. AREAS COVERED: This review provides the reader with updated results from both preclinical and human studies for each of the aurora kinase inhibitors (AKI) that are currently being investigated. The paper also covers in detail the late breaking and phase I data presented for AKIs thereby allowing the reader to compare and contrast individual and classrelated effects of AKIs. EXPERT OPINION: While the successful development and approval of an AKI for anti cancer therapy remains unresolved, pre-clinical identification of resistant mechanisms would help design better early phase clinical trials where relevant combinations may be evaluated prior to phase II testing. The authors believe that aurora kinases are important anti-cancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted and complimentary anti-cancer mechanism, expand the available armamentarium against cancer. PMID- 21556292 TI - Sources of heterogeneity in hepatitis B virus (HBV) seroprevalence estimates from U.S. adult incarcerated populations: A systematic review and meta-regression analysis. AB - HBV seroprevalence estimates from U.S. incarcerated populations are relatively high. However, the usefulness of these estimates for guiding HBV-related correctional healthcare policy is limited by wide variation in estimates across studies and little understanding of the sources of this variation. The authors systematically reviewed studies indexed from 1975-2005, meeting pre-specified criteria and reporting HBV seroprevalence estimates from U.S. adult incarcerated populations. Using meta-regression techniques, the authors investigated report type, geographical region, serum collection year, facility type, serum source, sampling procedures, sample characteristics, and measurement procedures as potential study-level sources of heterogeneity in prevalence estimates for common HBV seromarkers. In bivariable meta-regression analyses, mean age >=31 years was strongly associated with increased HBsAg prevalence (POR=2.6), and serum collection year before 1991 was strongly associated with increased prevalence of any positive marker (POR=2.0). Other moderate-to-strong associations were observed, but these were considered less certain because of small numbers of observations, influence of single studies, or potential confounding. Potential sources of heterogeneity should be considered when comparing HBV seroprevalence estimates in adult U.S. incarcerated populations and when developing HBV screening and vaccination protocols in correctional settings. PMID- 21556294 TI - Influenza in the 21st century: a call for papers. PMID- 21556295 TI - The costs of performance-based financing. PMID- 21556297 TI - Volunteers vital for counting births and deaths in Ghana. PMID- 21556298 TI - Vaccination: rattling the supply chain. PMID- 21556299 TI - Mental health beyond the crises. PMID- 21556300 TI - Opt-out provider-initiated HIV testing and counselling in primary care outpatient clinics in Zambia. AB - OBJECTIVE: To increase case-finding of infection with human immunodeficiency virus (HIV) in Zambia and their referral to HIV care and treatment by supplementing existing client-initiated voluntary counselling and testing (VCT), the dominant mode of HIV testing in the country. METHODS: Lay counsellors offered provider-initiated HIV testing and counselling (PITC) to all outpatients who attended primary clinics and did not know their HIV serostatus. Data on counselling and testing were collected in registers. Outcomes of interest included HIV testing coverage, the acceptability of testing, the proportion testing HIV-positive (HIV+), the proportion enrolling in HIV care and treatment and the time between testing and enrolment. FINDINGS: After the addition of PITC to VCT, the number tested for HIV infection in the nine clinics was twice the number undergoing VCT alone. Over 30 months, 44,420 patients were counselled under PITC and 31,197 patients, 44% of them men, accepted testing. Of those tested, 21% (6572) were HIV+; 38% of these HIV+ patients (2515) enrolled in HIV care and treatment. The median time between testing and enrolment was 6 days. The acceptability of testing rose over time. CONCLUSION: The introduction of routine PITC using lay counsellors into health-care clinics in Lusaka, Zambia, dramatically increased the uptake and acceptability of HIV testing. Moreover, PITC was incorporated rapidly into primary care outpatient departments. Maximizing the number of patients who proceed to HIV care and treatment remains a challenge and warrants further research. PMID- 21556301 TI - The effects of medical tourism: Thailand's experience. AB - OBJECTIVE: To explore the positive and negative effects of medical tourism on the economy, health staff and medical costs in Thailand. METHODS: The financial repercussions of medical tourism were estimated from commerce ministry data, with modifications and extrapolations. Survey data on 4755 foreign and Thai outpatients in two private hospitals were used to explore how medical tourism affects human resources. Trends in the relative prices of caesarean section, appendectomy, hernia repair, cholecystectomy and knee replacement in five private hospitals were examined. Focus groups and in-depth interviews with hospital managers and key informants from the public and private sectors were conducted to better understand stakeholders' motivations and practices in connection with these procedures and learn more about medical tourism. FINDINGS: Medical tourism generates the equivalent of 0.4% of Thailand's gross domestic product but has exacerbated the shortage of medical staff by luring more workers away from the private and public sectors towards hospitals catering to foreigners. This has raised costs in private hospitals substantially and is likely to raise them in public hospitals and in the universal health-care insurance covering most Thais as well. The "brain drain" may also undermine medical training in future. CONCLUSION: Medical tourism in Thailand, despite some benefits, has negative effects that could be mitigated by lifting the restrictions on the importation of qualified foreign physicians and by taxing tourists who visit the country solely for the purpose of seeking medical treatment. The revenue thus generated could then be used to train physicians and retain medical school professors. PMID- 21556302 TI - Trends in traffic collisions and injuries in Kyrgyzstan, 2003-2007. AB - OBJECTIVE: To assess the epidemiological data on motor vehicle collisions, injuries and deaths in Kyrgyzstan to inform evidence-based policy development. METHODS: Data on motor vehicle collision and injury statistics covering 2003-2007 were obtained from official sources provided by the Department of Traffic Safety and the Ministry of Health's Republican Medical Information Centre. The data were analysed and compared with data derived from studies in other low- and middle income countries. FINDINGS: Large heterogeneity between data sources was noted. Motor vehicle collisions caused by drivers increased twofold between 2003 and 2007. Reported motor vehicle collisions, deaths and injuries increased by 34%, 33% and 47%, respectively, over that period. Such increases were proportionately greater than the growth in population or in the number of registered motor vehicles. The proportion of injury attributable to motor vehicle collisions increased by 14% and the collision-related mortality rate increased by 39% in 2003-2007. CONCLUSION: In Kyrgyzstan, the number of motor vehicle collisions is rising and so is the number of those who are injured or killed in them. Reversing this trend will call for closer collaboration among relevant agencies and for a comprehensive surveillance system, along with operational improvements in emergency medical care, new and strictly enforced passenger safety laws and improvements to the transportation infrastructure. PMID- 21556303 TI - Cross-sectional assessment reveals high diabetes prevalence among newly-diagnosed tuberculosis cases. AB - OBJECTIVE: To estimate the contribution of clinically-confirmed diabetes mellitus to tuberculosis (TB) rates in communities where both diseases are prevalent as a way to identify opportunities for TB prevention among diabetic patients. METHODS: This is a prospective study in which TB patients >= 20 years old at TB clinics in the Texas-Mexico border were tested for diabetes. The risk of tuberculosis attributable to diabetes was estimated from statistics for the corresponding adult population. FINDINGS: The prevalence of diabetes among TB patients was 39% in Texas and 36% in Mexico. Diabetes contributed 25% of the TB cases studied, whereas human immunodeficiency virus (HIV) infection contributed 5% or fewer. Among TB patients, fewer Mexicans than Texans were aware that they had diabetes before this study (4% and 19%, respectively). Men were also less frequently aware than women that they had diabetes (P = 0.03). Patients who knew that they had diabetes before the study had an 8-year history of the disease, on average, before being diagnosed with TB. CONCLUSION: Patients with diabetes are at higher risk of contracting TB than non-diabetic patients. Integrating TB and diabetes control programmes worldwide would facilitate TB prevention among diabetes patients and increase the number of diabetics who learn of their condition, particularly among males. Such a strategy would lead to earlier case detection and improve the management of both TB and diabetes. PMID- 21556304 TI - Comparative effectiveness, safety and acceptability of medical abortion at home and in a clinic: a systematic review. AB - OBJECTIVE: To compare medical abortion practised at home and in clinics in terms of effectiveness, safety and acceptability. METHODS: A systematic search for randomized controlled trials and prospective cohort studies comparing home-based and clinic-based medical abortion was conducted. The Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE and Popline were searched. Failure to abort completely, side-effects and acceptability were the main outcomes of interest. Odds ratios and their 95% confidence intervals (CIs) were calculated. Estimates were pooled using a random-effects model. FINDINGS: Nine studies met the inclusion criteria (n = 4522 participants). All were prospective cohort studies that used mifepristone and misoprostol to induce abortion. Complete abortion was achieved by 86-97% of the women who underwent home-based abortion (n = 3478) and by 80-99% of those who underwent clinic-based abortion (n = 1044). Pooled analyses from all studies revealed no difference in complete abortion rates between groups (odds ratio = 0.8; 95% CI: 0.5-1.5). Serious complications from abortion were rare. Pain and vomiting lasted 0.3 days longer among women who took misoprostol at home rather than in clinic. Women who chose home-based medical abortion were more likely to be satisfied, to choose the method again and to recommend it to a friend than women who opted for medical abortion in a clinic. CONCLUSION: Home-based abortion is safe under the conditions in place in the included studies. Prospective cohort studies have shown no differences in effectiveness or acceptability between home-based and clinic-based medical abortion across countries. PMID- 21556305 TI - No-fault compensation following adverse events attributed to vaccination: a review of international programmes. AB - Programmes that provide no-fault compensation for an adverse event following vaccination have been implemented in 19 countries worldwide, the first in Germany in 1961 and the most recent in Hungary in 2005. We performed a review of these programmes and determined elements that were common to all of them: administration and funding, eligibility, process and decision-making, standard of proof, elements of compensation and litigation rights. Most programmes were administered by state or national governments except in Finland and Sweden where they are coordinated by pharmaceutical manufacturers. Although funding is usually from Treasury, Taiwan (China) and the United States of America impose a tax on vaccine doses distributed. Decisions on compensation are made using established criteria or assessed on a case-by-case basis, while the standard of proof required is usually less than that required for court cases. Benefits provided by programmes include medical costs, disability pensions and benefits for noneconomic loss and death. Most countries allow claimants to seek legal damages through the courts or a compensation scheme payout but not both. We conclude that a variety of programmes, based on ethical principles, have been successful and financially viable in developed countries throughout the world. We believe there is a strong argument for widespread implementation of these programmes in other developed countries. PMID- 21556306 TI - Strengthening of local vital events registration: lessons learnt from a voluntary sector initiative in a district in southern India. AB - PROBLEM: Birth and death registration rates are low in most parts of India. Poor registration rates are due to constraints in both the government system (supply side) and the general population (demand-side). APPROACH: We strengthened vital event registration at the local level within the existing legal framework by: (i) involving a non-profit organization as an interface between the government and the community; (ii) conducting supply-side interventions such as sensitization workshops for government officials, training for hospital staff and building data sharing partnerships between stakeholders; (iii) monitoring for vital events by active surveillance through lay-informants; and (iv) conducting demand-side interventions such as publicity campaigns, education of families and assistance with registration. LOCAL SETTING: In the government sector, registration is given low priority and there is an attitude of blaming the victim, ascribing low levels of vital event registration to "cultural reasons/ignorance ". In the community, low registration was due to lack of awareness about the importance of and procedures for registration. RELEVANT CHANGES: This initiative helped improve registration of births and deaths at the subdistrict level. Vital event registration was significantly associated with local equity stratifiers such as gender, socioeconomic status and geography. LESSONS LEARNT: The voluntary sector can interface effectively between the government and the community to strengthen vital registration. With political support from the government, outreach activities can dramatically improve vital event registration rates, especially in disadvantaged populations. The potential relevance of the data and the data collection process to stakeholders at the local level is a critical factor for success. PMID- 21556307 TI - Random demographic household surveys in highly mobile pastoral communities in Chad. AB - PROBLEM: Reliable demographic data is a central requirement for health planning and management, and for the implementation of adequate interventions. This study addresses the lack of demographic data on mobile pastoral communities in the Sahel. APPROACH: A total of 1081 Arab, Fulani and Gorane women and 2541 children (1336 boys and 1205 girls) were interviewed and registered by a biometric fingerprint scanner in five repeated random transect demographic and health surveys conducted from March 2007 to January 2008 in the Lake Chad region in Chad. LOCAL SETTING: Important determinants for the planning and implementation of household surveys among mobile pastoral communities include: environmental factors; availability of women for interviews; difficulties in defining "own" children; the need for information-education-communication campaigns; and informed consent of husbands in typically patriarchal societies. RELEVANT CHANGES: Due to their high mobility, only 5% (56/1081) of registered women were encountered twice. Therefore, it was not possible to establish a demographic and health cohort. LESSONS LEARNT: Prospective demographic and health cohorts are the most accurate method to assess child mortality and other demographic indices. However, their feasibility in a highly mobile pastoral setting remains to be shown. Future interdisciplinary scientific efforts need to target innovative methods, tools and approaches to include marginalized communities in operational health and demographic surveillance systems. PMID- 21556308 TI - The WHO policy package to combat antimicrobial resistance. PMID- 21556310 TI - Synthesis of dicationic diaryltriazines nucleic acid binding agents. AB - - The synthesis of 2,4-bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-1,3,5-triazine 6a and 2,4-bis[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]-1,3,5-triazine 6b in 3 steps from either 4-bromobenzamidine or 4-(carbamoyl)benzamidine is reported. The synthesis of 4,6-bis[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-2-dimethylamino 1,3,5-triazine 9a and 4,6-bis[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]-2 dimethylamino-1,3,5-triazine 9b in 2 steps from 1,4-dicyanobenzene is also described. The compounds 6b and 9b bind strongly to DNA model sequences and inhibit topoisomerase II from 2 microbial sources. Compounds 6a and 9a bind to both DNA and RNA model sequences whereas 6b and 9b essentially do not bind to the RNA model. PMID- 21556311 TI - A systematic review of nonrandomized controlled trials on the curative effects of aquatic exercise. AB - BACKGROUND: The objectives of this review were to integrate the evidence of curative effects through aquatic exercise and assess the quality of studies based on a review of nonrandomized controlled trials (nRCTs). METHODS: Study design was a systematic review of nonrandomized controlled trials. Trials were eligible if they were nonrandomized clinical trials. Studies included one treatment group in which aquatic exercise was applied. We searched the following databases from 2000 up to July 20, 2009: MEDLINE via PubMed, CINAHL, and Ichushi-Web. RESULTS: Twenty one trials met all inclusion criteria. Languages included were English (N = 9), Japanese (N = 11), and Korean (N = 1). Target diseases were knee and/or hip osteoarthritis, poliomyelitis, chronic kidney disease, discomforts of pregnancy, cardiovascular diseases, and rotator cuff tears. Many studies on nonspecific disease (healthy participants) were included. All studies reported significant effectiveness in at least one or more outcomes. However results of evaluations with the TREND and CLEAR-NPT checklists generally showed a remarkable lack of description in the studies. Furthermore, there was the problem of heterogeneity, and we were therefore not able to perform a meta-analysis. CONCLUSION: Because there was insufficient evidence on aquatic exercise due to poor methodological and reporting quality and heterogeneity of nRCTs, we were unable to offer any conclusions about the effects of this intervention. However, we were able to identify problems with current nRCTs of aquatic exercise, and propose a strategy of strengthening study quality, stressing the importance of study feasibility as a future research agenda objective. PMID- 21556312 TI - Pleiotropic effects of the HMG-CoA reductase inhibitors. AB - The HMG-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes. These secondary actions are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropy of statins and emphasizes the importance of randomized placebo-controlled trials to further elucidate this interesting phenomenon. PMID- 21556313 TI - Mortality associated with extremity injuries compared with other types of trauma. AB - BACKGROUND: The aim of this study was to evaluate one-month hospital mortality in victims with injuries of the extremities. METHODS: All accident victims admitted to the Hospital de Base in Sao Jose do Rio Preto, Brazil, during the period from July 2004 to June 2005, were evaluated in an observational study. Patients were classified using the Abbreviated Injury Scale (AIS). Patients with severe injuries of the extremities (AIS 3-4) were compared with those without injuries or with minor extremity injuries (AIS 0-2). RESULTS: A total of 3489 accident victims were evaluated; 3244 (92.98%) did not suffer injuries or had minor injuries of the extremities (AIS 0-2) and 245 (7.02%) had severe injuries (AIS 3 4). Of the 245 patients with AIS 3-4 extremity injuries, 13 (5.31%) patients died, and of those without severe injuries to the extremities, 34 (1.05%) died (Fisher's Exact test P = 0.0000, relative risk 5.063, 95% confidence interval [CI]: 2.707-9.467). CONCLUSION: Patients with injuries of the extremities are at greater risk of death than accident victims with other types of trauma. PMID- 21556314 TI - How to reduce your cancer risk: mechanisms and myths. AB - Cancer prevention continues to be a high research priority and the most optimal way to ultimately lower the economic and psychological burden of cancer. Many known risk factors associated with cancer are related to dietary and lifestyle factors and can be avoided. These risk factors include among others, smoking, obesity, alcohol, physical inactivity, and carcinogens in diet. This article reviews the biological mechanisms leading to cancer in association with these factors, highlights important achievable cancer prevention methods, addresses commonly asked questions about lifestyle and cancer, and dispels some of the myths about cancer prevention. PMID- 21556315 TI - Association between physician explanatory behaviors and substandard care in adjudicated cases in Japan. AB - BACKGROUND: When a physician provides an insufficient explanation to a patient, such as regarding diagnosis, treatment, drug use, or prognosis, the physician is deemed to have delivered substandard care. It is likely that the standards applied to physicians' explanations have changed as a result of the increased importance of patients' rights of self-determination. However, little or no research on decisions in medical malpractice cases has been conducted with respect to this issue. METHODS: Based on decisions made in 366 medical malpractice cases between 1979 and 2008 focused primarily on the physician's duty to explain relevant issues to patients, we examined the association between physicians' explanatory behaviors and court decisions with respect to breaches of duty. RESULTS: We found that physicians' explanatory behaviors, including relevant and specific explanations provided before treatment or surgery, were important for fulfilling a physician's duty to explain. The data also revealed that six of the 16 types of explanatory behaviors had improved during the past three decades. However, these improvements did not contribute to the fulfillment of the physician's duty to explain. CONCLUSION: We found that there was an association between physicians' explanatory behaviors and judicial decisions concerning substandard care, and courts were increasingly likely to consider inadequate explanatory behaviors to be a breach of the duty of care. PMID- 21556316 TI - Importance of innate mucosal immunity and the promises it holds. AB - The body defense mechanism has evolved to protect animals from invading pathogenic microorganisms and cancer. It is able to generate a diverse variety of cells and molecules capable of specifically recognizing and eliminating a limitless variety of foreign invaders. These cells and molecules act together in a dynamic network and are known as the immune system. Innate mucosal immunity consists of various recognition receptor molecules, including toll-like receptors, NOD-like receptors, and RIG-I-like receptors. These recognition receptor molecules recognize various invading pathogens effectively, and generate an immune response to stop their entry and neutralize their adverse consequences, such as tissue damage. Furthermore, they regulate the adaptive response in cases of severe infection and also help generate a memory response. Most infections occur through the mucosa. It is important to understand the initial host defense response or innate immunity at the mucosal surface to control these infections and protect the system. The aim of this review is to discuss the effects and functions of various innate mucosal agents and their importance in understanding the physiological immune response, as well as their roles in developing new interventions. PMID- 21556317 TI - Critical appraisal of trastuzumab in treatment of advanced stomach cancer. AB - Advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. In North America, about 70% of cases are advanced or metastatic when diagnosed, which is higher than the 50% reported in Japan. This difference in presentation is reflected in 5-year overall survival, which is about 20% in North America and 40%-60% in Japan. Despite numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Systemic chemotherapy provides palliation and prolongs survival, but the prognosis remains poor. Several monotherapies and combined regimens are currently available and vary around the world. Additionally, several molecular targeting agents are under evaluation in international randomized studies. Human epidermal growth factor receptor-2 (HER 2) is overexpressed or amplified in approximately 22% of patients with gastric cancer. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is the first biological therapy that has showed a survival improvement by nearly three months (reduced risk of death by 26%). Therefore, trastuzumab in combination with cisplatin is a reasonable treatment option for patients with advanced gastric cancer who are HER-2 positive. This paper will focus on trastuzumab, its chemical and pharmacological characteristics, and the relevant efficacy, safety, and tolerability studies. PMID- 21556318 TI - Critical appraisal of nilotinib in frontline treatment of chronic myeloid leukemia. AB - The development of imatinib has revolutionized the treatment of chronic myeloid leukemia. Follow-up analysis of IRIS trial participants continues to demonstrate durable responses for imatinib at 400 mg/day. However, 10%-15% of patients with chronic myeloid leukemia will become imatinib-resistant or intolerant of adverse events. Phase II studies have shown that most of these patients will respond to second-generation tyrosine kinase inhibitors, such as nilotinib, dasatinib, and bosutinib. Both nilotinib and dasatinib have recently demonstrated clinical efficacy as frontline therapy in Phase III studies. In the ENESTnd trial, nilotinib 600-800 mg/day produced significantly higher major molecular rates and complete cytogenetic response rates in comparison with imatinib at 12 months. Recently, 18-month follow-up analysis of this trial continues to demonstrate superiority for nilotinib. It is unknown whether this will ultimately translate into improved long-term outcomes, such as event-free survival or overall survival. Nilotinib continues to be generally well tolerated and tends to produce less Grade 3/4 toxicity in frontline therapy when compared with its use following imatinib failure. With three tyrosine kinase inhibitors for potential frontline therapy and an active drug discovery pipeline, treatment for chronic myeloid leukemia is still subject to change with time as clinical algorithms continue to evolve. PMID- 21556319 TI - Predicting potential placebo effect in drug treated subjects. AB - Non-specific responses to treatment (commonly known as placebo response) are pervasive when treating mental illness. Subjects treated with an active drug may respond in part due to non-specific aspects of the treatment, i.e, those not related to the chemical effect of the drug. To determine the extent a subject responds due to the chemical effect of a drug, one must disentangle the specific drug effect from the non-specific placebo effect. This paper presents a unique statistical model that allows for the separate prediction of a specific effect and non-specific effects in drug treated subjects. Data from a clinical trial comparing fluoxetine to a placebo for treating depression is used to illustrate this methodology. PMID- 21556321 TI - What is "Narrative Bioethics". PMID- 21556320 TI - Toward a simulation-based tool for the treatment of vocal fold paralysis. AB - Advances in high-performance computing are enabling a new generation of software tools that employ computational modeling for surgical planning. Surgical management of laryngeal paralysis is one area where such computational tools could have a significant impact. The current paper describes a comprehensive effort to develop a software tool for planning medialization laryngoplasty where a prosthetic implant is inserted into the larynx in order to medialize the paralyzed vocal fold (VF). While this is one of the most common procedures used to restore voice in patients with VF paralysis, it has a relatively high revision rate, and the tool being developed is expected to improve surgical outcomes. This software tool models the biomechanics of airflow-induced vibration in the human larynx and incorporates sophisticated approaches for modeling the turbulent laryngeal flow, the complex dynamics of the VFs, as well as the production of voiced sound. The current paper describes the key elements of the modeling approach, presents computational results that demonstrate the utility of the approach and also describes some of the limitations and challenges. PMID- 21556322 TI - Developmental enhancement of adenylate kinase-AMPK metabolic signaling axis supports stem cell cardiac differentiation. AB - BACKGROUND: Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined. METHODS AND RESULTS: Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy-consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKalpha2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKalpha(Thr172). The cardiogenic growth factor TGF-beta promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of creatine kinase, the alternate phosphotransfer pathway, compensated for adenylate kinase-dependent energetic deficits. CONCLUSIONS: Developmental deployment and upregulation of the adenylate kinase/AMPK tandem provides a nucleocytosolic energetic and metabolic signaling vector integral to execution of stem cell cardiac differentiation. Targeted redistribution of the adenylate kinase-AMPK circuit associated with cell cycle and asymmetric cell division uncovers a regulator for cardiogenesis and heart tissue regeneration. PMID- 21556323 TI - Index cohesive force analysis reveals that the US market became prone to systemic collapses since 2002. AB - BACKGROUND: The 2007-2009 financial crisis, and its fallout, has strongly emphasized the need to define new ways and measures to study and assess the stock market dynamics. METHODOLOGY/PRINCIPAL FINDINGS: The S&P500 dynamics during 4/1999-4/2010 is investigated in terms of the index cohesive force (ICF--the balance between the stock correlations and the partial correlations after subtraction of the index contribution), and the Eigenvalue entropy of the stock correlation matrices. We found a rapid market transition at the end of 2001 from a flexible state of low ICF into a stiff (nonflexible) state of high ICF that is prone to market systemic collapses. The stiff state is also marked by strong effect of the market index on the stock-stock correlations as well as bursts of high stock correlations reminiscence of epileptic brain activity. CONCLUSIONS/SIGNIFICANCE: The market dynamical states, stability and transition between economic states was studies using new quantitative measures. Doing so shed new light on the origin and nature of the current crisis. The new approach is likely to be applicable to other classes of complex systems from gene networks to the human brain. PMID- 21556324 TI - Big words, halved brains and small worlds: complex brain networks of figurative language comprehension. AB - Language comprehension is a complex task that involves a wide network of brain regions. We used topological measures to qualify and quantify the functional connectivity of the networks used under various comprehension conditions. To that aim we developed a technique to represent functional networks based on EEG recordings, taking advantage of their excellent time resolution in order to capture the fast processes that occur during language comprehension. Networks were created by searching for a specific causal relation between areas, the negative feedback loop, which is ubiquitous in many systems. This method is a simple way to construct directed graphs using event-related activity, which can then be analyzed topologically. Brain activity was recorded while subjects read expressions of various types and indicated whether they found them meaningful. Slightly different functional networks were obtained for event-related activity evoked by each expression type. The differences reflect the special contribution of specific regions in each condition and the balance of hemispheric activity involved in comprehending different types of expressions and are consistent with the literature in the field. Our results indicate that representing event-related brain activity as a network using a simple temporal relation, such as the negative feedback loop, to indicate directional connectivity is a viable option for investigation which also derives new information about aspects not reflected in the classical methods for investigating brain activity. PMID- 21556325 TI - Arabidopsis CPR5 independently regulates seed germination and postgermination arrest of development through LOX pathway and ABA signaling. AB - The phytohormone abscisic acid (ABA) and the lipoxygenases (LOXs) pathway play important roles in seed germination and seedling growth and development. Here, we reported on the functional characterization of Arabidopsis CPR5 in the ABA signaling and LOX pathways. The cpr5 mutant was hypersensitive to ABA in the seed germination, cotyledon greening and root growth, whereas transgenic plants overexpressing CPR5 were insensitive. Genetic analysis demonstrated that CPR5 gene may be located downstream of the ABI1 in the ABA signaling pathway. However, the cpr5 mutant showed an ABA independent drought-resistant phenotype. It was also found that the cpr5 mutant was hypersensitive to NDGA and NDGA treatment aggravated the ABA-induced delay in the seed germination and cotyledon greening. Taken together, these results suggest that the CPR5 plays a regulatory role in the regulation of seed germination and early seedling growth through ABA and LOX pathways independently. PMID- 21556326 TI - Evolution of the karyopherin-beta family of nucleocytoplasmic transport factors; ancient origins and continued specialization. AB - BACKGROUND: Macromolecular transport across the nuclear envelope (NE) is achieved through nuclear pore complexes (NPCs) and requires karyopherin-betas (KAP-betas), a family of soluble receptors, for recognition of embedded transport signals within cargo. We recently demonstrated, through proteomic analysis of trypanosomes, that NPC architecture is likely highly conserved across the Eukaryota, which in turn suggests conservation of the transport mechanisms. To determine if KAP-beta diversity was similarly established early in eukaryotic evolution or if it was subsequently layered onto a conserved NPC, we chose to identify KAP-beta sequences in a diverse range of eukaryotes and to investigate their evolutionary history. RESULTS: Thirty six predicted proteomes were scanned for candidate KAP-beta family members. These resulting sequences were resolved into fifteen KAP-beta subfamilies which, due to broad supergroup representation, were most likely represented in the last eukaryotic common ancestor (LECA). Candidate members of each KAP-beta subfamily were found in all eukaryotic supergroups, except XPO6, which is absent from Archaeplastida. Phylogenetic reconstruction revealed the likely evolutionary relationships between these different subfamilies. Many species contain more than one representative of each KAP-beta subfamily; many duplications are apparently taxon-specific but others result from duplications occurring earlier in eukaryotic history. CONCLUSIONS: At least fifteen KAP-beta subfamilies were established early in eukaryote evolution and likely before the LECA. In addition we identified expansions at multiple stages within eukaryote evolution, including a multicellular plant-specific KAP beta, together with frequent secondary losses. Taken with evidence for early establishment of NPC architecture, these data demonstrate that multiple pathways for nucleocytoplasmic transport were established prior to the radiation of modern eukaryotes but that selective pressure continues to sculpt the KAP-beta family. PMID- 21556327 TI - Evidence for a fourteenth mtDNA-encoded protein in the female-transmitted mtDNA of marine Mussels (Bivalvia: Mytilidae). AB - BACKGROUND: A novel feature for animal mitochondrial genomes has been recently established: i.e., the presence of additional, lineage-specific, mtDNA-encoded proteins with functional significance. This feature has been observed in freshwater mussels with doubly uniparental inheritance of mtDNA (DUI). The latter unique system of mtDNA transmission, which also exists in some marine mussels and marine clams, is characterized by one mt genome inherited from the female parent (F mtDNA) and one mt genome inherited from the male parent (M mtDNA). In freshwater mussels, the novel mtDNA-encoded proteins have been shown to be mt genome-specific (i.e., one novel protein for F genomes and one novel protein for M genomes). It has been hypothesized that these novel, F- and M-specific, mtDNA encoded proteins (and/or other F- and/or M-specific mtDNA sequences) could be responsible for the different modes of mtDNA transmission in bivalves but this remains to be demonstrated. METHODOLOGY/PRINCIPAL FINDINGS: We investigated all complete (or nearly complete) female- and male-transmitted marine mussel mtDNAs previously sequenced for the presence of ORFs that could have functional importance in these bivalves. Our results confirm the presence of a novel F genome-specific mt ORF, of significant length (>100aa) and located in the control region, that most likely has functional significance in marine mussels. The identification of this ORF in five Mytilus species suggests that it has been maintained in the mytilid lineage (subfamily Mytilinae) for ~13 million years. Furthermore, this ORF likely has a homologue in the F mt genome of Musculista senhousia, a DUI-containing mytilid species in the subfamily Crenellinae. We present evidence supporting the functionality of this F-specific ORF at the transcriptional, amino acid and nucleotide levels. CONCLUSIONS/SIGNIFICANCE: Our results offer support for the hypothesis that "novel F genome-specific mitochondrial genes" are involved in key biological functions in bivalve species with DUI. PMID- 21556328 TI - Free radical exposure creates paler carotenoid-based ornaments: a possible interaction in the expression of black and red traits. AB - Oxidative stress could be a key selective force shaping the expression of colored traits produced by the primary animal pigments in integuments: carotenoids and melanins. However, the impact of oxidative stress on melanic ornaments has only recently been explored, whereas its role in the expression of carotenoid-based traits is not fully understood. An interesting study case is that of those animal species simultaneously expressing both kinds of ornaments, such as the red-legged partridge (Alectoris rufa). In this bird, individuals exposed to an exogenous source of free radicals (diquat) during their development produced larger eumelanin-based (black) plumage traits than controls. Here, we show that the same red-legged partridges exposed to diquat simultaneously developed paler carotenoid based ornaments (red beak and eye rings), and carried lower circulating carotenoid levels as well as lower levels of some lipids involved in carotenoid transport in the bloodstream (i.e., cholesterol). Moreover, partridges treated with a hormone that stimulates eumelanin production (i.e., alpha-melanocyte stimulating hormone) also increased blood carotenoid levels, but this effect was not mirrored in the expression of carotenoid-based traits. The redness of carotenoid-based ornaments and the size of a conspicuous eumelanic trait (the black bib) were negatively correlated in control birds, suggesting a physiological trade-off during development. These findings contradict recent studies questioning the sensitivity of carotenoids to oxidative stress. Nonetheless, the impact of free radicals on plasma carotenoids seems to be partially mediated by changes in cholesterol metabolism, and not by direct carotenoid destruction/consumption. The results highlight the capacity of oxidative stress to create multiple phenotypes during development through differential effects on carotenoids and melanins, raising questions about evolutionary constraints involved in the production of multiple ornaments by the same organism. PMID- 21556329 TI - A new approach to age-period-cohort analysis using partial least squares regression: the trend in blood pressure in the Glasgow Alumni cohort. AB - Due to a problem of identification, how to estimate the distinct effects of age, time period and cohort has been a controversial issue in the analysis of trends in health outcomes in epidemiology. In this study, we propose a novel approach, partial least squares (PLS) analysis, to separate the effects of age, period, and cohort. Our example for illustration is taken from the Glasgow Alumni cohort. A total of 15,322 students (11,755 men and 3,567 women) received medical screening at the Glasgow University between 1948 and 1968. The aim is to investigate the secular trends in blood pressure over 1925 and 1950 while taking into account the year of examination and age at examination. We excluded students born before 1925 or aged over 25 years at examination and those with missing values in confounders from the analyses, resulting in 12,546 and 12,516 students for analysis of systolic and diastolic blood pressure, respectively. PLS analysis shows that both systolic and diastolic blood pressure increased with students' age, and students born later had on average lower blood pressure (SBP: -0.17 mmHg/per year [95% confidence intervals: -0.19 to -0.15] for men and -0.25 [-0.28 to -0.22] for women; DBP: -0.14 [-0.15 to -0.13] for men; -0.09 [-0.11 to -0.07] for women). PLS also shows a decreasing trend in blood pressure over the examination period. As identification is not a problem for PLS, it provides a flexible modelling strategy for age-period-cohort analysis. More emphasis is then required to clarify the substantive and conceptual issues surrounding the definitions and interpretations of age, period and cohort effects. PMID- 21556330 TI - Mastering the canonical loop of serine protease inhibitors: enhancing potency by optimising the internal hydrogen bond network. AB - BACKGROUND: Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internal hydrogen bond network and disulfide bond(s). The smallest of these is sunflower trypsin inhibitor (SFTI-1), a potent and broad-range protease inhibitor. Recently, we re-engineered the contact beta-sheet of SFTI-1 to produce a selective inhibitor of kallikrein related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitors from reaching optimal binding affinity. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the effect of amino acid substitutions on the internal hydrogen bonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutions favouring internal hydrogen bond formation directly correlated with increased potency of inhibition in vitro. This produced a second generation inhibitor (SFTI-FCQR Asn(14)) which displayed both a 125-fold increased capacity to inhibit KLK4 (K(i) = 0.0386+/-0.0060 nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn(14) was stable in cell culture and bioavailable in mice when administered by intraperitoneal perfusion. CONCLUSION/SIGNIFICANCE: These findings highlight the importance of conserving structural rigidity of the binding loop in addition to optimising protease/inhibitor contacts when re-engineering canonical serine protease inhibitors. PMID- 21556333 TI - Tag SNP polymorphism of CCL2 and its role in clinical tuberculosis in Han Chinese pediatric population. AB - BACKGROUND: Chemokine (C-C motif) ligand 2 CCL2/MCP-1 is among the key signaling molecules of innate immunity; in particular, it is involved in recruitment of mononuclear and other cells in response to infection, including tuberculosis (TB) and is essential for granuloma formation. METHODOLOGY/PRINCIPAL FINDINGS: We identified a tag SNP for the CCL2/MCP-1 gene (rs4586 C/T). In order to understand whether this SNP may serve to evaluate the contribution of the CCL2 gene to the expression of TB disease, we further analysed distribution of its alleles and genotypes in 301 TB cases versus 338 non-infected controls (all BCG vaccinated) representing a high-risk pediatric population of North China. In the male TB subgroup, the C allele was identified in a higher rate (P = 0.045), and, acting dominantly, was found to be a risk factor for clinical TB (P = 0.029). Homozygous TT genotype was significantly associated with lower CSF mononuclear leukocyte (ML) counts in patients with tuberculous meningitis (TBM) (P = 0.001). CONCLUSIONS/SIGNIFICANCE: The present study found an association of the CCL2 tag SNP rs4586 C allele and pediatric TB disease in males, suggesting that gender may affect the susceptibility to TB even in children. The association of homozygous TT genotype with decreased CSF mononuclear leukocyte (ML) count not only suggests a clinical significance of this SNP, but indicates its potential to assist in the clinical assessment of suspected TBM, where delay is critical and diagnosis is difficult. PMID- 21556334 TI - Gamma rhythms in the brain. PMID- 21556335 TI - The next step for motor proteins. PMID- 21556340 TI - The relationship between cellular adhesion and surface roughness for polyurethane modified by microwave plasma radiation. AB - Surface modification of medical polymers is carried out to improve biocompatibility. In this study, conventional polyurethane was exposed to microwave plasma treatment with oxygen and argon gases for 30 seconds and 60 seconds. Attenuated total reflection Fourier transform infrared spectra investigations of irradiated samples indicated the presence of functional groups. Atomic force microscope images of samples irradiated with inert and active gases indicated the nanometric topography of the sample surfaces. Samples irradiated by oxygen plasma indicated high roughness compared with those irradiated by inert plasma for the different lengths of time. In addition, surface roughness increased with time, which can be due to a reduction of contact angle of samples irradiated by oxygen plasma. Contact angle analysis indicated a reduction in samples irradiated with both types of plasma. However, samples irradiated with oxygen plasma indicated lower contact angle compared with those irradiated by argon plasma. Cellular investigations with unrestricted somatic stem cells showed better adhesion, cell growth, and proliferation among samples radiated by oxygen plasma for longer than for normal samples. PMID- 21556341 TI - Composite electrospun nanomembranes of fish scale collagen peptides/chito oligosaccharides: antibacterial properties and potential for wound dressing. AB - PURPOSE: The objective of the present investigation was to evaluate the antibacterial properties and the biocompatibility of composite electrospun nanofibrous membranes (NFMs) with low-molecular-weight fish scale collagen peptides (FSCP) and chito-oligosaccharide (COS), to determine their potential for use as wound dressings. METHODS: Low-molecular-weight FSCP were combined with COS to prepare nanofibers by electrospinning, and polyvinyl alcohol (PVA) was used for enhancing fiber-forming ability. Transmission electron microscope and scanning electron microscope methods were used to observe bacterial adhesion and the bacterial cell membrane. Fibroblast cell viability was determined using the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The best FSCP/COS mass ratio for electrospinning was 2:1, and the nanofibers had small dimensions ranging from 50 to 100 nm. The NFM showed good antibacterial activities against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. The antibacterial activity against S. aureus was higher than against E. coli. The pili and adhesive fimbriae of E. coli promoted bacterial adhesion to the NFM surfaces, and S. aureus biofilms aided S. aureus adhesion on the surface of NFMs. Damage to the bacterial cell membrane indicates that the NFMs could lead to the release of intracellular materials, particularly with S. aureus. In addition, FSCP/COS NFM rapidly increased the permeability of the outer membranes of E. coli. The electrospun NFM with FSCP and COS had good biocompatibility in vitro and supported proliferation of human skin fibroblasts. CONCLUSION: FSCP are superior to mammalian collagen, and have feasibility and potency for wound dressings. FSCP/COS NFMs had good anti-bactericidal activity that improved with increased COS, and showed good biocompatibility in vitro and supported the proliferation of fibroblasts. PMID- 21556342 TI - Time-dependent effect in green synthesis of silver nanoparticles. AB - The application of "green" chemistry rules to nanoscience and nanotechnology is very important in the preparation of various nanomaterials. In this work, we successfully developed an eco-friendly chemistry method for preparing silver nanoparticles (Ag-NPs) in natural polymeric media. The colloidal Ag-NPs were synthesized in an aqueous solution using silver nitrate, gelatin, and glucose as a silver precursor, stabilizer, and reducing agent, respectively. The properties of synthesized colloidal Ag-NPs were studied at different reaction times. The ultraviolet-visible (UV-vis) spectra were in excellent agreement with the obtained nanostructure studies performed by transmission electron microscopy (TEM) and their size distributions. The prepared samples were also characterized by X-ray diffraction (XRD) and atomic force microscopy (AFM). The use of eco friendly reagents, such as gelatin and glucose, provides green and economic attributes to this work. PMID- 21556343 TI - Development and optimization of solid lipid nanoparticle formulation for ophthalmic delivery of chloramphenicol using a Box-Behnken design. AB - The purpose of the present study was to optimize a solid lipid nanoparticle (SLN) of chloramphenicol by investigating the relationship between design factors and experimental data using response surface methodology. A Box-Behnken design was constructed using solid lipid (X(1)), surfactant (X(2)), and drug/lipid ratio (X(3)) level as independent factors. SLN was successfully prepared by a modified method of melt-emulsion ultrasonication and low temperature-solidification technique using glyceryl monostearate as the solid lipid, and poloxamer 188 as the surfactant. The dependent variables were entrapment efficiency (EE), drug loading (DL), and turbidity. Properties of SLN such as the morphology, particle size, zeta potential, EE, DL, and drug release behavior were investigated, respectively. As a result, the nanoparticle designed showed nearly spherical particles with a mean particle size of 248 nm. The polydispersity index of particle size was 0.277 +/- 0.058 and zeta potential was -8.74 mV. The EE (%) and DL (%) could reach up to 83.29% +/- 1.23% and 10.11% +/- 2.02%, respectively. In vitro release studies showed a burst release at the initial stage followed by a prolonged release of chloramphenicol from SLN up to 48 hours. The release kinetics of the optimized formulation best fitted the Peppas-Korsmeyer model. These results indicated that the chloramphenicol-loaded SLN could potentially be exploited as a delivery system with improved drug entrapment efficiency and controlled drug release. PMID- 21556344 TI - Oil components modulate the skin delivery of 5-aminolevulinic acid and its ester prodrug from oil-in-water and water-in-oil nanoemulsions. AB - The study evaluated the potential of nanoemulsions for the topical delivery of 5 aminolevulinic acid (ALA) and methyl ALA (mALA). The drugs were incorporated in oil-in-water (O/W) and water-in-oil (W/O) formulations obtained by using soybean oil or squalene as the oil phase. The droplet size, zeta potential, and environmental polarity of the nanocarriers were assessed as physicochemical properties. The O/W and W/O emulsions showed diameters of 216-256 and 18-125 nm, which, respectively, were within the range of submicron- and nano-sized dispersions. In vitro diffusion experiments using Franz-type cells and porcine skin were performed. Nude mice were used, and skin fluorescence derived from protoporphyrin IX was documented by confocal laser scanning microscopy (CLSM). The loading of ALA or mALA into the emulsions resulted in slower release across cellulose membranes. The release rate and skin flux of topical drug application were adjusted by changing the type of nanocarrier, the soybean oil O/W systems showing the highest skin permeation. This formulation increased ALA flux via porcine skin to 180 nmol/cm(2)/h, which was 2.6-fold that of the aqueous control. The CLSM results showed that soybean oil systems promoted mALA permeation to deeper layers of the skin from ~100 MUm to ~140 MUm, which would be beneficial for treating subepidermal and subcutaneous lesions. Drug permeation from W/O systems did not surpass that from the aqueous solution. An in vivo dermal irritation test indicated that the emulsions were safe for topical administration of ALA and mALA. PMID- 21556345 TI - Increased paclitaxel cytotoxicity against cancer cell lines using a novel functionalized carbon nanotube. AB - Potential applications of carbon nanotubes have attracted many researchers in the field of drug delivery systems. In this study, multiwalled carbon nanotubes (MWNTs) were first functionalized using hyperbranched poly citric acid (PCA) to improve their hydrophilicity and functionality. Then, paclitaxel (PTX), a potent anticancer agent, was conjugated to the carboxyl functional groups of poly citric acid via a cleavable ester bond to obtain a MWNT-g-PCA-PTX conjugate. Drug content of the conjugate was about 38% (w/w). The particle size of MWNT-g-PCA and MWNT-g-PCA-PTX was approximately 125 and 200 nm, respectively. Atomic force microscopy and transmission electron microscopy images showed a curved shape for MWNT-g-PCA and MWNT-g-PCA-PTX, which was in contrast with the straight or linear conformation expected from carbon nanotubes. It seems that the high hydrophilicity of poly citric acid and high hydrophobicity of MWNTs led to conformational changes from a linear state to a curved state. Paclitaxel can be released from the MWNT-g-PCA-PTX conjugates faster at pH 6.8 and 5.0 than at pH 7.4, which was suitable for the release of the drug in tumor tissues and tumor cells. In vitro cytotoxicity studies were evaluated in the A549 and SKOV3 cell lines. MWNT-g-PCA had an insignificant cytotoxic effect on both cell lines. MWNT g-PCA-PTX had more of a cytotoxic effect than the free drug over a shorter incubation time (eg, 24 hours versus 48 hours), which suggests improved cell penetration of MWNT-g-PCA-PTX. Therefore, paclitaxel conjugated to MWNT-g-PCA is promising for cancer therapeutics. PMID- 21556346 TI - An efficient calcium phosphate nanoparticle-based nonviral vector for gene delivery. AB - BACKGROUND: Smaller nanoparticles facilitate the delivery of DNA into cells through endocytosis and improve transfection efficiency. The aim of this study was to determine whether protamine sulfate-coated calcium phosphate (PS-CaP) could stabilize particle size and enhance transfection efficiency. METHODS: pEGFP C1 green fluorescence protein was employed as an indicator of transfection efficiency. Atomic force microscopy was used to evaluate the morphology and the size of the particles, and an MTT assay was introduced to detect cell viability and inhibition. The classical calcium phosphate method was used as the control. RESULTS: Atomic force microscopy images showed that the PS-CaP were much smaller than classical calcium phosphate particles. In 293 FT, HEK 293, and NIH 3T3 cells, the transfection efficiency of PS-CaP was higher than for the classical calcium phosphate particles. The difference in efficiencies implies that the smaller nanoparticles may promote the delivery of DNA into cells through endocytosis and could improve transfection efficiency. In addition, PS-CaP could be used to transfect HEK 293 cells after one week of storage at 4 degrees C with a lesser extent of efficiency loss compared with classical calcium phosphate, indicating that protamine sulfate may increase the stability of calcium phosphate nanoparticles. The cell viability inhibition assay indicated that both nanoparticles show similar low cell toxicity. CONCLUSION: PS-CaP can be used as a better nonviral transfection vector compared with classical calcium phosphate. PMID- 21556347 TI - Dispersion stability and exothermic properties of DNA-functionalized single walled carbon nanotubes. AB - Carbon nanotubes act as a photon antenna that serves as an effective "molecular heater" around the near-infrared (NIR) region. This exothermic generation can be used as a possible heating source for hyperthermia therapy. The current study reports the dispersible and exothermic properties with NIR irradiation for single walled carbon nanotubes (SWNTs) treated with a strong acid (acid-treated SWNTs), and the SWNTs further functionalized with double-stranded DNA (DNA-functionalized SWNTs: DNA-SWNTs). DNA-SWNTs significantly improved the dispersibility of SWNTs when compared with the acid-treated SWNTs. The binding ratio of the acid-treated SWNT and DNA was calculated to be 3.1 (DNA/SWNTs) from the phosphorous content in the DNA-SWNT. This interaction of the SWNTs and DNA would contribute to the stable dispersion of the DNA-SWNTs in a culture medium. With NIR irradiation by a halogen lamp light source, the acid-treated SWNTs and the DNA-SWNTs showed strong heat evolution in vitro (in a culture medium) and in vivo (in the subcutaneous tissue of a mouse) condition without any invasive effect on the non-SWNT area. The results of this study suggested that the functionalization with DNA was an efficient approach to improve the dispersibility of SWNTs in body fluids, and the DNA-SWNT would be a promising source for photo-induced exothermic generation. PMID- 21556348 TI - Optimization of single-walled carbon nanotube solubility by noncovalent PEGylation using experimental design methods. AB - In this study, noncovalent functionalization of single-walled carbon nanotubes (SWCNTs) with phospholipid-polyethylene glycols (Pl-PEGs) was performed to improve the solubility of SWCNTs in aqueous solution. Two kinds of PEG derivatives, ie, Pl-PEG 2000 and Pl-PEG 5000, were used for the PEGylation process. An experimental design technique (D-optimal design and second-order polynomial equations) was applied to investigate the effect of variables on PEGylation and the solubility of SWCNTs. The type of PEG derivative was selected as a qualitative parameter, and the PEG/SWCNT weight ratio and sonication time were applied as quantitative variables for the experimental design. Optimization was performed for two responses, aqueous solubility and loading efficiency. The grafting of PEG to the carbon nanostructure was determined by thermogravimetric analysis, Raman spectroscopy, and scanning electron microscopy. Aqueous solubility and loading efficiency were determined by ultraviolet-visible spectrophotometry and measurement of free amine groups, respectively. Results showed that Pl-PEGs were grafted onto SWCNTs. Aqueous solubility of 0.84 mg/mL and loading efficiency of nearly 98% were achieved for the prepared Pl-PEG 5000 SWCNT conjugates. Evaluation of functionalized SWCNTs showed that our noncovalent functionalization protocol could considerably increase aqueous solubility, which is an essential criterion in the design of a carbon nanotube-based drug delivery system and its biodistribution. PMID- 21556349 TI - Satisfaction survey on the critical care response team services in a teaching hospital. AB - INTRODUCTION: Patient care and safety is the main goal and mission of any health care provider. We surveyed nurses in the wards and obtained their feedback about the quality of care delivered by the Critical Care Response Team (CCRT). METHODS: Our hospital has 900 beds. A self-administered survey was given onsite to all ward nurses. Survey items were identified, discussed, reviewed, piloted, and finalized over a 3-month period in a focus group discussion format during three CCRT core group meetings. Responses were anonymous and collected by the nurses onsite. RESULTS: The total number of returned and analyzed surveys was 274 (98.6%). Ninety-seven percent agreed that CCRT staff arrived in a timely manner. Ninety-four percent reported that CCRT staff helped in managing sick patients and ~70% reported that it strengthened team dynamics. Only 50% of the nurses felt CCRT staff improved competence at the bedside. The overall satisfaction was 100%; none of the nurses were dissatisfied with the team. CONCLUSION: The CCRT helped manage sick patients in the wards. However, CRRT staff should remember to involve and communicate with the team initiator and the patient's physician to optimize patient health care. PMID- 21556350 TI - Traumeel - an emerging option to nonsteroidal anti-inflammatory drugs in the management of acute musculoskeletal injuries. AB - Musculoskeletal injuries are on the rise. First-line management of such injuries usually employs the RICE (rest, ice, compression, and elevation) approach to limit excessive inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also commonly used to limit inflammation and to control pain. Traumeel((r)), a preparation with bioregulatory effects is also used to treat the symptoms associated with acute musculoskeletal injuries, including pain and swelling. Traumeel is a fixed combination of biological and mineral extracts, which aims to apply stimuli to multiple targets to restore normal functioning of regulatory mechanisms. This paper presents the accumulating evidence of Traumeel's action on the inflammatory process, and of its efficacy and tolerability in randomized trials, as well as observational and surveillance studies for the treatment of musculoskeletal injuries. Traumeel has shown comparable effectiveness to NSAIDs in terms of reducing symptoms of inflammation, accelerating recovery, and improving mobility, with a favorable safety profile. While continued research and development is ongoing to broaden the clinical evidence of Traumeel in acute musculoskeletal injury and to further establish its benefits, current information suggests that Traumeel may be considered as an anti-inflammatory agent that is at least as effective and appears to be better tolerated than NSAIDs. PMID- 21556351 TI - Appendiceal pus in a hernia sac simulating strangulated femoral hernia: a case report. AB - Acute appendicitis involving the hernia sac is infrequent but well-documented in medical literature. In most instances, it occurs within the right inguinal (Amyand's hernia) or right femoral hernia (de Garengeot hernia). The diagnosis is always mistaken for incarcerated groin hernia. During surgery, the appendix itself, either perforated or strangulated, is most commonly encountered within the hernia sac. In very rare occasions, only appendiceal pus is found in the hernia sac. In this paper, we report the case of a 90-year-old woman with acute appendicitis and a tender mass in the right groin. Typical findings of acute appendicitis by computed tomography (CT) and incarcerated femoral hernia with groin cellulitis misled us into preoperative diagnosis of strangulated femoral hernia. Acute phlegmonous inflammation of the incarcerated femoral hernia sac containing pus only and acute suppurative appendicitis were found intraoperatively. This case presents a rare complication of acute appendicitis and the first report of CT-documented appendiceal pus-contained femoral hernia. Knowledge of this rare condition is helpful in establishing preoperative diagnosis and patient management decisions. PMID- 21556352 TI - Irvalec inserts into the plasma membrane causing rapid loss of integrity and necrotic cell death in tumor cells. AB - Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca(2+) influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn(2+). Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity. PMID- 21556353 TI - A soluble acetylcholinesterase provides chemical defense against xenobiotics in the pinewood nematode. AB - The pinewood nematode genome encodes at least three distinct acetylcholinesterases (AChEs). To understand physiological roles of the three pinewood nematode AChEs (BxACE-1, BxACE-2, and BxACE-3), BxACE-3 in particular, their tissue distribution and inhibition profiles were investigated. Immunohistochemistry revealed that BxACE-1 and BxACE-2 were distributed in neuronal tissues. In contrast, BxACE-3 was detected from some specific tissues and extracted without the aid of detergent, suggesting its soluble nature unlike BxACE-1 and BxACE-2. When present together, BxAChE3 significantly reduced the inhibition of BxACE-1 and BxACE-2 by cholinesterase inhibitors. Knockdown of BxACE-3 by RNA interference significantly increased the toxicity of three nematicidal compounds, supporting the protective role of BxACE-3 against chemicals. In summary, BxACE-3 appears to have a non-neuronal function of chemical defense whereas both BxACE-1 and BxACE-2 have classical neuronal function of synaptic transmission. PMID- 21556354 TI - Interleukin and growth factor levels in subretinal fluid in rhegmatogenous retinal detachment: a case-control study. AB - BACKGROUND: Rhegmatogenous retinal detachment (RRD) is a major cause of visual loss in developed countries. Proliferative vitreoretinopathy (PVR), an eye-sight threatening complication of RRD surgery, resembles a wound-healing process with inflammation, scar tissue formation, and membrane contraction. This study was performed to determine the possible involvement of a wide range of cytokines in the future development of PVR, and to identify predictors of PVR and visual outcome. METHODOLOGY: A multiplex immunoassay was used for the simultaneous detection of 29 different cytokines in subretinal fluid samples from patients with primary RRD. Of 306 samples that were collected and stored in our BioBank between 2001 and 2008, 21 samples from patients who developed postoperative PVR were compared with 54 age-, sex-, and storage-time-matched RRD control patients who had an uncomplicated postoperative course during the overall follow-up period. FINDINGS: Levels of IL-1alpha, IL-2, IL-3, IL-6, VEGF, and ICAM-1 were significantly higher (P<0.05) in patients who developed postoperative PVR after reattachment surgery than in patients with an uncomplicated postoperative course, whereas levels of IL-1beta, IL-4, IL-5, IL-7, IL-9, IL-10, IL-11, IL-12p70, IL 13, IL-15, IL-17, IL-18, IL-21, IL-22, IL-23, IL-25, IL-33, TNF-alpha, IFN-gamma, IGF-1, bFGF, HGF, and NGF were not (P>0.05). Multivariate logistic regression analysis revealed that IL-3 (P = 0.001), IL-6 (P = 0.047), ICAM-1 (P = 0.010), and preoperative visual acuity (P = 0.026) were independent predictors of postoperative PVR. Linear regression analysis showed that ICAM-1 (P = 0.005) and preoperative logMAR visual acuity (P = 0.001) were predictive of final visual outcome after primary RRD repair. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that after RRD onset an exaggerated response of certain cytokines may predispose to PVR. Sampling at a time close to the onset of primary RRD may thus provide clues as to which biological events may initiate the development of PVR and, most importantly, may provide a means for therapeutic control. PMID- 21556355 TI - The relationship among oceanography, prey fields, and beaked whale foraging habitat in the Tongue of the Ocean. AB - Beaked whales, specifically Blainville's (Mesoplodon densirostris) and Cuvier's (Ziphius cavirostris), are known to feed in the Tongue of the Ocean, Bahamas. These whales can be reliably detected and often localized within the Atlantic Undersea Test and Evaluation Center (AUTEC) acoustic sensor system. The AUTEC range is a regularly spaced bottom mounted hydrophone array covering >350 nm(2) providing a valuable network to record anthropogenic noise and marine mammal vocalizations. Assessments of the potential risks of noise exposure to beaked whales have historically occurred in the absence of information about the physical and biological environments in which these animals are distributed. In the fall of 2008, we used a downward looking 38 kHz SIMRAD EK60 echosounder to measure prey scattering layers concurrent with fine scale turbulence measurements from an autonomous turbulence profiler. Using an 8 km, 4-leaf clover sampling pattern, we completed a total of 7.5 repeat surveys with concurrently measured physical and biological oceanographic parameters, so as to examine the spatiotemporal scales and relationships among turbulence levels, biological scattering layers, and beaked whale foraging activity. We found a strong correlation among increased prey density and ocean vertical structure relative to increased click densities. Understanding the habitats of these whales and their utilization patterns will improve future models of beaked whale habitat as well as allowing more comprehensive assessments of exposure risk to anthropogenic sound. PMID- 21556356 TI - Pan-European distribution of white-nose syndrome fungus (Geomyces destructans) not associated with mass mortality. AB - BACKGROUND: The dramatic mass mortalities amongst hibernating bats in Northeastern America caused by "white nose-syndrome" (WNS) continue to threaten populations of different bat species. The cold-loving fungus, Geomyces destructans, is the most likely causative agent leading to extensive destruction of the skin, particularly the wing membranes. Recent investigations in Europe confirmed the presence of the fungus G. destructans without associated mass mortality in hibernating bats in six countries but its distribution remains poorly known. METHODOLOGY/PRINCIPAL FINDINGS: We collected data on the presence of bats with white fungal growth in 12 countries in Europe between 2003 and 2010 and conducted morphological and genetic analysis to confirm the identity of the fungus as Geomyces destructans. Our results demonstrate the presence of the fungus in eight countries spanning over 2000 km from West to East and provide compelling photographic evidence for its presence in another four countries including Romania, and Turkey. Furthermore, matching prevalence data of a hibernaculum monitored over two consecutive years with data from across Europe show that the temporal occurrence of the fungus, which first becomes visible around February, peaks in March but can still be seen in some torpid bats in May or June, is strikingly similar throughout Europe. Finally, we isolated and cultured G. destructans from a cave wall adjacent to a bat with fungal growth. CONCLUSIONS/SIGNIFICANCE: G. destructans is widely found over large areas of the European continent without associated mass mortalities in bats, suggesting that the fungus is native to Europe. The characterisation of the temporal variation in G. destructans growth on bats provides reference data for studying the spatio temporal dynamic of the fungus. Finally, the presence of G. destructans spores on cave walls suggests that hibernacula could act as passive vectors and/or reservoirs for G. destructans and therefore, might play an important role in the transmission process. PMID- 21556357 TI - Health systems and sustainability: doctors and consumers differ on threats and solutions. AB - BACKGROUND: Healthcare systems face the problem of insufficient resources to meet the needs of ageing populations and increasing demands for access to new treatments. It is unclear whether doctors and consumers agree on the main challenges to health system sustainability. METHODOLOGY: We conducted a mail survey of Australian doctors (specialists and general practitioners) and a computer assisted telephone interview (CATI) of consumers to determine their views on contributors to increasing health care costs, rationing of services and involvement in health resource allocation decisions. Differences in responses are reported as odds ratios (OR) and 99% confidence intervals (CI). RESULTS: Of 2948 doctors, 1139 (38.6%) responded; 533 of 826 consumers responded (64.5% response). Doctors were more concerned than consumers with the effects of an ageing population (OR 3.0; 99% CI 1.7, 5.4), and costs of new drugs and technologies (OR 5.1; CI 3.3, 8.0), but less likely to consider pharmaceutical promotional activities as a cost driver (OR 0.29, CI 0.22, 0.39). Doctors were more likely than consumers to view 'community demand' for new technologies as a major cost driver, (OR 1.6; 1.2, 2.2), but less likely to attribute increased costs to patients failing to take responsibility for their own health (OR 0.35; 0.24, 0.49). Like doctors, the majority of consumers saw a need for public consultation in decisions about funding for new treatments. CONCLUSIONS: Australian doctors and consumers hold different views on the sustainability of the healthcare system, and a number of key issues relating to costs, cost drivers, roles and responsibilities. Doctors recognise their dual responsibility to patients and society, see an important role for physicians in influencing resource allocation, and acknowledge their lack of skills in assessing treatments of marginal value. Consumers recognise cost pressures on the health system, but express willingness to be involved in health care decision making. PMID- 21556358 TI - Sharing data for public health research by members of an international online diabetes social network. AB - BACKGROUND: Surveillance and response to diabetes may be accelerated through engaging online diabetes social networks (SNs) in consented research. We tested the willingness of an online diabetes community to share data for public health research by providing members with a privacy-preserving social networking software application for rapid temporal-geographic surveillance of glycemic control. METHODS AND FINDINGS: SN-mediated collection of cross-sectional, member reported data from an international online diabetes SN entered into a software application we made available in a "Facebook-like" environment to enable reporting, charting and optional sharing of recent hemoglobin A1c values through a geographic display. Self-enrollment by 17% (n = 1,136) of n = 6,500 active members representing 32 countries and 50 US states. Data were current with 83.1% of most recent A1c values reported obtained within the past 90 days. Sharing was high with 81.4% of users permitting data donation to the community display. 34.1% of users also displayed their A1cs on their SN profile page. Users selecting the most permissive sharing options had a lower average A1c (6.8%) than users not sharing with the community (7.1%, p = .038). 95% of users permitted re-contact. Unadjusted aggregate A1c reported by US users closely resembled aggregate 2007 2008 NHANES estimates (respectively, 6.9% and 6.9%, p = 0.85). CONCLUSIONS: Success within an early adopter community demonstrates that online SNs may comprise efficient platforms for bidirectional communication with and data acquisition from disease populations. Advancing this model for cohort and translational science and for use as a complementary surveillance approach will require understanding of inherent selection and publication (sharing) biases in the data and a technology model that supports autonomy, anonymity and privacy. PMID- 21556359 TI - Novel autism subtype-dependent genetic variants are revealed by quantitative trait and subphenotype association analyses of published GWAS data. AB - The heterogeneity of symptoms associated with autism spectrum disorders (ASDs) has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL), were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression) than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders. PMID- 21556360 TI - Evolutionary history of hunter-gatherer marriage practices. AB - BACKGROUND: The universality of marriage in human societies around the world suggests a deep evolutionary history of institutionalized pair-bonding that stems back at least to early modern humans. However, marriage practices vary considerably from culture to culture, ranging from strict prescriptions and arranged marriages in some societies to mostly unregulated courtship in others, presence to absence of brideservice and brideprice, and polyandrous to polygynous unions. The ancestral state of early human marriage is not well known given the lack of conclusive archaeological evidence. METHODOLOGY: Comparative phylogenetic analyses using data from contemporary hunter-gatherers around the world may allow for the reconstruction of ancestral human cultural traits. We attempt to reconstruct ancestral marriage practices using hunter-gatherer phylogenies based on mitochondrial DNA sequences. RESULTS: Arranged marriages are inferred to go back at least to first modern human migrations out of Africa. Reconstructions are equivocal on whether or not earlier human marriages were arranged because several African hunter-gatherers have courtship marriages. Phylogenetic reconstructions suggest that marriages in early ancestral human societies probably had low levels of polygyny (low reproductive skew) and reciprocal exchanges between the families of marital partners (i.e., brideservice or brideprice). DISCUSSION: Phylogenetic results suggest a deep history of regulated exchange of mates and resources among lineages that enhanced the complexity of human meta-group social structure with coalitions and alliances spanning across multiple residential communities. PMID- 21556361 TI - How to obtain NNT from Cohen's d: comparison of two methods. AB - BACKGROUND: In the literature we find many indices of size of treatment effect (effect size: ES). The preferred index of treatment effect in evidence-based medicine is the number needed to treat (NNT), while the most common one in the medical literature is Cohen's d when the outcome is continuous. There is confusion about how to convert Cohen's d into NNT. METHODS: We conducted meta analyses of individual patient data from 10 randomized controlled trials of second generation antipsychotics for schizophrenia (n = 4278) to produce Cohen's d and NNTs for various definitions of response, using cutoffs of 10% through 90% reduction on the symptom severity scale. These actual NNTs were compared with NNTs calculated from Cohen's d according to two proposed methods in the literature (Kraemer, et al., Biological Psychiatry, 2006; Furukawa, Lancet, 1999). RESULTS: NNTs from Kraemer's method overlapped with the actual NNTs in 56%, while those based on Furukawa's method fell within the observed ranges of NNTs in 97% of the examined instances. For various definitions of response corresponding with 10% through 70% symptom reduction where we observed a non small number of responders, the degree of agreement for the former method was at a chance level (ANOVA ICC of 0.12, p = 0.22) but that for the latter method was ANOVA ICC of 0.86 (95%CI: 0.55 to 0.95, p<0.01). CONCLUSIONS: Furukawa's method allows more accurate prediction of NNTs from Cohen's d. Kraemer's method gives a wrong impression that NNT is constant for a given d even when the event rate differs. PMID- 21556362 TI - Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults. AB - BACKGROUND: Previous studies have demonstrated that fetuin-A is related to insulin resistance among subjects with normal glucose tolerance but not patients with type 2 diabetes. There are limited data available concerning fetuin-A and insulin resistance in Chinese. We aimed to study the association of fetuin-A with insulin resistance among participants with or without type 2 diabetes in a large sample size of adults aged 40 and older. METHODOLOGY AND PRINCIPAL FINDINGS: A community-based cross-sectional study was performed among 5,227 Chinese adults. The average age of our study was 61.5+/-9.9 years. Serum fetuin-A concentrations were not significantly different between male and female (296.9 vs. 292.9 mg/l, p = 0.11). Compared with the lowest quartile, the highest quartile of serum fetuin A revealed a significant higher proportion of type 2 diabetic patients (34.8% vs. 27.3%, p<0.0001). In the multinomial logit models, the risk of type 2 diabetes was associated with each one quartile increase of serum fetuin-A concentrations when referenced not only to normal glucose tolerance (OR 1.24, 95% CI 1.07-1.43, p = 0.004) but also to impaired glucose regulation (OR 1.25, 95% CI 1.08-1.44, p = 0.003, respectively), after adjustment for age, sex, community, current smoking, and current drinking. The logistic regression analysis showed that fetuin-A were associated with elevated HOMA-IR and fasting serum insulin both among the participants with or without type 2 diabetes in the full adjusted analysis. There was no significant association between elevated serum fetuin-A concentrations and impaired glucose regulation (all p>=0.12). CONCLUSIONS AND SIGNIFICANCE: Higher fetuin-A concentrations were associated with type 2 diabetes and insulin resistance in middle aged and elderly Chinese. PMID- 21556363 TI - Perceived object stability depends on multisensory estimates of gravity. AB - BACKGROUND: How does the brain estimate object stability? Objects fall over when the gravity-projected centre-of-mass lies outside the point or area of support. To estimate an object's stability visually, the brain must integrate information across the shape and compare its orientation to gravity. When observers lie on their sides, gravity is perceived as tilted toward body orientation, consistent with a representation of gravity derived from multisensory information. We exploited this to test whether vestibular and kinesthetic information affect this visual task or whether the brain estimates object stability solely from visual information. METHODOLOGY/PRINCIPAL FINDINGS: In three body orientations, participants viewed images of objects close to a table edge. We measured the critical angle at which each object appeared equally likely to fall over or right itself. Perceived gravity was measured using the subjective visual vertical. The results show that the perceived critical angle was significantly biased in the same direction as the subjective visual vertical (i.e., towards the multisensory estimate of gravity). CONCLUSIONS/SIGNIFICANCE: Our results rule out a general explanation that the brain depends solely on visual heuristics and assumptions about object stability. Instead, they suggest that multisensory estimates of gravity govern the perceived stability of objects, resulting in objects appearing more stable than they are when the head is tilted in the same direction in which they fall. PMID- 21556364 TI - Dose-dependent onset of regenerative program in neutron irradiated mouse skin. AB - BACKGROUND: Tissue response to irradiation is not easily recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons. METHODOLOGY/PRINCIPAL FINDINGS: To monitor general response to irradiation and individual animal to animal variation, we performed gene and protein expression analysis with both pooled and individual mouse samples. A high-throughput gene expression analysis, by DNA oligonucleotide microarray was done with three months old C57Bl/6 mice irradiated with 0.2 and 1 Gy of mono-energetic 14 MeV neutron compared to sham irradiated controls. The results on 440 irradiation modulated genes, partially validated by quantitative real time RT-PCR, showed a dose-dependent up-regulation of a sub class of keratin and keratin associated proteins, and members of the S100 family of Ca(2+)-binding proteins. Immunohistochemistry confirmed mRNA expression data enabled mapping of protein expression. Interestingly, proteins up-regulated in thickening epidermis: keratin 6 and S100A8 showed the most significant up regulation and the least mouse-to-mouse variation following 0.2 Gy irradiation, in a concerted effort toward skin tissue regeneration. Conversely, mice irradiated at 1 Gy showed most evidence of apoptosis (Caspase-3 and TUNEL staining) and most 8-oxo-G accumulation at 24 h post-irradiation. Moreover, no cell proliferation accompanied 1 Gy exposure as shown by Ki67 immunohistochemistry. CONCLUSIONS/SIGNIFICANCE: The dose-dependent differential gene expression at the tissue level following in vivo exposure to neutron radiation is reminiscent of the onset of re-epithelialization and wound healing and depends on the proportion of cells carrying multiple chromosomal lesions in the entire tissue. Thus, this study presents in vivo evidence of a skin regenerative program exerted independently from DNA repair-associated pathways. PMID- 21556365 TI - Methamphetamine inhibits the glucose uptake by human neurons and astrocytes: stabilization by acetyl-L-carnitine. AB - Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 uM increased the uptake while 200 uM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial beta-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers. PMID- 21556366 TI - Predictive and prognostic impact of TP53 mutations and MDM2 promoter genotype in primary breast cancer patients treated with epirubicin or paclitaxel. AB - BACKGROUND: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy. EXPERIMENTAL DESIGN: Each patient was randomly assigned to treatment with epirubicin 90 mg/m(2) (n = 109) or paclitaxel 200 mg/m(2) (n = 114) every 3rd week as monotherapy for 4-6 cycles. Patients obtaining a suboptimal response on first line treatment requiring further chemotherapy received the opposite regimen. Time from last patient inclusion to follow-up censoring was 69 months. Each patient had snap-frozen tumor tissue specimens collected prior to commencing chemotherapy. PRINCIPAL FINDINGS: While TP53 and CHEK2 mutations predicted resistance to epirubicin, MDM2 status did not. Neither TP53/CHEK2 mutations nor MDM2 status was associated with paclitaxel response. Remarkably, TP53 mutations (p = 0.007) but also MDM2 309TG/GG genotype status (p = 0.012) were associated with a poor disease-specific survival among patients having paclitaxel but not patients having epirubicin first-line. The effect of MDM2 status was observed among individuals harbouring wild-type TP53 (p = 0.039) but not among individuals with TP53 mutated tumors (p>0.5). CONCLUSION: TP53 and CHEK2 mutations were associated with lack of response to epirubicin monotherapy. In contrast, TP53 mutations and MDM2 309G allele status conferred poor disease-specific survival among patients treated with primary paclitaxel but not epirubicin monotherapy. PMID- 21556367 TI - Apoptosis at inflection point in liquid culture of budding yeasts. AB - Budding yeasts are highly suitable for aging studies, because the number of bud scars (stage) proportionally correlates with age. Its maximum stages are known to reach at 20-30 stages on an isolated agar medium. However, their stage dynamics in a liquid culture is virtually unknown. We investigate the population dynamics by counting scars in each cell. Here one cell division produces one new cell and one bud scar. This simple rule leads to a conservation law: "The total number of bud scars is equal to the total number of cells." We find a large discrepancy: extremely fewer cells with over 5 scars than expected. Almost all cells with 6 or more scars disappear within a short period of time in the late log phase (corresponds to the inflection point). This discrepancy is confirmed directly by the microscopic observations of broken cells. This finding implies apoptosis in older cells (6 scars or more). PMID- 21556368 TI - Infant milk feeding influences adult bone health: a prospective study from birth to 32 years. AB - BACKGROUND: Peak bone mass, attained by early adulthood, is influenced by genetic and life-style factors. Early infant feeding and duration of breastfeeding in particular, associate with several health-related parameters in childhood. The aim of this study was to examine whether the effects of early infant feeding extend to peak bone mass and other bone health characteristics at adult age. METHODS AND FINDINGS: A cohort of 158 adults (76 males) born in Helsinki, Finland, 1975, prospectively followed up from birth, underwent physical examination and bone densitometry to study bone area, bone mineral content (BMC), and bone mineral density (BMD) at 32 years of age. Life-style factors relevant for bone health were recorded. For data analysis the cohort was divided into three equal-size groups according to the total duration of breastfeeding (BF): Short (<=3 months), Intermediate and Prolonged (>=7 months) BF groups. In males short BF is associated with higher bone area, BMC, and BMD compared to longer BF. Males in the Short BF group had on average 4.7% higher whole body BMD than males in the Prolonged BF group. In multivariate analysis, after controlling for multiple confounding factors, the influence of BF duration on adult bone characteristics persisted in males. Differences between the three feeding groups were observed in lumbar spine bone area and BMC, and whole body BMD (MANCOVA; p = 0.025, p = 0.013, and p = 0.048, respectively), favoring the Short BF group. In women no differences were observed. CONCLUSIONS: In men, early infant milk feeding may have a significant impact on adult bone health. A potential explanation is that the calcium and phosphate contents were strikingly higher in formula milk and commercial cow milk/cow milk dilutions as opposed to human milk. Our novel finding merits further studies to determine means to ensure optimal bone mass development in infants with prolonged breastfeeding. PMID- 21556369 TI - Postural control during the Stroop test in dyslexic and non dyslexic teenagers. AB - Postural control in quiet stance although simple still requires some cognitive resources; dual cognitive tasks influence further postural control. The present study examines whether or not dyslexic teenagers experience postural instability when performing a Stroop dual task for which their performances are known to be poor. Fifteen dyslexics and twelve non-dyslexics (14 to 17 years old) were recruited from the same school. They were asked to perform three tasks: (1) fixate a target, (2) perform an interference Stroop test (naming the colour or the word rather than reading the word), (3) performing flexibility Stroop task: the subject performed the interference task as in (2) except when the word was in a box, in which case he had to read the word. Postural performances were measured with a force platform. The results showed a main task effect on the variance of speed of body sway only: such variance was higher in the flexibility task than for the other two tasks. No group effect was found for any of the parameters of posture (surface, mediolateral and anteroposterior sway, variance of speed). Further wavelet analysis in the time-frequency domain revealed an increase in the spectral power of the medium frequency range believed to be related to cerebellum control; an accompanying increase in the cancellation time of the high frequency band related to reflexive loops occurred for non-dyslexics only. These effects occurred for the flexibility task and could be due to its high cognitive difficulty. Dyslexics displayed shorter cancellation time for the medium frequency band for all tasks, suggesting less efficient cerebellar control, perhaps of eye fixation and attention influencing body sway. We conclude that there is no evidence for a primary posture deficit in 15 year old teenagers who come from the general population and who were recruited in schools. PMID- 21556370 TI - The effect of interpersonal psychotherapy and other psychodynamic therapies versus 'treatment as usual' in patients with major depressive disorder. AB - BACKGROUND: Major depressive disorder afflicts an estimated 17% of individuals during their lifetimes at tremendous suffering and costs. Interpersonal psychotherapy and other psychodynamic therapies may be effective interventions for major depressive disorder, but the effects have only had limited assessment in systematic reviews. METHODS/PRINCIPAL FINDINGS: Cochrane systematic review methodology with meta-analysis and trial sequential analysis of randomized trials comparing the effect of psychodynamic therapies versus 'treatment as usual' for major depressive disorder. To be included the participants had to be older than 17 years with a primary diagnosis of major depressive disorder. Altogether, we included six trials randomizing a total of 648 participants. Five trials assessed 'interpersonal psychotherapy' and only one trial assessed 'psychodynamic psychotherapy'. All six trials had high risk of bias. Meta-analysis on all six trials showed that the psychodynamic interventions significantly reduced depressive symptoms on the 17-item Hamilton Rating Scale for Depression (mean difference -3.12 (95% confidence interval -4.39 to -1.86;P<0.00001), no heterogeneity) compared with 'treatment as usual'. Trial sequential analysis confirmed this result. DISCUSSION: We did not find convincing evidence supporting or refuting the effect of interpersonal psychotherapy or psychodynamic therapy compared with 'treatment as usual' for patients with major depressive disorder. The potential beneficial effect seems small and effects on major outcomes are unknown. Randomized trials with low risk of systematic errors and low risk of random errors are needed. PMID- 21556371 TI - Coenzyme Q10 reduces ethanol-induced apoptosis in corneal fibroblasts. AB - Dilute ethanol (EtOH) is a widely used agent to remove the corneal epithelium during the modern refractive surgery. The application of EtOH may cause the underlying corneal fibroblasts to undergo apoptosis. This study was designed to investigate the protective effect and potential mechanism of the respiratory chain coenzyme Q(10) (CoQ(10)), an electron transporter of the mitochondrial respiratory chain and a ubiquitous free radical scavenger, against EtOH-induced apoptosis of corneal fibroblasts. Corneal fibroblasts were pretreated with CoQ(10) (10 uM) for 2 h, followed by exposure to different concentrations of EtOH (0.4, 2, 4, and 20%) for 20 s. After indicated incubation period (2-12 h), MTT assay was used to examine cell viability. Treated cells were further assessed by flow cytometry to identify apoptosis. Reactive oxygen species (ROS) and the change in mitochondrial membrane potential were assessed using dichlorodihydrofluorescein diacetate/2',7'-dichlorofluorescein (DCFH-DA/DCF) assays and flow-cytometric analysis of JC-1 staining, respectively. The activity and expression of caspases 2, 3, 8, and 9 were evaluated with a colorimetric assay and western blot analysis. We found that EtOH treatment significantly decreased the viability of corneal fibroblasts characterized by a higher percentage of apoptotic cells. CoQ(10) could antagonize the apoptosis inducing effect of EtOH. The inhibition of cell apoptosis by CoQ(10) was significant at 8 and 12 h after EtOH exposure. In EtOH-exposed corneal fibroblasts, CoQ(10) pretreatment significantly reduced mitochondrial depolarization and ROS production at 30, 60, 90, and 120 min and inhibited the activation and expression of caspases 2 and 3 at 2 h after EtOH exposure. In summary, pretreatment with CoQ(10) can inhibit mitochondrial depolarization, caspase activation, and cell apoptosis. These findings support the proposition that CoQ(10) plays an antiapoptotic role in corneal fibroblasts after ethanol exposure. PMID- 21556372 TI - A neural correlate of the processing of multi-second time intervals in primate prefrontal cortex. AB - Several areas of the brain are known to participate in temporal processing. Neurons in the prefrontal cortex (PFC) are thought to contribute to perception of time intervals. However, it remains unclear whether the PFC itself can generate time intervals independently of external stimuli. Here we describe a group of PFC neurons in area 9 that became active when monkeys recognized a particular elapsed time within the range of 1-7 seconds. Another group of area 9 neurons became active only when subjects reproduced a specific interval without external cues. Both types of neurons were individually tuned to recognize or reproduce particular intervals. Moreover, the injection of muscimol, a GABA agonist, into this area bilaterally resulted in an increase in the error rate during time interval reproduction. These results suggest that area 9 may process multi-second intervals not only in perceptual recognition, but also in internal generation of time intervals. PMID- 21556373 TI - Fractal analysis reveals reduced complexity of retinal vessels in CADASIL. AB - The Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) affects mainly small cerebral arteries and leads to disability and dementia. The relationship between clinical expression of the disease and progression of the microvessel pathology is, however, uncertain as we lack tools for imaging brain vessels in vivo. Ophthalmoscopy is regarded as a window into the cerebral microcirculation. In this study we carried out an ophthalmoscopic examination in subjects with CADASIL. Specifically, we performed fractal analysis of digital retinal photographs. Data are expressed as mean fractal dimension (mean-D), a parameter that reflects complexity of the retinal vessel branching. Ten subjects with genetically confirmed diagnosis of CADASIL and 10 sex and age-matched control subjects were enrolled. Fractal analysis of retinal digital images was performed by means of a computer-based program, and the data expressed as mean-D. Brain MRI lesion volume in FLAIR and T1-weighted images was assessed using MIPAV software. Paired t-test was used to disclose differences in mean-D between CADASIL and control groups. Spearman rank analysis was performed to evaluate potential associations between mean-D values and both disease duration and disease severity, the latter expressed as brain MRI lesion volumes, in the subjects with CADASIL. The results showed that mean-D value of patients (1.42+/-0.05; mean+/-SD) was lower than control (1.50+/-0.04; p = 0.002). Mean-D did not correlate with disease duration nor with MRI lesion volumes of the subjects with CADASIL. The findings suggest that fractal analysis is a sensitive tool to assess changes of retinal vessel branching, likely reflecting early brain microvessel alterations, in CADASIL patients. PMID- 21556374 TI - Unconventional secretion of tissue transglutaminase involves phospholipid dependent delivery into recycling endosomes. AB - Although endosomal compartments have been suggested to play a role in unconventional protein secretion, there is scarce experimental evidence for such involvement. Here we report that recycling endosomes are essential for externalization of cytoplasmic secretory protein tissue transglutaminase (tTG). The de novo synthesized cytoplasmic tTG does not follow the classical ER/Golgi dependent secretion pathway, but is targeted to perinuclear recycling endosomes, and is delivered inside these vesicles prior to externalization. On its route to the cell surface tTG interacts with internalized beta1 integrins inside the recycling endosomes and is secreted as a complex with recycled beta1 integrins. Inactivation of recycling endosomes, blocking endosome fusion with the plasma membrane, or downregulation of Rab11 GTPase that controls outbound trafficking of perinuclear recycling endosomes, all abrogate tTG secretion. The initial recruitment of cytoplasmic tTG to recycling endosomes and subsequent externalization depend on its binding to phosphoinositides on endosomal membranes. These findings begin to unravel the unconventional mechanism of tTG secretion which utilizes the long loop of endosomal recycling pathway and indicate involvement of endosomal trafficking in non-classical protein secretion. PMID- 21556375 TI - The host defense proteome of human and bovine milk. AB - Milk is the single source of nutrients for the newborn mammal. The composition of milk of different mammals has been adapted during evolution of the species to fulfill the needs of the offspring. Milk not only provides nutrients, but it also serves as a medium for transfer of host defense components to the offspring. The host defense proteins in the milk of different mammalian species are expected to reveal signatures of evolution. The aim of this study is therefore to study the difference in the host defense proteome of human and bovine milk. We analyzed human and bovine milk using a shot-gun proteomics approach focusing on host defense-related proteins. In total, 268 proteins in human milk and 269 proteins in bovine milk were identified. Of these, 44 from human milk and 51 from bovine milk are related to the host defense system. Of these proteins, 33 were found in both species but with significantly different quantities. High concentrations of proteins involved in the mucosal immune system, immunoglobulin A, CD14, lactoferrin, and lysozyme, were present in human milk. The human newborn is known to be deficient for at least two of these proteins (immunoglobulin A and CD14). On the other hand, antimicrobial proteins (5 cathelicidins and lactoperoxidase) were abundant in bovine milk. The high concentration of lactoperoxidase is probably linked to the high amount of thiocyanate in the plant-based diet of cows. This first detailed analysis of host defense proteins in human and bovine milk is an important step in understanding the function of milk in the development of the immune system of these two mammals. PMID- 21556376 TI - Dedifferentiation of human primary thyrocytes into multilineage progenitor cells without gene introduction. AB - While identification and isolation of adult stem cells have potentially important implications, recent reports regarding dedifferentiation/reprogramming from differentiated cells have provided another clue to gain insight into source of tissue stem/progenitor cells. In this study, we developed a novel culture system to obtain dedifferentiated progenitor cells from normal human thyroid tissues. After enzymatic digestion, primary thyrocytes, expressing thyroglobulin, vimentin and cytokeratin-18, were cultured in a serum-free medium called SAGM. Although the vast majority of cells died, a small proportion (~0.5%) survived and proliferated. During initial cell expansion, thyroglobulin/cytokeratin-18 expression was gradually declined in the proliferating cells. Moreover, sorted cells expressing thyroid peroxidase gave rise to proliferating clones in SAGM. These data suggest that those cells are derived from thyroid follicular cells or at least thyroid-committed cells. The SAGM-grown cells did not express any thyroid-specific genes. However, after four-week incubation with FBS and TSH, cytokeratin-18, thyroglobulin, TSH receptor, PAX8 and TTF1 expressions re emerged. Moreover, surprisingly, the cells were capable of differentiating into neuronal or adipogenic lineage depending on differentiating conditions. In summary, we have developed a novel system to generate multilineage progenitor cells from normal human thyroid tissues. This seems to be achieved by dedifferentiation of thyroid follicular cells. The presently described culture system may be useful for regenerative medicine, but the primary importance will be as a tool to elucidate the mechanisms of thyroid diseases. PMID- 21556377 TI - The combination of homocysteine and C-reactive protein predicts the outcomes of Chinese patients with Parkinson's disease and vascular parkinsonism. AB - BACKGROUND: The elevation of plasma homocysteine (Hcy) and C-reactive protein (CRP) has been correlated to an increased risk of Parkinson's disease (PD) or vascular diseases. The association and clinical relevance of a combined assessment of Hcy and CRP levels in patients with PD and vascular parkinsonism (VP) are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional study of 88 Chinese patients with PD and VP using a clinical interview and the measurement of plasma Hcy and CRP to determine if Hcy and CRP levels in patients may predict the outcomes of the motor status, non-motor symptoms (NMS), disease severity, and cognitive declines. Each patient's NMS, cognitive deficit, disease severity, and motor status were assessed by the Nonmotor Symptoms Scale (NMSS), Mini-Mental State Examination (MMSE), the modified Hoehn and Yahr staging scale (H&Y), and the unified Parkinson's disease rating scale part III (UPDRS III), respectively. We found that 100% of patients with PD and VP presented with NMS. The UPDRS III significantly correlated with CRP (P = 0.011) and NMSS (P = 0.042) in PD patients. The H&Y was also correlated with Hcy (P = 0.002), CRP (P = 0.000), and NMSS (P = 0.023) in PD patients. In VP patients, the UPDRS III and H&Y were not significantly associated with NMSS, Hcy, CRP, or MMSE. Strong correlations were observed between Hcy and NMSS as well as between CRP and NMSS in PD and VP. CONCLUSIONS/SIGNIFICANCE: Our findings support the hypothesis that Hcy and CRP play important roles in the pathogenesis of PD. The combination of Hcy and CRP may be used to assess the progression of PD and VP. Whether or not anti-inflammatory medication could be used in the management of PD and VP will produce an interesting topic for further research. PMID- 21556378 TI - Dental cone beam computed tomography analyses of postoperative labial bone thickness in maxillary anterior implants: comparing immediate and delayed implant placement. AB - This study aimed to evaluate the influence of labial alveolar bone thickness and the corresponding vertical bone loss on postoperative gingival recessions around anterior maxillary dental implants. Using cone beam computed tomography (CBCT) scanning, the temporal changes of three-dimensional images of alveolar bone were monitored to determine hard and soft tissue outcomes of two different implant placement techniques: delayed two-stage and immediate placement. Furthermore, for the delayed two-stage placement, guided bone regeneration was applied using either nonresorbable or resorbable membranes combined with anorganic bovine bone matrix. The comparative results suggested that gingival recessions were significantly lower in delayed two-stage placement, especially when using a nonresorbable membrane, compared to immediate placement, and labial bone thickness, measured by CBCT, offered an effectual indicator to assess gingival recession in the anterior region. PMID- 21556379 TI - The clinical and histologic efficacy of xenograft granules for maxillary sinus floor augmentation. AB - The objective of this study was to investigate the potential of xenograft (cancellous bovine bone) granules to form vital bone in non-natural bone-forming areas of maxillary sinuses. Fourteen sinus augmentations were performed in 14 patients. Surgical outcomes were uneventful, and sufficient radiopaque volume was present radiographically to place dental implants in all sites. Clinical reentry at 6 months revealed bone formation at the osteotomy site. Histologic evaluation of the obtained bone cores revealed that xenograft granules were integrated and surrounded by woven bone and lamellar bone that were in close contact with the particles. The average percentage of newly formed bone at 6 months was 27.5% +/- 8.9%. Vital bone formation using the xenograft granules was supported by both clinical and histologic evidence. PMID- 21556380 TI - Ridge enlargement using deproteinized bovine bone and a bioresorbable collagen membrane: a tomodensitometric, histologic, and histomorphometric analysis. AB - The aim of this paper was to study, through a clinical case report, the behavior of deproteinized bovine bone (Bio-Oss) covered with a resorbable barrier membrane (Bio-Gide) when used as an onlay grafting material to obtain alveolar bone ridge enlargement. The presence of an existing bone edge allowed placement of an MK III groovy implant and creation of the required space for ridge enlargement, using xenograft particles (Bio-Oss) covered with a resorbable barrier membrane (Bio Gide), during the same surgical stage. Recording of anatomical landmarks in the three dimensions of space in relation to implant position allowed precise assessment of the graft behavior during the tomodensitometric examinations performed at 6 and 18 months postsurgery. A biopsy was performed at 9 months postsurgery for histologic and histomorphometric analyses. The tomodensitometric images allowed observation of the preservation of the grafted bone volume. The histologic analysis revealed vital bone formation with the remaining Bio-Oss particles; the histomorphometric analysis, at this stage, provided similar percentages of Bio-Oss (27.94%) and newly formed bone (24.07%). This clinical example confirms the biocompatible and osseoconductive properties of Bio-Oss, as well as stability of the bone graft volume. These different elements testify to the advantage of its use for alveolar ridge enlargement. PMID- 21556381 TI - Coverage of gingival recession defects using guided tissue regeneration with and without adjunctive enamel matrix derivative in a dog model. AB - The aim of this study was to clarify the adjunctive effect of enamel matrix derivative (EMD) on expanded polytetrafluoroethylene membrane guided tissue regeneration (GTR)-based root coverage by creating gingival recessions in beagle dogs. Recessions were treated with GTR + EMD, GTR alone, or neither GTR nor EMD (control). The control group was characterized by long junctional epithelium and little bone formation. The GTR + EMD group showed a statistically significant increase (P < .01) in new bone and cementum formation compared with the GTR group. The results of the present investigation suggest that the adjunctive use of EMD with GTR promotes formation of new bone and cementum without root resorption in recession-type defects in dogs. PMID- 21556382 TI - Multicenter retrospective analysis of 201 consecutively placed camlog dental implants. AB - Camlog tube-in-tube implants were introduced several years ago. This multicenter retrospective analysis evaluated the success rate of Root-Line and Screw-Line tube-in-tube implants in daily use. A total of 201 implants were placed in 96 patients with different indications and implantation procedures. Implants were analyzed retrospectively after a functional loading period of 12 to 78 months. At the end of the observation period, all but 1 implant fulfilled the success criteria, resulting in an implant survival rate of 99.5%. Individual case analysis of implants in special indications, such as immediate loading, short implants, and tilted implants, did not indicate any increased risk of implant failure. PMID- 21556383 TI - Clinical classification of complications in guided bone regeneration procedures by means of a nonresorbable membrane. AB - The goal of classifying complications in guided bone regeneration procedures with nonresorbable membranes is to provide the clinician with an instrument for easier identification of both the problem and treatment modality. A standardized terminology represents a key point for proper communication among clinicians and provides guidelines for managing these drawbacks. PMID- 21556384 TI - The mandibular retromolar area as a donor site in maxillofacial bone grafting: surgical notes. AB - Bone harvesting from the mandibular retromolar area represents an attractive approach to obtaining corticocancellous bone blocks for reconstruction of a deficient alveolar ridge. Knowledge of the local anatomy, adherence to proper surgical techniques, and judicious use of appropriate surgical armamentarium are paramount to minimizing operative hazards. The objective of this article is to review pertinent surgical notes related to the safe harvesting of corticocancellous bone blocks from the retromolar area using a trephine bur technique. PMID- 21556385 TI - Quantitative evaluation of extraction socket healing following the use of autologous platelet-rich fibrin matrix in humans. AB - Platelet-rich fibrin matrix (PRFM) is an autologous biologic material created by centrifugation of blood. This study quantified ridge changes associated with the healing of 21 extraction sites using PRFM alone as a graft. Standardized measurements of ridge width and height were recorded at extraction, after graft placement, and after 4 months of healing. Mean width resorption 3 and 5 mm apical to the crest was 0.32 mm (4.71% loss) and 0.57 mm (7.38% loss), respectively. Mean height resorption was 0.67 mm (7.13% loss). Sites grafted with PRFM alone displayed rapid clinical healing, minimal flap reopening, and excellent bone density. Advantages of PRFM alone include less surgical time, elimination of techniques and potential healing difficulties associated with membranes, and less resorption during healing, as compared to guided bone regeneration procedures. PMID- 21556386 TI - Multidisciplinary approach to a nonsyndromic oligodontia patient using advanced surgical techniques. AB - Treatment of a woman suffering from oligodontia and multiple diastemata with insufficient alveolar ridges in both the maxilla and mandible is described in this clinical report. The total number of missing teeth was 11 (excluding the wisdom teeth). The treatment strategy consisted of an interdisciplinary team approach of orthodontic, surgical, and prosthodontic phases. Sinus floor augmentation, alveolar ridge augmentation via vertical alveolar distraction, and lateral augmentation with ramus graft procedures were performed after fixed orthodontic treatment and prior to dental implant placement. Oral rehabilitation of the patient was completed with the placement of fixed prostheses in the maxillary and mandibular posterior edentulous areas. Early dental intervention improved the patient's appearance and minimized the onset of emotional and psychosocial problems. PMID- 21556387 TI - A decision tree for soft tissue grafting. AB - Periodontal plastic surgery is commonly performed for esthetic and physiologic reasons, such as alleviating root sensitivity, root caries, and cervical abrasion and facilitating plaque control at the affected site. Currently, there is a lack of information regarding the most appropriate treatment method for the various clinical situations encountered. The aims of this paper are to review and discuss the various clinical situations that require soft tissue grafting and to attempt to provide recommendations for the most predictable technique. Using MEDLINE and The Cochrane Library, a review of all available literature was performed. Papers published in peer-reviewed journals written in English were chosen and reviewed to validate the decision-making process when planning for soft tissue grafting. A decision tree was subsequently developed to guide clinicians to choose the most appropriate soft tissue grafting procedure by taking into consideration the following clinical parameters: etiology, purpose of the procedure, adjacent interproximal bone level, and overlying tissue thickness. The decision tree proposed serves as a guide for clinicians to select the most appropriate and predictable soft tissue grafting procedure to minimize unnecessary mistakes while providing the ultimate desired treatment outcome. PMID- 21556388 TI - Triazole: a unique building block for the construction of functional materials. AB - Over the past 50 years, numerous roads towards carbon-based materials have been explored, all of them being paved using mainly one functional group as the brick: acetylene. The acetylene group, or the carbon-carbon triple bond, is one of the oldest and simplest functional groups in chemistry, and although not present in any of the naturally occurring carbon allotropes, it is an essential tool to access their synthetic carbon-rich family. In general, two strategies towards the synthesis of pi-conjugated carbon-rich structures can be employed: (a) either the acetylene group serves as a building block to access acetylene-derived structures or (b) it serves as a synthetic tool to provide other, usually benzenoid, structures. The recently discovered copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, however, represents a new powerful alternative: it transforms the acetylene group into a five-membered heteroaromatic 1H-1,2,3-triazole (triazole) ring and this gives rise to new opportunities. Compared with all carbon aromatic non-functional rings, the triazole ring possesses three nitrogen atoms and, thus, can serve as a ligand to coordinate metals, or as a hydrogen bond acceptor and donor. This Feature Article summarises examples of using the triazole ring to construct conjugation- and/or function-related heteroaromatic materials, such as tuneable multichromophoric covalent ensembles, macrocyclic receptors or responsive foldamers. These recent examples, which open a new sub field within organic materials, started to appear only few years ago and represent "a few more bricks" on the road to carbon-rich functional materials. PMID- 21556389 TI - Slow excited state injection and charge recombination at star-shaped ruthenium polypyridyl compounds--TiO2 interfaces. AB - The excited states of two star-shaped nanometre-sized ruthenium polypyridyl compounds were largely unchanged when anchored to nanocrystalline TiO(2) thin films due to a highly symmetrical and rigid ligand structure that isolated the chromophoric core from the semiconductor. Interfacial electron transfer occurred on unusually slow time scales. PMID- 21556390 TI - Selective conversion of {Mo132} Keplerate ion into 4-electron reduced crown capped Keggin derivative [Te5Mo15O57](8-). A key intermediate to single-phase M1 multielement MoVTeO light-alkanes oxidation catalyst. AB - {Mo(132)} Keplerate anion reacts with tellurites to give a soluble precursor to produce in hydrothermal conditions single-phase M1 MoVTeO light-alkanes oxidation catalyst. Characterization of this Te-containing intermediate by single-crystal X ray diffraction, (125)Te NMR, UV-visible and redox titration reveals a molybdotellurite anion as a crown-capped Keggin derivative. PMID- 21556391 TI - Decarboxylative formation of N-alkyl pyrroles from 4-hydroxyproline. AB - N-Alkyl pyrroles are obtained in a single step from 4-hydroxyproline and aldehydes in just 15 min under microwave irradiation. PMID- 21556393 TI - One step entry to P,O- and P,N-type heterocyclic tertiary phosphine ligands and application in Suzuki-Miyaura cross-coupling reactions. AB - A direct synthesis of conformationally mobile P,O- and P,N-type heterocyclic phosphine ligands is described involving radical-mediated addition of diisobutylphosphine to olefinic-heterocycles. Palladium complexes of the P,N ligand were determined to be highly active in the Suzuki-Miyaura cross-coupling reactions, including deactivated aryl chlorides. PMID- 21556392 TI - Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids. AB - The pyrrole-2-aminoimidazole (P-2-AI) alkaloids are a growing family of marine alkaloids, now numbering well over 150 members, with high topographical and biological information content. Their intriguing structural complexity, rich and compact stereochemical content, high N to C ratio (~1 : 2), and increasingly studied biological activities are attracting a growing number of researchers from numerous disciplines world-wide. This review surveys advances in this area with a focus on the structural diversity, biosynthetic hypotheses with increasing, but still rare, verifying experimental studies, asymmetric syntheses, and biological studies, including cellular target receptor isolation studies, of this stimulating and exciting alkaloid family. PMID- 21556394 TI - Influence of DNA-binding on the photochromic equilibrium of a chromene derivative. AB - The photochromic properties of a chromene derivative, which contains a positively charged substituent, were investigated in the presence of ct DNA. Upon irradiation in the absence of DNA the colored quinoid open form is highly unstable and rapidly reverts back to the initial closed form (bleaching). In the presence of DNA the open form is significantly stabilized, presumably because of the association with the macromolecule. The kinetics of the bleaching reaction of the bound ligand were determined and employed to estimate the binding constant. PMID- 21556395 TI - A new type of polyhedron-based metal-organic frameworks with interpenetrating cationic and anionic nets demonstrating ion exchange, adsorption and luminescent properties. AB - An interesting new MOF, built with interpenetrating cationic (MOF-A(+)) and anionic (MOF-B(-)) nets that do not require counter ions to balance charge, together with an architectural strategy focused on the use of MOPs as nodes and MOCs as spacers for the generation of 3D frameworks, is reported. PMID- 21556396 TI - Analyte-induced formation of partial duplexes for the preparation of a label-free electrochemiluminescent aptasensor. AB - Analyte-induced formation of partial duplexes was used for biosensor development with cocaine as a model. The cocaine-aptamer interaction resulted in formation of a partial double strand section in the aptamer, where Ru(phen)(3)(2+) was intercalated for electrochemiluminescent analysis of cocaine. PMID- 21556397 TI - Acid controlled diastereoselectivity in asymmetric aldol reaction of cycloketones with aldehydes using enamine-based organocatalysts. AB - The example of syn-aldol reaction of cyclohexanone to aldehyde was demonstrated based on chiral diamine organocatalysts and it was realized either by increasing the molecular size of acid additives or by introducing a hydrogen-bond donor into acid additives. PMID- 21556398 TI - New insights into the intercalation chemistry of Al(OH)3. AB - This paper reports a number of recent developments in the intercalation chemistry of Al(OH)(3). From Rietveld refinement and solid-state NMR, it has been possible to develop a structural model for the recently reported [M(II)Al(4)(OH)(12)](NO(3))(2).yH(2)O family of layered double hydroxides (LDHs). The M(2+) cations occupy half of the octahedral holes in the Al(OH)(3) layers, and it is thought that there is complete ordering of the metal ions while the interlayer nitrate anions are highly disordered. Filling the remainder of the octahedral holes in the layers proved impossible. While the intercalation of Li salts into Al(OH)(3) is facile, it was found that the intercalation of M(II) salts is much more capricious. Only with Co, Ni, Cu, and Zn nitrates and Zn sulfate were phase-pure LDHs produced. In other cases, there is either no reaction or a phase believed to be an LDH forms concomitantly with impurity phases. Reacting Al(OH)(3) with mixtures of M(II) salts can lead to the production of three-metal M(II)-M(II)'-Al LDHs, but it is necessary to control precisely the starting ratios of the two M(II) salts in the reaction gel because Al(OH)(3) displays selective intercalation of M nitrate (Li > Ni > Co ~ Zn). The three-metal M(II)-M(II)'-Al LDHs exhibit facile ion exchange intercalation, which has been investigated in the first energy dispersive X-ray diffraction study of a chemical reaction system performed on Beamline I12 of the Diamond Light Source. PMID- 21556399 TI - Proliferation behavior of E. coli in a three-dimensional in vitro tumor model. AB - Advances in genetic engineering of non-pathogenic Escherichia coli (E. coli) have made this organism an attractive candidate for gene delivery vehicle. However, proliferation and transport behaviors of E. coli in three-dimensional (3D) tumor environment are still unclear. To this end, we developed a novel microfluidics based tumor model that permitted direct in situ visualization of E. coli in a 3D environment with densely packed tumor cells (B16.F10 or EMT6). The E. coli was engineered to co-express two proteins invasin and mCherry (inv(+)) so that they had the ability to enter mammalian cells and could be visualized via fluorescence microscopy. E. coli expressing mCherry alone (inv(-)) was used as the control counterpart. The inv(-) bacteria proliferated to a higher extent than inv(+) bacteria in both the 3D tumor model and a 2D monolayer culture model. Meanwhile, the proliferation appeared to be tumor cell type dependent since bacteria did not proliferate as well in the EMT6 model compared to the B16.F10 model. These differences in bacterial proliferation were likely to be caused by inhibitors secreted by tumor cells, as suggested by our data from the bacterial-tumor cell monolayer co-culture experiment. The bacterial proliferation provided a driving force for E. coli spreading in the 3D interstitial space of tumors. These findings are useful for researchers to develop novel strategies for improvement of bacteria-mediated oncolysis or gene delivery in cancer treatment. PMID- 21556400 TI - Nickel N-heterocyclic carbene-pyridine complexes that exhibit selectivity for electrocatalytic reduction of carbon dioxide over water. AB - We report a homologous series of nickel(II) complexes supported by N-heterocyclic carbene-pyridine ((R)bimpy, R = Me, Et, Pr) ligands that exhibit high selectivity for reducing carbon dioxide over water under electrocatalytic conditions. PMID- 21556401 TI - Fe2O3-supported nano-gold catalyzed one-pot synthesis of N-alkylated anilines from nitroarenes and alcohols. AB - Here, we show the one-step synthesis of N-alkylated anilines from nitrobenzenes and alcohols catalyzed by nano-gold catalyst. The yields to N-alkylated anilines were ~90% under mild conditions. The mechanism of this reaction was explored. It shows promise for clean and simple synthesis of N-alkylated anilines. PMID- 21556402 TI - Arginine conjugates of metallo-supramolecular cylinders prescribe helicity and enhance DNA junction binding and cellular activity. AB - The conjugation of arginine residues at the ends of a metallo-supramolecular triple-helical cylinder enables absolute control over the helicity of the cylinder core, and boosts the DNA junction recognition by the complexes and their activity against a cancer cell line. PMID- 21556403 TI - Photoluminescent properties of Prussian Blue (PB) nanoshells and polypyrrole (PPy)/PB core/shell nanoparticles prepared via miniemulsion (periphery) polymerization. AB - We fabricated PPy/PB core/shell nanoparticles via one-step miniemulsion polymerization using a metallosurfactant of EPE-Fe. The defined hollow structure endows PB nanoshells with an emission band at 612 nm. On incorporating PPy inside PB shells, a blue shift and enhanced fluorescence were observed due to charge transfer from PPy to PB. PMID- 21556404 TI - Computational prediction and experimental verification of pyridine-based helical oligoamides containing four repeating units per helical turn. AB - Aided by high level ab initio computational modeling, we successfully designed and experimentally proved a new set of backbone-rigidified pyridine-based folding oligoamides that require approximately four repeating units to form a helical turn. PMID- 21556405 TI - A facile approach to synthesize high-quality Zn(x)Cu(y)InS(1.5+x+0.5y) nanocrystal emitters. AB - A facile approach to synthesize Zn(x)Cu(y)InS(1.5+x+0.5y) nanocrystal emitters was presented. The compositions of these nanocrystals were precisely controlled, and the relative PL quantum yields were up to 40%, with tunable emissions in 450 640 nm. PMID- 21556406 TI - Solution and solid-state interactions in a supramolecular ruthenium photosensitizer-polyoxometalate aggregate. AB - The intermolecular interactions between a ruthenium-based photosensitizer ([Ru(tbbpy)(2)(biH(2))](2+)) and a molecular metal oxide ([beta-Mo(8)O(26)](4-)) are investigated in solution and in the solid state. The supramolecular interactions were studied using (1)H-NMR, UV-Vis and emission spectroscopy, ESI mass spectrometry and single-crystal X-ray diffraction. The formation of supramolecular aggregates was observed both in the crystal lattice and in solution. In addition, it is shown that aggregation in solution can be controlled by the competitive formation of ion pairs. PMID- 21556407 TI - Novel protection-deprotection strategies in diazeniumdiolate chemistry: synthesis of V-IPA/NO. AB - Synthesis of previously inaccessible, potentially liver selective HNO donor V IPA/NO ([iPrHN(3)-N(1)(O(1))=N(2)-O(2)-R], where R = vinyl) is reported here. A novel fluoride-labile TOM group at O-2 in conjunction with MOM protection at N-3 in IPA/NO is employed. The strategy developed is also extended to synthesis of other NO-releasing prodrugs and has applications in diversity-oriented synthesis of HNO- and NO-prodrugs. PMID- 21556408 TI - Calculated strain response of vibrational modes for H-containing point defects in diamond. AB - The low mass of hydrogen leads to highly localised, high-frequency vibrational modes associated with H-containing defects in crystalline materials. In addition to vibrational spectroscopy, the presence of hydrogen in diamond has been identified from several experimental techniques. In particular, paramagnetic resonance shows that H is often associated with lattice vacancies, but in many cases the microscopic structure of the defects remains to be determined. We present the results of first-principles density-functional modelling of selected H-containing point defects, reporting both the calculated frequencies and the change in frequencies with applied strain. We show that more constrained environments lead to significantly larger strain-related shifts in frequency than more open environments, such as where the H is associated with lattice vacancies. PMID- 21556409 TI - H atom adsorption and diffusion on Si(110)-(1*1) and (2*1) surfaces. AB - We present a periodic density-functional study of hydrogen adsorption and diffusion on the Si(110)-(1*1) and (2*1) surfaces, and identify a local reconstruction that stabilizes the clean Si(110)-(1*1) by 0.51 eV. Hydrogen saturates the dangling bonds of surface Si atoms on both reconstructions and the different structures can be identified from their simulated scanning tunneling microscopy/current image tunneling spectroscopy (STM/CITS) images. Hydrogen diffusion on both reconstructions will proceed preferentially along zigzag rows, in between two adjacent rows. The mobility of the hydrogen atom is higher on the (2*1) reconstruction. Diffusion of a hydrogen vacancy on a monohydride Si(110) surface will proceed along one zigzag row and is slightly more difficult (0.2 eV and 0.6 eV on (1*1) and (2*1), respectively) than hydrogen atom diffusion on the clean surface. PMID- 21556410 TI - Testing the use of molecular dynamics to simulate fluorophore motions and FRET. AB - Fluorescence resonance energy transfer (FRET) is commonly used to determine the proximity of fluorophores, but usually many assumptions are required to gain a quantitative relationship between the likelihood of energy transfer and fluorophore separation. Molecular Dynamics (MD) simulations provide one way of checking these assumptions, but before using simulations to study complex systems it is important to make sure that they can correctly model the motions of fluorophores and the likely FRET efficiency in a simple system. Here we simulate a well characterised situation of independent fluorophores in solution so that we can compare the predictions with expected values. Our simulations reproduce the experimental fluorescence anisotropy of Alexafluor488 and predict that of AlexaFluor568. At the ensemble level we are able to reproduce the expected isotropic and dynamic motion of the fluorophores as well as the FRET efficiency of the system. At the level of single donor-acceptor pairs, however, very long simulations are required to adequately sample the translational motion of the fluorophores and more surprisingly also the rotational motion. Our studies demonstrate how MD simulations can be used in more complex systems to check if the dynamic orientation averaging regime applies, if the fluorophores have isotropic orientational motion, to calculate the likely values of the orientation factor kappa(2) and to determine the FRET efficiency of the system in both dynamic and static orientational averaging regimes. We also show that it is possible in some situations to create system specific relationships between FRET efficiency and fluorophore separation that can be used to interpret experimental data and find any correlations between kappa(2) and separation that may influence distance measurements. PMID- 21556411 TI - Nanoscale copper sulfide hollow spheres with phase-engineered composition: covellite (CuS), digenite (Cu1.8S), chalcocite (Cu2S). AB - Covellite (CuS), digenite (Cu(1.8)S) and chalcocite (Cu(2)S) are prepared as nanoscaled hollow spheres by reaction at the liquid-to-liquid phase boundary of a w/o-microemulsion. According to electron microscopy (SEM, STEM, TEM, HRTEM) the hollow spheres exhibit an outer diameter of 32-36 nm, a wall thickness of 8-12 nm and an inner cavity of 8-16 nm in diameter. The phase composition is determined based on HRTEM, electron-energy loss spectroscopy, X-ray powder diffraction and thermal analysis. In face of the advanced morphology of the hollow spheres, precise control of its phase composition is nevertheless possible by adjusting the experimental conditions (i.e. type and concentration of the copper precursor, concentration of ammonia inside of the micelle). Such phase-engineering of nanoscale hollow spheres is firstly observed and might allow adjusting even further compositions/structures as well as tailoring of phase-specific properties in the future. PMID- 21556412 TI - Lateral redistribution of trapped charges in nitride/oxide/Si (NOS) investigated by electrostatic force microscopy. AB - Charge decay and lateral spreading properties were characterized by modified electrostatic force microscopy (EFM) under a high vacuum at elevated temperatures. Variations in the charge profiles were modeled with the maximum charge density (rho(m)) and the lateral spreading distance (Delta(s)), as extracted from the EFM potential line profiles. The scaling limitation of nitride trap memory is discussed based on the projected lateral spreading distances for holes and electrons, which were determined to be approximately 18 nm and 12 nm, respectively, at room temperature. PMID- 21556413 TI - Solvent controlled mechanistic dichotomy in a Au(III)-catalyzed, heterocyclization triggered, Nazarov reaction. AB - Tandem Au(III)-catalyzed heterocyclization/Nazarov cyclizations leading to substituted carbocycle fused furans are described. An interesting dichotomy of reaction pathways as a function of solvent, confirmed by the isolation and trapping of reaction intermediates, provided a basis for computational studies that supported the experimental findings. PMID- 21556414 TI - Au(PPh3)OPOF2-catalyzed intramolecular [4+2] cycloaddition reaction of dienynes. AB - Solvolysis of Au(PPh(3))PF(6) afforded Au(PPh(3))OPOF(2) which is an effective catalyst in the intramolecular [4+2] cycloaddition of unactivated dienynes bearing a terminal alkyne. PMID- 21556415 TI - Spin trapping of hydroxyl radicals on Cu/HY zeolites suspended in aqueous solution. AB - Hydroxyl radical intermediates are trapped in calcined Cu/HY zeolites in the presence of oxygen and water. This suggests that hydrogen peroxide is formed in situ from oxygen. Bronsted acids enhance the formation of the radicals. PMID- 21556416 TI - Nitrogen self-doped nanosized TiO2 sheets with exposed {001} facets for enhanced visible-light photocatalytic activity. AB - Nitrogen self-doped TiO(2) nanosheets with exposed {001} facets (ca. 67%) were synthesized by solvothermal treatment of TiN in a HNO(3)-HF ethanol solution and exhibited much higher visible-light photocatalytic H(2)-production activity than nitrogen doped TiO(2) microcrystallites with exposed {001} facets (ca. 60%) by a factor of 4.1. PMID- 21556417 TI - H-bonding-driven gel formation of a phenylacetylene macrocycle. AB - An amide-containing phenylacetylene macrocycle (PAM) has been synthesized and its gelation properties were studied in different solvents. Surprisingly, this macrocycle forms organogels at low concentration in many polar and apolar solvents. XRD and FTIR analysis suggest that this macrocycle forms stable supramolecular assemblies owing to H-bonding. Scanning electron microscopy analyses show the formation of bundles of nanofibrils, demonstrating the long range organization of this material. PMID- 21556418 TI - The {001} facets-dependent high photoactivity of BiOCl nanosheets. AB - BiOCl nanosheets (BiOCl NSs) were synthesized by hydrolyzing a hierarchical flowerlike molecular precursor (Bi(n)(Tu)(x)Cl(3n), Tu = thiourea). High photoactivity of {001} facets of BiOCl NSs was observed, and the mechanism was discussed. PMID- 21556419 TI - Wavelength-controlled supramolecular photocyclodimerization of anthracenecarboxylate mediated by gamma-cyclodextrins. AB - Stereochemical outcomes were critically tuned by excitation wavelength in the supramolecular photocyclodimerization of 2-anthracenecarboxylic acid mediated by native and diamino-modified gamma-cyclodextrins. PMID- 21556420 TI - Complete solid state photoisomerization of bis(dipyrazolylstyrylpyridine)iron(II) to change magnetic properties. AB - Iron(II) complexes of Z- and E-2,6-di(1H-pyrazol-1-yl)-4-styrylpyridine (Z-2 and E-2, respectively) exhibited visible light photoisomerization from Z-2 to E-2, both in solution and in solid phases. Z-2 occupied the high-spin state over the full temperature range examined, whereas E-2 displayed a spin crossover phenomenon between 100 K and 300 K. PMID- 21556421 TI - Molecularly imprinted solid-phase extraction combined with ultrasound-assisted dispersive liquid-liquid microextraction for the determination of four Sudan dyes in sausage samples. AB - A simple and highly selective molecularly imprinted solid-phase extraction (MISPE) combined with ultrasound-assisted dispersive liquid-liquid microextraction (DLLME) was developed for the determination of four Sudan dye (I, II, III, and IV) residues in sausage products. The novel molecularly imprinted microspheres (MIMs) synthesized by aqueous suspension polymerization using phenylamine-naphthol as the dummy template show high affinity to the four Sudan dyes and were applied as selective sorbents of MISPE-DLLME to overcome the drawbacks of template leakage in quantitative analysis. Good linearity was obtained in a range of 0.005-2.0 MUg g(-1) and the average recoveries of the four Sudan dyes at three spiked levels ranged from 86.3 to 107.5%. The MISPE-DLLME HPLC protocol significantly improved the purification and enrichment of the analytes and eliminated the template leakage of the conventional MISPE on quantitative analysis. PMID- 21556422 TI - First enantioselective iron-porphyrin-catalyzed sulfide oxidation with aqueous hydrogen peroxide. AB - The asymmetric oxidation of sulfides by H(2)O(2) to give optically active sulfoxides (ee up to 90%) was carried out in methanol and water using chiral water-soluble iron porphyrins as catalysts. PMID- 21556423 TI - Assessment of radionuclide and metal contamination in a thorium rich area in Norway. AB - The Fen Central Complex in southern Norway, a geologically well investigated area of magmatic carbonatite rocks, is assumed to be among the world largest natural reservoirs of thorium ((232)Th). These rocks, also rich in iron (Fe), niobium (Nb), uranium ((238)U) and rare earth elements (REE), were mined in several past centuries. Waste locations, giving rise to enhanced levels of both radionuclides and metals, are now situated in the area. Estimation of radionuclide and metal contamination of the environment and radiological risk assessment were done in this study. The average outdoor gamma dose rate measured in Fen, 2.71 MUGy h(-1), was significantly higher than the world average dose rate of 0.059 MUGy h(-1). The annual exposure dose from terrestrial gamma radiation, related to outdoor occupancy, was in the range 0.18-9.82 mSv. The total activity concentrations of (232)Th and (238)U in soil ranged from 69 to 6581 and from 49 to 130 Bq kg(-1), respectively. Enhanced concentrations were also identified for metals, arsenic (As), lead (Pb), chromium (Cr) and zinc (Zn), in the vicinity of former mining sites. Both radionuclide and heavy metal concentrations suggested leaching, mobilization and distribution from rocks into the soil. Correlation analysis indicated different origins for (232)Th and (238)U, but same or similar for (232)Th and metals As, Cr, Zn, nickel (Ni) and cadmium (Cd). The results from in situ size fractionation of water demonstrated radionuclides predominately present as colloids and low molecular mass (LMM) species, being potentially mobile and available for uptake in aquatic organisms of Norsjo Lake. Transfer factors, calculated for different plant species, showed the highest radionuclide accumulation in mosses and lichens. Uptake in trees was, as expected, lower. Relationship analysis of (232)Th and (238)U concentrations in moss and soil samples showed a significant positive linear correlation. PMID- 21556424 TI - Hollow microspheres with a tungsten carbide kernel for PEMFC application. AB - Tungsten carbide microspheres comprising an outer shell and a compact kernel prepared by a simple hydrothermal method exhibit very high surface area promoting a high dispersion of platinum nanoparticles, and an exceptionally high electrochemically active surface area (EAS) stability compared to the usual Pt/C electrocatalysts used for PEMFC application. PMID- 21556425 TI - Photoresponsive amphiphiles based on azobenzene-dendritic glycerol conjugates show switchable transport behavior. AB - The synthesis and aggregation behavior of photo-switchable, nonionic dendritic amphiphiles was investigated with regard to transport and release of guest molecules. The correlation between the critical micelle concentration and the switching ability is shown. PMID- 21556426 TI - Single step elaboration of size-tuned Pt loaded titania nanofibres. AB - Conductive titania nanofibres supporting Pt nanoparticles were synthesised in a one-pot method based on the electrospinning technique. The dimensions of both the oxide fibres and platinum particles were tuneable, leading to versatile nanomaterials with possible applications as electrodes for energy conversion devices. PMID- 21556427 TI - A dodecameric self-assembled calix[4]arene aggregate with two types of cavities. AB - Twelve molecules of beta-carbonyl-para-octyl-calix[4]arene assemble in an aggregate containing two types of cavities filled by water molecules and they pack in a cubic structure. Both the aggregates and the packing resemble that observed for inverse micelles. PMID- 21556428 TI - Small-world rheology: an introduction to probe-based active microrheology. AB - We introduce active, probe-based microrheological techniques for measuring the flow and deformation of complex fluids. These techniques are ideal for mechanical characterization either when little sample is available, or when samples show significant spatial heterogeneity. We review recent results, paying particular attention to comparing and contrasting rheological parameters obtained from micro and macro-rheological techniques. PMID- 21556429 TI - Cation non-stoichiometry in multi-component oxide nanoparticles by solution chemistry: a case study on CaWO4 for tailored structural properties. AB - Chemical composition directly determines the structure and properties of almost all bulk inorganic solids, which are however popularly dismissed in the literature as a cause of property changes when studying multi-component oxide nanostructures by solution chemistries. The current work focuses on this subject through a systematic case study on CaWO(4) nanocrystals. CaWO(4) nanocrystals were prepared using room-temperature solution chemistry, in which a capping agent of citric acid was employed for kinetic grain size control. Sample characterizations by a set of techniques indicated that 5-7 nm CaWO(4) was obtained at room temperature, showing a pure-phase of tetrahedral scheelite structure. The molar ratio of Ca(2+) to W(6+) was found to be 1.2:1, apparently deviating from the unity expected for the stoichiometric CaWO(4). Such nonstoichiometry was further modulated via iso-valent incorporation of smaller Zn(2+) to the Ca(2+)-sites in CaWO(4). It is found that with increasing the Zn(2+) content, there appeared transformation from high to low nonstoichiometry, though a pure scheelite-typed structure was retained. Such a nonstoichiometry was primarily represented by excessive cations like Zn(2+) and/or Ca(2+) within the surface disorder layers, which in turn showed a great impact on the structure and properties as demonstrated by a lattice contraction, band-gap narrowing, luminescence quenching, as well as improved conductivity. The property changes were rationalized in terms of surface structural disorder, electro-negativity discrepancy, and effective activation on the mobile protons. Consequently, systematic control over the non-stoichiometry for single-phase multi-component oxide nanostructures by solution chemistry is proven fundamentally important, which may help to achieve quantitatively the structure-property relationship for materials design and performance optimization. PMID- 21556430 TI - Au-impregnated polyacrylonitrile (PAN)/polythiophene (PTH) core-shell nanofibers with high-performance semiconducting properties. AB - FETs based on Au-impregnated polyacrylonitrile (PAN)/polythiophene (PTH) core shell nanofibers have been fabricated and exhibit high mobility (~2.0 cm(2) V(-1) s(-1)). PMID- 21556431 TI - Asymmetric hydrogenation of alkenes lacking coordinating groups. AB - Asymmetric hydrogenation of olefins is one of the most important reactions for the synthesis of optically active compounds, especially in industry. Chiral iridium catalysts based on P,N ligands have strongly expanded their application range. In contrast to rhodium and ruthenium diphosphine complexes they do not require the presence of a coordinating group near the C=C bond and, therefore, allow highly enantioselective hydrogenations of largely unfunctionalized alkenes. PMID- 21556432 TI - The palladium-catalyzed cyanation of indole C-H bonds with the combination of NH4HCO3 and DMSO as a safe cyanide source. AB - A palladium-catalyzed cyanation of the 3-position of indole sp(2) C-H bonds by the combination of NH(4)HCO(3) and DMSO as the "CN" source was achieved to provide aromatic nitriles in moderate to good yields with excellent regioselectivity. It represents a practical and safe cyanation method. PMID- 21556433 TI - Facile formation of a meso-meso linked porphyrin dimer catalyzed by a manganese(IV)-oxo porphyrin. AB - A manganese(IV)-oxo porphyrin catalyzes C-C bond formation between zinc porphyrins at the meso-position with a two-electron oxidant to afford the meso meso linked porphyrin dimer efficiently. The meso-meso linked dimer is formed via formation of the porphyrin radical cation, and the rate-determining step in the catalytic cycle is the formation of a manganese(IV)-oxo porphyrin with a two electron oxidant. PMID- 21556434 TI - A long-lived luminescence and EPR bimodal lanthanide-based probe for free radicals. AB - We developed a novel spin-labeled terbium complex Tb(3+)/cs124-DTPA-TEMPO (1) by covalently labeling a nitroxide radical on the terbium complex for monitoring free radicals of various areas. This lanthanide complex probe shows a high EPR signal which resulted from the nitroxide radical moiety, and is weakly luminescent which resulted from the intramolecular quenching effect of the nitroxide radical on sensitised terbium luminescence. The intensity of both the EPR and luminescence can be modulated by eliminating the paramagnetism of the nitroxide radical through recognition of a carbon-centered radical analyte and thus gives a quantification of the analyte. We have preliminarily applied this probe in the luminescent detection of model carbon-centered radicals and hydroxyl radicals (.OH). This probe is water-soluble and contains lanthanide-luminescence properties, favorable for the time-resolved luminescence technique. The investigation of the intramolecular quenching process has showed that the labeled nitroxide radical quenches multiple excited states of the terbium complex, resulting in highly efficient quenching of terbium luminescence. This probe is the first example of intramolecular modulation of lanthanide luminescence by a nitroxide radical. PMID- 21556435 TI - Dielectric barrier discharge non-thermal micro-plasma for the excitation and emission spectrometric detection of ammonia. AB - Dielectric-barrier discharge (DBD) in argon as a cold source is used for the excitation of gaseous inorganic small molecules at atmospheric pressure. By choosing ammonia as a model molecule, the excitation process and the characteristics of the emission spectra are investigated. The emission spectra are recorded by designing either an open-end or an enclosed DBD excitation/emission source. The enclosed excitation mode effectively eliminates the background emissions arising from the ambient air components, especially those from nitrogen. Two emission lines attributed to the excitation of ammonia, i.e., 326.2 and 336.5 nm, are clearly isolated from the background emission spectra of argon, providing the basis for quantitative analysis. A detection limit of 0.37 ppm is achieved within a linear range of 1.2-35 ppm by monitoring at 326.2 nm. In practice, gaseous samples containing ammonia collected in a public toilet are excited in an enclosed excitation source and the emission at 326.2 nm is monitored for quantitative analysis. An ammonia concentration of 2.4 ppm is derived in the original atmospheric sample, and a spiking recovery of 94.7% is achieved at a 10 ppm ammonia level. This study shows that DBD cold excitation in combination with optical emission spectrometry (OES) offers a promising approach for the detection of ammonia pollution. PMID- 21556436 TI - CH activation and CH2 double activation of indolines by radical translocation: understanding the chemistry of the indolinyl radical. AB - CH activation and CH(2) double activation of indolines at C2 may be achieved efficiently through radical translocation. The fate of the C2 indolinyl radical is dictated by the substitution at C3. Fragmentation, cyclisation and tandem cyclisation reactions leading to indole, azaheterocycle and azapropellane formation, respectively, are reported. PMID- 21556437 TI - Locked vs. unlocked nucleic acids (LNA vs. UNA): contrasting structures work towards common therapeutic goals. AB - Oligonucleotide chemistry has been developed greatly over the past three decades, with many advances in increasing nuclease resistance, enhancing duplex stability and assisting with cellular uptake. Locked nucleic acid (LNA) is a structurally rigid modification that increases the binding affinity of a modified oligonucleotide. In contrast, unlocked nucleic acid (UNA) is a highly flexible modification, which can be used to modulate duplex characteristics. In this tutorial review, we will compare the synthetic routes to both of these modifications, contrast the structural features, examine the hybridization properties of LNA and UNA modified duplexes, and discuss how they have been applied within biotechnology and drug research. LNA has found widespread use in antisense oligonucleotide technology, where it can stabilize interactions with target RNA and protect from cellular nucleases. The newly emerging field of siRNAs has made use of LNA and, recently, also UNA. These modifications are able to increase double-stranded RNA stability in serum and decrease off-target effects seen with conventional siRNAs. LNA and UNA are also emerging as versatile modifications for aptamers. Their application to known aptamer structures has opened up the possibility of future selection of LNA-modified aptamers. Each of these oligonucleotide technologies has the potential to become a new type of therapy to treat a wide variety of diseases, and LNA and UNA will no doubt play a part in future developments of therapeutic and diagnostic oligonucleotides. PMID- 21556438 TI - Linear, high molecular weight polyethylene from a discrete, mononuclear phosphinoarenesulfonate complex of nickel(II). AB - A well-defined, homogeneous catalyst, [(Ph)(2-(2',6'-(OMe)(2)-C(6)H(3)) C(6)H(4))P(2-SO(3)-C(6)H(4))]Ni(Ph)PPh(3), in which a single, bulky ortho biphenyl substituent on the chelating phosphine blocks one axial position, is very active for formation of linear polyethylene (M(n) = 403,000 g mol(-1), M(w)/M(n) = 1.87). PMID- 21556439 TI - Active thionium species mediated functionalization at the 2alpha-position of indole derivatives. AB - A combination of dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride (TFAA) mediates functionalization at the 2alpha-position of indole derivatives. Carbon and heteroatom nucleophiles were directly introduced via a one-pot procedure in excellent yields. PMID- 21556440 TI - Impurities within carbon nanotubes govern the electrochemical oxidation of substituted hydrazines. AB - Electrochemistry and electrocatalysis on carbon nanomaterials is at the forefront of research. The presence of carbonaceous and metallic impurities within carbon nanotubes (CNTs) is a persistent problem. Here we show that the electrochemistry of the entire group of hydrazine compounds is governed by impurities within single-walled, double-walled and few-walled CNTs. The oxidation of organic substituted hydrazines at CNTs is driven by nanographitic impurities, in contrast to unsubstituted hydrazine, for which the electrochemistry is driven by metallic impurities within CNTs. This finding is unexpected, as one would assume that a whole group of compounds would be susceptible to "electrocatalysis" by only one type of impurity. This discovery should be taken into account when predicting the susceptibility of whole groups of compounds to electrocatalysis by metallic or nanographitic impurities. Our findings have strong implications on the electrochemical sensing of hydrazines and on the use of hydrazines as fuels for nanomotors. PMID- 21556441 TI - Water whiskers in high electric fields. AB - In electrostatic fields of the order of volts per Angstrom long whiskers of up to 12 water molecules form that have been observed in the field ion microscope. Here we present a detailed analysis on the basis of the density functional theory that substantiates the earlier claims. We present whisker structures and energetics, lower and upper threshold fields, and fragmentation patterns. PMID- 21556442 TI - Interactions of oxygen and ethylene with submonolayer Ag films supported on Ni(111). AB - We investigate the oxidation of, and the reaction of ethylene with, Ni(111) with and without sub-monolayer Ag adlayers as a function of temperature. The addition of Ag to Ni(111) is shown to enhance the activity towards the ethylene epoxidation reaction, and increase the temperature at which ethylene oxide is stable on the surface. We present a systematic study of the formation of chemisorbed oxygen on the Ag-Ni(111) surfaces and correlate the presence and absence of O(1-) and O(2-) surface species with the reactivity towards ethylene. By characterizing the samples with low-energy electron microscopy (LEEM) in combination with X-ray photoelectron spectroscopy (XPS), we have identified specific growth of silver on step-edge sites and successfully increased the temperature at which the produced ethylene oxide remains stable, a trait which is desirable for catalysis. PMID- 21556443 TI - ZnO hierarchical structures for efficient quasi-solid dye-sensitized solar cells. AB - We report a direct precipitation method for mass production of ZnO microflowers (MFs) containing hierarchical structures. The ZnO MFs are constructed by interlaced single crystalline and porous nanosheets which are ideal photoanode material for dye-sensitized solar cells (DSCs) because the MFs can largely improve the energy harvesting performance and the efficiency of DSCs. Compared with other forms of nano-sized structures, the novel hierarchical structures show obvious advantages in DSC application because of their large surface area for dye loading, good light scattering efficiency and excellent electrical transport property. The quasi-solid state DSCs fabricated with the MF hierarchical structures exhibited an efficiency of 4.12%, much higher than that of ZnO nanoparticle-based DSCs, indicating a great potential for the development of highly-efficient quasi-solid DSCs. PMID- 21556444 TI - Preferential carbene insertion into Ge-H vs. other heavier group 14 hydrides via samarium carbenoids. AB - The relative reactivities of Zn, Al, and Sm carbenoids in the chemoselective carbene insertion reaction of heavier group 14 hydrides were studied. By variation of the reaction protocols using Sm carbenoids, insertion reaction can favour the Ge-H bonds to give Ge-alkylated derivatives in good to high yield. PMID- 21556445 TI - Left ventricular dysfunction in sickle cell disease: the value of an electrocardiographic marker of increased risk of arrhythmia. PMID- 21556446 TI - Occurrence and pattern of congenital heart diseases in a rural area of sub Saharan Africa. AB - The extent of congenital heart disease in Cameroon remains largely unknown. The aim of this study was to determine the occurrence and pattern of congenital heart diseases in the Cardiac Centre of St Elizabeth Catholic General Hospital, situated in a rural area of Cameroon. METHODS: Between November 2002 and November 2008, a population of 2 123 patients with suspected cardiac pathologies were consulted at St Elizabeth Catholic General Hospital referral cardiac centre. Of these patients, 292 subjects were recruited for the study, based on detection of (1) precordial murmurs and/or cardiomegaly on chest X-ray examination, or (2) congenital heart diseases on transthoracic Doppler echocardiography examination. RESULTS: Congenital heart diseases and inorganic murmurs were found in 95.5 and 4.5% of the patients, respectively. Congenital heart diseases included tetralogy of Fallot (26.1%), isolated ventricular septal defect (38.8%), atrioventricular cushion defect (7.3%), isolated atrial septal defect (2.8%), arterial duct cases (12.4%), common arterial trunk (1.3%), isolated stenosis of the pulmonary artery (2.6%), coarctation of the aorta (1.1%), congenital mitral valve regurgitation (1.2%), atresia of the triscupid valve (1.6%), double-outlet right ventricle (2.1%), anomalous pulmonary venous return (1.5%) and left isomerism (1.2%). CONCLUSION: Our data show that there is a high occurrence of congenital heart disease in this hospital in a rural zone of sub-Saharan Africa and that isolated ventricular septal defect is the predominant pathology. Post-surgical follow up remains very challenging as many parents cannot afford their children's medical treatment or are generally not well educated. PMID- 21556447 TI - Efficacy of intramuscular methyl prednisolone in preventing restenosis after coronary artery stenting with bare-metal stainless steel stent: a double-blind, randomised, controlled clinical trial. AB - The aim of this study was to compare the mid-term outcome of patients receiving intramuscular methyl prednisolone before and after the procedure of coronary artery stenting. The study was conducted during 2007 and 2008 and compared the two arms of the study for the rate of restenosis six months after stenting. The control arm (100 patients) received only the usual preventive measures but the glucocorticoid arm (100 patients) received two doses of intramuscular methyl prednisolone (40 mg) at two-week intervals, the first at the time of the procedure. They also received the usual preventive measures There was no statistically significant difference between the two arms for the rate of restenosis. When separately analysing for three vessels and for gender, there was no statistically significant difference either. Lowering the dose of corticosteroid would greatly reduce the efficacy for preventing restenosis after coronary artery stenting. Therefore, if we are to achieve acceptable effectiveness with intramuscular prednisolone, we should administer increased doses at shorter intervals, which could be the target of further studies. However, there would be more chance of side effects with increased frequency of dosing. PMID- 21556448 TI - Cardiovascular and electrocardiographic changes in Nigerians with a normal pregnancy. AB - INTRODUCTION: Pregnancy is associated with major haemodynamic and cardiac changes, which can mimic or precipitate cardiac diseases. There is a paucity of this kind of data among pregnant Nigerian women. This study was aimed at describing the cardiovascular and electrocardiographic changes found among healthy pregnant Nigerian women. METHODS: This was an age-matched control study of 69 consecutive normal pregnant and 70 healthy non-pregnant controls. The study protocol included history, physical examination and 12-lead electrocardiography. RESULTS: Diastolic blood pressure < 60 mmHg was significantly commoner among pregnant subjects than controls (64.7 vs 24.3%, respectively, p < 0.005). Mean heart rate was higher among pregnant women (88.34 +/- 11.46 bpm) than the controls (75.16 +/- 12.22 bpm, p = 0.020). Pregnant subjects also had a higher proportion of left ventricular hypertrophy (LVH) (10.2 vs 0%, p < 0.05) than non pregnant controls. Abnormal cardiac findings included a loud second heart sound (P(2)), missed beats and systolic murmurs (41.2% in pregnant subjects vs 12.9% in non-pregnant controls, p < 0.05). Negroid-pattern ST-segment elevation was commoner among controls (24.3%) than pregnant subjects (2.9%, p < 0.005). Arrhythmias were rare among the study participants. CONCLUSION: Significant findings on examination were low diastolic blood pressure and a systolic ejection murmur. However, ECG changes showed a normal frontal-plane QRS axis, normal PR interval, significantly rare normal Negroidpattern ST elevation, significant LVH based on Araoye RI > 12 mm and a rarity of all forms of arrhythmias. These data may help resolve some cardiac diagnostic difficulties during pregnancy. PMID- 21556449 TI - P-wave dispersion: relationship to left ventricular function in sickle cell anaemia. AB - BACKGROUND: The prognostic implications of P-wave dispersion in patients with a variety of cardiac disease conditions are increasingly being recognised. The relationship between P-wave dispersion and left ventricular function in sickle cell anaemia is unknown. OBJECTIVE: This study was aimed at evaluating the relationship between P-wave dispersion and left ventricular function in adult Nigerian sickle cell anaemia patients. METHODS: Between February and August 2007, a total of 62 sickle cell anaemia patients (aged 18-44 years; mean 28.27 +/- 5.58) enrolled in the study. These were drawn from patients attending the adult sickle cell clinic of the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu. An equal number of age- and gender-matched normal subjects served as controls. All the participants were evaluated with electrocardiography and echocardiography. P-wave dispersion was defined as the difference between the maximum and minimum P-wave duration measured in a 12-lead electrocardiogram. RESULTS: P-wave duration and P-wave dispersion were significantly higher in patients than in controls. Significant correlation was demonstrated between P wave dispersion and age in the patients (r = 0.387; p = 0.031). A comparison of subsets of sickle cell anaemia patients and controls with comparable haematocrit values (30-35%) showed significantly higher P-wave duration and P-wave dispersion in the patients than in the controls. The P-wave duration in patients and controls, respectively, was 111.10 +/- 14.53 ms and 89.14 +/- 16.45 ms (t = 3.141; p = 0.006). P-wave dispersion was 64.44 +/- 15.86 ms in the patients and 36.43 +/- 10.35 ms in the controls (t = 2.752; p = 0.013). Significant negative correlation was found between P-wave dispersion and left ventricular transmitral E/A ratio (r = -0.289; p = 0.023). CONCLUSION: These findings suggest that P-wave dispersion could be useful in the evaluation of sickle cell patients with left ventricular diastolic dysfunction. Further prospective studies are recommended to evaluate its prognostic implication on the long-term disease outcome in sickle cell disease patients. PMID- 21556450 TI - Achieving blood preSsure goals sTudy in uncontrolled hypeRtensive pAtients treated with a fixed-dose combination of ramipriL/hydrochlorothiazide: the ASTRAL study. AB - BACKGROUND: Hypertension is a common cardiovascular disease, affecting adults worldwide and it accounts for up to 30% of all deaths. The need for better control of arterial hypertension justifies observational studies designed to better understand the real-life management of hypertensive patients. The ASTRAL study was primarily designed to evaluate the percentage of hypertensive patients achieving blood pressure goals after eight weeks of treatment with a fixeddose combination of ramipril/hydrochlorothiazide (HCTZ). METHODS: The study was a multi-centre, non-comparative, Open-label, observational study conducted in 36 centres in five sub-Saharan African countries, namely Cameroon, Congo Brazzaville, Democratic Republic of Congo (DRC), Madagascar and Nigeria. Four hundred and forty-nine men and women 18 years of age or older with hypertension not controlled by an ACE inhibitor, a diuretic or any other monotherapy or anti hypertensive combination not containing a diuretic in a fixed dose were considered eligible for inclusion in this eight-week study. The study consisted of three visits, visit one (V1) at baseline, visit two (V2) after four weeks and visit three (V3) after eight weeks. RESULTS: The mean age of the patients was 54.7 +/- 11.7 years (20-90 years) and most were categorised by the WHO criteria as either overweight or obese (71.6%). After four and eight weeks of treatment with the study drug, systolic and diastolic blood pressures significantly changed from baseline: -24.7/-14.2 mmHg (p < 0.001) and -31.7/-17.9 mmHg (p < 0.001), respectively. There were 60.2% of the non-diabetics on prior monotherapy who, at eight weeks, fulfilled the primary blood pressure goal for SBP and DBP, versus 26.5% of the diabetic patients, also on monotherapy. Few adverse events were reported, with facial oedema and dry cough recurring twice in two patients. CONCLUSION: Fixed-dose combination of ramipril/HCTZ is therefore effective, tolerable and has a good safety profile for blood pressure control in black Africans. PMID- 21556451 TI - Serum high-sensitivity C-reactive protein, amyloid associated protein and N terminal proBNP levels do not predict reversible myocardial ischaemia. AB - AIM: The aim of this study was to detect any relationship between serum high sensitivity C-reactive protein (hs-CRP), serum amyloid-associated protein (SAA) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and reversible myocardial ischaemia during cardiovascular exercise tests and to determine whether these biomarkers could predict transient myocardial ischaemia. METHODS: Ninety-six patients (36 women, 60 men, mean age 57 +/- 8.5 years) were included in the study. Venous blood samples were taken from patients before and 15 minutes after exercise testing. SAA and hs-CRP were analysed using immunonephelometric assays (Dade-Behring, BN II, Marburg, Germany). NT-proBNP (pg/ml) was determined using the immulite 1 000 chemiluminescence immunoassay system (Siemens Medical Solution Diagnostics, Deerfiled, USA). Forty-eight patients (18 women, 30 men) with positive exercise tests were allocated to the exercise-positive group and 48 (18 women, 30 men) with negative exercise tests were put in the exercise-negative group. Coronary angiography was performed on all patients in the exercise positive group. RESULTS: There was no difference between the levels of hs-CRP, SAA and NT-pro-BNP before and after exercise testing in both of the exercise groups. CONCLUSION: Serum levels of hs-CRP, SAA and NT-proBNP could not predict the occurrence of reversible myocardial ischaemia during exercise. Large-scale clinical studies are needed to clarify the status of hs-CRP, SAA and NT-proBNP with exercise. PMID- 21556452 TI - Isolated left ventricular non-compaction with normal ejection fraction. AB - Isolated left ventricular non-compaction (LVNC) is a genetic disease that is being increasingly recognised in patients presenting with heart failure of unknown origin. In this case report, we describe a patient with classic LVNC without clinical heart failure and with normal left ventricular ejection fraction. PMID- 21556453 TI - Reversible myocardial stunning due to carbon monoxide exposure. AB - We report on a 37-year-old patient who suffered from myocardial stunning after exposure to carbon monoxide, despite having normal coronary arteries. As myocardial ischaemia may be asymptomatic in these patients, close monitoring with serial electrocardiography and of serum cardiac enzymes and troponins is recommended. PMID- 21556454 TI - Secondary intracardiac Burkitt-like lymphoma in the absence of HIV infection. AB - Malignant lymphoma can involve the cardiac cavity or myocardium as a mass. Since clinical symptoms of its cardiac involvement are usually absent or non-specific, they may be undetected during life. Burkitt-like lymphoma (BLL) is a highly aggressive B-cell lymphoma with a high proliferative rate. Histopathological characteristics are considered borderline between those of classic Burkitt lymphoma and diffuse large B-cell lymphoma. Extensive cardiac involvement of BLL is rare and poorly documented in the literature. We report the case of a child with BLL, presenting with extensive infiltration of the heart in the absence of HIV infection, and with right-sided heart failure and positional dyspnoea as the major clinical problems. We highlight the challenges for diagnosis and adequate treatment in poor settings like ours. PMID- 21556455 TI - Affordable hypertension therapy for diabetic patients. PMID- 21556456 TI - Simultaneous treatment of blood pressure and cholesterol beats the 'SILO' approach in lowering cardiovascular risk: results of the CRUCIAL study. PMID- 21556457 TI - Primary prevention with statins is more cost-effective. PMID- 21556458 TI - Stroke prevention in atrial fibrillation. PMID- 21556459 TI - Stroke risk reduction: focus of the new ESC guidelines. PMID- 21556460 TI - Prasugrel offers consistent platelet control in appropriate patients requiring treatment. PMID- 21556461 TI - Substantial evidence for colorectal cancer reduction with daily low-dose aspirin. PMID- 21556462 TI - The relationship between indices of iron status and selected anthropometric cardiovascular disease risk markers in an African population: the THUSA study. AB - There is evidence that certain indices of iron status are associated with anthropometric measures, which are used independently as markers of cardiovascular disease (CVD) risk. This study examined whether this association exists in an African population. The study was a cross-sectional comparative study that examined a total of 1 854 African participants. Ferritin was positively associated with body mass index (BMI), waist circumference (WC), waist to-hip ratio (WHR), percentage body fat and subscapular skinfold thickness. Serum ferritin concentration was higher in the high-WHR category than the normal-WHR category for both genders. Additionally, WC and WHR increased with increasing ferritin concentrations in both genders. Serum iron was lower in the obese than the normal-weight and pre-obese women only. In this population-based study, increased serum ferritin concentrations associated positively with increased WHR and WC, indicating that individuals or populations at risk of iron overload as defined by high serum ferritin concentrations may be at a greater risk of developing CVD. PMID- 21556463 TI - Castleman's disease. Update on pathogenesis. AB - Castleman's disease (CD) is an unusual lymphoproliferative disorder that may mimic lymphoma clinically and pathologically. It is classified clinically as localized and multicentric types, and pathologically as hyaline vascular and plasma cell types. It is associated with increased risk of lymphoma and follicular dendritic cell tumors. The pathogenesis of CD is still controversial and complex. Active research is ongoing to highlight more on the etiopathogenesis of this entity. The aim of this article is to review the literature on pathogenesis of CD and to focus on the possible role of viruses in the development of this disease. PMID- 21556464 TI - Marginal mandibular branch of the facial nerve in human fetuses. AB - OBJECTIVE: To observe the course of the marginal mandibular branch (MMB) and its relation to the inferior border of the mandible and facial vessels. METHODS: This study was conducted in the Department of Anatomy, Gulhane Military Medical Academy, Etlik, Ankara, Turkey from February 2009 to April 2010. The 44 hemi-face specimens of 22 fetuses were selected for this study, and dissected under a stereomicroscope. The MMB relationship was evaluated between adjacent structures (like vessels and muscles) and the lower border of the mandible. RESULTS: We found a number of one to 4 branches of the MMB. The MMB ran laterally to the facial vein in 42 (95.5%) of the 44 specimens. All the branches of the MMB ran laterally to the facial artery in 30 (68.2%) of the 44 specimens. In 2 specimens, it ran medially to the facial artery. In 10 specimens, the facial artery ran between 2 branches of the MMB. In 2 specimens, the 2 branches of the MMB ran between facial artery and vein. There were no statistical differences between the left and right sides, and in both genders. CONCLUSION: The inferior border of the mandible may be an important landmark to avoid injury to the MMB of the facial nerve. It is for this reason, that surgeons who are willing to operate on this area should have a true knowledge and accurate judgement regarding the anatomy of this branch. PMID- 21556465 TI - p63 expression in randomized odontogenic cysts. AB - OBJECTIVE: To find out the immunohistochemical assessment of p63 expression in odontogenic cysts based on the differences among their clinical behaviors. METHODS: This study was carried out on 34 archival paraffin-embedded specimens of odontogenic cysts. We obtained the specimens from the Pathology Department of Babol University of Medical Sciences, Babol, Iran from March 2003 to February 2008. The specimens comprised 12 dentigerous cysts, 9 radicular cysts, and 13 keratocystic odontogenic tumors (KCOTs). The immunohistochemical technique was performed using the Envision system for evaluation of p63 expression. RESULTS: The KCOT revealed the highest p63 expression and the differences between the 3 groups was statistically significant. CONCLUSION: P63 expression might be helpful when identifying cyst types with more aggressive and invasive phenotype. PMID- 21556466 TI - L-arginine-glycine amidinotransferase, betaine-homocysteine S-methyltransferase, and neuropolypeptide H3 are diminished in renal clear cell carcinoma of humans. AB - OBJECTIVE: To identify renal clear cell carcinoma-associated marker proteins. METHODS: Twelve patients with renal cell carcinoma (RCC) were collected and processed in the Department of Urology, Renmin Hospital, Wuhan University, China, between January 2008 and September 2009. Two-dimensional polyacrylamide gel electrophoresis and matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) were employed to investigate differentially expressed protein spots between RCC tissues and adjacent normal tissues, then reverse transcription polymerase chain reaction and western blot were employed to confirm the proteomic results. RESULTS: One protein spot was upregulated, 13 were downregulated, and 22 were absent in RCC tissues. Four of the absent proteins were L-arginine-glycine amidinotransferase (AGAT), Betaine-homocysteine S methyltransferase (BHMT), Ketohexokinase (KHK), and Neuropolypeptide h3 (NPh3). The reverse transcriptase-polymerase chain reaction analysis demonstrated mRNA expression of AGAT, BHMT, and Nph3 was significantly decreased in 12 RCC tissues. In addition, Western blot analysis showed AGAT protein was absent in 11/12, BHMT in 9/12, and Nph3 in 5/12 RCC tissues. CONCLUSION: Absence of AGAT, BHMT, and Nph3 is common events in clear cell RCC; hence, it may be involved in the development of RCC; therefore, they have the potential to be tumor markers for diagnosis, treatment, and prognosis of RCC patients. PMID- 21556467 TI - Expression of transforming growth factor-beta 1 and connective tissue growth factor in women with pelvic organ prolapse. AB - OBJECTIVE: To investigate the presence of transforming growth factor-beta 1 (TGF beta1) and connective tissue growth factor (CTGF) in women with pelvic organ prolapse (POP). METHODS: This study was conducted from May to December 2009. Fifty patients with POP that underwent vaginal hysterectomy in the Department of Gynecology, Renmin Hospital of Wuhan University, Hubei, Wuhan, China were enrolled in this study. They were divided into: Group 1 (n=10); Group 2 (n=10); and Group 3 (n=10) according to Pelvic Organ Prolapse Quantitation (POP-Q). Meanwhile, 20 cases treated by vaginal hysterectomy for other benign gynecological diseases were selected as the control group. Immunohistochemical staining and Western blot were performed to detect the expression of TGF-beta1 and CTGF. RESULTS: Immunohistochemical staining of TGF-beta1 and CTGF were mainly expressed in the cytoplasm of fibroblast cells. The expression of TGF-beta1 and CTGF protein was significantly negatively correlated with POP-Q stage. There were significantly positive correlations between the expression of TGF-beta1 and CTGF protein. The expression of TGF-beta1 protein among the 3 POP groups were all significantly lower than that of the control group, while there was no significant differences in the expression of TGF-beta1 protein among the POP groups, excluding the comparison between Groups 1 and 3. The expression of CTGF protein in the 3 POP groups were all significantly lower than that of the control group, and significant differences were also detected among the 3 POP groups. CONCLUSION: In this study, we found that the TGF-beta1 and CTGF protein expression may be associated with POP, especially in POP-Q stages. PMID- 21556468 TI - In vitro antimicrobial activity of propolis, BioPure MTAD, sodium hypochlorite, and chlorhexidine on Enterococcus faecalis and Candida albicans. AB - OBJECTIVE: To evaluate the antimicrobial effect by measuring the minimum inhibitory concentration MIC and minimum bactericidal concentration MBC of propolis, BioPure MTAD, 5% sodium hypochlorite (NaOCl), and 2% chlorhexidine CHX on Enterococcus faecalis (E. faecalis) and Candida albicans (C. albicans) in vitro. METHODS: This study was performed in the Faculty of Dentistry and Pharmacy at Erciyes University, Kayseri, Turkey from February to April 2010. Ethanol extract of propolis (EEP) was prepared from propolis collected from Kayseri, Turkey, and proper media for microorganisms were prepared using sterile broth medium to give final concentrations between 0.002-2.4 mg/ml for propolis, 0.000125-0.512 mg/ml for CHX, and 1:2-1:4096 dilutions for NaOCl and BioPure MTAD. Using the macrobroth dilution method, MIC, and MBC values of irrigants on the growth of E. faecalis and C. albicans were determined. RESULTS: Propolis and other irrigants were found to be effective on C. albicans and E. faecalis. Propolis and NaOCl were more effective in lower concentrations on C. albicans than on E. faecalis. In contrast, CHX and MTAD were more effective in lower concentrations on E. faecalis than on C. albicans. CONCLUSION: Propolis showed antimicrobial activity against E. faecalis and C. albicans. It appears that propolis is an effective intracanal irrigant in eradicating E. faecalis and C. albicans. PMID- 21556469 TI - Drug susceptibility pattern of Mycobacterium tuberculosis isolates against conventional anti-tuberculosis drugs in Dhaka, Bangladesh. AB - OBJECTIVE: To investigate the drug susceptibility pattern of isolated Mycobacterium tuberculosis (M. tuberculosis) against conventional anti tuberculosis drugs in Dhaka, Bangladesh. METHODS: Sputum samples from 101 suspected new and previously treated patients were collected and M. tuberculosis was identified by microscopic observation and Ziehl-Neelsen staining. Drug susceptibility was performed against 4 anti-tuberculosis drugs, and the obtained data was analyzed. This study was performed in the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders Hospital, Dhaka, Bangladesh between October 2008 and November 2009. RESULTS: Among 101 suspected, 59 (58.4%) cases were identified as M. tuberculosis and the drug susceptibility pattern of 50 positives isolates was studied against 4 anti tuberculosis drugs. Out of these 50 isolates of M. tuberculosis, 25 (50%) were sensitive to all drugs, and 25 (50%) were resistant to one or more drugs. Among 50 positive patients, 37 (74%) were new cases, and 13 (26%) were previously treated cases. Among 37 new cases, 14 (37.8%) cases were resistant to one or more drugs, whereas 11 out of 13( 84.6%) treated cases were resistant to one or more drugs. Among the 50 positive isolates, 26% demonstrated resistance to isoniazid, 12% to rifampicin, 22% to streptomycin, 20% to ethambutol, and 8% to multi drug resistance. CONCLUSION: The emergence of drug resistant M. tuberculosis isolates in Dhaka is alarming, which is currently 5-fold higher than last decade. Strict measures should be taken to control and prevent drug-resistant tuberculosis. PMID- 21556470 TI - Device-associated infection rates and bacterial resistance in the intensive care units of a Turkish referral hospital. AB - OBJECTIVE: To determine device-associated infection (DAI) rates, and the microbiological and antibiotic resistance profiles of infecting pathogens in our hospital. METHODS: Prospective surveillance of healthcare-associated infections was performed from January 2007 to March 2010 in 4 different intensive care units (ICUs) of SB Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey. RESULTS: During the study period, 6,005 patients were followed-up in ICUs for a total of 46,355 patient-days. The total number of DAIs was 969. Catheter associated urinary tract infection (CAUTI) was the most common DAI (55.3% of DAIs; 11.9 cases per 1000 catheter-days), followed by ventilator-associated pneumonia (VAP) (38.9% of DAIs; 21.2 cases per 1000 ventilator-days), and central line-associated blood stream infection (CLABSI) (5.8% of DAIs; 2.8 cases per 1000 central line-days). The most frequently isolated pathogens in patients with VAP were Acinetobacter species (24.5%) and Escherichia coli in CAUTI (24.2%). Coagulase negative Staphylococci and Candida species were the leading pathogens in patients with CLABSI. CONCLUSION: We observed considerably high rates of VAP and CAUTI and a high rate of CLABSI in our ICUs when compared with the National Healthcare Safety Network data. These findings emphasize the need to improve infection control practices and management of invasive device use in our hospital. PMID- 21556471 TI - Treatment planning for high dose rate brachytherapy of cervical cancer based on total dose constraints. AB - OBJECTIVE: To compare the inverse planning optimization based on total dose constraints versus conventional treatment plan (point A planning method) for cervical carcinoma, and evaluate the benefit of CT-based image-guided brachytherapy. METHODS: We prospectively analyzed data of 10 consecutive patients with cervical cancer treated with external beam radiotherapy to the whole pelvis (45 Gy in 25 fractions) followed by high-dose-rate (HDR) brachytherapy (21 Gy in 3 fractions). For treatment planning of HDR brachytherapy, the basic equations of the linear-quadratic model were used to calculate the physical dose for each brachytherapy fraction needed to achieve a given total iso-effective dose for the whole treatment. Specific dosimetric parameters are evaluated for high risk (HR CTV), intermediate risk (IR CTV) clinical target volumes, and organs at risk (OARs). RESULTS: In conventional plans, the HR CTV was well covered in only 15/31, and the IR CTV in 7/31 of the brachytherapy implants, while dose constraints of OARs bladder and rectum were respected in 28/31 and 14/31 implants. After optimization, the HR CTV and IR CTV dose constraints were respected in all the implants, and the bladder and rectum of cases dose constraints were respected in 25/31 and 17/31 of cases. CONCLUSION: Point A is a poor surrogate of target dose. Significant differences between point doses and dose volume histogram parameters indicate the need for inverse planning in image guided brachytherapy of cervical cancer. PMID- 21556472 TI - Repair of large abdominal wall defects using the ProceedTM surgical mesh with open intra-peritonium onlay method. AB - OBJECTIVE: To report our experience with the use of ProceedTM, Ethicon, Norderstedt, Germany surgical mesh in the management of large abdominal wall defects with the open intra-peritonium onlay method. METHODS: Thirty-six patients with large incisional hernia or defects resulting from tumor resection carried out at the Department of General Surgery, the First Affiliated Hospital, General Hospital of People's Liberation Army, China between May 2007 and June 2010 were studied. The abdominal wall defect was repaired using ProceedTM mesh with the intra-peritonium onlay method. Different parameters were evaluated considering the complications such as seroma, hematoma, wound infection, mesh infection, chronic pain, wound sinus, and recurrences. RESULTS: All 36 defects were repaired using ProceedTM mesh. The mean size of the defects was 160 cm2 (range = 120-600 cm2). Eleven patients (30.6%) developed a complication (6 seromas, one minor wound infection, one wound sinus, 2 pulmonary infection, and one urinary tract infection). The mean follow-up period was 28 months (range 6-36 months). There were no cases of intestinal fistula or problems related to intestinal adhesion and chronic wound pain. No hernia recurrence, or mesh infection occurred. CONCLUSION: The intra-peritoneum repair technique for a large abdominal wall defect using ProceedTM mesh is a feasible and safe method, with no major complications. PMID- 21556473 TI - Vitamin A status in wheezing Saudi children. AB - OBJECTIVE: To examine the serum retinol levels of wheezing children, and to investigate the relation as an biochemical indicator of vitamin A status in wheezing children between serum levels of retinol and severity of wheezing. METHODS: A prospective cohort study including 400 wheezing Saudi children aged 3 36 months, who were treated in the pediatrics ward of Ohoud Public Hospital in Al Madinah, Kingdom of Saudi Arabia between January 2009 and August 2010. Patients were subdivided according to the course of wheeze into 93 patients with persistent wheeze, and 307 patients with acute wheeze. Severity of wheeze was graded mild, moderate, and severe. RESULTS: Among the persistent wheezing patients 9.7% had deficient, and 20.4% had marginal serum vitamin A concentration, while in the acute wheezing patients, 1.6% had deficient, and 8.1% had marginal serum vitamin A concentrations. Results revealed that the prevalence of deficient and marginal vitamin A concentration is higher in the persistent than in the acute wheezing group (p<0.05). Serum vitamin A was related to wheezing severity. Deficient serum vitamin A was found only in severe wheezing groups. CONCLUSION: Wheezing Saudi infants had prevalent deficiency and marginal deficiency of vitamin A. Serum vitamin A concentrations were related to the wheezing severity and course. PMID- 21556474 TI - Hand hygiene compliance rate among healthcare professionals. AB - OBJECTIVE: To motivate healthcare professionals, with a focus on improving hand hygiene compliance. METHODS: An observational, prospective, longitudinal study was conducted on the evaluation of hand hygiene compliance at Hera General Hospital, Makkah, Kingdom of Saudi Arabia from May 2009 to May 2010. Four components to improve hand hygiene compliance were implied; daily audit, monthly staff education; quarterly workshops of hand hygiene, and education material distribution. The compliance rate was calculated by its adherence with number of opportunities. RESULTS: Of total 163 healthcare professionals were surveyed for hand hygiene compliance; 57 (35%) were doctors, 92 (56.4%) nurses, and 14 (8.6%) patient care technicians. The overall compliance rate was 50.3%, and its distribution among staff was as follows; doctors 49.1%, nurses 52.2%, and technicians 42.8%. The highest compliance rate among doctors and nurses was found in surgical units. A low compliance in high intensity patient care area was observed such as in the emergency room and out patient department. The patient care technicians showed highly variable results, as their compliance rate was 100% in medical units while 0% in various other clinical areas. CONCLUSION: The overall hand hygiene compliance rate of healthcare professionals reached 50% after a long education campaign, and was highest among the nurses. Further study is needed to explore the reasons for non-compliance. PMID- 21556475 TI - Medical students' knowledge of ionizing radiation and radiation protection. AB - OBJECTIVE: To assess the knowledge of fourth-year medical students in ionizing radiation, and to study the effect of a 3-hour lecture in correcting their misconceptions. METHODS: A cohort study was conducted on fourth-year medical students at King Abdul-Aziz University, Jeddah, Kingdom of Saudi Arabia during the academic year 2009-2010. A 7-question multiple choice test-type questionnaire administered before, and after a 3-hour didactic lecture was used to assess their knowledge. The data was collected from December 2009 to February 2010. The lecture was given to 333 (72%) participants, out of the total of 459 fourth-year medical students. It covered topics in ionizing radiation and radiation protection. The questionnaire was validated and analyzed by 6 content experts. RESULTS: Of the 333 who attended the lecture, only 253 (76%) students completed the pre- and post questionnaire, and were included in this study. The average student score improved from 47-78% representing a gain of 31% in knowledge (p=0.01). CONCLUSION: The results indicated that the fourth-year medical students' knowledge regarding ionizing radiation and radiation protection is inadequate. Additional lectures in radiation protection significantly improved their knowledge of the topic, and correct their current misunderstanding. This study has shown that even with one dedicated lecture, students can learn, and absorb general principles regarding ionizing radiation. PMID- 21556476 TI - Cardiac arrest as a result of ventricular tachycardia in a trauma patient. AB - Cardiac arrest is classified based on whether it is treatable using defibrillation or not. It is classified as shockable rhythm (ventricular fibrillation and pulseless ventricular tachycardia, or non-shockable (asystole and pulseless electrical activity). We present a case of a 72-year-old male Saudi patient not known to have any medical illness that was involved in a road traffic accident. He was brought in dead on arrival, and initially managed as a case of trauma, only to discover later that he had ventricular tachycardia just before the trauma. He was successfully resuscitated and discharged after 8 days. PMID- 21556477 TI - Acute life threatening events associated with hypocalcemia and vitamin D deficiency in early infancy. A single center experience from the Kingdom of Saudi Arabia. PMID- 21556478 TI - Prevalence of IgG antibodies against Toxoplasma gondii among Syrian females of childbearing age. PMID- 21556479 TI - Osteopoikilosis. PMID- 21556480 TI - Extremely elevated erythrocyte sedimentation rate. Etiology at a tertiary care center in Saudi Arabia. PMID- 21556481 TI - Medication administration errors in Eastern Saudi Arabia. PMID- 21556482 TI - The effect of nurse-patient language barrier on patients' satisfaction. PMID- 21556483 TI - S1P is associated with protection in human and experimental cerebral malaria. AB - Cerebral malaria (CM) is associated with excessive inflammatory responses and endothelial activation. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid implicated in regulating vascular integrity, inflammation and T-cell migration. We hypothesized that altered S1P signaling during malaria contributes to endothelial activation and inflammation, and show that plasma S1P levels were decreased in Ugandan children with CM compared with children with uncomplicated malaria. Using the Plasmodium berghei ANKA (PbA) model of experimental CM (ECM), we demonstrate that humanized S1P lyase (hS1PL)(-/-) mice with reduced S1P lyase activity (resulting in increased bio-available S1P) had improved survival compared with wild-type littermates. Prophylactic and therapeutic treatment of infected mice with compounds that modulate the S1P pathway and are in human trials for other conditions (FTY720 or LX2931) significantly improved survival in ECM. FTY720 treatment improved vascular integrity as indicated by reduced levels of soluble intercellular adhesion molecule (sICAM), increased angiopoietin 1 (Ang1) (regulator of endothelial quiescence) levels, and decreased Evans blue dye leakage into brain parenchyma. Furthermore, treatment with FTY720 decreased IFNgamma levels in plasma as well as CD4(+) and CD8(+) T-cell infiltration into the brain. Finally, when administered during infection in combination with artesunate, FTY720 treatment resulted in increased survival to ECM. These findings implicate dysregulation of the S1P pathway in the pathogenesis of human and murine CM and suggest a novel therapeutic strategy to improve clinical outcome in severe malaria. PMID- 21556484 TI - Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. AB - This issue of Molecular Medicine contains 14 original research reports and state of-the-art reviews on histone deacetylase inhibitors (HDACi's), which are being studied in models of a broad range of diseases not related to the proapoptotic properties used to treat cancer. The spectrum of these diseases responsive to HDACi's is for the most part due to several antiinflammatory properties, often observed in vitro but importantly also in animal models. One unifying property is a reduction in cytokine production as well as inhibition of cytokine postreceptor signaling. Distinct from their use in cancer, the reduction in inflammation by HDACi's is consistently observed at low concentrations compared with the higher concentrations required for killing tumor cells. This characteristic makes HDACi's attractive candidates for treating chronic diseases, since low doses are well tolerated. For example, low oral doses of the HDACi givinostat have been used in children to reduce arthritis and are well tolerated. In addition to the antiinflammatory properties, HDACi's have shown promise in models of neurodegenerative disorders, and HDACi's also hold promise to drive HIV-1 out of latently infected cells. No one molecular mechanism accounts for the non-cancer related properties of HDACi's, since there are 18 genes coding for histone deacetylases. Rather, there are mechanisms unique for the pathological process of specific cell types. In this overview, we summarize the preclinical data on HDACi's for therapy in a wide spectrum of diseases unrelated to the treatment of cancer. The data suggest the use of HDACi's in treating autoimmune as well as chronic inflammatory diseases. PMID- 21556485 TI - Translational research and therapeutic perspectives in dysferlinopathies. AB - Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene, encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) and the second most common being LGMD. Symptoms generally appear at the end of childhood and, although disease progression is typically slow, walking impairments eventually result. Dysferlin is a modular type II transmembrane protein for which numerous binding partners have been identified. Although dysferlin function is only partially elucidated, this large protein contains seven calcium sensor C2 domains, shown to play a key role in muscle membrane repair. On the basis of this major function, along with detailed clinical observations, it has been possible to design various therapeutic approaches for dysferlin-deficient patients. Among them, exon-skipping and minigene transfer strategies have been evaluated at the preclinical level and, to date, represent promising approaches for clinical trials. This review aims to summarize the pathophysiology of dysferlinopathies and to evaluate the therapeutic potential for treatments currently under development. PMID- 21556486 TI - Non-authoritative parents and impact on drug use: the perception of adolescent children. AB - OBJECTIVE: To evaluate the association between drug use and parenting styles perceived by Brazilian adolescent children. METHODS: This cross-sectional study enrolled adolescents aged 14 to 19 years that used the Servico Nacional de Orientacoes e Informacoes sobre a Prevencao do Uso Indevido de Drogas (VIVAVOZ). A total of 232 adolescents participated in the study. Phone interviews were conducted using the Parental Responsiveness and Demandingness Scale, which classifies maternal and paternal styles perceived by adolescent children as authoritative, neglectful, indulgent or authoritarian. Sociodemographic variables were collected and an instrument was used to assess monthly drug use and abuse. RESULTS: Maternal and paternal parenting styles perceived as neglectful, indulgent or authoritarian (non-authoritative) were significantly associated with drug use (odds ratio [OR] = 2.8; 95% confidence interval [95%CI], 1.3-5.7 for mothers and OR = 2.8; 95%CI, 1.3-6.3 for fathers). Non-authoritative styles also had a significant association with tobacco use in the previous month in the analysis of maternal (OR = 2.7; 95%CI, 1.2-6.5) and paternal (OR = 3.9; 95%CI, 1.4-10.7) styles, and use of cocaine/crack in the previous month (OR = 3.9; 95%CI, 1.1-13.8) and abuse of any drug (OR = 2.2; 95%CI, 1.0-5.1) only for the paternal style. Logistic regression revealed that maternal style (OR = 3.3; 95%CI, 1.1-9.8), adolescent sex (OR = 3.2; 95%CI, 1.5-7.2) and age (OR = 2.8; 95%CI, 1.2-6.2) were associated with drug use. CONCLUSIONS: Adolescents that perceived their mothers as non-authoritative had greater chances of using drugs. There was a strong association between non-authoritative paternal styles and adolescent drug abuse. PMID- 21556487 TI - Effect of place of birth and transport on morbidity and mortality of preterm newborns. AB - OBJECTIVE: To evaluate the effect of place of birth and transport on morbidity and mortality of preterm newborns in the southern region of Brazil. METHODS: This cohort study included preterm newborns transported to a reference intensive care unit (transport group = 61) and followed up until discharge. Data about care in hospital of origin and transport were obtained at admission. This group was compared with infants born in the maternity ward of the reference hospital paired according to gestational age (control group = 123). Primary outcome was death, and secondary outcomes were changes in blood glucose, temperature and oxygen saturation at admission and the incidence of necrotizing enterocolitis, bronchopulmonary dysplasia and sepsis. Relative risk (RR) was used to evaluate the association between variables and outcome. The level of significance was set at alpha = 5% and beta = 90%. RESULTS: Mean travel distance was 91 km. Mean gestational age was 34 weeks. Of the neonates in the transport group, 23% (n = 14) did not receive pediatric care in the delivery room. During transportation, 33% of newborns were accompanied by a pediatrician, and the equipment available was: incubator (57%), infusion pump (13%), oximeter (49%) and device for blood glucose test (21%). The transport group had a greater incidence of hyperglycemia (RR = 3.2; 2.3-4.4), hypoglycemia (RR = 2.4; 1.4-4.0), hyperthermia (RR = 2.5; 1.6-3.9), and hypoxemia (RR = 2.2; 1.6-3.0). The percentage of deaths was 18% in the transport group and 8.9% in the control group (RR = 2.0; 1.0-2.6). CONCLUSIONS: This study revealed deficiencies in neonatal care and transport. Perinatal care and transport should be better organized in the northeastern region of Rio Grande do Sul, Brazil. PMID- 21556488 TI - Phlebotomine sandflies (Diptera: Psychodidae) in Governador Valadares, a transmission area for American tegumentary leishmaniasis in State of Minas Gerais, Brazil. AB - INTRODUCTION: A study on the phlebotomine sandfly fauna was carried out in an endemic area for American tegumentary leishmaniasis in the municipality of Governador Valadares, in the State of Minas Gerais, Brazil. METHODS: Captures were undertaken using HP light traps in four districts, on three nights per month, for one year (from January to December 2008). Correlations between climatic factors (temperature, relative air humidity and rainfall) and the numbers of sandflies collected was observed. RESULTS: 5,413 phlebotomine specimens were caught and were identified as belonging to 12 species. Of these specimens, 2,851 (52%) were females and 2,562 (48%) were males. CONCLUSIONS: Lutzomyia intermedia predominated (29.9% of the species caught), thus suggesting that they were responsible for transmission of American tegumentary leishmaniasis, together with L. whitmani, which was also found in the area (4.3%). The presence of L. longipalpis (11.9%), the main vector for visceral leishmaniasis in Brazil, is an important finding, which makes rigorous entomological surveillance of the area necessary. PMID- 21556489 TI - Health-related quality of life in patients with Chagas disease. AB - INTRODUCTION: Chagas disease (ChD) is a chronic illness related to significant morbidity and mortality that can affect the quality of life (QoL) of infected patients. However, there are few studies regarding QoL in ChD. The objectives of this study are to construct a health-related QoL (HRQoL) profile of ChD patients and compare this with a non-ChD (NChD) group to identify factors associated with the worst HRQoL scores in ChD patients. METHODS: HRQoL was investigated in 125 patients with ChD and 21 NChD individuals using the Medical Outcomes Study 36 item Short-Form (SF-36) and the Minnesota Living with Heart Failure Questionnaire (MLWHFQ). Patients were submitted to a standard protocol that included clinical examination, ECG, Holter monitoring, Doppler echocardiogram and autonomic function tests. RESULTS: HRQoL scores were significantly worse among the ChD group compared to the NChD group in the SF-36 domains of physical functioning and role-emotional and in the MLWHFQ scale. For the ChD group, univariate analysis showed that HRQoL score quartiles were associated with level of education, sex, marital status, use of medication, functional classification and cardiovascular and gastrointestinal symptoms. In the multivariate analysis, female sex, fewer years of education, single status, worst functional classification, presence of cardiovascular and gastrointestinal symptoms, associated illnesses, Doppler echocardiographic abnormalities and ventricular arrhythmia detected during Holter monitoring were predictors of lower HRQoL scores. CONCLUSIONS: ChD patients showed worse HRQoL scores compared to NChD. For the ChD group, sociodemographic and clinical variables were associated with worst scores. PMID- 21556490 TI - Malacological survey of Biomphalaria snails in municipalities along the Estrada Real in the southeast of the State of Minas Gerais, Brazil. AB - INTRODUCTION: The increasing practice of ecotourism and rural tourism in the State of Minas Gerais, Brazil, highlights the importance of studies concerning the occurrence of potential intermediate hosts of Schistosoma mansoni. This study aimed to identify species of Biomphalaria snails in municipalities along the Estrada Real, an important Brazilian tourism project. METHODS: The specimens were collected in different water collections of 36 municipalities along the Estrada Real in the southeast of the State of Minas Gerais. Biomphalaria species were characterized using both morphological and molecular approaches. The research was conducted between August 2005 and September 2009 and all the sites visited were georeferenced using GPS. RESULTS: Six Biomphalaria species were found in 30 of the 36 municipalities studied: glabrata, tenagophila, straminea, peregrina, occidentalis and schrammi. The first three species of Biomphalaria, recognized as intermediate hosts of S. mansoni, were present in 33.3%, 47.2% and 8.3% of the municipalities studied, respectively. The mollusks were found in different types of water collections and no infection by S. mansoni was detected. The highest occurrence of Biomphalaria concentration was verified in the area covered by the Caminho Novo route (Diamantina/MG to Rio de Janeiro/RJ). CONCLUSIONS: Considering the occurrence of schistosomiasis in the State of Minas Gerais and the socioeconomic repercussions involved in the Estrada Real Project, this work focuses on the vulnerability of water collections due to the presence of Biomphalaria mollusks and emphasizes the need for epidemiological surveillance and sanitary and educational measures integrated with the local community and tourism sectors. PMID- 21556491 TI - [The bats and rabies in the Western region of the State of Sao Paulo, Brazil]. AB - INTRODUCTION: The Polo da Alta Sorocabana Laboratory in Presidente Prudente, SP, in partnership with other research institutions, conducted studies related to bats from the western region of the State of Sao Paulo, Brazil. Thus, certain situations were investigated, including: a) isolation of the rabies virus from 2006 to 2008; b) identification of respective antigenic variants; and c) characterization of daytime shelters of Desmodus rotundus vampire bats. METHODS: Samples for examination originated from nonhematophagous bats forwarded to the laboratory and subjected to direct fluorescent antibody test and mouse inoculation test. Positive samples were characterized by the monoclonal antibody test. Regarding the bats, they were identified and classified and mapping of their shelters was also performed. RESULTS: The laboratory received 1,113 nonhematophagous bats for rabies diagnosis, 11 (1%) of which were positives, and among the positive samples, 5 (45.5%) presented antigenic variant 3 (from the bat Desmodus rotundus) and 4 (36.5%) were compatible with samples derived from Brazilian insectivorous bats. Sixteen vampire bat shelters were investigated and observation confirmed the presence of another 3 species of nonhematophagous bats coexisting with them. CONCLUSIONS: The experiments showed that at least 3 antigenic variants of rabies virus are circulating in the region and that the cohabitation of vampire bats with nonhematophagous bats could be related to the dissemination of the rabies virus. PMID- 21556492 TI - [Monitoring the susceptibility of Triatoma sordida Stal, 1859 (Hemiptera: Reduviidae) to deltamethrin insecticide, in Central-Western Brazil]. AB - INTRODUCTION: Triatoma sordida Stal, 1859 populations were investigated for susceptibility to deltamethrin. METHODS: This study aimed to analyze the resistance of 11 populations of insects from the States of Goias, Mato Grosso and Mato Grosso do Sul by topical application bioassays. RESULTS: The estimated LD50 and RR50 showed high levels of susceptibility (LD50 < 1 and RR50 < 2). However, analysis of the slope of the dose response curve showed that the populations of insects in the towns of Firminopolis/GO, Posse/GO, Poxoreu/MT, Douradina/MS and Aparecida do Taboado/MS present great probability of evolving resistance and, thus, are more likely to tolerate treatment with deltamethrin. CONCLUSIONS: Small changes in susceptibility and low levels of resistance were detected, but the temporal changes of susceptibility should be continuously monitored to adequately guide the actions of vector-control of DC. PMID- 21556493 TI - C-ha-ras enhances the neoplastic transformation of human breast epithelial-cells treated with chemical carcinogens. AB - The present study was carried out with the purpose of analyzing the additive effect of c-Ha-ras oncogene on tumorigenesis in human breast epithelial cells (HBEC) treated with chemical carcinogens. A human breast epithelial cell (HBEC) line, MCF-10F, previously treated with dimethylbenz(a) anthracene (DMBA) and benzo(a)pyrene (BP) was used in these studies. The MCF-10F cells, DMBA and/or BP transformed cells originated from the clones D3-1 and BP1 which were transfected with the plasmid pH06T1 containing the human T24 mutated c-Ha-ras oncogene and termed MCF-10F-Tras, D3-1-Tras and BP1-Tras, respectively. Whereas the c-Ha-ras transfected cells presented altered morphology, increased anchorage independent growth in agar-methocel, invasiveness and tumorigenicity, the MCF-10F cells, the clones D3 and BP1 were not tumorigenic. Importantly, whereas MCF-10F-Tras was slightly tumorigenic, the D3-1-Tras and BP1-Tras transfected cells were 100% tumorigenic in the SCID mice; and the tumors thus obtained were poorly differentiated carcinomas. DNA fingerprinting confirmed that the tumors derived originated from the cell lineage used. It was concluded that c-Ha ras induces an additive effect on the expression of tumorigenesis in human breast epithelial cell line MCF-10F treated with chemical carcinogens. Our work provide a model for analyzing the role of c-Ha-ras in human breast cancer. PMID- 21556494 TI - Alteration of telomeric repeat length in adult and childhood solid neoplasias. AB - The ends of human chromosome contain unique structures referred to as telomeres which confer genetic stability to the chromosomes, but due to the end replication problem, cell division both in vivo and in vitro reduce the average telomere length in normal somatic cells. We have measured the length of terminal restriction fragments (TRFs) at the telomeric ends in 215 adult and 156 pediatric solid neoplasias. Reduced TRFs were detected in 52 adult tumors (24.2%) and 33 pediatric tumors (21.2%), while elongated TRFs were detected in 19 adult tumors and seven pediatric tumors. Our results indicate that while TRF lengths are altered in a fraction of various kinds of tumor, many tumors consist of cells with TRF lengths which do not differ from those of adjacent normal tissue. PMID- 21556495 TI - Augmentation of protective immunotherapy against metastatic esb lymphoma-cells by combining immune cell transfer with host irradiation, antigen restimulation and/or anti-tnf-alpha antibody treatment. AB - To develop effective immunotherapies against disseminated metastatic tumor cells we have tried to improve the overall protective immunity effect by combining adoptive immune cell therapy (ADI) with other treatment modalities. In contrast to other groups who use in vitro cultured effector cells we use for ADI only in situ activated anti-tumor immune cells. The immunotherapy studies were performed with the lymphoma variant ESb which metastasizes to multiple visceral organs and can develop immune escape variants. In the absence of additional exogenous cytokines, peritoneal effector cells (PEC), generated from intra-pinna tumor immunized and i.p. re-stimulated mice, were able to transfer protective immunity and anti-tumor DTH reactivity into syngeneic mice with disseminated ESb tumor cells. We describe the protective immune capacity of PEC in comparison to immune cells from lymph nodes or spleens of immunized mice and test for possible synergistic interactions of the latter with PEC. The adoptive immunotherapy effect seen with immune PEC could be augmented by host irradiation and by combination with active specific immunization (ASI) using previously established virus modified tumor vaccines. In an attempt to study the possible role of cytokines in this system, we tested the effect of neutralizing antibodies to TNF alpha and IFN-gamma on the therapeutic effect. Anti-TNF-alpha but not anti IFN gamma antibody treatment augmented the immunotherapeutic effectiveness of immune PEC mediated ADI. PMID- 21556496 TI - In frame deletion of intron-7 in the p53 gene in a human tonsil tumor. AB - We here report a unique intron deletion in the p53 gene. Analysis of a human tonsil tumor that expressed elevated levels of p53 showed a deletion of the entire intron 7 in one of the p53 alleles, leaving the coding sequence intact. The significance of the intron 7 deletion for the development of the tonsil tumor is discussed. PMID- 21556497 TI - Antitumoral activity of flavone L-86-8275. AB - L 86-8275, a flavone of novel structure, was shown to be a kinase inhibitor and to possess surprising potent antiproliferative potency (IC50=0.1-0.15 mu M) on various tumor cell lines after long period of incubation. Short period of incubation was significantly less effective (IC50=133 mu M). In vitro L 86-8275 showed almost no cross-resistance on L 1210 mouse leukemia tumor cell line 110 fold resistant to doxorubicin. In vivo significant antitumoral effects were seen with xenografted lung, colon, mammary and ovarian tumors as well as glioblastoma. T/C values ranged from 29 to 86% and were comparable to standard chemotherapeutic treatment. Optimal schedule required daily oral application of L 86-8275. PMID- 21556498 TI - Differential expression of glutathione-s-transferase isozymes in murine and human skin tumors. AB - Glutathione S-transferases (GSTs) are a family of widely distributed multifunctional enzymes present in a number of organs and species. GSTs participate in the detoxification of a wide variety of xenobiotics and their metabolites. Mammalian GSTs have been grouped into three major classes alpha, mu and pi. The differential expression of specific GST isozymes has been reported as a phenotypic marker for the preneoplastic lesions and neoplastic tissues in liver and other extracutaneous organs of rat and other species including humans. However, the expression of GST isozymes in skin cancer is not known. In the present study, therefore, employing Western blot analysis, we assessed the GST isozyme expression in experimentally-induced murine skin tumors and clinically obtained human skin basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). As compared to normal murine skin showing high levels of GST-pi, significantly lower expression of GST-pi was observed in murine skin papillomas and carcinomas induced chemically in SENCAR mice or by chronic ultraviolet B radiation in SKH-1 hairless mice. Similar results were also observed for GST-mu isozyme. On the other hand, compared to normal murine skin where the expression of GST-alpha isozyme was not detectable, significant levels of this GST isozyme were observed in all the murine skin papillomas and carcinomas. In case of human skin BCCs and SCCs, variable GST isozyme patterns were evident, however in each case, GST-pi was found to be significantly underexpressed as compared to that in skin from healthy subjects. Our results suggest that altered phenotypic expression of GST isozymes may be a useful marker for skin cancer. PMID- 21556499 TI - Cytokine gene-modified vaccines for immunotherapy of cancer (review). AB - Cytokine gene therapy has recently become a new prospective modality in the treatment of cancer. Active immunization with gene-modified tumour cells in experimental systems employs either live Vaccines at subthreshold, non tumorigenic doses, or irradiated cytokine-producing vaccines. The effects exerted on tumour cells by the vaccine-produced cytokines are usually pleiomorphic, either direct (cytolysis, upregulation of MHC, TAA, or adhesion molecule expression, terminal differentiation) or indirect (recruitment, amplification and activation of APC, helper and defence effector cells, damage of the blood supply) or both. The aim of this article is to review and summarize recent results of the cytokine gene therapy in experimental tumour systems, as well as to discuss the prospects and limitations of this novel approach in the management of cancer patients. The review is primarily focused on the therapeutic vaccination; however, when relevant, the results obtained with preventive vaccination are also briefly discussed. PMID- 21556500 TI - DNA fragility and repair capability are separate genetic phenotypes - studies on in-situ nick translation and chromosome breakage. AB - Three separate experiments, designed to minimize the DNA repair process following exposures to mutagens, were performed to determine whether DNA repair capability is the sole factor responsible for differential mutagen sensitivity. These experiments included (i) very short bleomycin pulse treatments (2, 5 and 10 min), (ii) ionizing irradiation and (iii) bleomycin treatment with DNA repair inhibited by ethanol. Three lymphoblastoid cell lines, derived (i) from a patient with ataxia telangiectasia (AT), (ii) a patient with lupus erythematosus and (iii) a normal blood donor, were used as test cells. Mutagen sensitivity was measured either by the frequency of chromatid breaks or by grain counts in in situ nick translation preparations. In all cases, sensitivity rating followed the same pattern: AT>lupus>normal. The results support the notion that mutagen sensitivity may depend on two separate phenotype: intrinsic DNA fragility and repair capability. PMID- 21556501 TI - Influence of dietary-fat on growth of mda-mb231 human breast carcinomas maintained in female athymic nude-mice. AB - The purpose of this study was to assess the effects of the type of dietary fat [corn oil (controls), olive oil, linseed oil, primrose oil, canola oil and fish (Menhaden) oil] and the amount of dietary fat on the growth of MDA-MB231 human breast carcinomas in female athymic nude mice. The different types of fats examined in these studies differ widely in their omega-3, -6 and -9 fatty acid contents, fatty acid chain length and their degree of unsaturation. These fats were fed to the carcinoma bearing mice at 20% of the diet by weight and for 5 to 8 weeks. No significant effect of these diets on mouse body weight gains throughout the study was observed. Compared to the corn oil controls, none of the dietary fats significantly affected the growth of the human breast carcinomas in these animals, with the exception of fish oil which consistently and significantly (P<0.05 to P<0.001) suppressed carcinoma growth. DNA synthesis of the human breast carcinomas derived from the fish oil fed mice was assessed by BrdU and PCNA labeling indices and by H-3-thymidine autoradiographic analysis. Despite the fact that the carcinomas derived from the fish oil fed mice were significantly smaller than the carcinomas from the corn oil fed mice, there were no significant differences in any of these parameters of DNA synthesis between the two groups (corn oil and fish oil) of carcinomas. In contrast, in the human breast carcinomas derived from the fish oil fed mice, a significant increase (P<0.01 to P<0.001) in the rate of (125)IUrd loss (K-L/day) and a significant increase (P<0.05 to P<0.001) in the cell loss factor (phi) (phi=1-T-P/T-D) was observed, compared to carcinomas derived from corn oil fed mice. Analysis of the human breast carcinomas for TBARS, a measure of secondary products of lipid peroxidation, revealed that the carcinomas derived from the fish oil fed mice had significantly increased (P<0.001) concentrations of these products compared to carcinomas derived from corn oil fed mice. These results provide evidence that the suppression of growth of human breast carcinoma MDA-MB231 in athymic nude mice by dietary fish oil appears to be due primarily to an increase in the loss of cells from the carcinomas in lieu of a suppression of DNA synthesis, a phenomenon that may be due to the increased concentration of lipid peroxidation products in the tumor tissue. In the studies designed to examine the effect of the amount of fat on growth of MDA-MB231 human breast carcinomas in athymic nude mice, one group of mice was fed a high fat diet (corn oil, 29%) and a second group of mice was fed a low fat diet (corn oil, 1.8%). Both diets were fed at a restricted level, i.e., 65% of ad libitum. A third group of mice was fed a high fat diet (corn oil, 18.1%) ad libitum. The diets were formulated to assure that mice of each group consumed equal amounts of protein, vitamins, minerals and fiber; mice fed the high fat diets (ad libitum and restricted) consumed equal amounts of fat. Growth of the human breast carcinomas in mice fed the high fat and low fat restricted diets was not significantly different despite the large difference in fat consumption. Growth of the carcinomas in mice fed the high fat diet ad libitum was substantially greater than carcinoma growth in mice fed the restricted high fat diet (P<0.001) despite equal amounts of fat consumption. These results demonstrate that in an environment of energy (caloric) restriction, high levels of dietary fat will not enhance growth of MDA-MB231 human breast carcinomas in athymic nude mice, thus emphasizing the important role for energy (calories) in the enhancement of mammary (breast) tumorigenic processes by high fat diets. PMID- 21556502 TI - Results of a clinical multicentric randomized phase-ii study of nonsmall cell lung-cancer treated with vinorelbine Cisplatin versus vinorelbine alone. AB - From July 1992 to December 1993, 62 patients with non-small cell lung cancer (NSCLC) were admitted to a multicentric randomized study. The patients were treated with vinorelbine (V) alone at a dose of 25 mg/m(2)/i.v. weekly or with V at a dose of 25 mg/m(2)/i.v. on day 1 and 8 plus cisplatin at a dose of 80 mg/m(2)/i.v. on day 1 every 3-4 weeks (VP). An objective response was observed in 42% of patients treated with VP versus 12.5% of those treated with vinorelbine alone (p=0.038). There was no significant difference in the median survival duration between the two groups (38 versus 30 weeks for VP and V, respectively). Toxicity was tolerable but more severe in the VP regimen. These data suggest that V is an active agent in NSCLC and that the VP regimen may yield results comparable to other cisplatin combinations for treatment of these tumors. PMID- 21556503 TI - Effect of tumor size on the association between ps2 and cathepsin-d in primary breast-cancer. AB - Previous studies have shown that pS2 and cathepsin D are linked in lymph node positive (N+) tumours, but not in tumours from lymph node negative (N-) patients. The purpose of this study was to understand whether or not size would effect the relationship between pS2 and cathepsin D. Findings were further extended to some subgroups of tumours obtained stratifying for T and N and particularly to the small (TI) but aggressive (N+) cancers (T1/N+) and to those of size greater than 2 cm (T2 and T3) but yet node negative (T2+T3/N-). Oestrogen (ER) and progesterone (PR) receptors, pS2 and cathepsin D concentrations were therefore assayed in 355 primary breast cancers. ER, PR, pS2 and cathepsin D did not correlate to nodal status and size of the tumours; no significant differences in the expression of these four biological factors between infiltrating ductal carcinomas without special features (NOS) and non-NOS carcinomas were found. Multivariate analysis performed among cathepsin D, ER, PR and pS2 indicated that, in T1 tumours, pS2 was the most important variable and the best predictor in cathepsin D determination, while such association was absent in T2 and T3 tumours. pS2 and cathepsin D significantly associated also in tumours obtained from N+ patients, and such correlation was highest in T1 tumours with positive axillary nodes (N+/T1). pS2 and cathepsin D did not associate in tumours taken from N- patients. Considering the NOS carcinomas, correlation between pS2 and cathepsin D in the N+, T1 and N+/T1 subgroups was higher in the poorly differentiated grade 3 with respect to grade 1 and grade 2 cancers. The data suggest that pS2 could have a role in cathepsin D expression and we hypothesise that such control could be an early biological event occurring in the development and progression of particularly aggressive (N+/grade 3), small (T1) breast cancers. PMID- 21556504 TI - Relationship between Moloney murine sarcoma-virus tissue tropism and tumor development. AB - Previous work from our laboratory has demonstrated that a clone of Moloney murine sarcoma virus (MoMuSV-349) inoculated intraperitoneally into newborn BALB/c mice induces multiorgan disseminated angiosarcomatous tumors. These tumors develop in two stages: sarcomatous and angiosarcomatous. The present report investigates the relationship between tumor stage development and viral replication within the target cells using the technique of in situ hybridization. A nonradioactive RNA probe (riboprobe) labeled with digoxigenin-linked uridine triphosphate (DIG-UTP) was used to detect the presence of MoMuSV-349 in frozen tissue sections. Infected and control mice were euthanized at various times post-inoculation and tissues were collected for in situ hybridization. The riboprobe hybridized to macrophages, splenic reticular cells, mesothelial cells, megakaryocytes, Kupffer cells and neoplastic (spindled and endothelial) cells in mice infected with MoMuSV-349. The riboprobe failed to hybridize to any tissues in the non-infected mice. Cells hybridizing with the riboprobe were detected as early as 3 days post inoculation. As the neoplasms progressed from the sarcomatous to angiosarcomatous type there was a shift in cellular target hybridized by the riboprobe from spindled cells to endothelial cells. Positive labeling of endothelial cells during the angiosarcomatous stage of tumor development suggests-that viral replication correlates with cellular proliferation. This demonstrates that in situ hybridization utilizing a non-radioactive riboprobe was useful for a pathogenesis study involving MoMuSV-349. PMID- 21556505 TI - Fish analysis of supernumerary ring chromosome in dermatofibrosarcoma protuberans. AB - We describe the light- and electron microscopic, immunohistochemical, cell culture characteristics and cytogenetic findings of a case of dermatofibrosarcoma protuberans (DFSP). Cytogenetically, the lesion exhibited trisomy 8 and a supernumerary ring chromosome as the only clonal abnormalities found in about 35% of the cells analyzed. FISH-analysis of metaphase chromosomes revealed that the ring chromosome contained chromosome 17 sequences. Hybridization with a chromosome 17 centromere specific probe gave three signals in about 19% of the interphase nuclei suggesting that the ring also had a centromere derived from chromosome 17. These observations add to the evidence that supernumerary ring chromosomes, preferentially derived from chromosome 17, and trisomy 8 are non random abnormalities in DFSP. Our findings also demonstrate the usefulness of FISH for identifying the origin of marker ring chromosomes. PMID- 21556506 TI - Induction of p-glycoprotein, glutathione-s-transferase-pi, catalase, C-fos and C erbb1 in rodent cell-lines after exposure to Doxorubicin, ethanol and caffeine. AB - Murine NIH-3T3 cells were exposed to doxorubicin (DOX, 1 mu g/ml), ethanol (EtOH, 0.2%) and caffeine (CAFF, 200 mu g/ml) and analyzed for the induction of resistance proteins (P-glycoprotein, glutathione S-transferase-pi, catalase) and oncoproteins (c-EOS, c-ERBB1). P-glycoprotein (P-170), glutathione S-transferase pi (GST-pi) and catalase (CAT) levels were found to be elevated after exposure of the cells to doxorubicin. In EtOH-treated cells the P-170 level was moderately increased (12 to 36 h after exposure), whereas the GST-pi and CAT levels were greatly increased (1 to 48 h). CAFF caused a moderate increase of P-170 (12 to 36 h) and of GST-pi (6 to 72 h). The accumulation of rhodamine 123 was reduced after the level of the resistance proteins had risen. After exposure to DOX, c-FOS was expressed moderately whereas c-ERBB1 was expressed strongly. Both oncoproteins showed a significant increase after exposure to EtOH. Only a moderate increase of c-FOS was seen after exposure to CAFF. Five out of seven additionally investigated rodent cell lines showed an increase in the expression of P-170, GST pi and c-FOS after exposure to DOX, EtOH or CAFF. PMID- 21556507 TI - Expression mechanism of human uterine endometrial cancer-specific fucosylated carbohydrate chains - aberrant alpha-1-]4-fucosyl-transferases in uterine endometrial cancer-derived cell-lines with type-I carbohydrate chain. AB - Cells of uterine endometrial cancer cell line SNG-II were classified into two groups according to their reactivity with anti-uterine endometrial cancer monoclonal antibody (MSN-1), whose recognition antigen is mainly the Lewis(b) antigens; those that strongly reacted with MSN-1 (SNG-S group) and those that weakly reacted with it (SNG-W group). The SNG-S showed a higher activity of a 1- >4-fucosyltransferase activity than that of the SNG-W. The expression of Lewis(b) antigen was stronger in the SNG-S than that in the SNG-W. Therefore, the expression of uterine endometrial cancer-specific fucosylated carbohydrate could be mainly controlled by alpha-fucosyltransferase activities. PMID- 21556508 TI - Expression of nse and pgp-9.5 in nonsmall-cell lung-cancers. AB - In NSCLC, neuron-specific; enolase (NSE) and protein-gene product 9.5 (PGP 9.5) were found in 12/14 squamous carcinomas, 1/1 large cell carcinomas and 2/10 adenocarcinomas in characteristic zonal patterns. PGP 9.5 was expressed predominantly in PCNA positive cells adjacent to blood vessels, while the greatest intensity of NSE stain was located in PCNA negative cells distant from vessels, in the centre of tumour masses. NSE expression was unrelated to the distribution of squamous cytokeratins 10 and 13. These studies suggest that expression of PGP 9.5 and NSE in NSCLC may be related to the proliferative or metabolic status of tumour cells. PMID- 21556509 TI - Prevalence of C-erbb3 expression in squamous-cell carcinomas of the cervix as determined by the monoclonal-antibody rtj2. AB - The c-erbB3 protein is a member of the type 1 tyrosine kinase growth factor receptor family. We report on the production and characterisation of a monoclonal antibody, RTJ2, raised against a synthetic peptide from the cytoplasmic domain of the molecule. The antibody is specific for c-erbB3 protein as determined by Western blotting, immunoprecipitation and immunocytochemistry. Using this monoclonal antibody we have evaluated the prevalence of expression of the c-erbB3 protein in 72 squamous cell carcinomas of the cervix. 17 of the 72 (23.6%) tumours were found to overexpress c-erbB3 protein relative to the levels seen in the normal epithelium. Overexpression was not correlated with stage, grade or histologic subtype of the tumours. The high incidence of c-erbB3 overexpression relative to the normal tissue suggests a possible role for c-erbB3 in the oncogenesis of cervical epithelium. PMID- 21556510 TI - High-frequency of loss of expression and allelic deletion of the apc and mcc genes in human prostate-cancer. AB - Loss of heterozygosity (LOH) or allelic deletion at various loci has been reported in the majority of human tumors. The frequently deleted targets are believed to be tumor suppressor genes. Recent studies have identified the APC and MCC genes at 5q21, as putative tumor suppressor genes. The APC and MCC genes have been implicated in the development of familial adenomatous polyposis coli and cancers of the gastrointestinal tract, ovary, breast and lung. In the present study, we investigated a possible role of the APC and MCC genes in prostate cancer development. mRNA expression of the APC and MCC genes and LOH at the APC and MCC loci were determined in prostate cancer tissues from 28 patients and 5 human prostatic adenocarcinoma cell lines. Of the informative cases, the frequency of LOH at the APC and MCC loci was 63% (10/16) and 54% (7/13), respectively. Overall, 65% (15/23) of the informative cases showed LOH at the APC and/or MCC gene. All prostate cancer cell lines showed homozygosity at all APC and MCC polymorphic sites studied. Approximately half (57%) of the tumor tissues examined showed a decreased expression of APC and MCC mRNA. Our data suggest that the APC and MCC genes may be involved in the formation of human prostate cancer (HPC). PMID- 21556511 TI - Carcinoma-cells express IL-8 and the IL-8 receptor - their inhibition attenuates the growth of carcinoma-cells. AB - We investigated the expression of IL-8 and the IL-8 receptor (IL-8R) in human carcinoma cells and the role of IL-8 and IL-8R in the growth of carcinoma cells. IL-8 mRNA was detected in 16 of 20 (80%) carcinoma cell lines and 20 of 24 (83.3%) cancer tissues by Northern blot analysis. IL-8R mRNA was expressed in 7 of 11 (63.6%) carcinoma cell lines by reverse transcriptase polymerase chain reaction (RT-PCR). Neutrophil chemotactic activity in the culture supernatant of carcinoma cell lines correlated with immunoreactive IL-X concentration. Growth of carcinoma cells was significantly inhibited in the presence of anti-IL-8 antibody or IL-8R antisense oligonucleotide. These results revealed that IL-8 and IL-8R are expressed in the majority of carcinoma cells and suggest that they might play a role in the growth of carcinoma cells. PMID- 21556512 TI - Evaluation of prognostic-significance of p53 gene alterations in patients with surgically resected lung-cancer. AB - Clinical significance of p53 gene alterations, as a prognostic factor, was assessed in 69 patients with surgically resected lung cancer. The p53 gene alterations (exon 5-9) were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method of genomic DNA. The p53 gene alterations were detected in all histological types of lung cancer, with a positive rate of 45% (31/69). In the alteration-positive group, patients in the advanced stages of III and IV were seen more frequently than in the negative group (58% vs. 21%, p<0.05). Such a difference was not observed in other parameters such as age, gender, histological type and smoking habit. The prognosis was, on a whole, poorer in the alteration-positive group than for the negative one (5-year survival rate: 19.3% vs. 40.6%, MST: 17 months vs. 36 months), but the difference did not reach statistical significance. However, in the case of females (p<0.05), adenocarcinoma (p<0.01), early stages of I and II (p<0.05) and non-smokers (p<0.005), a significantly poorer prognosis was observed in the gene alteration-positive group than for the -negative one. These results suggest that the p53 gene alteration may be a useful prognostic factor in certain subgroups with lung resected for cancer. PMID- 21556513 TI - High-incidence of allelic loss at the rb gene locus in advanced human ovarian cancer. AB - We examined 26 ovarian cancers for allelic losses at the loci of five tumor suppressor genes, p53, DCC, RB, APC and WT1. The loss of the p53 gene was most common among these five loci (13/20, 65%). The incidence of allelic loss at the RB locus was significantly higher in advanced stage (III-IV) (6/12, 50%) than in early stage (I-II) tumors (1/14, 7%). There were no cases in which the RB gene was lost but the p53 gene was retained. These results indicate that allelic loss of the RB gene locus occurs later than that of the p53 gene and plays a role in the progression of ovarian cancer. PMID- 21556514 TI - Mushroom toxins and cancer (review). AB - Significant advances have been made in recent years in cancer research concerning the chemistry and biological action of the various mushroom hydrazines and related chemicals as well as two mushrooms, Agaricus bisporus and Gyromitra esculenta. In addition, there is limited information involving the teratogenic effects of some of these mycotoxins. It is apparent that a series of these chemicals, as well as the feeding of two raw mushrooms, induce many cancers in experimental animals. Even though recent findings in the chemistry field indicate that the baked mushroom might act similarly to the raw mushroom with regard to cancer induction, no such studies to date have been undertaken. Thus far cancer epidemiologists have not initiated any research in revealing the effect of mushroom consumption in humans. The practical, frequent question as to whether to cease the consumption of some of the baked mushrooms cannot be answered until additional critical information becomes available. At present, there is no reason for the public to panic. PMID- 21556515 TI - Tnp-alpha determination in serum and pleural effusion in patients with lung cancer. AB - The relationship between Tumor Necrosis Factor-alpha (TNF-alpha) in the serum and pleural fluid of lung cancer patients and the extent and the histological cell type was studied. TNF-(a)lpha level was determined in the serum of 68 patients with lung cancer [51 non-small cell lung cancer (NSCLC) and 17 small cell lung cancer (SCLC)] and in pleural fluid of 30 patients with lung cancer (22 NSCLC, 11 of them positive for neoplastic cells and 8 SCLC, 7 of them positive). Sera of 31 healthy subjects and the pleural fluid of 15 non-malignant pleural effusions were tested as controls. TNF-alpha serum level was increased in patients with lung cancer (healthy subjects 7.8+/-3.3 pg/ml; lung cancer 16.2+/-9.1 pg/ml), in NSCLC as well as SCLC and a relationship with the extent of the disease was found in both the histological types. In pleural fluid, no differences of TNF-alpha level were observed between neoplastic and benign inflammatory effusion, between SCLC and NSCLC or between cases positive and negative for the presence of neoplastic cells. Serum TNF-alpha may be an indicator of tumour burden; conversely, TNF alpha in pleural fluid, was unable to discriminate between neoplastic and benign effusion. PMID- 21556516 TI - A nonradioactive automated protocol to study protein-DNA interactions by dnase-I footprinting. AB - Regulation of gene expression is operated, at transcriptional level, by the interactions between proteins (transcription factors) and elements present within eukaryotic and viral promoters (transcription signals) exhibiting specific nucleotide sequences. In this study we performed DNase I cleavage and analysis of the cleavage products using the Pharmacia ALF(TM) DNA sequencing system. As model system we employed the long terminal repeat (LTR) of the human immunodeficiency type I (HIV-1) virus, containing the DNA sequences recognized by a number of transcription factors, including NF-kB, Sp1 and TFIID. The main conclusion of our experiments is that automated analysis of DNAse I footprinting employing the ALF DNA sequencing system is a fast and reliable technique to study protein-DNA interactions. PMID- 21556517 TI - Loss of heterozygosity on chromosome 16q, expression of her2/neu and p53 mutations in endometrial cancer. AB - We analyzed endometrial adenocarcinomas for mutations of the p53 anti-oncogene, expression of the HER2/neu oncogene and for loss of heterozygosity on chromosome 16q. p53 mutations were found in 3 of 25 tumors. Elevated expression of HER2/neu found in 7 of 24 tumors involves a mechanism other than gene amplification. LOH on chromosome 16q22-24 was observed in 4 of 13 informative tumors. Four of 25 endometrial tumors exhibited two or more alterations. Tumors with the highest HER2/neu protein level exhibited a negative progesterone receptor status. Accumulation of these changes may determine the biological behaviour of a subset of endometrial tumors. PMID- 21556518 TI - Changing trends in the management of chronic granulocytic-leukemia. AB - Current evidence strongly implicates the chromosome translocation t(9;22) as the cause of chronic granulocytic leukemia (CGL). Therefore, the identification of the genetic aberrancy through either cytogenetic or molecular methods is a requirement for diagnosis. Furthermore, qualitative and quantitative methods of detecting t(9;22) are useful in monitoring response status and disease progression. Advances have been made in the management of the disease in its chronic phase, but the blast phase of CGL remains terminal. In this review, the available treatment options in chronic-phase CGL are discussed. PMID- 21556519 TI - In-vivo analysis of hpv e7 protein association with prb, p107 and p130. AB - The two-hybrid system was used to detect interactions in vivo between HPV E7 and three 'Rb-like proteins', pRb, p107 and p130. The association between pE7 and pRb parallel the oncogenic potential of the specific HPV types. In contrast, the interaction between pE7 and p107 or p130 differ. While the HPV 16 E7 protein associates with the 'Rb-like' proteins strongly, both HPV 18 and 6b E7 proteins bind more weakly. We tested several HPV 6 E7 mutants carrying single amino acid mutations. Substitution of the glycine at position 22 with an aspartate was the only mutation capable of increasing the ability of HPV 6 E7 protein to bind pRb. However, association with p107 and p130 by the HPV 6 E7 protein was also increased by mutation of the arginine at position 4 with an aspartate. These data suggest that pRb, p107 and p130 interact with similar but non-identical domains of pE7. In addition, we used amphotropic retroviruses encoding the HPV 18 E6 and the different E7 genes to analyze their immortalizing activity. The wild-type HPV Is and 16 E7 genes complemented the HPV 18 E6 gene to immortalize human keratinocytes. In comparison, none of the cells infected with HPV 6 E7, wildtype or mutant- encoding retroviruses, became immortal. Thus, our data suggest that HPV 6 E7 lacks a property independent of pRb-association which is required for immortalization of human keratinocytes. PMID- 21556520 TI - Episome generated C-myc antisense RNA inhibits growth and tumorigenicity of a human neuroendocrine tumor-cell line. AB - The neuroepithelioma cell line CHP100 expresses low but detectable amounts of N myc protein together with large amounts of c-myc protein. We have recently demonstrated that antisense inhibition of N-myc expression in CHP100 cells leads to decreased in vitro growth and alterations in cellular morphology without affecting tumorigenicity in nude mice. In this study we report the construction of an episomally replicating vector designed to generate RNA antisense to part of the human c-myc gene. Such a Vector is able to inhibit c-myc expression in cell lines carrying multiple copies of the gene. Inhibition of c-myc expression leads to a decrease of in vitro growth and cloning efficiency and in vivo tumorigenicity of CHP100 cells. Our findings suggest that N-myc and c-myc subserve different functions in regulating the biology of CHP100 cells. PMID- 21556521 TI - Loss of wild-type p53 and C-erbb2 amplification correlates with high-grade breast carcinomas. AB - Breast cancer is the most common cancer in women in the western world. Two of the most frequently occuring chromosomal abnormalities in human breast carcinoma are the loss of p53 tumour suppressor gene function and the amplification of the c erbB2 oncogene. Previous studies have demonstrated the role of p53 gene product in the maintenance of chromosomal stability and the correlation between c-erbB2 amplification and breast carcinogenesis. In this study we have examined the existence of a possible correlation between these genetic alterations in a panel of 83 malignant breast tumours (69 adeno and 14 lobular carcinomas). The status of a related gene, c-erbB3, was also examined. With the aid of microsattelite marker TP53CA loss of heterozygosity (LOH) was detected in the p53 locus in 49% of the tumours. Histochemical analysis of 64 of these tumours with the p53 antibody CM1 demonstrated staining, indicative of an elevated steady-state level of p53 protein in 23 rumours (36%). Amplification of the c-erbB2 gene was detected in 20 of 75 tumours analysed (27%). In the tumours with c-erbB2 amplification 12 also had p53 LOH. In at least another 2 tumours there was increased p53 protein level but no LOH. Therefore in 75% of the tumours with c erbB2 amplification there was evidence of loss of normal p53 function. There was no evidence of c-erbB3 amplification in any of the 75 rumours analysed. The data presented demonstrates a strong correlation between the loss of p53 and tumour grade (p<0.00545), and a strong association between c-erbB2, but not c-erbB3, amplification and loss of p53 (p<0.0170). PMID- 21556522 TI - Absence of somatic mutations in the coding region of the waf1/cip1 gene in human breast, lung and ovarian carcinomas - a polymorphism at codon-31. AB - Seventy-four invasive ductal, breast carcinomas, 73 non-small cell lung carcinomas and 36 ovarian adenocarcinomas, obtained from 183 unrelated patients, were investigated for mutations in the WAF1/CIP1 coding sequence by reverse transcriptase-polymerase chain reaction-single strand conformation polymorphism analysis. No somatic mutations were present in the WAF1/CIP1 open reading frame (ORF) in tumor samples. A polymorphism at codon 31 was observed in 16 (8.7%) cancer patients and in 9 (8.8%) of 102 unrelated normal individuals. The polymorphic allele changes the codon 31 AGC to AGA, thus implying an aminoacid substitution from serine to arginine, and creates a Hga-1 restriction site which might be useful for deletion studies. The polymorphism was present in the heterozygous state, except for the case of a 70-year-old male lung cancer patient who was homozygous: Our results indicate that the coding region of WAF1/CIP1 is not a frequent target for somatic mutations in breast, lung and ovarian cancer. PMID- 21556523 TI - K-ras mutation in colorectal carcinomas from singapore. AB - 54 sporadic colorectal cancers were analyzed for aberrations in the K-ras oncogene. DNA was extracted from frozen tissues obtained from surgical resection and analyzed for mutations in codons 12, 13 and 61 of the K-ras oncogene using single strand conformation polymorphism analysis (SSCP) and direct sequencing. Point mutations in the K-ras oncogene were found in 26/54 (48%) cases, all of which resulted in amino acid substitutions. No other types of mutations (e.g. insertions or deletions) were found. 4 of the mutations were at codon 12, 22 in codon 13 and only 1 was a codon 61 mutant. G-->A transitions were found to be predominant. A remarkable finding was the high preponderance of (13)Gly-(13)Ser mutations (54%). No correlation was observed between K-ras mutations and tumor location, Dukes' stage, differentiation levels, age or sex of the patient. PMID- 21556524 TI - The response of a rodent fibrosarcoma to combined treatment with photodynamic therapy and radiotherapy. AB - The response of a rodent fibrosarcoma to photodynamic therapy (PDT), radiotherapy (RT) or combined PDT and RT was examined. PDT used intravenous polyhaematoporphyrin (PHP) and interstitial illumination with 630 nm light (300 or 400J). RT was given as an external beam of gamma-rays (15, 20 or 25 Gy). Both PDT and RT induced a significant delay in tumour growth when applied alone. PHP given alone, without subsequent illumination, did not alter the response of the tumour to RT. The effect of combining PDT and RT was dependent on the dose of light administered, but not, in most cases, on either the radiation dose or the sequence in which the two treatments were given. Using 300J of light, all combined treatments produced additive tumour growth delays. In contrast, sub additive tumour responses were observed following most combined treatments using 400J of light. PMID- 21556525 TI - Analysis of phosphorylation level of DNA topoisomerase-ii-alpha and topoisomerase ii-Beta in human hela-cells. AB - We have studied the phosphorylation of DNA topoisomerases II in HeLa cells focusing on the beta isoform of the enzyme which is very difficult to analyze because of its instability. In proliferating cells, we observed that both the a and beta isozymes are labeled after cell incubation with (32)p. The phosphorylation of beta enzyme occurs to a low extent, thus reflecting the expression of topoisomerases II during cell cycle. In cells treated with etoposide, the activity of topoisomerase II is inhibited and the level of phosphorylation decreases, suggesting a possible cooperation between this modification and drug response. PMID- 21556526 TI - Preclinical studies of gossypol in prostate carcinoma. AB - Hormone refractory prostate cancer remains an incurable disease and the discovery of newer agents with higher cytotoxic activity is required. Gossypol is a phenolic compound isolated from cottonseed oil which has been shown to have anti spermatogenic effects. In in vitro studies, gossypol appears to inhibit the growth of rat prostate cancer cell line MAT-LyLu and human prostate adenocarcinoma cell lines PC-3, LNCaP and DU-145. In vive, gossypol appeared to inhibit tumor growth of subcutaneously implanted MAT-LyLu cells in Copenhagen rats. Gossypol may be an active agent for the treatment of hormone refractory metastatic prostate cancer. PMID- 21556527 TI - The v-erba oncogene - a superb tool for dissecting the involvement of nuclear hormone receptors in differentiation and neoplasia (review). AB - The v-erbA oncogene has been discovered as one of the two viral oncogenes carried by the avian leukemia retrovirus AEV. It is derived from the c-erbA protooncogene which encodes the alpha form of the nuclear receptor for the thyroid hormone triiodothyronine (T3R). This receptor belongs to a large family of nuclear hormone receptors that function as ligand-regulated transcription factors and the v-erbA oncoprotein has been shown to function as an antagonist of normal T3R and related receptors in the control of transcription. It is thus the first dominant negative transcription factor acting as an oncogene described to date. Functional and biochemical dissections of this oncogene have brought many informations on the mechanisms of action of normal receptors and on the ways through which altered receptors can contribute to oncogenic transformation. The v-erbA model is widely used as a reference to investigate the involvement of nuclear hormone receptors in the development of human cancers. PMID- 21556528 TI - Radiation-induced irreversible g(0) g(1) block is abolished in human-diploid fibroblasts transfected with the human papilloma-virus e6 gene - implication of the p53-cip1 waf1 pathway. AB - It has been shown previously with human diploid fibroblasts that a fraction of cells remains irreversibly blocked in the G(0)/G(1) phase of the cell cycle when the cells are irradiated in confluent, density-inhibited cultures and released by subculture to low density. In the present study we demonstrate that this G(0)/G(1) block is abolished when a human fibroblast cell strain is transfected with the human papilloma virus 16 E6 gene. Corresponding to the abolition of the G(0)/G(1) block in the E6-transfected cells, the expression of both the p53 and WAF1 genes is also abolished, suggesting that the p53 pathway of DNA damage response may be involved in this phenomenon. PMID- 21556529 TI - Rflp analysis of the L-myc oncogene in head and neck-cancer - relationship study with susceptibility and disease progression. AB - The L-myc DNA restriction fragment length polymorphism (RFLF), revealed by EcoRI digestion, has been evaluated in a case-control study including 161 head and neck cancer (HNSCC) patients and 160 normal healthy individuals with similar smoking and alcohol habits. No significant difference in the distribution of L-myc genotypes (LL, LS or SS) was found between the two populations implying thus no predisposition to head and neck tumour by either allele. There was no significant association between L-myc genotypes and the usual clinicopathological features such as T staging, differentiation status and lymph node involvement. Moreover, follow-up data from 154 patients was obtained and correlated with the L-myc pattern. No significant difference was observed in metastasis occurrence, multiple cancer incidence and survival data in the patients classified according to the L-myc genotypes; only a trend to preferentially develop metastasis in lung for patients with S allele was noted. In conclusion, our data shows that the L myc typing does not contribute to HNSCC risk or prognosis assessment. A review of L-myc RFLP published studies shows contradictory results even on the same type of tumour and emphasizes the lacunae in understanding the biological role of L-myc for valid interpretation of L-myc allelic associations with cancer susceptibility or prognosis. PMID- 21556530 TI - Transcriptional antagonism between p53 and sv40 T-antigen. AB - In this communication we show that overexpression of the human TATA-binding protein (TBP) activates a synthetic promoter with p53-binding sites in the presence of wild-type p53. No activation is observed in the absence of wild-type p53 in Saos-2 cells. Perhaps, TBP is limiting in these cells for the p53-mediated activation, and p53 activates promoters with p53-binding sites via its interaction with TBP. Using in vivo transient transfection-transcription assays, we also show that wild-type human p53 inhibits simian virus 40 (SV40) late promoter transactivation by SV40 T antigen, but excess T antigen partially releases this inhibition. Recently both T antigen and p53 have been shown to interact with TBP. The inhibition of T antigen-mediated SV40 late promoter activation by p53 or the inhibition of p53-mediated activation of a promoter with p53-binding sites by T antigen is not released by an overexpression of TBP. Thus, the transcriptional antagonism between p53 and T antigen are not at the level of competition for TBP. Possibly, the two proteins poison each other so that they cannot interact with the transcription machinery. PMID- 21556531 TI - Human oncoprotein mdm2 interacts with the tata-binding protein in-vitro and in vivo. AB - Human oncoprotein MDM2 inhibits p53-induced transcriptional activation of promoters containing p53-binding sites. In this report we show that MDM2 interacts with the human TATA binding protein (TBP), in vivo and in. vitro, in the absence of p53. The C-terminal boundary of the TBP-binding domain on MDM2 resides between amino acids 221 and 276, whereas the N-terminal boundary is beyond amino acid 120. Thus, the acidic domain of MDM2 overlaps with the TBP binding domain and is needed for the interaction. The C-terminal conserved domain of TBP is required for MDM2 binding. MDM2-TBP interaction suggests a p53 independent, transcription regulatory role of MDM2. PMID- 21556532 TI - Effect of protein-intake on tumor-growth and host survival in tumor-bearing animals. AB - Nutritional repletion of the tumor-bearing host remains controversial. The present study was performed to determine the effect of protein intake on tumor growth and host survival in tumor-bearing animals. Forty-three female C2H mice with subcutaneous mammary tumor implants (MA 16/C) were randomized to receive standard protein diet or an isocaloric, protein-depleted diet ad libitum per os. Body weight and tumor volume were measured throughout the study and ail animals were maintained on these diets until death. Body weight was significantly greater in animals receiving standard protein intake compared to those given the protein depleted diet. However, tumor growth was significantly stimulated and host survival reduced in animals given standard protein diet compared to animals maintained on protein-depleted diet. Thus, exogenous protein intake preferentially benefitted tumor versus host anabolism in this animal model with significant reduction in host survival. PMID- 21556533 TI - Analysis of carcinoma of the endometrium treated with post operative radiotherapy. AB - An audit was carried out of post-operative radiotherapy given for carcinoma of the endometrium at the Christie Hospital between the years of 1984-86. 139 patients were treated following total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO). 54 patients were treated with vaginal brachytherapy alone, 55 had pelvic brick external beam irradiation and 30 patients had both external beam irradiation and vaginal brachytherapy. Overall survival was 84% at 5 years, with a 5.8% local recurrence rate. Histological grade was a prognostic factor for survival (p=0.023) and relapse (p=0.002). Tumour stage was a significant prognostic factor for survival (p=0.011), but not relapse. Survival for stage IB disease was 100% at 5 years with no local recurrence. Major treatment related morbidity was 1.4%, overall; for vaginal brachytherapy alone 0%; for external beam therapy 2%; and combined therapy 3%. Given their good prognosis, and the small but definite risk of major morbidity, patients with stage IB disease may not need postoperative external beam irradiation. PMID- 21556534 TI - The phosphorylation connection to cancer (review). AB - Despite our incomplete comprehension of how growth factor-stimulation of cells is linked to the cell cycle and of how the G(1)/S checkpoint is linked to initiation in DNA replication there is an unparalleled wealth of experimental evidence to connect protein phosphorylation to molecular mechanisms of carcinogenesis. Many growth factors, growth factor receptors with tyrosine kinase activity (insulin receptor, EGFR, PDGFR, CSF1R, NGFR, HGFR), nonreceptor serine/threonine or tyrosine kinases (c-Raf-1, cMos, c-Abl, c-Src) and cyclin D1 are encoded by oncogenes mutated or overexpressed in a variety of human tumors; the physiological functions of oncoproteins that are involved in gene expression and replication (c-Jun, T-antigen, c-Myc, c-Myb) as well as p53, RB and CDK4 tumor suppressor proteins and replication factor A are also regulated by phosphorylation, ms genes transduce growth factor receptor signals to protein kinase C (PKC) or to c-Raf-1 triggering two different cascades of protein kinases, the PKC and MAPK signaling pathways both targeting nuclear proteins. Thus cancer can be considered as a disease of the signaling pathways. PMID- 21556535 TI - Biochemical and biologic effects of somatostatin therapy on tumor-growth and host metabolism. AB - Somatostatin has been shown to have direct antiproliferative activity against various animal and human tumors and may be useful for long-term treatment of cancer patients. However, the metabolic effects of long-term somatostatin therapy have not been studied in the tumor-bearing host. It is known that somatostatin inhibits growth hormone and insulin secretion, and has inhibitory functions at all levels of the gastrointestinal tract. These properties may be especially detrimental to the tumor-bearing host which already suffers the cachectic effect of malignancy. This study examined the effect of the long-term somatostatin analogue octreotide (SMS) on host and tumor tissues in rats bearing a mammary adenocarcinoma (MAC-33). In vitro studies demonstrate that SMS (10-1000 ng/ml) has no direct effect on tumor cell proliferation in this model. Thirty female tumor-bearing Lewis rats were randomized to two groups. The treatment group received 175 mu g/kg SMS injections ip twice daily for 25 days; the placebo group received saline injections by the same route and schedule. Biochemical studies revealed a significant increase in tumor and liver protein/DNA ratio and decreased skeletal muscle protein/DNA content as a result of SMS treatment. These alterations in tumor and muscle composition are indicative of tumor growth and host catabolism. Biologic parameters demonstrated no significant change in carcass weight, tumor weight, or tumor metastasis from SMS treatment. Thus, a discordance is found between gross biologic parameters (indicating no significant effect of SMS) and more subtle biochemical indices (indicating progressive tumor growth and muscle protein catabolism). SMS therapy may produce adverse biochemical effects on host muscle which simulate cachexia when used chronically in the tumor-bearing host. PMID- 21556536 TI - Systemic administration of 4-amidinoindanon-1-(2'-amidino)-hydrazone, a new inhibitor of s-adenosylmethionine decarboxylase, produces cytostasis of human prostate-cancer in athymic nude-mice. AB - CGP 48664A, a new S-adenosylmethionine decarboxylase inhibitor, blocks the production of spermidine and spermine, two polyamines that play critical roles in cellular proliferation. Under in vitro conditions, CGP 48664A produced cytostasis of the human prostate cancer cell lines LNCaP, LNCaP-LN3, PC-3M, and PC-3M-MM2 in a dose-dependent manner. This cytostasis was reversed by the addition of exogenous polyamines to the culture medium. LNCaP-LN3 cells or PC-3M-MM2 cells were implanted into the prostate of nude mice. Daily administration of CGP 48664A significantly inhibited tumor size and serum levels of prostate-specific antigen in mice implanted with LNCaP-LN3 cells. The therapeutic effect was related to the time the treatment was initiated, the volume of disease, and the length of treatment. CGP 48664A was not effective against the fast-growing PC-3M-MM2 tumor. These data suggest that to broaden its effectiveness, CGP 48664A should be combined with other cytoreductive agents. PMID- 21556537 TI - Effect of chemopreventive agents on posttranslational plasmamembrane association of ras-p21 during chemoprevention of azoxymethane-induced colon carcinogenesis. AB - Accumulating data suggest that activation of ms proto-oncogenes and inactivation of tumor suppressor genes induce malignant phenotype in colonic cells. However, the transforming ability of ras oncogenes critically depends on correct localization of ras-p21 in plasma membrane. In our previous studies, we demonstrated a strong correlation between the modulation of ras activation (both in terms of mutational activation and over-expression of ras genes) by chemopreventive agents and colon tumor outcome during different stages of azoxymethane (AOM)-induced colon carcinogenesis. In the present study, which is a part of our ongoing investigations on the role of ras in chemoprevention of colon cancer, we studied the effect of D,L-alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and piroxicam, a non-steroidal antiinflammatory drug (NSAID), on the post-translational membrane association of ras-p21 during AOM-induced colon carcinogenesis. Groups of male F344 rats were fed the modified AIN-76A diets containing 0, 150 ppm piroxicam or 4000 ppm DFMO, and administered s.c. AOM dissolved in normal saline at a dose rate of 15 mg/kg body weight/week for 4 weeks. Vehicle control groups received equal volume of normal saline. Groups of animals were then sacrificed at 4, 16, 24, and 32 weeks after last AOM or saline injection and their colonic mucosa and tumors were analyzed for cytoplasmic as well as membrane bound ras-p21 levels. AOM-treatment resulted in increasingly higher levels of membrane-bound ras-p21 with advancing stages of colon tumorigenesis without any significant changes in cytoplasmic ras p21. Dietary DFMO significantly suppressed AOM-induced membrane-bound ras-p21 in a time-dependent manner. Administration of piroxicam though resulted in significant inhibition of membrane-bound ras-p21, but concomitantly increased the cytosolic levels of ras-p21. Inhibition of membrane-bound ras-p21 levels by DFMO and piroxicam strongly correlated with the suppression of AOM-induced colon tumorigenesis by these agents. Data from the present and earlier studies suggest that DFMO may afford chemoprevention by suppressing DNA and protein biosynthesis by depleting intracellular polyamines, whereas piroxicam may exert its antitumor activity by interfering with post-translational membrane localization of ras-p21, in addition to modulating arachidonic acid metabolism. PMID- 21556538 TI - Localization of peroxisome proliferator-activated receptor in mouse and rat tissues and demonstration of its nuclear translocation in transfected cv-1 cells. AB - Hepatocarcinogenesis in rodents induced by nongenotoxic peroxisome proliferators is postulated to be a receptor-mediated process. The peroxisome proliferator activated receptors (PPAR) are members of the steroid hormone receptor superfamily, which participate in ligand-dependent transcriptional activation of peroxisomal fatty acid beta oxidation enzyme system genes in liver parenchymal cells of rats and mice. In order to study the tissue distribution and cellular localization of PPAR, we raised polyclonal antibodies against PPAR using a recombinant rat PPAR (rPPAR) expressed as a glutathione-S-transferase-rPPAR fusion protein. On immunoblot analysis the antibodies specifically recognized a 55 kDa PPAR protein in rat, mouse and human liver homogenates. Immunoblotting also showed that in the mouse and rat, PPAR is expressed in liver, kidney and heart, and only weakly in brain and testis. Immunohistochemical localization in the rat and mouse revealed that PPAR is highly expressed in perivenular (i.e., those surrounding hepatic vein) hepatocytes and very weakly in the cytoplasm of remaining hepatocytes. In the kidney, PPAR was visualized predominantly in the p(3) segments of proximal convoluted tubular epithelium. CV-1 cells transiently transfected with rPPAR cDNA construct showed predominant cytoplasmic fluorescence; treatment of these cells with ciprofibrate, a peroxisome proliferator, resulted in the nuclear translocation of PPAR signal. PMID- 21556539 TI - A human embryonic antigen associated with spontaneous-abortion is expressed on the cell-surface of a tumor promoter-treated bloom-syndrome B-lymphoblastoid cell line. AB - We detected stable expression of a human embryonic antigen associated with spontaneous abortion (HEAAb) on the cell surface of a tumor promoter (TPA) treated B-lymphoblastoid cell line (BS-SHY) originating from Bloom syndrome (BS). We used indirect immunofluorescence (IF) and diluted serum from numerous patients who had recurrent spontaneous abortions (RSAs). With the use of the panning procedure, we separated characteristic cells expressing strong HEAAb. The BS-SHY HEAAb cells separated would be useful for measuring serum antibody (against HEAAb) produced in the immune system of recurrent aborters. Using HEAAb proteins, we conducted Western blot (WB) analysis for the amino acid sequencing (MW, 77 KD). Amino acid sequencing data indicated that HEAAb had 87.5% homology to the immunoglobulin (Ig) VHIII region in the framework, and that differences were due to 2 amino acid alterations; from Gly (G) to Val (V) at the ninth residue and from Gly (G) to asp (D) at the sixteenth residue. No identical mutations were reported in the framework region of IgV(H)III. Even though the exact mechanism of TPA-induced HEAAb expression remains unknown, TPA increases BS SCE from 70 SCE per cell level to approximately 100, thus, it seems plausible that SCE plays some role in the expression of HEAAb, and plays a role in Ig disappearance from BS-SHY HEAAb cells. Correlation of SCE, mutations causing Ig disappearance and HEAAb expression is discussed. PMID- 21556540 TI - Inhibition of b16 melanoma metastasis by administration of g(m3)- or gg3- liposomes - blocking adhesion of melanoma-cells to endothelial-cells (antiadhesion therapy) via inhibition of g(m3)-gg3cer or g(m3)-laccer interaction. AB - Tumor cell (TC) metastasis is initiated by selective adhesion of TCs to target structures such as basement membrane and endotheliaI cells (ECs), followed by transvascular migration of TCs. Variants of murine B16 melanoma having different metastatic potentials (in the order BL6 greater than or equal to F10>F1>WA4) have been characterized by the same decreasing order of cell surface G(M3) expression level, relative adhesiveness to nonactivated ECs, and relative degree of G(M3) dependent adhesion to Gg3Cer- or LacCer-coated plates. Degree of integrin dependent cell adhesion and adhesion to IL-1-activated ECs was similar for BL6, F10, and F1. These results suggest that metastatic potential of these B16 variants is closely dependent on relative adhesion to nonactivated ECs, which is based on G(M3)-Gg3Cer or G(M3)-LacCer interaction. This possibility has been supported by further studies showing that blocking of G(M3)-dependent melanoma adhesion by mu M-order concentrations of G(M3) or Gg3Cer in liposomes, or by sialidase treatment of melanoma cells, strongly inhibited BL6 metastasis to lung. Paragloboside or sialylparagloboside did not affect G(M3)-dependent BL6 cell adhesion and did not inhibit metastasis. Spontaneous metastasis from subcutaneously-grown tumors was significantly reduced if G(M3)- or Gg3Cer liposomes were intravenously injected during tumor growth. Thus, blocking of TC adhesion to nonactivated ECs based on carbohydrate-carbohydrate interaction may provide effective anti-adhesion therapy against tumor progression, in analogy to the antimetastatic effect produced by blocking of integrin-dependent cell adhesion. PMID- 21556541 TI - Dose intensification by the simultaneous use of rhg-csf and anticancer chemotherapy. AB - We have studied the simultaneous administration of rhG-CSF with doxorubicin, the latter given by continuous infusion either intra-arterially or intravenously, in a group of patients with various sarcomas. This has enabled us to substantially increase the dosage intensity of doxorubicin with a marked decrease in both hematologic and oral toxicity. While the data concerning anti-tumor activity is preliminary we believe that this combination has been responsible for a substantial increase in the effectiveness of doxorubicin in controlling the sarcomas. No adverse effect from combining doxorubicin given by infusion with rhG CSF has been noted to date. PMID- 21556542 TI - Functional expression of sv40 in normal human prostatic epithelial and fibroblastic cells - differentiation pattern of nontumorigenic cell-lines. AB - To study mesenchymal-epithelial interactions associated with the normal and pathological human prostate, we have developed a model of well differentiated human prostate epithelial and fibroblastic cells. Normal human prostatic cells, either of epithelial or fibroblastic origins were successfully transfected with SV40 and strains with extended lifespan were selected until the crisis was reached, within 20 and 30 passages for the epithelial and fibroblastic cells, respectively. Only a few clones emerged from the crisis: PNT1A (Cussenot et al: J Urol 143: 881-886, 1991), PNT1B and PNT2 epithelial cell lines. Successful immortalisation was achieved only with SV40 expressing both large T and small t oncogenes, while attempts to immortalise with a vector expressing SV40 large T alone have given a few strains showing no extended lifespan and no cells which overcame the crisis. A PNT2 subclone named PNT2-LSD which developed spontaneously (less serum dependent) was selected, characterised and included in the analysed series. The epithelial cell lines displayed a differentiation pattern which has been classified as follows (from high to low): PNT2>PNT2-LSD>PNT1A>PNT1B. Differentiation features studied were (i) the colony-forming ability of the PNT2 and PNT2-LSD compared to PNT1A and PNT1B, (ii) their respective doubling time of 39, 29, 30 and 28 hours, (iii) their decreasing serum dependency, (iv) the expression of cytokeratin 19 (a feature of well differentiated luminal cells of the glandular prostate) for PNT2 and PNT2-LSD. Furthermore, the mesenchymal derived pflsv1 cells were confirmed to be of fibroblastic nature. None of the cell lines analysed showed any tumourigenicity in nude mice over a period of 12 months. Serum deprivation and direct steroid withdrawal during the culture triggered cell death by apoptosis, an event which could be overcome by EGF stimulation, particularly for the well differentiated PNT2 cells. This interesting characteristic, which is similar to the high apoptotic rate observed ipl vivo for normal prostate, particularly after castration should lead, together with the other properties of these cell lines, to a better understanding of the biology of the different cell compartments involved in the progression of prostate towards neoplasia. PMID- 21556543 TI - Expression of desmoglein-I cell-adhesion molecule in primary tumors and metastatic lymph-nodes of esophageal cancer. AB - The expression of desmoglein I (DGI) in both primary turners and metastatic lymph node of esophageal carcinoma was studied immunohistochemically in 102 patients using an anti-DGI monoclonal antibody. Normal squamous epithelial cells strongly expressed DGI at their cell-cell boundaries. DGI expression in the tumors was divided into DGI (++), DGI (+), DGI (-) according to the staining intensity. DGI (+) or DG (-) tumors had lymph node metastases more frequently than DGI (++) tumors (p<0.01). DGI expression was the same or of less intensity, than in the primary tumor in 128 (85%) out of 151 metastatic lymph nodes. These results indicate that reduction or loss of DGI expression may promote lymph node metastases. PMID- 21556544 TI - Monoclonal-antibodies 5g8 and 2h6 are complementary immunohistochemical markers of lung carcinomas. AB - Two murine monoclonal antibodies (MAbs) 5G8 and 2H6 were generated by fusing spleen cells obtained from mice immunized with human fetal tissue extract (14 weeks, Nonidet P-40 membrane fraction) from the early first trimester, followed by a booster injection of a lung cancer cell line. The MAb 5G8 recognized antigens with a molecular weight of 90, 50, 20 kDa, was neuraminidase-resistant and showed cross-reactivity with both carcinoembryonic antigen and non-specific cross-reacting antigen. The MAb 2H6 reacted with a sialomucin whose molecular weight was more than 1000 kDa and was different from previously known tumor associated-marker antigens. The distribution of the MAb-recognizing antigens in various tissues was investigated immunohistochemically. In malignant epithelial tumors of the lung, acinar adenocarcinoma and bronchioloalveolar carcinoma were positive for both MAbs; papillary adenocarcinoma, squamous cell carcinoma, and adenoid cystic carcinoma were positive only for MAb 5G8; solid carcinoma with mucin formation, small cell carcinoma, and large cell carcinoma were positive only for MAb 2H6. The combination of the two MAbs covered almost all histological types of lung carcinomas (23 of 24 cases) except carcinoid tumors. MAbs 5G8 and 2H6 reacted also with a restricted number of adenocarcinomas of the other organs. MAb 5G8 did not react with normal fetal or adult tissues, except for metaplastic gastric mucosa, acinar cells of the breast and leucocytes, whereas MAb 2H6 reacted with the surface epithelium of the stomach and colon, the Brunner gland of the duodenum and uterine cervix as well as the epithelium of the fetal digestive tract. Thus, MAb 2H6 which recognized oncofetal sialomucin, played a complementary role to MAb 5G8 as a CEA-related MAb in the immunohistochemical diagnosis of lung carcinomas. PMID- 21556545 TI - Prognostic-significance of proliferating cell nuclear antigen (pcna) in adenocarcinoma of the lung. AB - The aim of the study was to investigate the prognostic value of the proliferating cell nuclear antigen (PCNA) expression in non-small cell lung carcinomas (NSCLC). Two hundred and sixteen patients with previously untreated NSCLC entered into this investigation. For assessment of PCNA expression the streptavidin biotinylated peroxidase complex method was performed using imnuunohistochemistry and Mab PC10. The tumors were scored for the percentage of PCNA-positive cells (low proliferative activity less than or equal to 25%; high proliferative activity >25%). Univariate analyses of all patients showed a trend that those with high proliferating tumors had shorter survival times than those with lower proliferating tumors. Similar results were obtained when the analysis was restricted to squamous cell carcinomas. Patients with adenocarcinomas and with high proliferating tumors had significantly shorter survival times than those with low proliferating tumors (p=0.028). No correlation was found between extent of tumors or metastasis and expression of PCNA. The multivariate analysis including age, sex, extent of tumors and metastasis as well as PCNA revealed a highly significant influence of extent of tumors (p=0.007) and metastasis (p=0.003) whereas all other factors including PCNA were of no significant influence. PMID- 21556546 TI - Clinical modulation of epirubicin resistance by lonidamine in patients with advanced soft-tissue sarcomas. AB - To determine if lonidamine (LND) could reverse anthracycline resistance In patients with advanced, soft-tissue sarcomas, thirty-six patients were treated with epirubicin (EPI) 120 mg/m(2) i.v. every 3 weeks. Progressive patients were given the same chemotherapy regimen on day 4 in combination with oral LND, 150 mg on day 1, 300 mg on day 2, and 450 mg on days 3 to 5. Among 35 evaluable patients there were 2 complete responses and 3 partial responses (PR) for an overall response rate of 14%. In the group treated with EPI+LND (24 evaluable patients) 2 PR were observed, lasting 3 and 10 months respectively. The overall survivall was 11.5 months. The most common side-effects were myelotoxicity, nausea and vomiting. Clinical cardiotoxicity was. not observed. Only in one patient a >20% decrease in LVEF from baseline was recorded. LND related toxicities were mild to moderate myalgia and photophobia. In a pharmacokinetic study performed parallel to the clinical study, no difference was observed between the parameters derived from EPI and EPI+LND curves except for Vapp. This study indicates that LND may circumvent clinical resistance in some cases without altering chemotherapy related toxicity. PMID- 21556547 TI - Mapping of chromosome-3 alterations in human breast-cancer using microsatellite PCR markers - correlation with clinical-variables. AB - Human breast tumours were analyzed with polymorphic microsatellite markers specific to chromosome 3p. Allelic imbalance (AI) was observed in 34% of the tumours. Microsatellite markers from two regions showed higher percentage of imbalance suggesting the presence of tumour suppressor genes or genes important for malignancy. Microsatellite instability was also found, implying errors in DNA replication. No significant correlation was found between AI and conventional prognostic variables. However, a striking correlation was found between AI and tumour S-phase fraction; AI was also significantly correlated with low steroid receptor content. A multivariate model including prognostic variables, showed that AI was without exception a significant prognostic variable; patients having tumours with AI had approximately a four-fold increase in relative risk of death. We conclude that screening for 3p deletions gives prognostic information and further investigations should reveal whether this finding could assist in treatment of the disease. PMID- 21556548 TI - E1a-3y1 cell-specific toxicity of tea polyphenols and their killing mechanism. AB - To screen carcinostatic components in foodstuffs, the toxicity of tea polyphenols was compared between rat 3Y1 diploid fibroblasts and a variety of their virally transformed cells. Among tea polyphenols tested, epigallocatechin gallate killed 3Y1 cells transformed by E1A gene of human adenovirus type 12 (E1A-3Y1 cells) at a 100 times lower concentration than the parental 3Y1 cells. Epigallocatechin gallate also exerted a strong E1A-3Y1 cell-specific toxicity, while epicatechin and epicatechin gallate did not. When the activity of three antioxidant enzymes was compared between 3Y1 and its transformants, catalase activity was markedly low in the latter, especially in E1A-3Y1 cells, and the substrate of the enzyme, hydrogen peroxide, exerted a toxicity specific to this cell line. Then the inhibitory activities of various chemicals on E1A-3Y1 cell-specific toxicity of phospholipids or catechol were examined. Among lipoxygenase inhibitors, all of the polyphenolic compounds inhibited the toxicity of phospholipids, but not a nonpolyphenolic inhibitor (clofibrate). Two phospholipase A,inhibitors (dexamethasone and quinacrine) did not inhibit the toxicity. These results indicate that the triphenol structure of the B ring is essential for the E1A-3Y1 cell-specific toxicity of tea polyphenols, and that the decrease in catalase activity is partially responsible for the higher sensitivity of E1A-3Y1 cells against the polyphenols. The inhibitory effect of polyphenolic lipoxygenase inhibitors is ascribed at least in part to their antioxidant activities. PMID- 21556549 TI - Serum placental-type alkaline-phosphatase levels in patients with epithelial ovarian-carcinoma. AB - Serum placental alkaline phosphatase (PLAP)-type immunoreactivity was measured in 190 women with epithelial ovarian malignancy, 27 women with borderline ovarian cancer and 334 control subjects with non-neoplastic or benign gynaecological disease. Smoking, ABO blood group and menopausal status affect serum concentrations of PLAP and results were corrected for these. Circulating levels were elevated in patients with cancer and increased with stage. Levels were unaltered in borderline ovarian disease. Two-year stage corrected survival analysis demonstrated a significant worsening of prognosis in patients with serum PLAP-type levels greater than the 100th centile for controls. PMID- 21556550 TI - Implication of retinoic Acid receptor-Beta in renal-cell carcinoma. AB - The retinoic acid receptor (RAR) beta gene is located in a region on chromosome 3p, which is frequently deleted in renal cell carcinoma. Since retinoic acid (RA) can inhibit cell proliferation and tumor formation, loss of RAR beta might contribute to oncogenesis of the kidney. This prompted us to examine RAR beta expression in 12 primary kidney tumors and 11 renal cancer cell lines. Five tumors expressed RAR beta at severely reduced levels, three of which have retained one gene copy. In one tumor an aberrant larger transcript was expressed. Only three cell lines showed detectable expression of RAR beta, albeit at low levels in comparison with normal kidney cells, and in most cases RA could not inhibit cell proliferation. To investigate the involvement of RARB in RA dependent growth control, we stably transfected RAR beta expression vectors into two of the renal cancer cell lines. RAR beta-expressing clones' derived from SK RC-35 showed a markedly reduced proliferation in the presence of RA, whereas the growth of parental cells was not affected. Transfectants derived from SK-RC-48, also showed inhibition of growth when exposed to RA. However, these transfectants responded only to high doses of RA. Taken together, our data support the possibility that RAR beta is implicated in the development of renal cell carcinomas. PMID- 21556551 TI - Cytogenetic findings in pediatric germ-cell tumors. AB - Three pediatric germ cell tumors (GCT) were cytogenetically analyzed. A mediastinal mature teratoma in a 15-year-old girl had a balanced t(8;22)(p21;q12) as the sole clonal aberration, an intrathoracic immature teratoma in a 2-year-old girl had the complex karyotype 46,XX,der(6) ins(6;2)(q15;q11q23),de1(8)(q22), 1O,der(12)t(10;12),(q22;q22- 23),der(16)t(1;16)(q12;q11),+mar and a congenital presacral endodermal sinus tumor was characterized by the karyotype 47,XY,add(11)(p15),der(13)t(1;13)(q21;p13),add(14)(p13),d e1(15)(q24),+der(?)t(?;11)(?;q13). The present three tumors had no chromosome aberration in common, nor has any specific change been detected in the 13 previously reported cytogenetically aberrant pediatric GCT. The karyotypic picture comes across as far more heterogeneous than that of GCT of adults. Whereas gain of 12p material, in the vast majority through i(12)(p10) formation, dominates in the adult setting, the most common cytogenetic abnormalities in pediatric GCT seem to be unbalanced recombinations leading to gain of 1q. Other recurrent changes include, in decreasing order of frequency, numerical and structural aberrations leading to gain of 8q and 12p, loss of distal 1p, +3, loss of 7q22-32, -10, -13 and -18. PMID- 21556552 TI - Expression and tyrosine phosphorylation of phosphatidyl-inositol-3 kinase in human gastric-cancer cells - its correlation with cell-growth. AB - To reveal the signaling pathway leading to oncogenecity of human cancer cells, we examined the expression and tyrosine-phosphorylation of phosphatidylinositol (PI) 3 kinase in cancer cell lines. Of the 14 cell lines examined, two poorly differentiated human gastric cancer cell lines, NUGC-4 and MKN-45, which were previously found to have aberrant elevation of tyrosine phosphorylation showed elevated levels of PI-3 kinase 85-kDa subunit expression. In these cells, tyrosine-phosphorylation and overall activity of PI-3 kinase were apparently elevated, compared with normal human fibroblasts and another well differentiated gastric cancer cell line, MKN-28. Treatment of these cells with tyrosine kinase inhibitor, genistein, strongly suppressed the PI-3 kinase activity. Furthermore, wortmannin, a potent inhibitor of PI-3 kinase, strongly suppressed the growth of these gastric cancer cells. These results suggest that the growth signaling via tyrosine phosphorylation is required for the activation of PI-3 kinase in NUGC4 and MKN-45, and that this activation plays an important role in oncogenic growth of these cells. However, these two cell lines showed different responses of PI-3 kinase to acid-treatment and tyrosine kinase inhibitors. In MKN-45, activation of PI-3 kinase appeared to be constitutive, and could be relevant to the oncogenic nature of the cell line. PMID- 21556553 TI - Intravital microscopy in tumor biology - current status and future perspectives (review). AB - To date, most progress in biomedical research is reported from cellular and/or molecular studies identifying important disease mechanisms and suggesting novel strategies in cancer therapy. Although these findings are fundamental for the understanding and treatment of neoplastic disease they often fail to be demonstrable in vivo. Many tumors resist complete eradication by anti-cancer agents indicating that caution has to be exercised in the extrapolation of in vitro observations to the clinical situation. This review emphasizes intravital microscopy as a quantitative method to analyze in vivo mechanisms of neoplastic disease and to test the in vivo function of novel strategies in cancer therapy derived from in vitro observations. Intravital microscopy facilitates a comprehensive analysis of the tumor microcirculation and microenvironment which should aid to improve the current understanding of tumor biology. PMID- 21556554 TI - Effects of C-myc antisense transcripts on differentiation of k562 cells. AB - An antisense myc plasmid, containing a portion of exon 2 of the human c-myc gene, was cloned into the pDOL retroviral vector which was used to transfect human K562 erythroleukemia cells. All the retroviral vector transformants showed slower growth rates than the parental K562 cells. No detectable difference in the sense myc RNA level was observed, but the reduction of myc protein levels in the antisense myc transformants varied between 21% and 96%. Most antisense myc transformants contain higher percentage of hemoglobin-producing cells, but no proportionate correlation with the myc protein levels was observed. The results suggest that myc protein is necessary but not sufficient for the regulation of differentiation and growth arrest of K562 cells. PMID- 21556555 TI - A phase-ii study testing weekly platinum derivative combination chemotherapy as 2nd-line treatment in patients with advanced small-cell lung-cancer. AB - A phase II trial was conducted to determine the effectiveness of weekly administration of cisplatin (25 mg/m(2) on day 1) and carboplatin (100 mg/m(2) on day 1) as salvage chemotherapy for patients with small cell lung cancer after first-line chemotherapy without platinum derivatives. Of 40 eligible patients, 38 were evaluable for response. Interval between last course of first-line chemotherapy and first course of salvage therapy was less than 3 months in 34 and greater in 4. Five partial responses (13%; confidence interval at 95%:0.01-0.25) were documented (including 4 in patients with a treatment-free interval <3 months) as well as 8 no change, 21 progressions and 4 early deaths due to malignant disease. Toxicity consisted mainly of moderate thrombopenia and leucopenia. Grade I nephrotoxicity was observed in 6 patients. In conclusion, weekly administration of moderate doses of cisplatin and carboplatin as salvage chemotherapy for small cell lung cancer appeared feasible and was associated with a moderate but definitive anticancer activity. PMID- 21556556 TI - Natural-killer cell-mediated cytotoxicity of blood-lymphocytes from patients with malignant mesothelioma treated by intrapleural interleukin-2. AB - The most impressive biological effect of recombinant Interleukin-2 (rIL-2) is the generation of nonspecific killer cells that have lytic activity for a variety of tumor cells. Numerous studies have shown that these non specific killer cells might be of NK cell lineage even though they are different from resident NK-cell. We have examined the kinetics of the NK cell-mediated cytotoxicity of blood lymphocytes in patients after intrapleural rIL-2 administered for the treatment of pleural cancer. Escalating doses of rIL-2 were administered by intrapleural route to treat 11 patients with malignant pleural effusions due to malignant pleural mesothelioma (4 stage I, 4 stage II, 2 stage III, 1 stage IV). Two patients received respectively 3 cycles and 2 cycles of treatment. Peripheral blood lymphocyte cytotoxicity was assessed by an in vitro, chromium release microcytotoxicity assay against K562 cell line. Preliminary results indicate: (i) an important and prolonged increase in the cytotoxic response of blood lymphocytes in all patients but one having a clinical response and (ii) a lack of cytotoxicity or a baseline cytotoxic response of blood lymphocytes in all patients but one with no clinical response. These results likely point out the significance of NK-activity in the IL-2-induced antitumoral response and the interest of this in vitro assay for screening patients for further cycles of treatment. PMID- 21556557 TI - Early detection of cancer-associated gene alterations in DNA isolated from rat feces during intestinal tumor-induction with 1,2-dimethylhydrazine. AB - A highly sensitive mutation detection method was applied to reveal tarry K-ras alterations in exfoliated intestinal epithelium of Fischer-344 rats during the course of 1,2-dimethylhydrazine (DMH)-induced carcinogenesis. Ten weekly s.c. injections of DMH (50 mg/kg) in combination with consumption of a low-fiber diet resulted in 100% incidence of intestinal tumors at 20 weeks after initial DMH injection. Analysis of DNA extracted from fresh fecal samples obtained individually showed that proportion of codon 12 K-ras oncogene mutant alleles (G- >A transition at the second position of codon 12) was increased in some rats at 4 weeks and clearly in all rats at 8 weeks after initial DMH injection, i.e. much earlier than the first tumors appeared (14 weeks). A gradual increase of mutant K ras fraction in DNA samples extracted from feces led to an extremely high level of the mutant reaching 10% of the oncogene alleles at the end of the experiment (20 weeks). K- and H-ras oncogene and p53 tumor suppressor gene mutations were analyzed in the resulting colon and duodenal tumors. 14 of 17 colon tumors had K P as mutations (11 - G-->A transition at codon 12 second base; 3 - G-->A transition at codon 13 second base). G-->A transitions at codon 12 first base of H-ras were detected in 3 colon tumors. All 5 duodenal tumors induced in the experiment had G-->A transition at codon 12 second base of K-ras. 3 of these tumors also had H-ras mutations. No mutation was detected within exons 4-7 of p53 gene indicating that p53 alterations may not be involved in the rapid development of tumors induced by high doses of DMH. Our observations suggest that detection of K-ras mutations in stool samples are predictive of later tumor development from a very early stage. PMID- 21556558 TI - Phase-I and phase-ii trials of a laboratory-derived synergistic combination of Cisplatin and 2'-deoxy-5-azacytidine. AB - Phase I and phase II trials of a laboratory-derived synergistic combination of cisplatin (cDDP) and 2'-deoxy-5-azacytidine (5-aza-CdR) were conducted. The maximum tolerated doses (MTDs) were 50 mg/m(2) of 5-aza-CdR and 75 mg/m(2) of cDDP. A response rate of 17% (90% confidence interval (CI) = 0%-37%) was observed in patients with metastatic carcinoma of unknown primary (UPC). The 5-aza CdR/cDDP combination was safely administered at doses mirroring concentrations that significantly lessen cDDP resistance of human ovarian cancer cells in vitro. While the observed response rate did not warrant further study in UPC, evaluation of this regimen should be considered in patients with cDDP-resistant ovarian cancer. PMID- 21556559 TI - Cell-mediated-immunity and immunotherapy in ovarian-cancer (review). AB - The natural containment of ovarian cancer to the peritoneal cavity makes this mileau attractive for examining the immune status within a 'malignant environment'. Such investigations have yielded further insight into host-tumor responses. Immunological strategies have been employed in ovarian cancer either as single agents or combined with chemotherapy and although achieving responses have limited success. The understanding of cytokine inter-relationships, refinement of monoclonal antibody therapy and the potential genetic manipulation will enhance immunological strategies. This review will address aspects of our present knowledge of immune status in ovarian cancer, examine clinical studies incorporating immune agents and potential future therapies. PMID- 21556560 TI - Mutations in DNA-polymerase-Beta occur in breast, prostate and colorectal tumors. AB - To determine the tissue specificity of the potential mutations in DNA polymerase beta (pol beta), alterations in the pol beta were examined in breast, prostate, and colorectal primary tumors. The pol beta is known to contribute to mammalian base excision repair and replication. Similar to colorectal cancer, a high occurrence of mutations as 87-bp deletion in the catalytic domain of the pol beta removing 29 amino acids was observed in breast cancer. Contrary to breast and colorectal tumors, a low occurrence of mutation as a single base (T) deletion at the position coding for amino acid 181 of the pol beta was associated with prostate cancer. The missing T changed the codon from TTC to TCA (phenylalanine to serine), causing a frame shift. PMID- 21556561 TI - Status of the mdm-2 and waf-1 genes in mouse epidermal jb6 variants harboring wild-type p53 - a p53-independent induction of waf-1. AB - Mutational inactivation of the p53 tumor suppressor gene has been found not to be involved in preneoplastic-to-neoplastic progression in mouse JB6 variants. To examine the role of an inactivated p53 pathway in this tumor promotion/progression model, we have studied the possible alteration of the MDM-2 oncogene, a gene whose product binds to and inactivates p53, and WAF-1 tumor suppressor gene, a gene transcriptionally controlled by p53 that mediates p53 tumor suppression. Alteration of either of these two genes might mimic p53 inactivation in cells expressing wild-type p53. Northern analysis revealed that MDM-2 expression was, in general, upregulated in neoplastic JB6 cells as compared with preneoplastic cells. This higher expression was not due to the gene amplification. Mutational analysis of WAF-1 revealed a) no point mutation in neoplastic cells; b) two polymorphic sites; and c) three nucleotide disagreements with the published sequence. Expression of the WAF-1 gene was also found to be, in general, higher in neoplastic cells, and induced by TPA and/or TNF-alpha in a p53-independent manner. The overall induced level of WAF-1 mRNA was higher in apoptosis sensitive cells after TPA/TNF-alpha treatment, suggesting a role of WAF 1 in mediating apoptosis. We conclude from this study that a) there is no evidence for mutational inactivation of WAF-1 that might mimic p53 inactivation in the JB6 model; b) elevated expression of MDM-2 and/or WAF-1 might be involved in neoplastic progression; and c) there is a p53-independent pathway controlling WAF-1 expression which may mediate p53-independent apoptosis. PMID- 21556562 TI - The characterization of nuclear-DNA content, the proliferative activity and the immunohistochemical expression of gfap, vim, leu-7, s-100, p53 and cathepsin-d in human glioblastoma multiformes (hgbms) versus human gbm cell-lines grafted into the brains of nude-mice. AB - Experimental models relating to human glioblastoma multiformes (hGBMs) involve the intracranial or intracerebral injection of human GBM cells into nude mice or rats. The aim of the present study was to compare a number of biological characteristics of hGBMs as opposed to experimental GBMs obtained by grafting either human U87 or U373 glioblastoma cells into the brains of nude mice. Biological assessments involve four distinct sets of parameters, i.e. i) the determination of the nuclear DNA content, ii) the determination of proliferative activity, iii) the assessment of p53 nuclear phosphoprotein immunohistochemical reactivity, and iv) the assessment of GFAP, VIM, LEU-7, S-100 and CAT D protein immunohistochemical reactivity. While most of the human glioblastoma multiformes (hGBMs) under study were immunohistochemically reactive to GFAP, S-100, LEU-7 and VIM as indeed were the experimental U373 GBMs, the U87 ones were reactive to VIM only. Furthermore, the U87 GBMs appeared to be more aggressive than the U373 ones since the former were associated with a shorter tumor-bearing mouse survival time than the latter. Such aggressiveness was further associated with a proliferative activity and a cathepsin D immunoreactivity, both of which were markedly higher in the U87 GBMs than in the U373 GBMs. These two experimental GBM models also exhibited tumors which were predominantly diploid. The present study shows that it is possible to set up experimentally in vivo models which strongly mimic human glioblastoma multiformes. Such models consist of grafting human glioblastoma cell lines, namely U87 and U373, into the brains of nude mice. However, while it is true that experimental GBMs closely resemble the hGBMs with respect to some biological characteristics, they also differ in many other significant biological characteristics. PMID- 21556563 TI - A novel model for metastasis suppression involving regulation of nuclear precursor messenger-RNA stability. AB - Our previous data correlated urokinase plasminogen activator (uPA) gene activation with metastasis in different rat mammary carcinomas, However, inconsistent with this was the suppression of the uPA gene in the metastatic rat mammary carcinoma cell line, BC1. We have now re-examined this cell line, selecting in vivo specifically for those BC1 cells capable of lung metastasis. We demonstrate that within the polyclonal BC1 cell line, it is possible to enrich for a metastatic sub-population which synthesizes 4 to 5-fold higher levels of uPA mRNA and enzyme activity. Therefore, the ability of a BC1 cell to metastasize appears to correlate with its escape from suppression of the uPA gene in this tumour. The results are consistent with the mechanism of uPA gene activation in metastatic DMBA-8 rat mammary tumour cells, and suggest a novel model of tumour progression based on regulation of pre-mRNA stability. PMID- 21556564 TI - Deregulation of tyrosine kinases in a rat macrophage tumor - ectopic expression of lck. AB - AK-5, a spontaneous rat macrophage tumor has 2-3 fold higher membrane-associated tyrosine kinase (TK) activity than normal peritoneal macrophages. lck, the lymphoid-specific TK, is expressed ectopically in AK-5. p56(lck), the protein product of lck, was detected in AK-5 by immunoprecipitation. The surface proteins CD4 and CD8 to which p56(lck) is complexed in lymphocytes are not present an the surface of AK-5. The transcripts of hck, a gene expressed predominantly in myeloid cells are markedly reduced in AK-5. The genomic organization of lck is unaltered. Although the total phosphotyrosine content of proteins is not altered significantly, there is a qualitative change in the profile of phosphotyrosine containing proteins. These results provide evidence for the ectopic expression of lck in a hematopoietic tumor and bolster the existing data implicating the participation of src family TKs in spontaneous neoplasms. PMID- 21556565 TI - Effective immune rejection of advanced metastasized cancer. AB - A cellular cancer therapy is described with unique efficiency even in late-stage disease. in situ activated tumor-immune T cells, induced in allogeneic, tumor resistant, MHC identical but superantigen different donor mice (B10.D2) could transfer strong graft-versus-leukemia (GvL) effects accompanied by only mild graft-versus-host (GvH) reactivity. Systemic immune cell transfer into 5 Gy irradiated DBA/2 mice bearing up to 4 week established syngeneic tumors and macrometastases led to massive infiltration of tumor tissues by CD4 and CD8 donor T lymphocytes. Upon interaction of immune CD4 donor T cells with host antigen presenting cells in synergy with immune CD8 donor T cells attacking the tumor cells directly, primary tumors (1.5 cm diameter) were encapsulated and rejected from the skin and liver metastases eradicated. For the first time, such adoptive cellular immunotherapy (ADI) was followed in individual live animals by P-31-NMR spectroscopy of primary tumors. An approximately 25,000 fold excess of metastatic tumor cells could be rejected as revealed quantitatively by FACScan analysis of lacZ gene transfected tumor cells. PMID- 21556566 TI - Immunohistochemical detection of ribonucleotide reductase in human breast-tumors. AB - Ribonucleotide reductase (RNR) consists of two non-identical subunits, R1 and R2 and is one of the key enzymes involved in DNA biosynthesis. RNR activity is considerably higher in malignant tumors than in normal tissues in the rat suggesting that RNR may play an important role in the pathogenesis of human tumors. In order to obtain immunological reagents to study the localization and level of expression of RNR in various human tissues, a synthetic peptide containing sequences corresponding to the COOH-terminal region of the human R2 subunit was used to generate rat monoclonal antibodies. The generated rat monoclonal antibodies (IgG) inhibited RNR enzymatic activity purified from murine P388 leukemia cells. These antibodies were used to immunohistochemically examine the distribution of RNR in a small panel of 8 malignant and 4 benign human breast tumors. Positive immunostaining for RNR was observed in the cytoplasm of human breast carcinoma cells in which a specific 44 kDa specific band of R2 subunit was also detected by Western blot analysis. The immunostaining was blocked by preabsorption of the antibody with an excess amount of the synthetic peptide immunogen. In 8 of 8 breast carcinomas, positive immunostaining for the R2 subunit was observed whereas noninvolved, adjacent breast tissue showed no staining with this antibody. In addition, few of the benign breast lesions exhibited staining with this antibody. These data indicate that these antibodies can immunohistochemically detect RNR in frozen or formalin-fixed, paraffin- embedded tissues and that there is a differential expression of RNR between breast tumors and non-involved breast tissue. Immunohistochemical detection of RNR using these antibodies may therefore be useful for the diagnosis of human breast tumors. PMID- 21556567 TI - Der(16)T(1-16) is a nonrandom secondary chromosome aberration in many types of human neoplasia, including myxoid liposarcoma, rhabdomyosarcoma and Philadelphia chromosome-positive acute lymphoblastic-leukemia. AB - An unbalanced translocation between chromosomes 1 and 16, der(16)t(1;16), resulting in trisomy 1q and loss of genetic material from 16q, has been thus far suggested to constitute a nonrandom secondary abnormality in two types of closely related solid tumors - Ewing sarcoma and peripheral primitive neuroepithelial tumor (PNET). We report on three cases of soft tissue tumors, a myxoid liposarcoma, a PNET and a rhabdomyosarcoma, and four cases of hematologic disorders, two acute lymphoblastic leukemias (ALL), an acute mixed leukemia and a refractory anemia, that in addition to primary chromosome abnormalities displayed the presence of the der(16)t(1;16). All three cases of acute leukemia were Philadelphia (Ph) chromosome-positive and all displayed both lymphoid and myeloid antigens. Our results and review of the literature indicate that the occurrence of der(16)t(1;16) is not limited to Ewing sarcoma and PNET, but that acquisition of this abnormality may represent a more general pathway of clonal evolution in several different tumor types including Ph chromosome-positive ALL, myxoid liposarcoma, rhabdomyosarcoma, breast cancer, endometrial adenocarcinoma, myelodysplastic syndromes, acute myeloid leukemia, retinoblastoma, and Wilms' tumor. PMID- 21556568 TI - Mechanisms of kaposis-sarcoma cell supernatant-induced vascular cell invasion. AB - Kaposi's sarcoma (KS) is a highly angiogenic lesion frequently associated with acquired immune deficiency syndrome. Histologically the lesions appear to contain proliferative 'spindle shaped' cells with a mixed smooth muscle-endothelial fibroblastic histotype and a conspicuous neovascularization, derived from host cell recruitment. Media conditioned by cultured KS cells (KS-CM) have angiogenic properties. KS-CM is able to promote endothelial and smooth muscle cell migration and invasion. The mechanisms of this KS-CM activity are still unknown. We hypothesize that KS-CM contains numerous factors with different roles in inducing the neo angiogenic process. We show that AIDS-IST-KS cell supernatants induce gelatinase A production and plasminogen activator (PA) up-regulation in vascular cells. KS-CM activity in vivo is heparin dependent. Also bFGF alone, a heparin dependent factor, alone can induce endothelial and smooth muscle cell invasion, MMP-2 production and PA activity. However, antibodies to bFGF do not block KS-CM activity and do not reduce the effect on PA up-regulation. This evidence suggests that heparin-binding factors other than bFGF may be present. Chromatography of KS CM on heparin-sepharose demonstrates the presence of two heparin-binding fractions with chemotactic and gelatinase A inducing activity. The flow through was also active. KS-CM absorption on heparin-sepharose beads did not modify its induction of PA activity, further evidence for the presence of non heparin binding factors as well. PMID- 21556569 TI - Antagonists of bombesin/gastrin-releasing Peptide inhibit growth of jar human choriocarcinoma cells and production of cyclic-amp in-vitro. AB - The effects of bombesin/GRP antagonists RC-3095 and RC-3940-II on the in vitro proliferation of JAR human choriocarcinoma cells were evaluated. Antagonists RC 3095 and RC-3940-II effectively inhibited growth of cultured JAR cells, inducing a dose- and time-dependent decrease in the number of treated cells. RC-3940-II was more potent than RC-3095 in inhibiting the growth of JAR cells. Addition of RC-3940-II to JAR cell cultures significantly inhibited the cell proliferation at concentrations as low as 1 nM, while 10 nM RC-3095 was required for a similar effect. Receptor binding studies demonstrated the presence of a single class of binding sites for bombesin on JAR cells. RC-3940-II displaced [I-125]Tyr(4) bombesin bound to the receptors. When JAR cells were cultured in the presence of 10 nM RC-3095 or RC-3940-II for 72 h, cAMP levels in the incubation medium were decreased by 70-80%, compared to the controls. These results suggest that bombesin/GRP antagonists RC-3095 and RC-3940-II inhibit the proliferation of JAR human chorionic adenocarcinoma cells in vitro and that these effects may involve intracellular cAMP pathway. PMID- 21556570 TI - Karyotypic aberrations in an anal-canal malignant-melanoma and its local metastasis. AB - Tissue samples from a malignant melanoma of the anal canal and its local metastasis were short-term cultured and analyzed cytogenetically. Complex chromosome aberrations were found in the primary tumor, yielding the karyotype 49 50,X,-Y,der(1)t(1;13)(q44;q12),+der(2)t(2;8) (q31;q12),der(6)t(5;6)(q13;q21),+del(6)(q12q21),+7, der(8)t(6;8)(p12;p21),del(11)(p11),der(11)t(11;12) (p15;q24),der(15)t(6;15)(p21;p11-13),+der(20)t(1;20) (q12;q13),der(22)t(11;22)(p11;p11)[34]/88-100,idemx2[3]. In the local metastasis, the same near-tetraploid abnormal clone was detected, indicating that the cell population was clonally stable during tumor progression. This is the first malignant melanoma of the anal canal that has been cytogenetically characterized. PMID- 21556571 TI - Rearrangement of chromosomal bands-3p13-14 in 2 hamartomas of the breast. AB - Cytogenetic aberrations have until now not been reported in mammary hamartomas. The finding of multiple, karyotypically abnormal clones in short-term cultures from 2 such tumors supports the interpretation that these are genuinely neoplastic lesions. The deletion del (3) (p13p14) and trisomy 18, both known to occur as primary chromosome abnormalities in breast carcinoma, were among the clonal changes in one case each. Since both tumors had structural abnormalities of 3p13-14, admittedly leading to different derivative chromosomes, rearrangement of this region might represent a unifying feature in the genesis of mammary hamartomas. PMID- 21556572 TI - Biological and clinical relevance of proliferative activity in inflammatory breast-cancer. AB - The hormone receptor status and proliferative activity characteristics of inflammatory breast cancer (IBC) were studied in a series of 46 patients. ER and PgR were measured by the DCC method and proliferative activity was by the H-3 thymidine autoradiographic labeling index (H-3-Tdr-LI). Tumors were ER and PgR positive in 42% and 38% of cases, respectively, whereas median H-3-Tdr-LI was 3.8%. With regard to clinical aspects, overall survival (OS) was not affected by either ER status (36 cases) or H-3-Tdr-LI value (33 cases). On the contrary, PgR(+) status was able to individualize women with a significantly higher probability of OS (X(2) by long rank test, p=0.03) after 35 months of follow-up. In the subgroup of 14 patients subjected to double biopsy performed before and after administration of primary polychemotherapy, the tumor proliferative activity variations were not related to clinical outcome. PMID- 21556573 TI - Cancer antigen expression and chromosomal changes in a carcinogen-transformed bloom-syndrome B-lymphoblastoid cell-line. AB - The phenomenon of sister chromatid exchange (SCE) is an interesting genetic event in metaphase chromosomes, even though its exact mechanism remains unknown. The fact that SCE can take place, whether 'spontaneously' or induced by various agents, is in itself important, for such an event, involving damage and possible repair of bilateral loci in chromosomes, presents opportunities for modification of the cell characters (e.g. oncogene activation). BS B- lymphoblastoid cell lines with high SCE levels were highly susceptible to malignant transformation by chemical carcinogenesis, in which cancer antigens are expressed on the cell surface with the disappearance of immunoglobulin (Ig), when the number of SCE exceeded 140 SCE per cell (over the baseline of 70 SCE per cell). The existence of an increased level of SCE which might cause unequal recombination between either sister chromatids or chromatids of homologous chromosomes may reflect phenomena secondary to malignant transformation or may have played a key role in initiation and maintenance of expression of the oncogenes and the antigens associated with cancers. PMID- 21556574 TI - Phase i/ii trial of 5-Fluorouracil, leucovorin, Zidovudine and dipyridamole for patients with metastatic colorectal-cancer, renal-cell carcinoma and malignant melanoma. AB - We conducted a phase I/II trial of 5-fluorouracil (5-FU), calcium leucovorin (LV), zidovudine (AZT) and dipyridamole (DP), (FLAP) in patients with metastatic colorectal cancer, renal cell carcinoma and malignant melanoma. AZT and DP were given to enhance the biochemical modulation and antitumor activity of 5-FU and LV. All patients received 5-FU (370 mg/m(2) i.v. bolus day 0-4), LV (50 mg/m(2) p.o. every 4 h day 0-4) and DP (50 mg/m(2) p.o. every 6 h days 0-27). In the phase I portion of the study, AZT was dose escalated in cohorts of 5 patients each, from 50 mg p.o. every 6 h days 0-27 to the MTD of 200 mg p.o. every 6 h days 0-27. Thirty-three patients received 200 mg of AZT in the phase II portion of the trial. Eleven patients developed grade III and 5 patients developed grade IV leukopenia. Four patients developed grade III and 21 patients developed grade IV neutropenia, with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. Fifty-eight percent (19 of 33) of patients required dose reductions of AZT for hematologic toxicity (13 of 19 in the first treatment cycle). At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%), no objective responses in 14 patients with renal cell carcinoma or in 14 patients with melanoma. FLAP does not have significant activity in melanoma, renal cell carcinoma or 5-FU-treated colorectal cancer patients, although it may have activity in untreated colon cancer. PMID- 21556575 TI - Cell-death by apoptosis following anticancer drug-treatment in-vitro. AB - The mechanism of cell death, apoptosis or necrosis, was determined morphologically and by DNA gel electrophoresis in 3 human leukaemic T-cell lines (CCRF-CEM.f2, CCRF-HSB and MOLT.4) after treatment with cytotoxic drugs. These include one hormone, dexamethasone (DXM); the DNA damaging agents, melphalan, cisplatin, bleomycin, mitomycin C and mithramycin; inhibitors of DNA synthesis, aphidicolin, cytosine arabinoside (Ara-C), methotrexate (MTX), 5-fluoro-2' deoxyuridine (FUdR) and 5-fluorouracil (5-FU); and other metabolic inhibitors, bromo-2'-deoxy-2'-uridine (BUdR), actinomycin D, 5-azacytidine (5-AC), cycloheximide, vincristine, etoposide and adriamycin. When cell death was assessed morphologically apoptotic cell death was apparent in the three cell lines 48 hours after all drug treatments. However, a distinct pattern of DNA breakdown was observed for each cell line. A smear of DNA on agarose gels was seen for CCRF-CEM.f2 with 5-FU and mithramycin treatments whilst CCRF-HSB cells showed a similar DNA profile after 5-FU and MTX treatments. All drug treatments of MOLT.4 cells produced a necrotic pattern of DNA degradation. Cycloheximide, an inhibitor of protein synthesis reduced DNA fragmentation of CCRF-CEM.f2 cells treated with DXM, MTX and FUdR indicating that protein synthesis is required for cytotoxicity by apoptosis. However, the extent of DNA fragmentation caused by 5 FU was not significantly affected by cycloheximide. These results indicate that at least morphological and electrophoretic criteria should be used to avoid differing conclusions about modes of cell death. PMID- 21556576 TI - Binding of the glucocorticoid and estrogen-receptors to the human h-ras oncogene sequences. AB - There is evidence that hormone regulation of cellular oncogenes plays an essential role in human cancer. The c-H-ras gene is implicated through both mutation and abnormal gene expression in many types of human cancer. Computer scanning of this gene has revealed two putative hormone response motifs: A possible Glucocorticoid Response Element (GRE) at position 1261 of the first intron of the H-ras1 gene and a putative Estrogen Response Element (ERE), at position 3007 of the fourth intron of the gene. In DNA binding assays, using the HeLa and LATK-cell lines, we showed specific binding of the corresponding receptors at both putative H-ras glucocorticoid and estrogen response sequences, suggesting that hormones could be contributing to H-ras transcriptional regulation through interaction with their corresponding Hormone Response Elements (HREs). PMID- 21556577 TI - Expression of activin and activin receptors in pc3 human prostatic-cancer cells. AB - PC3 human prostatic cancer cells, which are androgen-independent and hormone nonresponsive, were used to examine the possible presence and expression of activin and its receptors in this cell line because activin is a member of transforming growth factor beta (TGF beta) superfamily which has been found to have growth-inhibitory activity. We have studied whether PC3 cells transcribe mRNAs coding for beta A- and beta B-subunits of activin, and activin receptors I, II, and IIB, and whether PC3 cells produce activin proteins. The expression and localization of the mRNAs were elucidated by the reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization techniques. The presence of immunoreactivity for activin was determined by immunocytochemistry. We have observed that messenger RNAs encoding activin beta A-, beta B-subunits, and activin receptors I, II, and IIB, but not that of the alpha-subunit of inhibin, were expressed, and activin proteins, but not inhibin, are present in PC3 cells. Furthermore, the RT-PCR products were confirmed by DNA sequencing. We conclude that activins and their receptors are expressed in PC3 and suggest that activins may have autocrine functions in these cells. PMID- 21556578 TI - Tumoricidal function against human cervical-cancer cells in human peritoneal mesothelial cells - contribution of tumor-necrosis-factor-alpha. AB - The present study demonstrates the important and novel finding that human mesothelial cells possess tumoricidal activity. This cytotoxicity in mesothelial cells was induced by recombinant human interferon (rhIFN)-gamma and was measured against the human cervical carcinoma cell line, ME-180, by Cr-51-release, visual assessment and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide uptake assays. Tumor necrosis factor (TNF)-alpha-sensitive ME-180 cells were shown to be lysed by 24-h-rhIFN-gamma-treated-mesothelial cell-supernatants alone, which was partially inhibitable by anti-TNF-alpha. Induction of TNF-alpha in mesothelial cells was confirmed by Northern blotting. Our data describe a novel rhIFN-gamma-activated cytotoxic function in mesothelial cells, and suggest the involvement of TNF-alpha as one of the lytic mechanisms. These results are of extreme importance in relation to the future understanding of general local carcinogenic processes, and henceforth therapies. PMID- 21556579 TI - Changes in expression of neural cell-adhesion molecule ard desmoplakin associated with phenotypic transitions in cloned cell-lines from a nonsmall cell lung carcinoma. AB - 1 PT and 1 PT variant A clonal cell lines, both derived from the same neuroendocrine positive, undifferentiated large cell lung carcinoma, showed differences in their morphology, DNA content, presence of desmosomes and expression of NCAM and desmoplakin. Colonies of cells which morphologically resembled 1 PT variant A cells arose in cultures of the 1 PT clonal line following prolonged cultivation. Such transitions in cloned cells of NSCLC origin have not previously been reported. This transition was associated with increased expression of desmoplakin and downregulation of NCAM. A converse transition of 1 PT variant A cells to 1 PT-like cells could not be demonstrated. PMID- 21556580 TI - Amphiregulin is a potent mitogen in human pancreatic-cancer cells - correlation with patient survival. AB - The epidermal growth factor (EGF) receptor (EGFR) is activated by EGF and other EGF-like growth factors, including amphiregulin (AR). We characterized the localization and mitogenic action of AR in T3M4 and COLO-357 human pancreatic cancer cell lines and determined whether the presence of AR in human pancreatic cancers correlates with patient survival. Both T3M4 and COLO-357 cells were found to be extremely sensitive to AR, one-half maximal stimulation occurring at a concentration of 70 and 50 pM, respectively. The magnitude of the stimulatory effect was greater with AR than with EGF. Both cell lines exhibited AR immunostaining, which was present in a variable manner in the cytoplasm, nucleus and nucleoli. Immunohistochemical analysis of 62 pancreatic cancer tissues revealed the presence of nuclear and/or cytoplasmic AR immunoreactivity in the cancer cells. Cytoplasmic, but not nuclear localization of AR in the pancreatic cancer cells was associated with a statistically significant decrease in the post operative survival period. The presence of EGFR alone in the cancer cells did not correlate with decreased survival, whereas coexpression of cytoplasmic AR and EGFR was associated with shorter survival. Distant metastases did not always exhibit cytoplasmic AR immunoreactivity. These findings point to the existence of an EGFR: AR autocrine loop in human pancreatic cancer which may contribute to its biological aggressiveness. PMID- 21556581 TI - Transformation by v-erb-B - induction of apoptosis is abrogated in a myeloid cell line. AB - Oncogene transformation represents a means to analyse events involved in myeloproliferation and leukemogenesis. We have previously shown that v-erb-B transforms a myeloid cell line (FDCP-1) to growth factor independence and acts to modulate the lineage of these cells allowing induction of erythroid differentiation. In this report we have compared apoptosis in parental and v-erb B transformed FDCP-1 cells (FI v-erb-B). v-erb-B was found to protect these cells from apoptosis induced by IL-3 withdrawal, dexamethasone addition or serum withdrawal. In the case of IL-3 withdrawal, the suppression of apoptosis was reversed by herbimycin A, indicating that the effect was mediated through the tyrosine-kinase activity of the v-erb-B protein. The apoptotic protective effect exerted by v-erb-B for dexamethasone or serum withdrawal was seen despite growth suppression by these conditions. Taken together, these results indicate that transformation by this oncogene, in addition to its proliferation-enhancing properties, is due to its ability to inhibit apoptosis induced by growth factor withdrawal or growth suppression. The suppression of apoptosis induced by v-erb-B in hematopoietic cells appears to be important to the tumorigenic potential of this oncogene and may act as a means of in vivo tumor progression. PMID- 21556582 TI - Fibroblast-tumor interaction changes constitutive expression of IL-6 and IL-8 in human carcinoma-cells. AB - To examine whether expression of interleukin-6 (IL-6) and interleukin-8 (IL-8) in human carcinoma cells can be influenced by host fibroblasts, we investigated the expression of IL-6 and IL-8 mRNA in carcinoma cells cocultured with fibroblasts. Four human cancer cell lines, NUGC3 and GaCa gastric carcinoma cells, RERF-LCOK lung carcinoma cells, and GBK-1 gallbladder carcinoma cells, which constitutively express large amounts of both IL-6 and IL-8, were cocultured with murine 3T3 fibroblasts, in which IL-6 and IL-8 were not detected, under the same conditions. By Northern blot analysis, the expression of IL-6 mRNA was significantly decreased in NUGC3, GBK-1, and RERF-LCOK cells but was increased in GaCa cells. The expression of IL-8 mRNA was significantly increased in GaCa and GBK-1 cells but decreased in RERF-LCOK cells. Using cell-free conditioned medium, only the NUGC3-3T3 culture supernatant showed little effect on IL-6 and IL-8 mRNA expression in the NUGC3 cells, thereby suggesting that changes in IL-6 and IL-8 mRNA expression observed in the coculture experiment depended mainly on 3T3-NUGC3 contact and not on soluble factors. Similar changes in IL-6 and IL-8 mRNA expression were noted when NUGC3 cells were cultured with paraformaldehyde-fixed 3T3 cells or the 3T3 membrane fraction, thereby supporting this notion. Northern blot analysis of transplanted NUGC3 tumors in nude mice showed a decrease in IL-6 mRNA expression and augmentation of IL-8 mRNA expression. Sera from the NUGC3 bearing mice showed only small differences in IL-6 and IL-8. The downregulation of IL-6 mRNA was reversed 20 hours after NUGC3 cancer cells were separated from the in vivo grown NUGC3 tumors and cultured in vitro. These results suggest that tumors producing IL-6 or IL-8 can be differently modulated by the host cell mediated pathways, such as contact between fibroblast and tumor cells. PMID- 21556583 TI - Transformation by v-ras oncogene correlates with an increased drug-resistance in an epithelial thyroid-cell system. AB - The effects exerted by ms transformation upon sensitivity to anticancer drugs by using an epithelial cell system displaying different levels of ras expression which well correlate with different degrees of cell malignancy have been evaluated. The diminished drug accumulation of the transformed cell lines was found to be correlated with a depolarization of the cell membrane as observed by a flow cytometric analysis and not correlated with the multidrug resistance (mdr) protein. The most resistant cell line, MPTK-6, showed the lowest drug accumulation levels and the lowest membrane potential. These observations indicate that ras neoplastic transformation of the rat thyroid epithelial cells modifies the membrane potential and this modification is possibly involved in anticancer drugs resistance. PMID- 21556584 TI - Molecular abnormalities of chromosome-19 in malignant gliomas - preferential involvement of the 19q13.2-q13.4 region. AB - A deletion mapping analysis of chromosome 19 was performed on a series of 101 samples derived from malignant gliomas. A total of 35 tumors displayed different deletions for the loci studied (D19S21, D19S11, D19S74, D19S7, D19S8, CKM, and D19S22). In most instances, losses involving the long arm markers of chromosome 19 were observed, and only four samples were characterized by losses on the short arm. No tumor was found displaying loss of both short and long arm markers. The higher frequency of deletions was detected in tumors with a major oligodendroglial component: 76% of samples included in this group displayed losses at 19q. Among the astrocytic tumors, the frequency of 19q alterations varied as follows: 11% in pilocytic astrocytomas, 17% in astrocytomas grade II, 10% in anaplastic astrocytomas and 21% in glioblastoma multiforme. No ependymoma was found displaying allele loss on chromosome 19. The common region of overlap for the 19q deletions observed involves primarily the distal portion of the long arm, 19q13.2-q13.4. In agreement with previous reports, these data suggest the non-random involvement of a tumor suppressor gene located at 19q13 in the genesis or progression of malignant gliomas. PMID- 21556585 TI - Dipyridamole as a modulator of multidrug-resistance in tumor-cells in-vitro. AB - The aim of the present study was to investigate in vitro the effect on LoVo cells (LoVo-S, doxorubicin-sensitive, and LoVo-R, doxorubicin-resistant) on the association of dipyridamole and certain antiblastic drugs (doxorubicin, idarubicin, mitoxantrone, teniposide) with different mechanisms of action. The cells were treated for 48 hours with the drugs, or were left for 24 hours without treatment (recovery period). The results demonstrate that dipyridamole possesses an inhibitory effect on cell growth, and that it potentiates the cytotoxic effect of the tested antiblastic drugs, particularly on LoVo-R cells. In the recovery period the inhibitory effect of dipyridamole on LoVo-S and LoVo-R cells was reversible, while the effect of the antitumour drugs, either alone or in association with dipyridamole, persisted. We suggest that dipyridamole has a synergistic effect on LoVo cell growth when associated with antiblastics; the increased effect produced on LoVo-R cells is indicative for a reversion of multidrug resistance, probably via a mechanism related to transmembrane transport system. PMID- 21556586 TI - Effect of adenovirus-2 early region-4 products on e1-transformation. AB - We show that transformation of rat CREF fibroblasts by adenovirus-2 early regions 1A and 1B (E1) is stimulated by expression of the viral early region 4 (E4) products. Cotransfection of CREF cells with E1 and E4 did not affect the number of E1-transformed foci, but resulted in the formation of larger and more dense foci compared to E1 transfection alone. Cells obtained from these foci were capable of anchorage-independent growth. The adenovirus-2 E4 region encodes for a minimum of seven proteins, several of which have been shown to have distinct biological activities. To assay for the activity of these individual proteins on E1 transformation, we used expression vectors designed to encode single E4 proteins in the CREF cell transformation assay. By this strategy, we could show that two E4 proteins had a significant capacity to stimulate E1 transformation. Cotransfection of E1 and vectors encoding the E4-ORF1 or E4-ORF6 proteins resulted in the formation of large dense foci typical of E4-cotransformed cells. However, no single E4-ORF-expressing plasmid was sufficient to reproduce the stimulative effect on CREF cell transformation observed using the entire E4 region. PMID- 21556587 TI - Allelic status on 1p and 11p15 in neuroblastoma and benign ganglioneuroma. AB - A tumor suppressor gene responsible for neuroblastoma (NB) is thought to be located on 1p, while a gene(s) commonly involved in embryonal tumors in childhood is(are) located on 11p15. To determine whether and how those putative genes affect tumorigenesis of NB, a total of 25 NBs and two benign ganglioneuromas (GNs) were examined by Southern technique with polymorphic markers on chromosomes 1 and 11 for analysis of the loss of heterozygosity at these loci. Because NB often features an increased number of chromosomes, we performed a detailed examination of allelic status and then compared it with their prognostic factors. While allelic loss on 1p was observed in only four cases (16%), eight additional cases showed allelic imbalance on a portion of 1p, indicating that these cases featured 1p deletions, so that the total number of cases with a 1p deletion was 12 out of 25 NBs (48%). A 1p deletion was observed not only in disseminated cases (8/14 of stage III or TV), but also in several cases with localized tumors (4/11 of stage I or II, p=0.529). Moreover, one GN case showed a 1p deletion. However, allelic loss or imbalance on 11p15 was observed in only two NBs (8%). These data suggest that 1p deletion is an initial event of NE tumorigenesis rather than a later event associated with tumor progression, while deletion of 11p15 is related to the development of a small proportion of NBs. Cases with 1p deletion do not always follow an aggressive clinical course and may differentiate into GN. PMID- 21556588 TI - Rejection of murine melanoma-cells transfected with the intercellular-adhesion molecule-1 gene. AB - The effects of intercellular adhesion molecule-1 (ICAM-1) expression on-tumor rejection and induction of antitumor immunity in a murine melanoma system was studied. K1735 melanoma cells genetically engineered to express the murine ICAM-1 gene were rejected in immunocompetent hosts, and that this rejection was mediated by CD4(+) as well as by CD8(+) T lymphocytes. We also found that ICAM-1 transfected tumor cells provided costimulatory signals to both CD4(+) and CD8(+) T cells in vitro. In addition, immunization of mice with K1735-ICAM-1 transfectants induced protective immunity against the parental ICAM-1-negative tumor. Our findings suggest that ICAM-1 expression on nonimmunogenic tumor cells causes tumor rejection and augments tumor-specific immunity. PMID- 21556589 TI - Characterization of a new p53-mutated and hpv-negative human squamous-cell cervical carcinoma-derived cell-line. AB - A new cell line, designated IGR/Cut40, has been established from a stage II squamous cell carcinoma of the uterine cervix. These cells, which have a tetraploid DNA content and typical epithelial features, displayed a high proliferation rate and a powerful tumorigenic potential in immunodeficient mice. No human papillomavirus (HPV) DNA was detected using PCR and consensus primers. Sequencing of p53 cDNA revealed a mutation CGC(Arg)-->CAC(His) at codon 175 of the gene encoding for an abundant nuclear protein. IGR/Cut40 cell line should permit a better understanding of the HPV-infection-unrelated tumorigenesis of the uterine cervix. PMID- 21556590 TI - Oncogenic mutations in the rb1 gene in retinoblastoma tumors from patients from the kingdom of saudi-arabia. AB - Five retinoblastoma tumours from patients treated in the King Khaled Eye Specialist Hospital in Riyadh were analysed for mutations in the RB1 gene using single strand conformation polymorphism analysis and mutations were found in all of them. In one tumour the mutation in exon 11 was homozygous demonstrating the role of loss of heterozygosity in tumorigenesis. The mutation in the remaining 4 tumours were heterozygous and in only one case were two independent mutations found. Three mutations were insertions or deletions and the other three were point mutations of which 5 resulted in the generation of premature stop codons within the coding region of the gene and one is predicted to affect the correct splicing of the pre-mRNA. The nature of the mutations found in this series of patients from the Kingdom of Saudi Arabia, therefore, are similar to those found in other populations throughout the world and show no evidence for mutation hotspots within the RB1 gene. PMID- 21556591 TI - Analyses of linkage to 17q11-q23 in 3 French hereditary nonpolyposis colon-cancer families. AB - Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, accounting for approximately 6% of colorectal cancers. We performed linkage analyses with the aim of proving or excluding the existence of a susceptibility locus on 17q. Three HNPCC families (102 collected members, 25 colorectal cancers, 9 other cancers and 6 colorectal adenomas) were studied with 7 polymorphic DNA markers Mfd15, THRA 1, D17S800, D17S855, Mfd 188, 42D6, 46E6 localized in the 17q11-q23 region. After in vitro enzymatic amplification, the different alleles were separated by classic vertical poly-acrylamide gel electrophoresis or analyzed with the automatic sequencing machine 373A (Applied Biosystems). Results showed that none of the 7 studied markers of the chromosome 17q were linked to the HNPCC disease. PMID- 21556592 TI - Linkage analyses of 3 French families to Loci on chromosome-2p and chromosome-3p predisposing to hereditary nonpolyposis colon-cancer. AB - Hereditary, non-polyposis colon cancer (HNPCC) is caused by mutations in different loci. One gene causing HNPCC was mapped to chromosome 2p and recently a tight linkage between a polymorphic marker on the chromosome 3p and the disease locus has been demonstrated and these families also manifest signs of a general DNA replicator disorder. We report detailed genetic studies of three French HNPCC families with D2S123 and D3S1029. In one of the families (F 230), the segregation pattern for markers on chromosomes 2 and 3 suggests absence of linkage. The two other families are not informative enough to conclude on linkage status with chromosomes 2 and 3. If confirmed, this result would mean that the inherited colon cancer in this family is linked to another HNPCC gene. Implication for genetic counselling is discussed. Even with cloned genes, linkage analysis with flanking microsatellite markers for informative families may help to avoid tedious work of seeking point mutations in HNPCC genes. PMID- 21556593 TI - Radiolabeled metaiodobenzylguanidine (mibg) in diagnosis and therapy of neuroblastoma - results from basic research (review). AB - [I-131]mIBG, meta-iodobenzylguanidine, a catecholamine analogous compound, was synthesized by Wieland et al in 1979. It has been used for scintigraphic imaging of normal sympathetic tissue, of pheochromocytoma, and since 1983/84 also of neuroblastoma. Later, protocols for treatment of neuroblastoma stage IV using high dose [I-131]mIBG were established. In this review the basic mechanisms concerning uptake and storage of mIBG in neuroblastoma cells as well as the cytotoxic effects of unlabeled and radiolabeled mIBG are documented. Results of these investigations have promoted the development of new concepts for optimizing the application of mIBG in diagnosis and therapy of neuroblastoma. PMID- 21556594 TI - The effect of zymosan-induced generalized inflammation on tumor-growth in a rat renal-cell carcinoma model. AB - We investigated the inhibition of tumour growth by induction of a generalized inflammatory response. 45 Lewis rats were randomly divided in three groups. A rat renal cell carcinoma was transplanted subcutaneously on day one in group I and group II. When the tumour became measurable on day 16, a generalized inflammation was induced by intraperitoneal injection with a suspension of zymosan and paraffin in group I and in group III, consisting of non-tumour bearing animals. Group II was inoculated with paraffin only. Seven and 14 days following intraperitoneal injection two rats out both group I and group II were sacrificed in order to obtain tumour biopsies at different stages of a generalized inflammatory response. Spontaneous mortality occurred twice in group III, consisting of non-tumour bearing animals. On day 37 all surviving rats were killed. Microscopical examination was carried out on all tumours and on lungs, liver, spleen and kidneys. A generalized inflammation response was confirmed in group I and III through biologic and microscopic parameters. After a zymosan induced generalized inflammation response in the rat, tumour growth rate was significantly lower compared with paraffin treated animals. PMID- 21556595 TI - Analysis of C-myc messenger-RNA expression in primary breast carcinomas with clinical follow-up. AB - The level of c-myc messenger RNA was measured in 105 primary breast carcinoma samples and matched normal breast tissue from the same patients. Only tumors showing a greater than 2-fold increase in c-myc levels were considered to be overexpressed. Overexpression of c-myc mRNA was identified in 27.6% of tumor samples analysed and was significantly correlated with mitotic grade (p=0.05) and intense lymphocytic infiltrate (p=0.026) but not with other clinical and pathological variables such as size, necrosis, lymph node involvement, estrogen or progesterone receptor status, menopausal status, age or staging of the patients and increased risk of relapse or overall survival. Approximately 25% of the tumors contained overexpression of c-erbB-2 mRNA and simultaneous overexpression of the two oncogenes was seen in only five samples. Disease-free survival was significantly shorter in these patients (p=0.02) and this reduction remained significant after adjustment for nodal status. However, simultaneous overexpression of c-myc and c-erbB-2 did not improve significantly the prediction of risk of death. PMID- 21556596 TI - Studies on the effect of suramin on cell-proliferation of epithelial tissue renewal in the mouse. AB - The effect of a three-week treatment regimen with suramin (30, 60 or 90 mg/kg body weight) on the cell proliferation of small intestinal crypts and dorsal epidermis of the nude mouse was studied using standard auto-radiographic methods after in vivo pulse labeling with H-3-thymidine. Suramin was slightly toxic to the animals in a dose-dependent manner (p<0.01) as measured by the decrease of the rate of weight gain of the treated animals. In the small intestine suramin treatment led to crypt shrinkage (factor: about 70-80%; p<0.05) mainly by increasing the rate of cell loss out of the crypt epithelium (p<0.05) and to a lesser degree by inhibiting the proliferation of crypt cells. However, this suramin treatment scheme did not significantly affect the H-3-thymidine labeling index and the mitotic index of the basal cell layer of the epidermis. The present findings indicate that suramin can be used to approach the problem of differential homeostatic reactions of epithelial tissue renewal in vivo. PMID- 21556597 TI - Breast-carcinoma cell-lines with metastatic potential in mice. AB - We established and characterized three human breast carcinoma cell lines (two with metastatic potential) by in vivo-in vitro propagation of tumor tissues. Tissues were processed in culture as i) direct explants (n = 185); ii) cell suspensions obtained after enzymic digestion (n = 29); or iii) explants of xenografts established in vivo (n = 18). Tissues processed as explants or cell suspensions generated no viable cell lines. However, three cell lines (MAXF-401, MAXF-583 and OHSTMAM-4) were established from xenografts. All three showed characteristic features of human breast tumor tissue. All were tumorigenic in mice and MAXF-401 and MAXF-583 showed frequent distant metastasis following s.c. transplantation. All three overexpressed EGFR, p53 and c-erbB2 proteins. PMID- 21556598 TI - Expression of the human apurinic endonuclease gene (ape) in normal and malignant tissues. AB - Apurinic/apyrimidinic endonucleases initiate repair at sites of base loss produced by many carcinogens and maintain genetic stability by repairing abasic sites produced spontaneously. We examined whether expression of the main apurinic endonuclease of human cells, encoded by the APE gene, might be decreased in malignant cells and thus potentiate an elevated mutation rate. Northern blotting and in situ hybridisation were used to quantitate the level of APE mRNA in various normal tissues and in 24 different brain tumors. There were no differences in APE expression among the normal tissues, or between malignant astrocytomas and meningiomas and the surrounding normal brain tissues. This suggests that diminished expression of the apurinic endonuclease does not underly the induction of these cancers, or explain clinical variations in presentation and response to treatment. PMID- 21556599 TI - Induction of apoptosis in head and neck tumor-cell lines by anti-fas antibody. AB - Programmed cell death, currently termed apoptosis plays a key role in the maintenance of the steady state in continuously renewing tissues. Since little is known of apoptosis in head and neck tumors, we studied morphological changes in head and neck tumor-derived cell lines (KB, KBrc, HSC-2,3,4), induced by anti-Fas antibody. Light and electron microscopic examinations were carried out after culturing these cell lines with the antibody for 1-2 days. The antitumor effect of anti-Fas antibody on tumor cells differed with the cell lines. Most of the cell lines that were sensitive to anti-Pas antibody showed evidence of enhanced apoptosis when the cells were pretreated with interferon-gamma. The results suggest that the strategy of induction of apoptosis by anti-Fas antibody may be considered in treatment of some tumors of head and neck. PMID- 21556600 TI - Peripheral immunization against malignant rat glioma can induce effective antitumor immunity in the brain. AB - Using two malignant rat glioma cell lines, we tested to what extent peripheral immunization could affect tumor growth in the brain of syngeneic rats. Peripheral subcutaneous (s.c.) immunization was performed with autologous Newcastle-disease virus (NDV)-infected or non-infected live tumor cells. Thus immunized rats or non immunized controls were intracerebrally implanted with increasing numbers of the respective malignant glioma cells. Without immunization the mean survival time after intracerebral implantation of 1x10(4) TZ363 or RG2 glioma cells was 9 and 29 days respectively. After s.c. immunization with either NDV-infected or non infected TZ363 cells only 25% or less of challenged animals developed tumors in the brain. Immunization with NDV only had no effect. In RG2 glioma, s.c. immunization had no effect on tumor growth in the central nervous system and on survival time, no matter what kind of vaccine was used. These results clearly show, that in principle the efferent arm of the anti-tumor response can be effective accross the blood-brain barrier and extend into the microenvironment of the central nervous system. Whether or not glioma lines can induce this immunity and respond to it, seems to depend on their individual immunobiological characteristics. PMID- 21556601 TI - Alterations of p53 and k-ras genes in human colorectal-cancer with ulcerative colitis. AB - Using polymerase chain reaction and single strand conformation polymorphism assay, we examined genetic alterations of p53 and K-ras genes in multiple lesions of colorectal cancers that developed in three patients with ulcerative colitis. p53 gene mutations were found in two lesions and a K-ms gene mutation at codon 12 was found only in one. Neither was found in non-cancerous lesions. The results indicate that mutation of both genes may not be so frequent among Japanese patients. They were found only in very few cancerous lesions of each patient. Therefore, it is possible that the oncogenic process in each lesion is a consequence of rather independent events. Our preliminary results suggest the potential usefulness of CD44 variant forms as markers for dysplastic and cancerous tissues in ulcerative colitis. PMID- 21556602 TI - P-selectin-dependent adhesion of human cancer-cells - requirement for coexpression of a psgl-1-like core protein and the glycosylation process for sialosyl-le(x) or sialosyl-le(a). AB - We studied the cell surface expression of sialosyl-Le(x) (SLe(x)) and sialosyl Le(a) (SLe(a)) and its correlation with E-selectin- and P-selectin-dependent cell adhesion, employing 12 human cancer cell lines derived from solid tumors and 2 myelogenic leukemic cell lines, HL60 and U937. Among all the cell lines tested, there was a clear correlation between E-selectin-dependent adhesion and degree of SLe(x) and SLe(a) expression. None of the cell lines derived from solid tumors bound significantly to P-selectin, but leukemic cell lines HL60 and U937 bound strongly to P-selectin. The cDNA clone encoding P-selectin glycoprotein ligand-1 (PSGL-1) was transfected into colonic cancer HRT18 and lung cancer PC3 cells, which express SLe(x) and SLe(a) but normally do not bind to P-selectin, although they do bind to E-selectin. The resulting transfectants bound strongly to P selectin and equally well to E-selectin. A crude mucin fraction extracted from pooled human colonic cancer tissue bound to E-selectin but not to P-selectin. We conclude that tumor cell adhesion to P-selectin is highly dependent on expression of a specific core protein which appropriately assembles a specific carbohydrate to present to P-selectin. In contrast, E-selectin binds promiscuously to various types of SLe(x) and SLe(a) epitopes presented at the cell surface through N linked, O-linked, or lipid-linked structures. PMID- 21556603 TI - Long-term microcalorimetric findings in renal-cell carcinoma exposed to interferon-alpha-2a, interleukin-2 and 5-Fluorouracil. AB - The effect of chemotherapeutic and/or immunotherapeutic drugs on cells obtained from primarily cultured renal cell carcinoma (RCC) was investigated in a microcalorimetric study. This method enables the detection of heat flow in the submicrowatt range, which corresponds to a 1.0x10(-6) degrees C temperature change. The thermal power of 10 individual cell lines from patients with advanced RCC was measured by incubating cells with or without anti-cancer drugs (5 fluorouracil, interferon-alpha-2a, interleukin-2). Using a 4-channel microcalorimeter, it could be shown, that the combination of 5-FU with IFN-alpha 2a or IFN-alpha-2a plus IL-2 led to a significant reduction in thermal cell activity, compared with the addition of 5-FU on its own. These microcalorimetric observations appear to reflect the anti-neoplastic properties of the drugs tested in this study when compared with the findings in a calorimetric assay (MTT assay). PMID- 21556604 TI - Preliminary-results of preoperative axillary radioimmunoscintigraphy with in-111 b72.3 in breast-cancer. AB - Nineteen patients with clinical and mammographic diagnosis of breast cancer and 1 patient already mastectomized underwent radioimmunoscintigraphy (RIS) in order to evaluate the axillary node status before surgery. After histologic examination, ductal breast carcinomas were found in 17/19 patients and axillary metastases were found in 11 patients. RIS was performed with planar scintigraphies and SPET (Single Photon Emission Tomography) of mammary and axillary regions after intravenous injection of In-111 B72.3. Overall RIS sensitivity for breast tumors was 71% (12/17); according to the tumor site different RIS sensitivity was demonstrated (90% for lesions of external quadrants versus 43% for lesions of internal quadrants). RIS was negative in 2 patients with post-surgery diagnosis of mammary dysplasia. As regards axillary metastasis RIS sensitivity and specificity were 91% (10/11) and 78% (7/9), respectively. Human Anti-Murine Antibody (HAMA) production was shown in 16.7% (2/12) of the patients. The quantitation of In-111 B72.3 uptake (%I.D./g; mean+/-S.D.) was 0.0054+/-0.0021 in breast tumors, 0.0021+/-0.0011 in normal mammary tissue, 0.0053+/-0.0027 in axillary metastasis and 0.0032+/-0.008 in normal axillary nodes. Our data demonstrated that RIS can detect tumor spread to the axilla in patients with breast cancer. Larger pre-operative study is required to evaluate if RIS can alter the management of this disease. PMID- 21556605 TI - Vitamin-C, steroid and environmental carcinogenesis (review). AB - An attempt was made to investigate the relation between oxidative metabolism of neoplastic tissues and carcinogenesis from the point of view of the vitaminology/endocrinology fusion science. Our discussion was developed on the basis of maximum information available in- and outside our laboratory. We present 3 suggestions to throw new light on the phenomenon of eternal enigma - carcinogenesis. They are given as follows: i) the emergence of the oxidant criminal theory motivated us to refresh our old memory surrounding the metabolic characteristics of cancer cells with increased aerobic glycolysis. Evidence was presented to suggest that a neoplastic cell in its behavior can be classified as a facultative anaerobe, whereas a non-neoplastic cell belongs to the family of obligate aerobes. Information is also available to indicate that both glucocorticoid and vitamin C are working together to maintain concerted relationship between mitochondria and cytoplasm. On the basis of the information in paleontology, we propose to assume the metabolic characteristics of a neoplastic cell as an example of failed symbiosis between oxidant-intoxicated host cell (an anaerobe) and rebelling mitochondria (aerobes). ii) In view of the complexity of relation between the ever-changing environment and the humans as regards the cancer risk variations in time and space, we propose to assume the presence of a signal translation system as the intermediator between the outer environment and the target tissue. The steroid generating system, of which the implication to carcinogenesis is suggested in both human and non-human systems, may take over that role maintaining a cross talk with the hypothalamus-pituitary complex. One finds a good model of carcinogenesis in polymorphism of insects in which tranposon may well play important role in the induction of genetic transformation. iii) We should make further effort to explore the usefulness of vitamin C in cancer prevention. Worth consideration in this respect is our clinical experience that autoimmune disease and allergy are controlled through vitamin C infusion treatment by way of ACTH-linked stimulation of adrenocortical function - a modification of the hormonal milieu by use of vitamin C. PMID- 21556606 TI - Treatment of cervical-carcinoma by wertheim-meigs surgery - long-term follow-up results in a well-defined Swedish region. AB - In a retrospective analysis of a complete geographic series of cervical carcinomas treated by Wertheim-Meigs radical surgery, a number of important prognostic factors were evaluated and long-term survival data are presented. In all, 367 women with FIGO stage I-II tumors were included. The main histopathologic types were squamous cell carcinoma in 84% and adenocarcinoma in 12%. The mean age of the patients was 42.5 (range 19-68) years. In 125 women (34%), adjuvant radiotherapy was administered pre- or postoperatively. The median period of follow-up was 12 (range 2-27) years. In 88% of the specimens surgery (93% in stage I and 66% in stage II) was classified as radical with regard to the excision margins. This was an important and highly significant prognostic factor. If the margins were wide and free of tumor, the 10-year survival rate was 93%, but if margins were infiltrated by the tumor, the survival rate was 14%. Pelvic lymph node involvement was recorded in 52 cases (14%). The frequency of lymph node spread was associated with tumor stage (IA O%, IB 14%, IIA 32%). The probability of survival of the complete series was 93% at 5 years and 84% at 10 years. In cases of lymph node involvement, the 10-year survival rate was 57%. The preoperative tumor stage had a highly significant influence on long-term tumor specific survival. Tumor grade was also a significant prognostic factor, but not the histologic type (squamous, adenosquamous, or adenocarcinoma). Age and parity were also insignificant prognostic factors. The tumor recurred in 59 cases (16%). The mean time to relapse was 28 months. The 10-year survival was 29% for this group of patients. Peroperative complications were recorded in 50 patients (14%). Excessive bleeding (11%) and urinary tract injuries (3%) were most frequent. Postoperatively, 101 patients (28%) had some kind of complication associated with the surgical procedure. Surgical complications were more frequent among women over 50 years of age. Bladder dysfunction (11%) and obstruction of the ureter (8%) were recorded most frequently. In 19 cases (5.2%), urinary tract or intestinal fistulas were diagnosed during the period of follow-up. With increasing experience of the surgeons and fewer stage II tumors, the frequency of fistulas associated with the surgical procedure decreased to 2.4% during the latter part (1975-90) of the period. Adjunctive postoperative radiotherapy increased the risk of late complications. In 8 cases (6.4%), serious complications associated with the combination of surgery and radiotherapy were reported. PMID- 21556607 TI - Adrenocortical carcinoma - a clinical and immunohistochemical study. AB - Twenty-one patients with adrenocortical carcinoma (ACC) were investigated. No correlation was found between size of the primary tumour and the occurrence of metastases, and no correlation was observed between tumour diameter and the functional status of the tumour or survival. Cytokeratins (CK) were expressed in 31% and vimentin (VIM) in 41% of cases. Epithelial membrane antigen (EMA) was detected in one patient with a non-functioning tumour, whereas carcinoembryonic antigen (CEA) was absent in all rumours. The antigens investigated showed no correlation with the morphology or functional status of the tumour. The role of immunohistochemical characterization of this heterogeneous malignancy is discussed. PMID- 21556608 TI - Expression of epidermal growth-factor (EGF), matrix metalloproteinase-9 (mmp-9) and proliferating cell nuclear antigen (pcna) in esophageal cancer. AB - Expression of human epidermal growth factor (EGF) and matrix metalloproteinase-9 (MMP-9/gelatinase B) was examined immunohistochemically in 62 cases of surgically resected esophageal carcinomas, and the correlation between EGF expression and the proliferative activity of the tumors was studied by analysing the number of proliferating cell nuclear antigen (PCNA)-positive cells. Expression of EGF and MMP-9 was observed in 16 (38.1%) and 18 (42.9%) of the 42 superficial carcinomas and 8 (40%) and 14 (70%) of the 20 advanced carcinomas, respectively. The differences in the MMP-9 expression between the superficial carcinomas and the advanced carcinomas was significant (p<0.05). The synchronous expression of EGF and MMP-9 was observed in 15 (24.2%) of 62 carcinomas, i.e. 62.5% of the 24 EGF positive tumors expressed MMP-9, but there was no statistically significant correlation between the expression of EGF and MMP-9. The relationships between EGF expression and tumor proliferative activity and prognostic factors were investigated. The PCNA grades were significantly higher in tumors with EGF positive than those with EGF-negative expression (p<0.05) and the EGF expression showed a good correlation between the expression of MMP-9 and vascular invasion (p<0.01). The expression of MMP-9 was stronger in the advanced than the superficial carcinomas and there was a good correlation with vascular invasion (p<0.01). In a follow-up study of 55 patients, those with tumor that expressed MMP-9 or had a high PCNA grade showed a poor prognosis. Taken together, these observations suggest that both EGF and MMP-9 participate in the invasive phenotype in human esophageal carcinoma, but the expression of EGF is not directly related to the expression of MMP-9. Additional growth factors and cytokines may be involved in regulation of MMP-9 expression in this carcinoma. PMID- 21556609 TI - Radiosensitization with a 3-nitrotriazole (ak-2123). AB - We investigated to clarify the mechanism of action of AK-2123. V79 cells were used, and the effect of the substance was estimated with different end-points viz. induction of DNA breaks, micronuclei and clonogenic survival after hypoxic irradiation with different X-ray doses. After treatment with 0.1 mmol dm(-3) of the substance, sensitization by a factor of 1.8, 1.1 and 1.4 respectively, was calculated. By determining the enhancement ratio after treatment with the drug at 7-8 different concentrations varying between 0.001 and 50 mmol dm(-3), the concentration of the substance for half of the maximum sensitization (K-value) was estimated to be 40 mu mol dm(-3) (DNA breaks), 1200 mu mol dm(-3) (micronuclei) and 2000 mu mol dm(-3) (survival); the maximum sensitizer enhancement ratio was 2.4 (DNA breaks), 2.3 (micronuclei) and 2.4 (survival). No cytotoxic effects were found when the cells were treated with the drug in different concentrations for 30 minutes. However, after longer periods the compound was found to be cytotoxic both under aerobic and hypoxic conditions, in a concentration and time dependent manner. A post-irradiation enhancement of the sensitivity was noted when the drug was left in the medium for 24 hours after hypoxic as well as aerobic radiation exposure. PMID- 21556610 TI - Metaanalysis of 4 Swedish case-control studies on exposure to pesticides as risk factor for soft-tissue sarcoma including the relation to tumor-localization and histopathological type. AB - In four previous case-control studies we have shown an association between exposure to phenoxyacetic acids or chlorophenols and soft-tissue sarcoma (STS). These chemicals are contaminated by dioxins and dibenzofurans, some of which are known carcinogens in experimental animals. In a meta-analysis of our four studies we studied such exposure including the relation to tumour localization and histopathological type of STS. In total 434 histopathologically verified STS cases and 948 controls were included. Anatomical tumour localization was assessed by scrutinizing medical records for all cases. In the analysis stratification was made for age, vital status and study. Significantly increased risks were obtained for exposure to phenoxyacetic acids and chlorophenols, odds ratios 2.7 and 3.3, 95% confidence intervals 1.9-4.7 and 1.8-6.1, respectively. The increased risk was independent of histopathological subtype and anatomical site although especially high odds ratios were obtained for body sites close to areas where dermal contact may occur in sprayers. Phenoxyacetic acids and chlorophenols with their contaminating dioxins and dibenzofurans should be regarded as carcinogenic for STS regardless of tumour localization and histopathological type. PMID- 21556611 TI - Immunological profile of patients with ovarian-cancer under immunostimulation with murine monoclonal-antibodies. AB - The longer survival of ovarian cancer patients after immunostimulation has been connected with the induction of an anti-tumor activity triggered by cellular and humoral immune responses. Our interest was to study the long-term influence on the immune system in relation to the various levels of the HAMA response and the disease stage. The immunological profile was evaluated by regularly performing phenotyping and functional analysis of peripheral blood lymphocytes (PBL). We report the statistical analysis of immunological data obtained in a study with 77 ovarian cancer patients examined over a period of up to 28 months. The results demonstrate that these immunological data are important for monitoring cancer patients under immunotherapy whereas they provide no prognostic significance. PMID- 21556612 TI - Elevated levels of pro-cathepsin-d in the plasma of breast-cancer patients. AB - Changes in the expression and processing of cathepsin D (CD) have been shown to be associated with cancer invasion and metastasis. However, the value of CD as a prognostic marker remains controversial. Most studies have used immunological methods to measure the mature form of CD, although it is the precursor (pro-CD) that appears to be abnormally secreted by breast cancer cells. A sandwich-type ELISA has been developed that is specific for pro-CD. The assay employs a monoclonal antibody to mature CD as the capture reagent and a rabbit polyclonal to the pro fragment as the detector. The assay is specific for pro-CD and capable of quantitating this antigen in biological samples. Pro-CD levels were measured in plasma samples from 76 breast cancer patients and compared with 36 samples from normal control individuals. The plasmas of breast cancer patients showed elevated levels of pro-CD; 12% were more than two standard deviations above the mean for the normal samples. Immunoblots of the plasma samples using a CD monoclonal antibody revealed a band at the appropriate size for pro-CD that corresponded in intensity with the ELISA results. Affinity adsorption of breast cancer plasmas with pepstatin agarose followed by immunoblot analysis revealed a single protein band that correlated with pro-CD. Only trace amounts were detected in the normal control plasmas. These results demonstrate that cathepsin D is present in the plasma of breast cancer patients primarily in its precursor form and that it may be a useful prognostic indicator. PMID- 21556613 TI - Expression and localization of activin receptors in a human myeloid-leukemia cell line, thp-1. AB - THP-1, a human myeloid leukemia cell line, which secretes activin-A after phorbol ester induced cell differentiation, was used to examine the possible expression and presence of activin receptors because activin, a member of the transforming growth factor beta (TGF-beta) superfamily, has been found to be up-regulated by phorbol ester. We have studied whether THP-1 cells transcribe mRNAs encoding for activin receptors II and IIB by the reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization techniques. To confirm that THP-1 cells produce activin-A, we also determined the presence of immunoreactivity for activin-A by immunocytochemistry. We observed that messenger RNA encoding activin beta A-subunit was also expressed in THP-1 cells. Furthermore, the identity of RT PCR products was confirmed by DNA sequencing. These results indicate that activin A and its receptors are co-expressed in THP-1 cells and suggest that activin-A may have autocrine functions during cell proliferation in these cells. PMID- 21556614 TI - The gene encoding the p53-regulated inhibitor of cdks (pic1) is not expressed in the molt-4 leukemia-cell line with p53 truncated at the carboxyl-terminus, and harbors a nucleotide substitution at codon-31 in several other cancer cell-lines. AB - Entry into the cell cycle is governed by cyclins, cyclin-dependent kinases (CDKs) and CDK-inhibitors (CDKIs). The p53-regulated inhibitor of CDKs (PIC1) is a universal CDKI whose gene expression is directly induced by the p53 tumor suppressor protein. Reverse transcription and polymerase chain reaction revealed strong PIC1 gene expression in control MRC-5 human embryo lung cells, but relatively weaker bands in A549 lung carcinoma; Hep3B, Mahlavu, PLC/PRF/5 hepatocellular carcinoma; SiHa, CaSki, HeLa cervical carcinoma; T24 bladder carcinoma; MCF7 breast carcinoma; Raji Burkitt lymphoma; HT-1080 fibrosarcoma; and G-401 Wilms' tumor cell lines. These data are consistent with other results obtained by Northern and Western blot and immunoprecipitation techniques, indicating diminished PIC1 expression in cancer cells especially those harboring mutated p53, or human papillomavirus E6 oncoproteins which abrogate p53 activity. PIC1 gene expression was absent in the Molt-4 T-lymphoblastic leukemia cell line with a previously documented alternatively-spliced p53 transcript translating into p53 protein truncated at the carboxyl terminus. It is proposed that this aberrant p53 interferes with the binding of wild-type p53 and other transcription factors to the PIC1 promoter thereby abolishing PIC1 gene expression. This Molt-4 cell line could serve as a useful experimental system for studying the interaction between p53 and other cellular factors with the PIC1 gene. Single strand conformation polymorphism and direct cycle DNA sequencing analyses demonstrated a PIC1 variant (with an AGC to AGA substitution at codon 31 culminating in a serine to arginine replacement) in Mahlavu, PLC/PRF/5, SiHa, A549 and Raji cell lines. The higher proportion of the PIC1 variant in cancer cell lines (5/13 or 38%) compared with normal individuals (14%), coupled with differences between the predicted secondary structures of the normal and variant PIC1 proteins merit further investigations to elucidate the biological significance of this variant. PMID- 21556615 TI - Expression of timp-1, timp-2, 72-kda and 92-kda type-iv collagenase transcripts in human astrocytoma cell-lines - correlation with astrocytoma cell invasiveness. AB - Malignant astrocytomas are highly invasive neoplasms which infiltrate diffusely into regions of normal brain. As evidence to support one mechanism by which tumor cells are known to invade, we have previously shown that astrocytoma cell lines secrete a variety of matrix metalloproteinases (MMPs) and metalloproteinase inhibitors (Apodaca et al: Cancer Res 50: 2322-2329, 1990). In the present study we determined the expression of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, 72-kDa and 92-kDa type IV collagenase transcripts among human astrocytoma cell lines. In addition, we sought to correlate MMP and TIMP transcript levels with astrocytoma invasiveness. RNA from seven well characterized human astrocytoma cell lines was extracted before and after phorbol ester treatment and Northern blot analyses were performed using cDNA probes for the MMPs and TIMPs. All astrocytoma cell lines and normal human leptomeningeal cells were tested for their relative invasive potential using an in vitro invasion assay. There was variable expression of MMP and TIMP transcripts among astrocytoma cell lines. SF 188 was the only cell line to demonstrate a relative abundance of 72- and 92-kDa type IV collagenase transcripts over TIMP-1 and TIMP-2 transcript levels. Interestingly, this cell line was the most highly invasive in the in vitro invasion assay system. U 343 MG-A demonstrated relative abundance of TIMP-1 and 2 transcripts over 72- and 92-kDa type IV collagenase transcripts and was the least invasive cell line. Prior treatment of astrocytoma cell lines with phorbol ester upregulated TIMP-1 and 92-kDa type IV collagenase transcripts, but not TIMP 2 and 72-kDa type IV collagenase transcripts. We conclude that there is only partial correlation between MMP and TIMP transcript levels and in vitro cell invasiveness among the astrocytoma cell lines studied. Our analysis has led to the identification of an astrocytoma cell line, SF-188, which appears to overexpress the 72-kDa and 92-kDa type IV collagenase transcripts relative to low level TIMP-1 and TIMP-2 transcripts. This particular cell line will continue to be of considerable value in dissecting some of the molecular mechanisms involved in astrocytoma cell invasion. PMID- 21556616 TI - Perioperative heparin-therapy inhibits late death from metastatic cancer. AB - Low-dose heparin prophylaxis reduces postoperative death from fatal pulmonary embolism and its long-term anti-cancer effect has now been assessed in a retrospective study of 1250 patients, 336 of whom (30%) underwent operation for cancer. There was a striking reduction in three year mortality amongst those patients who received low dose heparin compared to unteated controls (7.6% vs. 12.5%, P=0.005). Death from disseminated malignancy was halved (9.2% vs. 21.4%). The mechanism remains unclear, but may reflect either the antithrombotic actions of heparin or a direct antitumour cell effect. PMID- 21556617 TI - Relationship between response rate and median survival in patients with advanced nonsmall cell lung-cancer - comparison of onconase(r) with other anticancer agents. AB - The role of systemic cytotoxic therapy for the treatment of advanced non-small cell lung cancer (NSCLC) remains controversial. The response rate (RR) and the median survival time (MST) are the two most frequently used parameters for the assessment of efficacy of the anti-cancer therapies. The relationship between the previously reported RRs and MSTs from published chemotherapy trials in patients with advanced NSCLC was examined using linear regression analysis. The MST of the thirty patients with advanced NSCLC treated with ONCONASE (ONC) as a single agent was 7.7 months which compared favorably with the MSTs of patients treated with a variety of chemotherapeutic regimens either as single agents or combinations, as well as placebo and supportive care only. Moreover, the toxicity profile of ONC compared favorably to the profiles of other chemotherapy regimens. ONC had a favorable impact on the overall MST, including patients with stage IV disease, patients with poor performance status, and patients previously treated with radiotherapy and chemotherapy. The MST of 5 patients who had a stabilization of previously progressive disease was 9.3 months. Based on its positive impact on the MST, ONC appears to have a single agent activity in patients with advanced NSCLC, and it should be further investigated, particularly in combination with synergistic drugs, in concurrently controlled and prospectively randomized clinical trials. The duration and the quality of survival should be considered as the most meaningful parameters in assessing clinical efficacy of anti-cancer agents. PMID- 21556618 TI - Presence of epstein-barr-virus in breast-carcinoma. AB - Epstein-Barr virus (EBV) is associated with human B cell lymphomas, but is also commonly found in the epithelial cells of undifferentiated nasopharyngeal carcinoma. As recent reports have also suggested a wider distribution particularly in lymphoepithelioma-like carcinomas, we investigated its presence in breast carcinomas of varying histology. Using PCR amplification of DNA extracted from paraffin sections, we found that EBV was present in 15/28 breast cancers. It seemed to be more prevalent in Paget's disease and in medullary carcinomas and less frequent in the invasive ductal cancers that constitute about 75% of breast carcinomas. This was confirmed by analysis of purified DNA extracted from a further 48 invasive ductal carcinomas: 19 were EBV positive. Latent membrane viral protein was detected by immunohistology in scattered epithelial tumour cells. The vast majority of lymphoid cells were unstained. A rough approximation indicates that there could be up to several hundred copies of the EBV genome per mu g of extracted tissue DNA. We were unable to demonstrate the presence of RNA by in situ hybridisation using fluorescein labeled EBER oligonucleotides but this may be due to technical reasons. No EBV DNA was found using PCR in the 12 normal breast specimens examined. These initial results suggest that the EBV genome is present in certain breast epithelial malignancies. PMID- 21556619 TI - The selective-inhibition of vascular-permeability factor (vpf) expression in ovarian-carcinoma cell-lines by gonadotropin-releasing-hormone (GnRH) agonist. AB - GnRH agonists have been found to be clinically useful in several hormone sensitive conditions, including cancer. However, there is controversy regarding a direct action of these agents on the pathologic tissue of a given disease process, in particular, tumors. In this study, we examined the effects of D Trp(6) -LHRH, a potent GnRH agonist, on the expression of an increasingly important angiogenesis factor, VPF (vascular permeability factor)/VEGF (vascular endothelial growth factor). Ovarian carcinoma cell lines exposed to D-Trp(6) LHRH in culture demonstrated a reversible inhibition of VPF mRNA expression and a parallel decrease in the endothelium-specific mitogenic activity of the conditioned media from these treated cultures. This study reports a novel activity of a GnRH agonist and provides a starting point to investigate the in vivo anti-angiogenic properties of GnRH peptide analogs. PMID- 21556620 TI - High-dose chemotherapy in the treatment of breast-cancer. AB - Dose is a critical determinant of the efficacy of chemotherapy. The dose response curve for virtually all anticancer agents is steep in both in vitro and in vivo experimental studies. However the application of the steep dose-response curve in the clinic has been troublesome for many years because of dose limiting bone marrow toxicity. Hematopoietic support with growth factors and/or peripheral stem cell transplantation now offers new possibilities to push doses up to levels where non-myeloid toxicity becomes dose limiting. Several trials applying high dose chemotherapy with stem cell support have been conducted in breast cancer. They showed a higher response rate and a higher percentage complete remissions compared with conventional treatment. Follow-up is short for most studies but some long-term complete remissions are reported. Developments in this field are reviewed. PMID- 21556621 TI - Computer-assisted quantitative description of chromatin pattern and DNA-ploidy level in ependymomas and choroid-plexus tumors. AB - Computer-assisted microscope analyses of Feulgen-stained nuclei were used to quantitatively describe the chromatin pattern and to determine the DNA ploidy level in a series of 70 cases including 46 low-grade (benign) ependymomas, 17 anaplastic (malignant) ependymomas, 3 choroid plexus papillomas (benign) and 4 choroid plexus carcinomas (malignant). While the quantitative description of the chromatin pattern was carried out by means of 14 morphonuclear parameters relating to geometric, densitometric and textural features, the DNA ploidy level was assessed by means of DNA histogram typing. Of these 70 cases, proliferative activity was assessed on 24, for which tissue was still available after the digital cell image analyses. This assessment was carried out by means of the determination of the immunohistochemical MIB-1 staining relating to the Ki-67 antigen. The results show that the determination of morphonuclear characteristics did not make it possible to distinguish between ependymal and choroid plexus tumours. Furthermore, neither the computer-assisted microscope analyses of morphonuclear characteritics nor the DNA ploidy level determination made it possible to distinguish between low-grade and anaplastic ependymomas. In sharp contrast, the determination of proliferative activity by means of the Ki-67 antigen immunohistochemical staining enabled such a distinction to be made. PMID- 21556622 TI - Similarity of the DNA-damage responsiveness and growth-suppressive properties of waf1/cip1 and gadd45. AB - The cellular responses to genotoxic stress are complex involving both p53 dependent and independent mechanisms. In the case of the GADD genes, many stresses eliciting growth arrest have been shown to induce these genes in a coordinate fashion regardless of p53 status, while the ionizing radiation response (IR) of GADD45 has been found to be strictly p53-dependent. In the current study, the response of GADD45 was compared to the p53-regulated genes WAF1/CIP1 and MDM2 in a panel of human lines with known p53 status and also in mouse embryo fibroblasts where one or both alleles of p53 had been deleted. After IR, all 3 genes showed very similar transcriptional responses as measured by rapid increases in mRNA. in a p53-dependent manner. Like GADD45, the WAF1/CIP1 induction by IR can be enhanced by the radiosensitizer iododeoxyuridine, and provides further evidence that DNA strand breaks can act as a signal for activation of the p53 pathway. In addition, caffeine, which blocks IR cell-cycle checkpoint activation, reduced IR induction for both genes. Unlike the case for IR, only WAF1/CIP1 showed a consistent similarity to GADD45 to DNA base-damaging agents, where appreciable induction occurred in cells regardless of p53 status. The similarity between WAF1/CIP1 and GADD45 also extended to their growth suppressive properties, and a combination of expression vectors for these genes suppressed growth appreciably more than either alone. A reasonable interpretation of these results is that growth suppression after DNA damage by either p53 dependent or independent pathways is mediated by the combined action of multiple downstream effecters including WAF1/CIP1 and GADD45. PMID- 21556623 TI - Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN alpha(2b). AB - Several forms of immunotherapy are apparently effective in inducing clinical remissions in metastatic renal cancer, but their benefit on survival times have not been demonstrated so far. The present analysis was designed to assess the effects of concomitant application of renal cancer vaccine and cytokines on DTH skin responses to tumor cell challenge, clinical remissions and patients survival. 40 patients with advanced RCC, all with distant metastases in at least one organ, were entered after nephrectomy into a protocol involving multiple vaccinations with Newcastle disease virus (NDV)-infected autologous irradiated tumor cells, with subsequent repetitive 3 bi-weekly cycles of low dose interleukin-2 (r-IL-2) and interferon-alpha(2b)/rIFN-alpha(2) s.c. (1.5 million r IL-2 Cetus units/m(2)/day and 3 million IFN-alpha IU/m(2)/day). In a pilot study the coadministration of a supplement of r-IL-2 proved to be important for augmentation of DTH responsiveness upon tumor cell challenge. Patients with aneuploid tumors vaccinated without r-IL-2 apparently developed an anergy to the vaccine throughout vaccination. In the main study, of the 40 evaluable RCC patients, 5 exhibited a complete response (CR), 6 displayed a partial remission (PR), 12 showed stable disease (SD, median 25 months) and 17 tumor progression. Survival distribution analysis predicted for all patients with stable disease a median survival of 31 months while CR+PR patients had a median survival >4 years. 23/40 (57.5%) patients (CR, PR and SD) appear to have a significant survival advantage compared to the patients with progressive disease during the treatment period and to a historic reference group. Further data analysis revealed that the number of metastatic sites was predictive of survival characteristics (p<0.05). A marked increase during 3 vaccinations of DTH anti-tumor reactivity predicted a survival advantage (35 vs 14 months), a correlation that was also significant by the Wilcoxon test. While the multi-modality treatment with autologous tumor vaccine and s.c. administration of IL-2 and IFN-alpha appears to be effective in advanced RCC, a randomized trial (ASI-IL-2/IFN-alpha vs IL-2/IFN-alpha without ASI) is now set up to help assess the role of ASI within the combined treatment regimen. PMID- 21556624 TI - P53 alterations show significant correlation with gene amplification and s-phase index in breast-cancer. AB - Correlation of p53 gene/protein alterations with incidence of oncogene amplification, a potential marker of prognosis, was evaluated in 26 fresh breast cancer samples. p53 gene was analyzed by SSCP and DNA sequencing while p53 protein status was investigated by immunohistochemistry (IH). Amplification of c erbB2/neu, c-myc, N-ras, int-2, hst, PRAD-1 and EGFR genes was studied by slot blot and in situ hybridizations. p53 alterations were found in 31% cases by SSCP and 42% by IH; gene amplification was detected in 27% cases. p53 gene alterations correlated significantly with gene amplification (p=0.006) and also with higher S phase index (p=0.026), aneuploidy (p=0.026) and negative progesterone receptor status (p=0.043). PMID- 21556625 TI - Activation of C-myc, C-Neu and int-2 oncogenes in the transformation of the human breast epithelial-cell line mcf-10f treated with chemical carcinogens in-vitro. AB - Genetic alterations of the c-myc, c-neu and int-2 oncogenes have been reported in human breast cancer. In order to determine if these oncogenes are activated at different stages of breast cancer progression, we are using an in vitro system in which human breast epithelial cells (MCF-10F) have been transformed with benzo(a)pyrene(BP) or dimethylbenz(a)anthracene (DMBA). DMBA-treated cells gave rise to clones D3 and D3-1, BP-treated cells gave rise to clones BP1 and BP1-E. BP1-E cell line, derived from BP1 cell line, was tumorigenic in SCID mice. Southern blot analysis detected gene amplification and rearrangement of the int-2 oncogene in BP1 and BP1-E cells, but no changes were detected in D3 and D3-1 cells. Amplification of c-neu gene was only observed in BP1 and BP1-E cell lines. Neither amplification nor rearrangement was detected for the c-myc gene. At the transcriptional level, Northern blot analysis showed that int-2 mRNA was increased 1.5, 1.8, 1.3 and 2.0-fold in the BP1, BP1-E, D3 and D3-1 cell lines respectively. c-neu mRNA was increased 8.0-fold in BP1 and BP-1E cells and c-myc mRNA was increased 1.5-fold in D3 cells, but no changes were detected in the other cell lines. The data indicate that BP treatment induces changes both at the genomic and transcriptional level. However, none of the differences explain the tumorigenic properties of the BP1-E cell line. DMBA treatment induces changes that are only reflected at transcriptional level for the two oncogenes studied. Whereas none of these oncogenes can be considered the driving force in the expression of the tumorigenic phenotype, the interaction among them or with other oncogenes in the expression of the transformation phenotype cannot be ruled out. PMID- 21556626 TI - Lh-rh and its antagonist cetrorelix inhibit growth of jar human choriocarcinoma cells in-vitro. AB - The effects of luteinizing hormone-releasing hormone (LH-RH), and LH-RH antagonist Cetrorelix, (SB-75, [Ac-D-Nal(2)(1),D-Phe(4-Cl)(2),D-Pal(3)(3),D Cit(6),D-Ala(10)]LH-RH) on cell growth and the production of hCG and cAMP in JAR human choriocarcinoma cells were examined in vitro. Both LH-RH and its antagonist SE-75, at 1 mu g concentration, inhibited the growth of JAR cells in cultures. When SE-75 (1 mu M) was given in combination with different doses (0.1 nM to 1 mu M) of LH-RH, it was found that 0.1 nM LH-RH nullified the inhibitory effect of SE 75 on cell growth, however, the 100 nM and 1 mu M doses of LH-RH caused a greater inhibition of cell proliferation than SE-75 alone. Incubation with LH-RH slightly increased the hCG production and the cAMP release in the cultured tumor cells. SE 75 alone or in combination with LH-RH reduced the hCG as well as the cAMP release from JAR human choriocarcinoma cells; however, the magnitude of the decrease was smaller for hCG than for cAMP. The effect of different doses of LH-RH, administered simultaneously with 1 mu M SE-75, on the cAMP production, was similar to that on cell growth: 0.1 nM LH-RH in combination with 1 mu M SE-75 caused a smaller inhibition of cAMP than SE-75 alone. However, when LH-RH was given at concentrations from 1 nM to 1 mu M together with 1 mu M SE-75, we observed a greater inhibition of cAMP than after SE-75 alone. The presence of low affinity LH-RH receptors on JAR cells was also demonstrated and competitive binding studies showed that agonist D-Trp(6)-LH-RH and antagonist SE-75 could bind to these receptors. Our findings provide new information on the effect of LH RH and antagonist SE-75 on the proliferation of JAR human choriocarcinoma cells and may offer a new insight on their mechanisms of action in the suppression of tumor cell growth and their influence on intracellular signal transduction pathways. Hormonal therapy based on Cetrorelix could be considered for the development of new approaches to treatment of patients with choriocarcinomas. PMID- 21556627 TI - Coexpression of C-erbb2 and int-2 oncogenes in invasive breast-cancer. AB - Invasive breast carcinomas of 19 premenopausal and 49 postmenopausal women were studied by Southern blot analysis for detection of c-erbB2 and int-2 oncogenes, and quantitation of c-erbB2 protein, p185 by ELISA. The data were correlated with the histological grade of the tumor and the patient's clinical status. Seventeen tumors (25.0%) showed genomic alteration in one or both oncogenes. c-erbB2 and int-2 amplification were expressed by 10 (14.7%) and 7 (10.2%) of the tumors respectively. c-erbB2 overexpression was found in 15 out of 68 tumors (22.1%). All tumors exhibiting amplification of c-erbB2 also showed overexpression of p185 protein, however 5 out of 15 tumors (33.3%) showing c-erbB2 overexpression did not show amplification. Rearrangement of c-erbB2 and int-2 oncogenes was observed in 4 out of 68 tumors (5.9%) and 2 of these tumors presented rearrangement of both oncogenes. A significant positive correlation was found between c-erbB2 amplification and p185 protein overexpression, and c-erbB2 and int-2 amplification. Oncogene alterations were more frequently detected in tumors with high histological grade, but no correlation was found with patient's age, menopausal or lymph node status. PMID- 21556628 TI - Up-regulation of a tumor-associated antigen (tag-72) by interferon-alpha and interferon-gamma in patients with cutaneous breast-cancer recurrences. AB - Up-regulation of a tumor-associated antigen (TAA) TAG-72 was investigated immunohistochemically in skin recurrences of 10 breast cancer patients treated with intralesional injections of natural interferons (nIFNs) alpha and gamma. Up regulation was assessed by comparing the immunoreactivity of pre-IFN and post-IFN specimens stained with monoclonal antibodies (MoAbs) B72.3 and CC49 at near end point dilutions. Varying degrees of enhanced immunoreactivity were detected in IFN-injected and non-IFN-injected lesions except in 1 patient with high constitutive expression of TAG-72 and another patient not expressing TAG-72. Thus, IFN-mediated up-regulation of TAG-72 can occur in patients whose breast cancer cells express this TAA, independently of the initial levels of antigenic expression. PMID- 21556629 TI - Combined effects of lonidamine and tamoxifen in human breast-cancer cell-lines. AB - The antiproliferative activity of lonidamine, alone or in combination with the antiestrogen tamoxifen, was studied on estrogen receptor-positive and estrogen receptor-negative human breast cancer cell lines. Lonidamine by itself induced an appreciable cytotoxic effect on all five cell lines, with 50% inhibitory concentrations (IC50) ranging from 19.5 to 54 mu M. The combination of lonidamine and tamoxifen, simultaneously administered or in sequence, provided additive effects on the estrogen receptor-negative MCF/DX cell line and a sub-additive interaction in the estrogen receptor-positive MCF7 cells. The negative interference between the two drugs could be ascribed to the marked reduction induced by lonidamine in the expression of estrogen receptor in the MCF7 cells. PMID- 21556630 TI - 2 gene families of mareks-disease virus (mdv) with a potential role in tumor induction in chicken (review). AB - Marek's disease virus (MDV) is one of the most oncogenic herpesviruses and the only cancer virus that has a successful vaccine. Based on the short-latency and polyclonal nature of the tumors, it is likely that MDV encodes its own oncogenes. Recent studies have provided insights into possible MDV genes involved in oncogenesis. We describe the characterization of two gene families encoded by the BamHI-H and I-2 fragments. The BamHI-H and I-2 fragments, located contiguously in the IR(L) region, are unique to oncogenic (serotype) MDV and consistently expressed in MDV-transformed tumors and T-cell lines. The structural alteration of the BamHI-H fragment, specifically the expansion of a 132 bp repeat, has been correlated with the attenuation of the oncogenicity of MDV. Several open-reading frames, some resulting from alternative splicing, can be identified. One of the open-reading frames, BHa, encodes a 7 Kd polypeptide. BHa shares limited homology with a T-cell lymphoma oncogene TLM and stimulates extended growth of chicken embryo fibroblasts, when transfected into the cell. The other gene implicated in latency or oncogenesis is Meg whose coding sequences span portion of the BamHI-I 2 and the Q(2) fragment. Meq has an interesting structure, resembling a chimera between Jun/Fos oncoproteins and WT-1 tumor suppressor protein. It contains a bZIP (basic leucine zipper) domain and a long proline-rich domain. The proline domain has trans-activating function, whereas the bZIP domain allows Meq to dimerize with a variety of transcriptional factors and expands the enhancer repertoire it acts on. As neoplastic transformation usually requires the complementation of multiple oncogenes, BHa and Meq could be two of the proteins participating in this process. PMID- 21556631 TI - Free-radicals dependent and independent pathways of cddp-mediated cytotoxicity and apoptosis in ovarian tumor-cell lines. AB - Cis-platinum (CDDP) is a chemotherapeutic drug widely used alone or in combination with other drugs in the treatment of cancer. However, many tumors become resistant to CDDP and the mechanisms of resistance are complex. The present study investigated the role of free radicals in CDDP-mediated cytotoxicity and apoptosis. Four human ovarian cancer cell lines were chosen for the study: two lines, 222 and A2780, are sensitive to CDDP and two lines, AD10 and C30 are resistant to CDDP. The importance of free radical formation was tested by the use of an inhibitor, 2,6 di-tert-butyl-4-methoxy phenol (BHA), that inhibits the production of free radicals and detoxifies free radicals. Cytotoxicity was assessed by the MTT assay and apoptosis assessed by flow cytometric analysis of DNA hypoploidy. Three of the 4 cell lines, 222, AD10, and C30, were completely inhibited by BHA in CDDP-mediated cytotoxicity. The CDDP sensitive A2780 cell line, however, was not inhibited by BHA, even at high non toxic concentrations of BHA. The DNA analysis for apoptosis paralleled the findings obtained in the cytotoxicity assay. In order to rule out that the A2780 cell line was not reactive to BHA, VP-16 mediated cytotoxicity was examined. All four cell lines were sensitive to VP-16 and all four were inhibited by BHA. In contrast, there was no detectable inhibition by BHA of actinomycin-D-mediated cytotoxicity in all four lines tested. Overall, the findings demonstrate that either free-radical dependent (CDDP, VP-16) or free radical-independent (CDDP, actinomycin-D) pathways of cytotoxicity and apoptosis are utilized by different drugs. Further, a single agent like CDDP can mediate killing by both a free radical-dependent and by a free-radical independent pathway. Therefore, new agents that are developed to reverse resistance by a particular drug must take into consideration alternative cytotoxic pathways mediated by the same drug. PMID- 21556632 TI - Absence of stimulatory effect of g-csf on the growth of human sarcoma-cells. AB - The Colony-Stimulating Factors (CSFs) are undergoing clinical trials for their ability to stimulate the regeneration of bone marrow in patients receiving anticancer chemotherapy. However, the reported effects on the growth of tumor cell lines of different derivations, including osteosarcoma, raise the possibility that the use of these cytokines may induce proliferative effects also in residual tumor cells. In this study, we have used a panel of 12 human osteosarcoma (2 cell lines and 10 primary cultures) and 7 Ewing's sarcoma cell lines (5 cell lines and 2 primary cultures) to evaluate the presence of the G-CSF receptor by RT-PCR and the effects of recombinant Human (rHu) G-CSF on their in vitro growth ability. RT-PCR did not reveal the presence of G-CSF receptor band in any of the osteosarcoma or Ewing's cell lines examined. Moreover, after exposure to rHuG-CSF, no significant stimulatory or inhibitory effects were observed in any of the cell lines. Therefore, G-CSF may be safely used to stimulate marrow regeneration after high-dose chemotherapy both in osteosarcoma and in Ewing's sarcoma. PMID- 21556633 TI - Of/Lb collagen promotes chemoinvasion of breast-cancer cells and directs epithelial-cell migration into granulation-tissue of experimental dermal wounds. AB - OF/LB collagen is a recently described once-fetal form of collagen, with laminin binding properties, composed of three alpha(1)(I)-sized chains, one of which displaying an unusually acidic pI. This collagen appears able to direct the migration of breast cancer cells through Matrigel, and of injury-activated epithelial cells into the underlying granulation stromal tissue. The effect exerted by OF/LB collagen in vitro appears preferentially linked to its acidic chain. The data reported strongly support the hypothesis that the presence and accumulation of OF/LB collagen in cancer may play a fundamental role in the invasive growth. PMID- 21556634 TI - Influence of chemotherapeutic-agents on the proliferation of capillary endothelial-cells and tumor angiogenesis in murine bladder-cancer. AB - The current studies investigated the potential of conventional chemotherapeutic agents to inhibit the proliferation of capillary endothelial cells and to affect tumor angiogenesis using a murine bladder cancer model. Endothelial cell lines were established from the skin and used for an in vitro target. The anti angiogenesis activity was assessed by an i.d. assay. Among the eight agents examined, adriamycin, 4-hydroperoxycyclophosphamide, and methotrexate preferentially inhibited the cell proliferation. However, these agents showed no influence on tumor angiogenesis. In contrast, mitomycin C, which was less cytotoxic to endothelial cells in vitro, showed a significant anti-angiogenesis activity. The data suggest that certain chemotherapeutic agents had anti angiogenesis activity distinct from cytotoxicity. PMID- 21556635 TI - Influence of retrovirally transduced human tumor-necrosis-factor-alpha on the expression of C-myc, k-ras, C-jun, p53, tgf-alpha, and cea in human colon carcinoma cell-lines. AB - Northern slot blot hybridization and immunohistochemical staining were applied for the characterization of tumor necrosis factor alpha (TNF)-transduced human colon carcinoma cell lines. A significant decrease in the CEA-specific mRNA and protein was observed in TNF-transduced tumor cells LS174T and LoVo while other probes (c-myc, K-ras, c-jun, p53, TGF alpha) as well as anti-K-ras- and anti-p53 antibodies failed to detect differences between cytokine-transduced and parental tumor cells. PMID- 21556636 TI - Weekly Cisplatin induction chemotherapy in high-risk cervical-cancer patients with bulky tumor - a phase-ii study. AB - In this study we evaluated efficacy and toxicity of a neoadjuvant chemotherapy regimen before radiation therapy or surgery in high-risk cevical cancer patients. Between January 1988 and July 1993, 37 out of 40 consecutive patients with bulky cervical carcinoma (>40 mm) received chemotherapy consisting of six (range 4-9) weekly courses of cisplatin (1 mg/kg), followed by radical surgery and/or radiotherapy. Thirty-six patients completed the planned sequence of treatment. Overall response rate was 65% after induction chemotherapy (complete 0% and partial 65%) and 73% (complete 57% and partial 16%) after definitive treatment. After a median follow-up of 23 (range 4-61) months the median duration of response was 29, 19 and 11 months for complete partial and non-responders respectively. Toxicities from induction chemotherapy were mild to moderate, reversible and tolerable and did not affect the subsequent application of the definitive treatment. The proposed cisplatin neoadjuvant chemotherapy regimen gave positive results in a good number of cases with low toxicity and without interfering with the definitive radio-surgical treatment of this group of high risk patients. The number of cisplatin courses for best effect remains to be established. PMID- 21556637 TI - Loss of Fatty-Acid delta(6) desaturating ability in human mammary epithelial cells that express an activated C-ha-ras oncogene. AB - The synthesis of essential fatty acids (EFAs) that have been shown to inhibit breast cancer cell growth in vitro and tumor growth in animals requires desaturation at C-6 of linoleic or alpha-linolenic acid. This observation, combined with reports that many tumors and tumor cell lines are deficient in Delta(6) desaturation and/or contain low levels of 6-desaturated EFAs, has led to the suggestion that loss of Delta(6) desaturating ability is relevant to the process of malignant transformation. This study was undertaken in search of direct evidence that malignant transformation of mammary epithelial cells alters EFA metabolism. We used two cell lines derived from the spontaneously immortalized human mammary epithelial cell line MCF-10A and expressing either the c-Ha-ras protooncogene (MCF-10AneoN) or an activated c-Ha-ras oncogene (MCF 10AneoT), and a cell line immortalized by transfection of human mammary epithelial cells with SV40 T antigen. We compared these cell lines in terms of ability to convert EFAs (30 mu M) to other EFAs of the same family. MCF-10AneoT cells lose the ability to perform Delta(6) and Delta(4) desaturations, whereas MCF-10AneoN cells and the SV40 T antigen-transformed cell line do not. No significant changes in growth response to culture with 6-desaturated EFAs were noted for MCF-10AneoT cells compared with MCF-10AneoN and parental MCF-10A cells, suggesting that FA metabolism alone cannot account for the effects of EFAs on the growth of neoplastic and non-neoplastic mammary epithelial cells. PMID- 21556638 TI - Preparation of mouse-human chimeric antibody against pancreatic cancer-associated mucin. AB - A murine monoclonal antibody, designated Nd2, was generated using a purified mucin from the human pancreatic cancer cell line SW1990 as the immunogen. Administration of Nd2 into the patients with pancreatic cancer has shown that Nd2 is of clinical use for in vivo diagnostics of pancreatic cancer. In this study, starting with a previously established hybridoma producing Nd2, we have established a transfected cell line expressing a recombinant chimeric Nd2 composed of mouse-derived antigen-binding variable regions and human-derived constant regions. The chimeric Nd2 was shown to bind purified mucin from SW1990 cells with the same dose-response curve as the original Nd2. Immunohistochemical experiments have shown that the reactivity of the chimeric Nd2 in normal and malignant pancreatic tissue is also the same as that of the original Nd2. Replacement of a substantial portion of the mouse protein makes this chimeric Nd2 more promising for clinical application than the original mouse-derived Nd2 because its antigenicity is expected to be reduced. PMID- 21556639 TI - P53 overexpression correlates with proliferative activity and prognosis in carcinomas of the pyriform sinus. AB - p53 overexpression and proliferative activity were investigated in 28 squamous cell carcinomas of the pyriform sinus of the hypopharynx prior to therapy, using DO1 and MIB-1 monoclonal antibodies in routinely processed biopsies. MIB-1 scores were associated with tumour histological grade (35.4% for grade 3 versus 23.8% for grade 2 cases; p=0.008) and survival (the median of survival was 23 months for cases with MIB-1 scores less than or equal to 33.8% but 11 months only for cases with MIB-1 scores >33.8%; p<0.001). p53 scores were associated with tumour histological grade (56.5% for grade 3 versus 37.1% for grade 2 cases; p=0.02) and survival (median of survival 20 months for cases with p53 scores less than or equal to 56.2% versus 11 months for cases with p53 scores >56.2%; p=0.002). Tumour histological grade was also correlated with prognosis (median of survival 50 months for grade 2 versus 14 months for grade 3 cases; p=0.03). In the multivariate analysis, only MIB-1 (p=0.001) and p53 scores (p=0.003) had an independent prognostic significance. A linear relationship between p53 and MIB-1 scores was observed (r=0.54; p=0.012). With the limitation due to the small number of cases, our findings indicate that p53 overexpression correlates with proliferative activity and survival in squamous cell carcinomas of the pyriform sinus, and suggest the use of p53 and MIB-1 immunostainings in the pretherapeutic assessment of the tumour aggressiveness. PMID- 21556640 TI - Vascular endothelial growth-factor expression and angiogenesis in nonsmall cell lung carcinomas. AB - Vascular endothelial growth factor (VEGF), a secreted endothelial-specific growth factor, and microvessel density was examined in 204 primary non-small cell lung carcinomas. The expression of VEGF was evaluated by immunohistochemical staining using an anti-VEGF antibody. Positive staining was obtained in 125 out of 204 cases (61%). Tumor vascularity was quantitatively assessed by microvessel counting after staining with the endothelial-specific marker factor VIII. The mean microvessel count for all patients was 9.6+/-10.4. Expression of VEGF was closely associated with increment of microvessel density. Postoperative follow-up of patients demonstrated a trend that survival time of patients with VEGF positive tumors was worse than that of patients with VEGF-negative tumors. In contrast, microvessel density was not a prognostic factor. PMID- 21556641 TI - Inhibition of experimental metastasis of human breast-carcinoma cells in athymic nude-mice by anti-alpha(5)beta(1) fibronectin receptor integrin antibodies. AB - We have investigated the role of the human alpha(5) beta(1) fibronectin receptor integrin in experimental metastasis. Treatment of human MDA-MB-231 breast carcinoma cells with monoclonal antibodies specific for alpha(5) or beta(1) integrin subunits prior to injection into the tail veins of 7 to 9 week old athymic nude mice significantly decreased the median number of lung colonies that were formed. In contrast, treatment of the cells with monoclonal antibodies specific for the alpha(2) subunit had no significant effect. In vitro, the anti alpha(5) and the anti-beta(1) monoclonal antibodies both strongly inhibited breast carcinoma cell adhesion to fibronectin, while only the anti-beta(1) monoclonal antibody inhibited adhesion to laminin. In a Boyden chamber invasion assay, the anti-beta(1) antibody almost completely inhibited invasion of the breast carcinoma cells through an artificial Matrigel basement membrane. The anti alpha(5) monoclonal antibody inhibited in vitro invasion approximately 30%, only if fibroblast conditioned medium was present as a chemoattractant. Cell migration on fibronectin could be inhibited by both the anti-alpha(5) and the anti-beta(1) monoclonal antibody. These results indicate that the alpha(5) beta(1) integrin fibronectin receptor on MDA-MB-231 human breast carcinoma cells plays an important role in experimental hematogenous metastasis and may function in this process by a combination of mechanisms, including tumor cell attachment to fibronectin and fibronectin-directed extravasation of tumor cells into the target organ. PMID- 21556642 TI - Primary organ-culture of nonneoplastic and neoplastic thyroid-tissue as multicellular spheroids. AB - Biopsy specimens from 5 papillary thyroid carcinomas (PC), 2 lymph node metastases (LM) from PC, 3 colloid goitres (CG) and 7 normal (N) thyroid tissue were maintained as three-dimensional structures in agar overlay culture for up to 6 weeks. This organ culture method provides a system that maintains the cellular complexity present in the original tissue, including the stromal elements. Organotypic cultures with a well defined surface architecture were obtained. Follicles present in the spheroids maintained a polarized epithelial cell layer. Immunohistochemical staining showed thyroglobulin expression in most spheroids after two weeks of culture. Proliferating cells were also observed after the same time period evaluated by proliferation cell nuclear antigen (PCNA) immunostaining. The spheroids obtained from one of the papillary carcinomas and the corresponding lymph node metastasis increased in volume size during the first three weeks of culture while in the other cases volume decreased. The proportion of connective tissue increased in most of the spheroids during the culture period and a partial collapse of follicles was observed in parallel. Papillary structures were observed in spheroids from papillary carcinomas and lymph node metastases. Our data indicate that viable organotypic spheroid cultures can be obtained and propagated in vitro from thyroid tissue. Such a system has a potential use for studying normal biological functions of thyroid tissue in vitro and this method may be of special value in studying mechanisms of invasive growth as well as effects of therapy on normal and neoplastic tissue taken from individual patients. PMID- 21556643 TI - Synergism between growth-factors in the control of glioma cell-proliferation, migration and invasion in-vitro. AB - Gliomas constitute more than 50% of primary brain tumours in man. Perhaps the most important hallmark of these tumours is their diffuse invasion of the normal brain structures. The biological factors involved in the control of both their proliferation and invasion are, however, not well known. We studied the expression of receptors for epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), and transforming growth factor beta-1 (TGF-beta 1) in low grade astrocytoma (IPNT-H)-, grade III astrocytoma (IPSB-18)-, and glioblastoma (IPRM-5)- derived cell lines. The effects of EGF, bFGF, PDGF, and TGF-beta 1 on proliferation, migration, and invasion in vitro were also investigated. When tested individually, EGF, bFGF and PDGF, were found to differentially stimulate proliferation, motility and invasion of the cell lines examined. When combined, these three growth factors acted synergistically to stimulate these biological properties. In addition, TGF-beta 1 exhibited positive and negative effects on the mitogenic action of the other growth factors in IPNT-H cells but inhibited their activity in IPSB-18 and IPRM-5 cells. Moreover, TGF-beta 1 was found to modulate negatively and positively the migration and invasion promoting action of the other growth factors in IPNT-H and IPSB-18 cells, while it strongly potentiated this action in IPRM-5 cells. These results suggest that all the growth factors examined may play key roles in the control of the biological properties of human glioma cells in vitro. Together with our findings that TGF-beta 1 is overexpressed in human glioblastoma in vivo, these results also suggest that co-operation between growth factors and TGF-beta 1 may be of central importance in tumour progression of gliomas. PMID- 21556644 TI - Rodent p53 suppresses the transforming activity of the activated Neu oncogene by modulating the Basal promoter activity of Neu. AB - The rat neu oncogene encodes a dominant transforming oncogene. The mouse wild type p53 suppresses the transforming activity of the neu oncogene while different p53 mutants demonstrate varying ability to repress neu-induced transformation. Suppression of neu-transforming activity is due to inhibition of transcription. Deletion analysis of the rat neu promoter shows that p53 represses the basal promoter activity of neu. Therefore, rodent p53 suppresses the transforming potential of neu by inhibiting transcription from the basal promoter of neu. PMID- 21556645 TI - Carcinoembryonic antigen in the diagnosis of lung-cancer using bronchoalveolar lavage - a comparative-study with healthy-subjects, chronic-bronchitis, respiratory-infections and interstitial pulmonary-diseases. AB - The use of serum CEA values in the prognosis and in monitoring the course of lung cancer is well accepted. However, the main problem presented by using serum CEA determinations for diagnosis is the lack of sensitivity. In this study, sensitivity was increased by determining CEA using bronchoalveolar lavage (BAL) of the affected lung. We studied CEA in the BAL of healthy subjects and patients with chronic bronchitis, respiratory infections and interstitial pulmonary diseases to observe if CEA could differentiate malignancies from benign pulmonary pathologies. Five groups of patients (previously described) were studied using BAL in the affected area of the patients with lung pathologies or in the middle lobe and lingula of healthy people. CEA was analyzed in the BAL using radioimmunoanalysis according to the Behring Institute recommendations. CEA levels in BAL of lung cancer patients were higher than in the other groups. No correlation was found between CEA concentrations in BAL and tumor histology. CEA studies in BAL may be useful in the diagnosis of lung cancer and in the screening of the high risk people to develop bronchial carcinoma. PMID- 21556646 TI - Establishment of a new human uterine cervical adenocarcinoma cell-line, siso, and its reactivity to anticancer reagents. AB - A human cell line, SiSo, was established from a patient afflicted with uterine cervical adenocarcinoma. The SiSo cell expresses MHC class I antigen, various kinds of adhesion molecules and tumor-associated antigens such as CA125, CEA and GA733. The secretion of CA125 antigen was markedly suppressed by anti-cancer reagents. However, their growth was not affected by any of the anti-cancer reagents tested, suggesting a discrepancy between inhibition of tumor growth and suppression of secretion of tumor-associated antigens after treatment with anti cancer reagents. The SiSo cell line will provide a tool for investigation of uterine adenocarcinoma. PMID- 21556647 TI - Effects of antisense oligonucleotides targeting k-ras expression in pancreatic cancer cell-lines. AB - The K-ras oncogene is activated in more than 75% of pancreatic cancers and represents a compelling target for therapeutic intervention. We have examined the potential of K-ras antisense oligonucleotides in human pancreatic cancer cell lines. Dose-dependent antiproliferative effects are seen, but these do not correlate with reduced K-ras levels in the treated cells. Although patterns of uptake can be altered by treatment with cationic lipids, this does not enhance antiproliferative effects nor reduce K-ras expression. The antisense approach requires considerable development before useful anti-cancer agents can emerge and alternative approaches are needed for K-ras to be a target for genetic intervention therapy for human cancer. PMID- 21556648 TI - Therapy for hepatocellular-carcinoma (review). AB - Hepatocellular carcinoma remains one of the commonest malignant tumours in the world. It usually arises on a background of hepatic cirrhosis which limits the possibility of resection or transplantation. The literature contains few good randomised trials of therapy for this common tumour. This review discusses the role of surgery and liver transplantation together with recent developments in medical therapy, namely chemoembolisation, percutaneous ethanol injection and hormonal treatment, and arrives at a consensus as to the place of these treatments in the current management of hepatoma. PMID- 21556649 TI - Alterations of mdm2 gene in x-ray transformed mouse 10t1/2 cell clones. AB - Radiation-induced malignant transformation develops by a stepwise accumulation of molecular changes including mutation, amplification or overexpression of certain genes. Amplification and/or overexpression of mdm2 may be one of several molecular mechanisms for an altered growth control leading to the transformed phenotype. In the present investigation, we examined amplification, level of expression as well as mutation of mdm2 in radiation-transformed mouse C3H 10T1/2 cell clones. None of the clones examined showed structural changes of the mdm2 gene. However, mdm2 was amplified in 8 of 30 and overexpressed in 3 of 11 independent X-ray (600 cGy) transformed 10T1/2 cell clones, as compared with nontransformed, control or ultraviolet light (UVL)-transformed clones. None of the clones showing amplification and overexpression of mdm2 were among the 9 with alterations in the p53 gene. These results suggest that although amplification of the mdm2 gene may play a role in the transformation of some 10T1/2 cells, radiation-induced malignant transformation probably arises as a consequence of genetic events that involve several different pathways. PMID- 21556650 TI - P53 and its implication in apoptosis (review). AB - The tumor suppressor protein p53 is one of the most important manipulators of the cell cycle. By interaction with targets such as WAF1/CIP1, mdm2 or GADD45 p53 functions as a negative or positive regulator of the cell cycle. After DNA damage p53 is implicated in growth arrest of cells in the G(1) phase of the cell cycle and in DNA repair and therefore p53 is regarded as a 'guardian of the genome'. Besides this protective role p53 participates in processes where cells are driven into programmed cell death. This controlled process called apoptosis is composed of a cascade of events which are dominantly influenced by p53. p53 plays a role in the initiation of cell suicide, directly or by interaction with cellular targets. A possible clinical implication of apoptosis and the implication of p53 in this process will be discussed. PMID- 21556651 TI - Both dietary calorie and fat affect the growth of transplanted mammary-tumors in riii/sa mice - the effect of calorie is more profound than the effect of fat. AB - The effects of dietary calories and/or fat on the growth of mammary tumor transplants, their expression of mouse mammary tumor virus (MMTV) and the incidence of lung metastasis were examined in RIII/Sa mice. Starting at 3-4 weeks of age, groups of female mice were fed either high isocaloric diets (16 kcal/day/mouse) containing 25% or 5% corn or fish oil or low isocaloric (10 kcal/day/mouse) diets containing 25% or 5% fish or corn oil. After one week, small pieces (2x2x2 mm) of tumor tissue, prepared from a transplantable mammary tumor, were inserted into the fourth pair of mammary glands of mice, and the mice maintained on their respective diets until sacrifice. All mice developed palpable tumors during a period of 3-4 weeks. After 12 weeks, all those mice that were assessed for tumor burden were sacrificed, tumor weight in each mouse determined, and the level of the expression of MMTV in the tumors evaluated by dot blot hybridization. Our results show that low isocalorie diets, regardless of the type or amount of fat, inhibited tumor growth by at least 60% in comparison to high isocalorie diets. However, mice fed low isocaloric diets containing fish oil were also found to produce smaller tumors (20-40%) as opposed to those mice fed similar, but corn oil containing diets. Fatty acid analyses of mammary tumors and liver tissue of mice fed corn oil and fish oil containing diets revealed that while normal and tumor tissues from both groups contained high levels of polyunsaturated fatty acids, the tissues of mice fed corn oil had the n-6, whereas the mice fed fish oil had the n-3 family of fatty acids. The levels of MMTV expression were found to be unaffected by either caloric or fat content in the diet. In a separate set of experiments, the effect of a low calorie diet on lung metastasis was determined, It was found that mice fed a low calorie diet produced significantly less metastatic lung nodules than those mice fed a high calorie diet: the mean survival time for the former group of mice was 106 days, as compared to only 71 days for the latter group of mice. In conclusion, we suggest that the amount of calories in a diet is more important than the amount or the type of fat in suppressing the growth of transplanted tumors and that a low calorie diet may also lower the incidence of lung metastasis. PMID- 21556652 TI - Distinct signaling mediates chloride secretion induced by tumor promoter bile salts and phorbol esters in human colonic cells. AB - Tumor promoter phorbol esters directly activate protein kinase C (PKC). Similarly tumor promoter bile salts activate PKC in the human colon epithelial cell line HT 29 cl.19A, as well as in platelets. Bile salts were also able to directly activate the purified brain enzyme. We designed experiments to investigate the effects of bile salts on Cl- secretion in HT-29cl.19A cell monolayers and the involvement of PKC in this process. Sodium deoxycholate (DOG) gradually evoked a slow increase of the short-circuit current (I-sc) in the Ussing chamber-mounted cell monolayers. By contrast, 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited a large increase in I-sc which rapidly plateaued. The I-sc response was representative of enhanced Cl- secretion, since it was abrogated in Cl--free medium, and was prevented by Cl- channel blocker diphenylamine-2-carbonylate as well as by bumetanide, a Na+/K+/Cl- transporter inhibitor. Sequential applications of TPA and DOC at suboptimal doses elicited additive effects. Neither DOC nor TPA increased the levels of cAMP in these cells. However DOG, at variance with TPA, increased the intracellular content of inositol trisphosphate, presumably due to triggering of the phosphoinositide pathway. From our studies and others, it is suggested that DOG-induced unspecific activation of some membrane-associated proteins, elicits a rise in Ca2+ from extracellular and internal sources which combines its effects with those due to PKC activation. PMID- 21556653 TI - New pseudononapeptide bombesin antagonists with C-terminal leu-psi(ch2n)tac-nh2 show high binding-affinity to bombesin/grp receptors on cfpac-1 human pancreatic cancer cells. AB - It has been demonstrated that bombesin/GRP antagonist D-Tpi(6),Leu(13)psi(CH2NH) Leu(14)-BN(6-14) (RC-3095) inhibits effectively the growth of pancreatic cancer and other tumors in experimental animals and in cell cultures. In an attempt to develop antagonists with still greater antitumor activity, several new pseudononapeptide bombesin/GRP antagonists containing C-terminal Leu psi(CH2N)Tac NH2 have been synthesized in our laboratory. In this study, we investigated the ability of four Leu(13)psi(CH2N)Tac(14)-BN(6-14) antagonists to inhibit the binding of bombesin to specific receptors for bombesin/GRP on CFPAC-1 human pancreatic cancer cells. Receptor binding assays were performed by incubating CFPAC-1 cells (5x10(4) cells/well) with 0.5 nM [I-125]-Tyr(4)-bombesin in the absence or presence of (1 pM to 10 mu M) unlabeled bombesin, GRP(14-27) and various antagonists for 2 h at 22 degrees C. Displacement assays showed that antagonist D-Tpi(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3910-II) with a similar structure to RC-3095, but a different C-terminal, had a binding affinity to CFPAC 1 cells 15 times higher than RC-3095. Three other antagonists, RC-3925-II, RC 3940-II and RC-3950-II contained the same C-terminal Leu psi(CH2N)Tac-NH2 as RC 3910-II, but had different N-terminal residues: D-Cpa, Hca and D-Phe, respectively. Among them, Hca(6),Leu(13)psi(CH2N)Tac(14)-BN(6-14) (RC-3940-II) showed the highest binding affinity to the receptors on CFPAC-1 cells, which was 50 times higher than that of RC-3095 or 3 times greater than RC-3910-II. Our findings suggest the merit of further investigation of pseudononapeptide bombesin/GRP antagonist RC-3940-II ind related analogs for a possible development of a new hormonal therapy for pancreatic cancer. PMID- 21556654 TI - Lack of microsatellite instability in human prostate-cancer. AB - DNA replication errors are especially frequent in repetitive DNA sequences, including microsatellites. Thus, microsatellites are sensitive indicators of the genetic instability observed in many types of human cancers, particularly colorectal cancer. We tested prostate carcinomas for the presence of microsatellite alleles not present in normal tissue from the same individuals. Analysis of 7 microsatellites in each of 30 patients revealed instability at only one microsatellite in one tumor. This level of microsatellite instability, considerably lower than that reported previously, may reflect differences in patient pools. We discuss the implications of the genetic stability of prostate cancers relative to other cancers. PMID- 21556655 TI - Altered growth-regulation of prostatic epithelial-cells by human papillomavirus induced transformation. AB - Six lines of human papillomavirus (HPV)-transformed prostatic epithelial cells, clonally-derived from transfection of three different parental cell strains, were analyzed for their ability to respond to stimulatory and inhibitory factors known to regulate prostatic cell growth. The cell lines were tested in a serum-free medium that was developed specifically for analysis of low-density growth of prostatic cells in order to mitigate any effects of autocrine factors. This medium has been used previously to characterize the growth regulatory pathways of primary cultures of prostatic epithelial cells derived from normal, benign prostatic hyperplasia (BPH), or adenocarcinoma tissues, as well as an SV40 transformed cell line (pRNS-1-1) that was derived from the same parental cell strain as four of the HPV-transformed lines used in the present study. The responses of the HPV-transformed cell lines to three essential mitogens in the medium - epidermal growth factor (EGF), bovine pituitary extract (BPE) and insulin-like growth factor (IGF) - were similar to those of primary cultures and pRNS-1-1, except that two of the HPV-transformed cell lines were IGF-independent for growth. The presence or absence of cholera toxin (CT), which acts synergistically with peptide growth factors, only mildly affected the proliferation of HPV-transformed cells, which is also true for primary cultures and pRNS-1-1. However, while hydrocortisone (HC) also has only minimal effect on the growth of primary cultures and pRNS-1-1, four of the HPV-transformed lines were very dependent on HC for growth. With regard to growth-inhibitory factors, all of the cell lines (HPV- or SV40- transformed) were insensitive to tumor necrosis factor-alpha (TNFalpha), which is a common feature of transformed cells. However, the cell lines remained sensitive to the growth-inhibitory properties of retinoic acid (RA) and transforming growth factor-beta (TGF(beta)). The HPV transformed cell lines were also inhibited by 1,25(OH)(2) vitamin D-3 [1,25(OH)(2)D-3], although pRNS-1-1 cells were not. Perhaps the most unexpected finding in our study was the apparent loss of responsiveness of all of the transformed lines to fibroblast growth factor (FGF). Alterations in FGF pathways have been described for prostatic cancer cell lines and changes in expression of FGF or receptors may be involved in prostatic carcinogenesis. Our study demonstrates that the availability of primary cultures, SV40- and HPV- transformed cell lines and a well-defined culture system will provide an opportunity to characterize the processes involved in malignant transformation of prostatic cells. PMID- 21556656 TI - Expression of activins and activin receptor messenger-rnas in lncap cells, a human prostatic adenocarcinoma cell-line. AB - An androgen-responsive human prostatic cell line, LNCaP, was examined for the expression of mRNAs encoding the inhibin/activin subunits and activin receptors as determined by reverse transcription polymerase chain reaction (RT-PCR) and hybridization. Messenger RNA of the beta A- and beta B-subunits of inhibin/activin and activin receptors I, II, and IIB were expressed in these cells. The specificity of the RT-PCR products was confirmed by DNA sequencing. However, the expression of the alpha subunit of inhibin was not observed. In addition, activin proteins were localized immunocytochemically in the cytoplasm of LNCaP cells. The expression of both activins and activin receptors in LNCaP cells suggests that activin may have an autocrine function in these cells. Since activin acts as a modulator of cell proliferation and differentiation in many biological systems and inhibin possesses antagonistic actions to those of activin, it is proposed that the proliferation of LNCaP cells may be associated with an imbalance between the expression of activins and inhibins. PMID- 21556657 TI - Serum interleukin-10 levels in patients affected with multiple-myeloma - correlation with the monoclonal component and disease progression. AB - Using a commercially available, competitive ELISA kit based on a polyclonal anti interleukin-10 antibody, serum interleukin-10 (IL-10) levels were quantified in samples of different groups of patients: 20 healthy controls (CTR), 11 monoclonal gammopathies of uncertain significance (MGUS), 17 multiple myelomas (MM), 10 cancer patients (CANCER), 13 cancer patients + MGUS (MGUS-CA) and 7 MGUS patients after surgical removal of concomitant cancer (MGUS-SRCC). Results show significant differences of both the median levels of IL-10 and the monoclonal component (MC) in CTR, MGUS and MM (patients with increasing concentrations in the mentioned order). The IL-10 levels found in the three groups of cancer patients showed serum levels higher than those observed in the controls. Moreover, the surgical cancer removal was related to an IL-10 decrease. A higly significant correlation between serum IL-10 levels and the corresponding MC was also found in the MM-bearing patients and to a lesser extent, in MGUS patients, indicating that serum IL-10 is parallel to the amount of the activated clone causing the monoclonal gammopathy. Since human myeloma lines, cultured in vitro may release significant amounts of IL-10, the data presented support the hypothesis that serum IL-10, measured in myelomatous patients may, at least in part, derive from the activated clone causing the monoclonal gammopathy. PMID- 21556658 TI - Morphological aspects of basement-membranes and their receptors in benign and malignant neoplasms (review). AB - We review the current knowledge on alterations of the major basement membrane (BM) components and their cellular integrin receptors in benign and malignant tumors of epithelial and mesenchymal origin. While benign tumors usually exhibit a continous BM, recent analyses provide evidence that invasive growth of carcinomas coincides with (a) a loss in a proper BM, (b) changes in the type of integrin receptor expression and (c) the retained ability of certain tumor cells to synthesize matrix components. This latter aspect has been regarded as a potentially beneficial 'host' mechanism against invasive growth. This assumption is strongly supported by the finding of a positive correlation between the extent of BM loss and both a lesser degree of tumor differentiation and a worse prognosis of tumor growth. The resulting concept indicates that in carcinomas an imbalance in the cell-matrix interaction is the leading element in invasive growth. In mesenchymal tumors a somewhat different role of the BM can be observed. Thus, the qualitative and quantitative expression of major BM components in benign mesenchymal tumors closely relates to the BM pattern of normal tissues providing a histogenetically oriented classification of benign mesenchymal tumors. Most well-differentiated sarcomas retain a BM pattern close to that of the histogenetically related tissue, although in poorly differentiated sarcomas no such attribution to a histogenetic orientation of the tumor cells can be found. PMID- 21556659 TI - Polynucleotide vaccination for cancer-treatment (review). AB - Inoculation with pure naked DNA in the form of plasmids can stimulate both antibody and T-cell responses in vivo against plasmid-encoded proteins. Peptide products derived from cytosolic degradation of fragments of tumour-specific proteins, expressed de novo under the transcriptional control of strong mammalian or viral promoter/enhancer signals might gain access to the MHC Class I presentation pathway, mimicking the presentation of viral proteins in infected cells. Presentation as neo-antigens or surrogate antigens in this novel context may be a means of breaking immunological tolerance, and may lead to the generation of tumour-specific immune responses. PMID- 21556660 TI - The aberrant p53 protein (review). AB - According to the current concept of carcinogenesis, neoplastic transformation consists of multistep accumulations of adverse genetic and epigenetic events. Recent advances in molecular genetics have demonstrated aberrations of oncogenes and tumor-suppressor genes in a variety of human cancers. The loss of wild-type p53 gene expression has exceptionally been implicated in the development of a wide variety of human cancers and it is generally accepted that p53 is a component in biochemical pathways central to human carcinogenesis. Although the role of the p53 gene in cancer genesis and development has fueled as many questions, study of p53 has come to the forefront of cancer research and detection of its abnormalities during the development of tumors may have diagnostic, prognostic and therapeutic implications. To be of value in clinical practice, immunohistochemical assessment of p53 protein should provide clinically relevant information. The degree of concordance between p53 gene mutation and the accumulation of p53 protein cannot be perfect, however, the immunohistochemical assay using anti-p53 antibodies is the most widely applicable approach for detection of tumors in routine investigations, particularly with regard to diagnosis or prognosis. PMID- 21556661 TI - Resistance to tgf-Beta-induced elimination of transformed-cells is required during tumor progression (review-hypothesis). AB - We present data that extend the present models of transformation and tumor cell progression by one essential step. In vitro, cocultivation of transformed and normal fibroblasts in the presence of TGF-beta leads to the specific elimination of transformed cells due to induction of apoptosis. This mechanism may represent an effective control step early in carcinogenesis. We propose that in vivo, this control mechanism eliminates arising transformed cells unless certain chemicals interfere with this process or the transformed cells have acquired resistance against it. Acquisition of resistance may be an essential requirement for tumor progression. PMID- 21556662 TI - Human prostatic-carcinoma cell-line lncap degrades luteinizing-hormone-releasing hormone. AB - Recent evidence suggests a direct antiproliferative effect of LHRH agonists on the prostatic carcinoma cell line LNCaP. In the present study the possible presence of a LHRH degrading activity (LHRH-DA) in soluble fractions of LNCaP cell homogenates has been investigated. The results obtained show that an LHRH-DA is present in the soluble fraction of LNCaP cells with apparent Km and Vmax values of 31.6 mu M and 4.5 pmol/min/mu g protein respectively. The degradation pattern of LHRH is characterized by two major initial degradation products identified as LHRH 1-5 and LHRH 1-6 fragments. The degradation of the tracer [pGlu-H-3]LHRH, used as a substrate, is inhibited by synthetic unlabelled LHRH (IC50 7.9 mu M) and by several LHRH agonists with different kinetics and potencies; the LHRH agonist [DSer-(tBu)(6),Gly(10)-Aza]LHRH was the most potent blocker of LHRH-DA present in LNCaP cells; this enzymatic activity is also inhibited in a dose dependent manner by somatostatin, TRH, bacitracin and dithiothreitol. The LHRH-DA present in the soluble fraction of LNCaP cells does not seem to be modified by the deprivation of steroids from the culture medium, In conclusion, the presence in LNCaP cells of a soluble peptidase able to degrade LHRH might reinforce the possibility that the prostate is a target for the action of LHRH and of LHRH analogs. PMID- 21556663 TI - Flow cytometric cellular DNA content and lymph-node metastasis in squamous-cell carcinoma of the oral cavity. AB - This prospective DNA flow cytometric study on 386 primary squamous cell carcinomas of the oral cavity showed that only 18% of the patients with diploid primary tumors had lymph node metastasis on admission compared to 52% of those with aneuploid carcinomas. The aneuploid group without evidence of lymph node involvement at the time of primary tumor treatment carried a 3-fold increased risk for developing late metastasis (23%) compared with the diploid group (8%). The clinical manifestation of occult metastasis in patients with diploid carcinomas was delayed by about two years compared to the aneuploid group. These ploidy-specific differences of the metastatic behaviour held true even if stratified with respect to tumor stage, histological grade and tumor localization. These results provide substantial evidence that cells with gross DNA content aberrations have a significantly higher probability of successfully producing a metastatic colony than flow cytometrically diploid tumor cells. An excellent 5-year survival rate of 90% in the diploid NO group in contrast to 52% in aneuploid NO cases and an even worse survival rate of 21% in patients with lymph node involvement at presentation underline the clinical importance of these findings. PMID- 21556664 TI - Benign and malignant myoepithelioma of salivary-gland - an immunohistochemical evaluation. AB - Three myoepitheliomas (MEOs) derived from the salivary glands were examined immunohistochemically. Proliferating cell nuclear antigen (PCNA)-positive cells were very rare (less than 2% of all tumor cells) in localized tumors of case 1 (epithelioid) (E-oid) cells) and case 2 (plasmacytoid) (P-toid) cells with a small number of spindle-shaped cells), but the percentage of PCNA-positive cells was high (21.8%) in case 3 (clear cells) exhibiting bone destruction. Strong c myc expression was detected in all the tumors, but p53 or c-erbB-2 protein was not detected in any of the cases. More than half of the clear cells were positive for epidermal growth factor (EGF), while fewer tumor cells in cases 1 and 2 expressed EGF. A few tumor cells in cases 2 and 3 were positive for EGF-receptor (R). Keratin was most prominent in the E-oid cells, The P-toid cells were most strongly positive for S-100 protein followed by the E-oid and clear cells. More than half of the spindle-shaped cells and one-third of the E-oid cells were positive for alpha-smooth muscle actin (alpha-SMA), but less than 5% of the clear cells and none of the P-toid cells were positive for alpha-SMA. These results suggest that tumor cells in MEO are heterogenous and have different proliferation activities. PMID- 21556665 TI - Model system for isolation of competent ovarian-carcinoma cells from fresh tumor tissue by a magnetic separation technique (macs). AB - Flow cytometric analysis of tumor cells in carcinomas is hampered by the presence of a variety of different cells in the tumor tissue and the surrounding stroma. To obtain single competent tumor cells, we have established a model system which can be applied to separate living cells from fresh ovarian carcinoma tissue. Due to the lack of tumor-cell surface specific antibodies, we isolated tumor cells by a procedure called 'negative tumor cell selection'. For this purpose, fresh ovarian carcinoma tissue, immediately after surgery, was subjected to mechanical disintegration using an automated mincing device to obtain a single-cell suspension (approximately 10(7) cells/g). Collagenase D (0.005%) was added to prevent further aggregation. Cells other than tumor cells were then labeled with a set of monoclonal antibodies directed to cell surface antigens: CD3 (T-cells), CD14 (monocytes), CD15 (granulocytes), CD45R (T-/B-cells) and 5B5 (fibroblasts). Anti-isotype antibodies coupled to ferrit microbeads were then reacted with the cell suspension and those cells reacting with the microbeads retained on a steel wool matrix in a magnetic field (1). Tumor cells not reacting with the microbeads were recovered by a simple wash of the steel wool matrix. All incubation steps were at 4 degrees C. This procedure, which takes about 2 hours, enables fast and simple isolation of single, living competent tumor cells from fresh tumor tissue and also from ascitic or pleuritic effusions. In a model system with cultured ovarian carcinoma cells and human leukocytes, tumor cell purity was about 93% and about 97% when re-subjected to the same procedure (respective recovery rates 75% and 50%). The still unlabeled tumor cells can subsequently be analyzed by flow cytometry or by central laser scanning microscopy for the presence of various surface antigens including receptors for proteases or growth factors. Moreover, after detergent treatment and fixation, flow cytometric multiparameter analysis such as simultaneous labeling of intracellular and surface antigens as well as nuclear DNA staining for ploidy and S-phase determination becomes possible. PMID- 21556666 TI - Expression of a tumor-suppressor gene and of various protooncogenes in human and murine adriamycin-resistant and sensitive cell-lines. AB - Besides established mechanisms involved in cellular drug resistance including P glycoprotein overexpression, topoisomerase alterations and xenobiotic detoxification, the hypothesis that proto-oncogene activation might also play a role in cell resistance has been postulated. This hypothesis has been tested by comparing the expression of various proto-oncogenes involved in signal transduction pathways (c-H-ras, c-g-ras, c-mil, c-myc, c-myb, c-fos), as well as the mdr gene and a tumor suppressor gene (p53) in different adriamycin-resistant (acquired or de novo) or sensitive cell lines, The implication of these variations in the process of chemoresistance is discussed. PMID- 21556667 TI - Prognostic evaluation of patients submitted to surgery for malignant pleural mesothelioma. AB - The role of surgical resection remains controversial in malignant pleural mesothelioma. The assessment of its impact on prognosis is complicated by a poor understanding of the prognostic factors in the disease. We therefore evaluated, through univariate and multivariate analysis, the role on prognosis of 24 variables in 57 patients submitted to surgery from 1985 to 1993. Sixteen patients had only exploratory thoracotomy and 12 minimal residual disease after surgery (no nodules >1 cm in diameter). Thirty-four cases had epithelial histotype, 6 sarcomatous and 17 mixed. Median survival for the whole group was 15.7 months. Multivariate analysis showed a highly significant influence on survival for minimal residual disease after surgery (p=0.0006), followed by TNM stage (p=0.01). Median survival for patients with TNM stage I disease was 36.3 months and for patients with minimal residual disease 33 months. In conclusion, these data suggest that patients with limited disease have a longer survival after surgery than those with extensive disease. At the same time, our results indicate that the achievement of significant disease reduction with surgery has a critical impact on the prognosis of pleural mesothelioma. PMID- 21556668 TI - PCR detection of clonal tcr gamma-gene rearrangements in a group of cutaneous T cell lymphomas including a case of localized pagetoid reticulosis expressing the gamma-delta tcr. AB - In this report, we describe the analysis of clonality performed using a PCR-based approach in a group of cutaneous T-cell lymphomas including a case of localised pagetoid reticulosis expressing the gamma delta T-cell receptor. For our PCR analysis DNA was extracted from frozen tissue of 10 cases of cutaneous T-cell lymphomas and subjected to polymerase chain reaction amplification using primers recognizing conserved sequences of the variable and joining regions of the T-cell receptor gamma chain gene. PCR products were then analyzed by high resolution non denaturing polyacrylamide gel electrophoresis. Clonal TCR gamma gene rearrangements were detected in all the cases investigated including the case of localised pagetoid reticulosis. The PCR-based approach used in this study may provide an alternative to conventional Southern blot analysis for the analysis of cutaneous T-cell lymphomas as it is easy to perform and requires only minimal amounts of DNA. The findings in localized pagetoid reticulosis are consistent with the proliferation of monoclonal T-cells in lesional skin of this condition and provide evidence for the lymphoproliferative nature of this clinically benign disorder. PMID- 21556669 TI - Growth suppressive efficacy of human lak cells against human lung-cancer implanted into scid mice. AB - The purpose of our study was to determine the efficacy of immunotherapy using human lymphokine activated killer (LAK) cells against a human-lung squamous-cell carcinoma cell line (RERF-LC-AI) implanted into severe combined immunodeficient (SCID) mice. A statistically significant growth suppressive effect on RERF-LC-AI implanted into SCID mice was observed when human LAK cells were administered into the caudal vein of the mice treated with a continuous supply (initiated prior to LAK cells injection) of rIL-2. The human LAK cells stained with PKH 2, a fluorescent dye, for later detection using flow cytometry were administered into the caudal vein of RERF-LC-AI bearing SCID mice; the cells persisted for 7 days in the implanted lung cancer tissue and in the mouse peripheral blood, but for 5 days in the mouse spleen. The number of infiltrated human LAK cells in each tissue increased dose-dependently with the number of injected cells. The results indicate that the antitumor effect most likely occurred during the early implantation period of the human LAK cells. These results demonstrate the applicability of this model to the in vivo study of human lung cancer therapy. PMID- 21556670 TI - Rapid non-genomic and concentration-dependent effects of progesterone in c4-I cells on the proposed tumor-marker - ratio between extracellular cgmp and cAMP levels. AB - The extracellular cGMP levels or the ratio between extracellular levels of cGMP and cAMP (cGMP(ex)/cAMP(ex)) have been proposed as tumor marker for premalignant and malignant diseases of the uterine cervix. More than 50% of cervical cancers occur in premenopausal women and detailed information about hormonal and drug effects on the extracellular levels of cyclic nucleotides is of importance. In the present study we have investigated the effect of progesterone (0.1-100 mu M), theophylline (1-1000 mu M), probenecid (0.1-100 mu M) and verapamil (0.1-100 mu M) on cGMP(ex)/cAMP(ex) of C4-I cells (a human cell line derived from a squamous carcinoma of the uterine cervix). Within 30 min progesterone caused a concentration-dependent elevation of cGMP(ex)/cAMP(ex), whereas the other compounds had no marked effect. Identical results were obtained for C4-I cells in monolayer and in suspension. The effects were explained by the observation that progesterone stimulated cGMP efflux, but inhibited the cAMP efflux. The other compounds inhibited the export of both nucleotides to a similar degree. The present data suggest that progesterone affects the export of cyclic nucleotides in non-genomic manner and may hamper the interpretation of cGMP(ex)/cAMP(ex) in the luteal phase in premenopausal women with cancer of the uterine cervix. PMID- 21556671 TI - Phase-I study of synthetic muc1 peptides in breast-cancer. AB - Exposed peptides in the repeat (VNTR) protein core of human mucin 1 (MUC1) could be a target for immunotherapy, as it is highly immunogenic in mice and a human cytotoxic T lymphocytes to MUC1 recognise the peptide. On this basis 13 patients were immunised with a MUC1 peptide - a 20 amino acids dimer conjugated with diphtheria toroid as carrier. In patients with established breast cancer increasing doses (0.15 mg, 0.25 mg, 0.5 mg, 1.0 mg) were used at 2 week intervals (3 injections). No toxicity was found, other than for DTH reaction to the diphtheria carrier; weak antibody and T cell proliferative responses were seen and weak DTH reaction in proportion of patients. The MUC1 peptide appears to be safe but in the form used was not highly immunogenic. PMID- 21556672 TI - The chemistry and biology of platinum complexes with the 1,2-diaminocyclohexane carrier ligand (review). AB - Dach-Pt compounds have been intensively studied because of their potential. efficacy against cisplatin-resistant tumors and their reduced nephrotoxicity and myelotoxicity compared to cisplatin and carboplatin. Because the dach carrier ligand can be H-3-labeled, the biotransformations of dach-Pt compounds have been studied in detail. Some of these biotransformation studies have provided new information about the likely cellular biotransformation pathways of Pt complexes in general. For example, biotransformation studies with 1,2 diaminocyclohexanedichloroplatinum(II) [Pt(dach)Cl-2] and 1,2 diaminocyclohexanemalonatoplatinum(II) [Pt(dach)(mal)] have shown that displacement of leaving ligands by HCO3- and PO4= are likely to represent important activation pathways for platinum(II) complexes in vivo and that the intracellular t(1/2) is much more rapid [15' for Pt(dach)Cl-2 and 30' for Pt(dach)(mal)] than predicted by previous in vitro experiments. Biotransformation studies with 1,2-diaminocyclohexanetetrachloroplatinum(IV) (ormaplatin) have suggested that Pt(II)-assisted Pt(IV) ligand exchange reactions can occur in vivo with platinum(IV) complexes. This is important for our understanding of platinum(IV) biotransformations because the specificity of Pt(II)-assisted Pt(IV) ligand exchange reactions is different than that for Pt(II) ligand exchange reactions. Finally, plasma biotransformation studies with ormaplatin in vivo have shown that ultrafilterable, active biotransformation products are cleared from the circulation much more rapidly than the ultrafilterable, inactive biotransformation products. This has lead to the suggestion that pharmacokinetic parameters based on the active biotransformation products are likely to be much more useful than pharmacokinetic parameters based on ultrafilterable platinum for predicting the efficacy and/or toxicity of platinum compound with chloro leaving ligands such as ormaplatin and cisplatin. Since dach-Pt compounds can overcome cisplatin resistance in some cancer cell lines but not in others, it is important to understand the mechanism(s) which determine(s) the carrier ligand specificity of resistance. A great deal has been learned about how dach-Pt compounds interact with DNA. The dach carier ligand constrains the N-Pt-N bond angle and can exist as 3 isomers with a total of 4 different non-planar conformations. These constraints do not appear to affect the rate or sequence specificity of Pt-DNA monoadduct formation, but do appear to alter the rate of monoadduct to diadduct conversions. The dach carrier ligand may also have significant effects on the conformation of DNA in the region of Pt-DNA adducts, although the biological consequences of these effects are not clear. Much less is known about the effects of the dach carrier ligand on the interactions of Pt compounds with proteins. Because Pt compounds primarily interact with nonadjacent amino acids on the surface of proteins, these interactions are not likely to be significantly affected by the conformation of dach-Pt compounds. However, the hydrophobicity of the dach carrier ligand may allow it to react with amino acid side chains in hydrophobic pockets that are inaccessible to cisplatin. At the cellular level, the dach carrier ligand appears to affect Pt accumulation in Pt resistant mouse L1210 cells, but has little effect on either Pt uptake or efflux in Pt-resistant human ovarian and colon carcinoma cell lines. While enhanced repair also appears to contribute to resistance in many eel lines, there is little or no difference in the repair of dach-Pt and cis-diammine-Pt adducts in any of the cell lines tested to date. Current data suggest that replicative bypass makes a significant contribution to platinum resistance and, in many cell lines, is the only process to predict the carrier ligand specificity of resistance. These data suggest that further elucidation of this process should add significantly to our understanding of platinum resistance and the role of platinum complexes with the dach carrier ligand in chemotherapy. PMID- 21556673 TI - Comparative-study of intramuscular ketorolac tromethamine and morphine in patients experiencing cancer pain. AB - Ketorolac tromethamine administered intramuscularly (i.m.) 10 mg 6-hourly was compared with morphine 10 mg i.m. 6-hourly in a randomised, double-blind, cross over trial for its analgesic efficacy and safety in 51 patients with moderate to severe cancer pain. There was no overall significant difference between the analgesic effect of the two treatments. 57% of ketorolac- and 74% of morphine treated patients changed their analgesic. Among these, significantly more patients stopped ketorolac than morphine due to pain (p=0.007) whilst more patients discontinued morphine than ketorolac because of adverse effects (p=0.001), predominantly emesis. Only one patient (2%) stopped ketorolac because of intolerance. Ketorolac shows promise as an effective and well tolerated analgesic for cancer pain and merits further study. PMID- 21556674 TI - How enhancers work - juxtapositioning of DNA control elements by synergistic interaction of Mars - (review-hypothesis). AB - The sites of attachment of chromatin loops to the nuclear matrix (MARs) seem to harbor transcriptional enhancers, promoters and origins of replication (ORIs). According to the model proposed, the cooperative interactions among classical nuclear matrix proteins which are abundant (topoisomerase II, histone H1, HMG I(Y), lamins A, B1, SAF-A, ARBP and others) bring together distant AT-rich classical MAR sequences causing looping of DNA. This process juxtaposes enhancers, ORIs, promoters, and other control elements that cohabit with MARs loaded with the less abundant transcription factors (TFs) facilitating productive interactions between enhancers and promoters or enhancers and core ORIs. The implications of the model in the interactions of oncoproteins with regulatory DNA elements and their integration into a chromatin and nuclear matrix environment are discussed. PMID- 21556675 TI - The expression of p53 tumor-suppressor protein during progression of gastric and colorectal carcinomas. AB - The expression of p53 was immunohistochemically determined in sets of biopsies from primary and recurrent colorectal (12) and gastric (17) tumours that had progressed to more advanged stages in the following 6-54 months. At presentation 7 carcinomas overexpressed p53 protein in the cell nucleus and 22 tumours had normal, undetectable levels of p53. In most patients, the p53 phenotype was maintained during the process of tumour progression. In two gastric and two colorectal carcinomas p53 overexpression was subsequently detected in recurrent tumour growth at the primary site and was also associated with the development of metastases. These results suggests that in some cases p53 alterations may contribute to the conversion to malignancy and in others to tumour progression and metastatic capacity. PMID- 21556676 TI - Absence of indigenous specific West Nile virus antibodies in Tyrolean blood donors. AB - In the last several years, West Nile virus (WNV) was proven to be present especially in the neighboring countries of Austria, such as Italy, Hungary, and the Czech Republic, as well as in eastern parts of Austria, where it was detected in migratory and domestic birds. In summer 2010, infections with WNV were reported from Romania and northern Greece with about 150 diseased and increasingly fatal cases. We tested the sera of 1,607 blood donors from North Tyrol (Austria) and South Tyrol (Italy) for antibodies against WNV by using IgG enzyme-linked immunosorbent assay (ELISA). Initial results of the ELISA tests showed seroprevalence rates of 46.2% in North Tyrol and 0.5% in South Tyrol, which turned out to be false-positive cross-reactions with antibodies against tick-borne encephalitis virus (TBEV) by adjacent neutralization assays. These results indicate that seropositivity against WNV requires confirmation by neutralization assays, as cross-reactivity with TBEV is frequent and because, currently, WNV is not endemic in the study area. PMID- 21556677 TI - Influenza-like illness in pregnant women during summertime: clinical, epidemiological and microbiological features. AB - It is not known whether influenza-like illnesses (ILI) in pregnant women caused by influenza virus, specifically, those caused by the 2009 Influenza A H1N1 virus (nH1N1), can be clinically distinguished from those caused by other agents. From 1st July 2009 until 20th September 2009, an observational study including all pregnant women presenting at Hospital Universitario La Paz with an ILI was carried out. A specific reverse-transcriptase polymerase chain reaction (RT-PCR) for nH1N1 in nasopharyngeal swabs was prospectively carried out in all patients. Retrospectively, samples were analysed for multiple respiratory virus panel (RT PCR microarray). Clinical, demographical and other microbiological variables were evaluated as well. A total of 45 pregnant women with ILI were admitted. Of these, 14 (31.1%) women had nH1N1 infection and 11 with a non-influenza ILI (35.48%) were positive for other viruses (five rhinovirus, four parainfluenza virus, one bocavirus and one adenovirus). In 20 patients, no aetiologic agent was identified. The clinical course of nH1N1 was mild, without deaths or severe complications. No significant differences were found when comparing the clinical presentation and course of patients with and without nH1N1 infection. Six women with nH1N1 infection received oseltamivir. Influenza and non-influenza ILI were clinically indistinguishable among pregnant women. Many ILI in pregnant women remain undiagnosed, despite undergoing an RT-PCR microarray for several respiratory viruses. PMID- 21556678 TI - Vascular cognitive impairment: disease mechanisms and therapeutic implications. AB - The prevalence of vascular cognitive impairment (VCI) is likely to increase as the population ages and cardiovascular disease survival improves. We provide an overview of the definition and disease mechanisms of VCI and present a systematic literature review of the current evidence for the pharmacologic and nonpharmacologic therapies used to treat the VCI symptoms of cognitive dysfunction or to modify VCI through primary and secondary prevention. The Cochrane Database of Systematic Reviews was searched from 2005 to October 2010 using the keywords "vascular dementia" or "vascular cognitive impairment and therapy." MEDLINE was searched for English-language articles published within the last 10 years using the combined Medical Subject Headings (MeSH) "therapeutics and dementia," "vascular" or "vascular cognitive impairment." Although cholinesterase inhibitors and memantine produce small cognitive improvements in patients with VCI, these drugs do not improve global clinical outcomes and have adverse effects and costs. Selective serotonin reuptake inhibitors and dihydropyridine calcium channel blockers may improve short-term cognitive function in patients with VCI. Anti-hypertensive therapy with an ACE inhibitor based regimen and statins may prevent the major subtype of VCI known as poststroke cognitive decline. Clinical and effectiveness studies with long-term follow-up are needed to determine the benefits and risks of pharmacologic and nonpharmacologic therapies to prevent and treat VCI. Given its growing health, social, and economic burden, the prevention and treatment of VCI are critical priorities for clinical care and research. PMID- 21556679 TI - Brain imaging in stroke: insight beyond diagnosis. AB - Stroke, whether hemorrhagic or ischemic in nature, has the ability to lead to devastating and debilitating patient outcomes, which not only has direct implications from a healthcare standpoint, but its effects are longstanding and they impact the community as a whole. For decades, the goal of advancement and refinement in imaging modalities has been to develop the most precise, convenient, widely available and reproducible interpretable modality for the detection of stroke, not only in its hyperacute phase, but a method to be able to predict its evolution through the natural course of disease. Diagnosis is one of the most important initial roles, which imaging fulfills after the identification of existent pathology. However, imaging fulfills an even more important goal by using a combination of imaging modalities and their precise interpretation, which lends itself to understanding the mechanisms and pathophysiology of underlying disease, and therefore guides therapeutic decision-making in a patient-tailored fashion. This review explores the most commonly used brain imaging modalities, computer tomography, and magnetic resonance imaging, with an aim to demonstrate their dynamic use in uncovering stroke mechanism, facilitating prognostication, and potentially guiding therapy. PMID- 21556680 TI - Treatment of acute ischemic stroke: beyond thrombolysis and supportive care. AB - The initial therapeutic approach to acute ischemic stroke consists of thrombolytic therapy and early initiation of supportive care, usually commenced prior to the determination of the underlying stroke etiology. Varying stroke mechanisms may call for specific, etiology-based treatment. The majority of strokes result from cardioembolism, large-vessel atherothromboembolism, and small vessel occlusive disease. There are scant data to support the use of acute anticoagulation therapy over anti-platelet therapy in cardioembolic stroke and large-vessel atherosclerosis, although it may be reasonable in a certain subset of patients. However, augmentation of blood flow with early surgery, stenting, or induced hypertension, may play a role in patients with large artery stenosis. The less commonly identified stroke mechanisms may warrant special consideration in treatment. Controversy remains regarding the optimal anti-thrombotic treatment of arterial dissection. Reversible cerebral vasoconstriction syndrome may benefit from therapy with calcium channel blockers, high-dose steroids, or magnesium, although spontaneous recovery may occur. Inflammatory vasculopathies, such as isolated angiitis of the central nervous system and temporal arteritis, require prompt diagnosis as the mainstay of therapy is immunosuppression. Cerebral venous thrombosis is a rare cause of stroke, but one that needs early identification and treatment with anticoagulation. Rapid determination of stroke mechanism is essential for making these critical early treatment decisions. PMID- 21556682 TI - Intramedullary malignant peripheral nerve sheath tumor. PMID- 21556683 TI - Detection of a morphogenetically novel Sarcocystis hominis-like in the context of a prevalence study in semi-intensively bred cattle in Italy. AB - The aim of this study was to determine the prevalence of sarcosporidiosis in semi intensively bred cattle in northwestern Italy. A diagnostic protocol was setup in which infected animals were identified by rapid histological examination of the esophagus, diaphragm, and heart and the detected Sarcocystis spp. were subsequently typed using conventional electron microscopy in combination with molecular techniques. Sarcosporidia cysts were detected in 78.1% of the animals and were seen most often in the esophagus. The cattle is intermediate host for Sarcocystis hominis (final host, humans and some primates), Sarcocystis cruzi (final host, domestic and wild canids), and Sarcocystis hirsuta (final host, wild and domestic cats).All these three species of Sarcocystis were identified, variously associated, with the following prevalence: S. cruzi (74.2%), S. hirsuta (1.8%), and S. hominis (42.7%). Furthermore, a new S. hominis-like (prevalence 18.5%), characterized by hook-like structures of villar protrusion and a different sequence of the 18S rRNA gene, was identified. The cattle sheds testing positive for zoonotic Sarcocystis were assessed for risk factors contributing to the maintenance of the parasite's life cycle. Significant associations emerged between consumption of raw meat by the farm owner, mountain pasturing, and absence of a sewerage system on the farm and cattle breed. Our study demonstrates that sarcosporidiosis may constitute a public health problem in Italy and indicates several issues to be addressed when planning surveillance and prevention actions. The applied diagnostic approach revealed that cattle can harbor a further type of Sarcocystis, of which life cycle and zoonotic potential should be investigated. PMID- 21556684 TI - The use of high-resolution 1H nuclear magnetic resonance (NMR) spectroscopy in the clinical diagnosis of Acanthamoeba. AB - Acanthamoeba are opportunistic protozoan pathogens that can produce sight threatening keratitis and fatal granulomatous encephalitis. The successful prognosis requires early diagnosis and differentiation of pathogenic Acanthamoeba spp. followed by aggressive treatment regimen. In this study, we tested the use of high-resolution (1)H NMR spectroscopy in the clinical diagnosis of Acanthamoeba. Using NMR spectroscopy combined with Pattern Recognition Analysis (PRA), we analysed variations in the biochemical 'fingerprint' of invasive and non-invasive Acanthamoeba, its closely related genus, Balamuthia mandrillaris, neuropathogenic Escherichia coli K1 strain E44, a laboratory strain of E. coli K 12, HB101, mammalian cells including human brain microvascular endothelial cells and monkey kidney cells. The findings revealed significant variations in the metabolites of amoebae, mammalian cells and bacteria. Interestingly, (1)H NMR spectra provided distinct biochemical profiles of clinical and non-clinical Acanthamoeba isolates highlighting the potential of (1)H NMR spectroscopy combined with PRA for the development of a novel diagnostic test that could rapidly identify pathogenic Acanthamoeba isolates with high sensitivity and specificity. PMID- 21556685 TI - Efficacy of sulfonamides and Baycox((r)) against Isospora suis in experimental infections of suckling piglets. AB - Sulfonamide treatment of piglets against neonatal coccidiosis has frequently been suggested in the literature. In order to evaluate the efficacy of sulfonamides against experimental Isospora suis infections in suckling piglets (oral infection with 1,500 sporulated oocysts of I. suis per piglet on the fourth day of life), two trials were conducted. In trial I, oral sulfadimidine (group Sulfa-Oral) was applied in doses of 100 mg/kg of body weight (BW) 1 day before infection and 75 mg/kg BW daily for the following 5 days, and sulfamethoxypyrimidine (SMP) was applied parenterally in daily doses of 75 mg/kg BW for the same time period. In trial II, SMP was applied parenterally in doses of 75 mg/kg BW (a) from the day of infection daily for 7 days (SMP-Standard), (b) for 2 days starting on the day of infection (SMP-Early), (c) for 3 days starting 2 days post-infection (d.p.i.; SMP-Middle), (d) for 2 days starting 5 d.p.i. (SMP-Late), and (e) every other day from the day of infection until 6 d.p.i. (SMP-Alternating), as well as (f) orally in doses of 75 mg/kg BW from the day of infection for 7 days (SMP-Oral). The sulfonamide-treated groups were compared to a toltrazuril-treated group (single oral treatment with Baycox(r) 5% suspension, 20 mg/kg BW 2 d.p.i.) and to a water treated Control group. Each group consisted of seven to nine piglets. The parameters evaluated were oocyst excretion and fecal consistency/diarrhea from 4 to 15 d.p.i. Sulfa-Oral, SMP-Early, and SMP-Late had no significant effect in reduction of oocyst excretion and diarrhea, whereas treatment for 3-7 days with SMP reduced both parasite shedding and diarrhea significantly. Oral treatment with SMP was comparable to parenteral application. Baycox(r) in a single application had the most pronounced effect and completely suppressed oocyst excretion and diarrhea during the examination period. It could be shown that repeated application of sulfonamides, provided that the appropriate time period after infection is covered, can in principle be used to control piglet coccidiosis; however, the amount of work required is considerable, and the practicability is poor. Due to the short half-life of sulfonamides in pigs and the lack of predictability of the time point of infection, an efficient application of sulfonamides to control piglet coccidiosis under field conditions appears unlikely. Baycox(r), on the other hand, applied once during the prepatent period of infection, had a lasting effect and can be used to most effectively control I. suis. PMID- 21556686 TI - Efficacy of ginkgolic acids against Cryptosporidium andersoni in cell culture. AB - Cryptosporidium is a worldwide waterborne parasite and the treatment is a severe problem in immunocompromised patients. In this study, we used the in vitro culture system to evaluate the anti-Cryptosporidium activity of ginkgolic acids (GAs), nitazoxanide (NTZ), garlicin (GAR), and artemether (ART). The growth of Cryptosporidium andersoni in HCT-8 cells was determined by real-time PCR assay. When exposed to 5.00 MUg/ml GAs or 10.00 MUg/ml NTZ for 48 h, the number of C. andersoni in cultures was on a very low lever, but the number of parasites did not significantly decrease when exposed to GAR and ART. Our results indicate that GAs could be a potential drug for the treatment of cryptosporidiosis. PMID- 21556687 TI - Genetic diversity of the malaria vaccine candidate merozoite surface protein 1 gene of Plasmodium vivax field isolates in Republic of Korea. AB - The Plasmodium vivax merozoite surface protein 1 (Pvmsp-1) locus codes for a major asexual blood-stage antigen currently proposed as a malaria vaccine candidate antigen. However, extensive polymorphism of this protein has been observed in isolates from different geographical areas. Here, we investigate the extent and the frequency of allelic diversity at the Pvmsp-1 locus in field isolates collected in the Republic of Korea during the past decade. Among the 45 Korean isolates, six Pvmsp-1 gene types (SKOR-I to SKOR-VI) were identified as unique combinations of type sequences in each variable block. Of these six different Pvmsp-1 gene types, two major Pvmsp-1 allelic types were found in 72% (SKOR-I) and 28% (SKOR-II) of field isolates collected in 1996 to 2000, and four different allelic types (SKOR-III to SKOR-VI) emerged in 70% (10-25%) of isolates collected in 2007 to 2009. These results suggest that allelic diversity of Pvmsp 1 increased in several variable regions, including the N- and C-terminals, after reemergence of P. vivax parasites in the Republic of Korea. PMID- 21556688 TI - Helminths of the kelp gull, Larus dominicanus, from the northern Patagonian coast. AB - The helminth community of Larus dominicanus (Charadriiformes) is reported from Peninsula Valdes, on the Patagonian coast, Argentina. From March 2000 to April 2004, 29 kelp gulls were collected and dissected. All the birds were parasitized by at least 2 of 18 parasite species: 2 cestodes (1 Tetrabothriidae, 1 Dilepididae), 10 trematodes (2 Echinostomatidae, 3 Microphallidae, 2 Gymnophallidae, 1 Philophthalmidae, 1 Dicrocoeliidae, 1 Diplostomatidae), 4 nematodes (2 Acuariidae, 1 Capillaridae, 1 Anisakidae), and 2 acanthocephalans (Polymorphidae). The mean intensity was 3,204 parasites per host, and all helminths parasitized the gastrointestinal tract or associated glands. The helminth community of L. dominicanus on the Peninsula Valdes coast seems to be richer than those reported by previous authors in other localities in Argentina. This could be due to a greater diversity in prey items available. Nine species are recorded for the first time from the kelp gull and seven species are recorded for the first time from Argentina. PMID- 21556689 TI - Chemical composition and larvicidal activity of Blumea densiflora essential oils against Anopheles anthropophagus: a malarial vector mosquito. AB - Blumea densiflora, an edible and medicinal plant, is chiefly distributed in Southeast Asia and South Asia. Essential oils extracted by steam distillation from B. densiflora were investigated for their chemical composition and larvicidal activity against Anopheles anthropophagus, the primary vector of malaria in China and other East Asian countries. Totally, 46 compounds were identified by gas chromatography and mass spectroscopy. The major chemical compounds identified were borneol (11.43%), germacrene D (8.66%), beta caryophyllene (6.68%), gamma-terpinene (4.35%), sabinene (4.34%), and beta bisabolene (4.24%). A series of concentrations of essential oil (that ranged from 6.25 to 150 ppm) were tested against A. anthropophagus fourth-instar larvae according to WHO recommendation. In general, larval mortality increased as concentration and exposure time increased, indicating a dose-dependent effect, and high insecticidal activity showed that 100% mortality occurred within 6 h at 150 ppm, 10 h at 100 ppm, 30 h at 50 ppm, and 30 h at 25 ppm essential oil concentration. The LC(50) values were 22.32 (after 12 h) and 10.55 ppm (after 24 h), and the LC(90) values were 54.04 (after 12 h) and 33.56 ppm (after 24 h). Pylarvex, the reference standard, had better larvicidal activity, causing 100% mortality within 2 h at 150 ppm and within 6 h at 6.25 ppm. The results clearly reveal that the essential oil of B. densiflora served as a potential, eco friendly mosquito larvicide against the malarial vector mosquito A. anthropophagus. PMID- 21556690 TI - Cloning and characterization of a novel enzyme: tyrosine hydroxylase from Schistosoma japonicum. AB - Catecholamines, such as dopamine and noradrenaline, play important roles as neuromuscular transmitters and modulators in all parasitic helminthes, including Schistosoma japonicum. S. japonicum tyrosine hydroxylase (SjTH) was amplified by rapid amplification of cDNA ends polymerase chain reaction that shows strong homology to Schistosoma mansoni tyrosine hydroxylase, the enzyme that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines. The SjTH transcripts encoded the protein of 463 amino acids and a predicted size of 54 kDa. Purified recombinant SjTH as an N-terminal histidine fusion protein expressed in Escherichia coli showed catalytic activity that was confirmed with (3)H tyrosine uptake. The purified enzyme was found to have the same absolute requirement for a tetrahydrobiopterin cofactor and similar sensitivity to be inhibited by high concentration of the substrate, tyrosine, as the mammalian enzyme. Also, purified SjTH showed characteristic inhibition by catecholamine products. The phosphorylated peptide from SjTH could interact with Sj14-3-3 signal protein. This evidence indicates that SjTH encodes a functional tyrosine hydroxylase that has catalytic properties similar to those of the mammalian hosts' enzyme, and its catalytic activity could be regulated by a phosphorylated or dephosphorylated form. This demonstration of SjTH further suggests that the parasites have the enzymatic capacity to synthesize catecholamines endogenously. PMID- 21556691 TI - Characterization of an immunomodulatory Der p 2-FIP-fve fusion protein produced in transformed rice suspension cell culture. AB - Der p 2, a major allergen of Dermatophagoides pteronyssinus mites, is one of the most clinically relevant allergens to allergic patients worldwide. FIP-fve protein (Fve) from the golden needle mushroom (Flammulina velutipes) is an immunomodulatory protein with potential Th1-skewed adjuvant properties. Here, we produced and immunologically evaluated a Der p 2-Fve fusion protein as a potential immunotherapeutic for allergic diseases. Using an inducible expression system in cultured rice suspension cells, the recombinant Der p 2-Fve fusion protein (designated as OsDp2Fve) was expressed in rice cells under the control of an alpha-amylase gene (alphaAmy8) promoter and secreted under sucrose starvation. OsDp2Fve was partially purified from the cultured medium. The conformation of Der p 2 in OsDp2Fve remains intact as reflected by its unaltered allergenicity, as assessed by human IgE ELISA and histamine release assays, compared to non-fusion Der p 2 protein. Furthermore, the Fve protein expressed in OsDp2Fve retains its in vitro lymphoproliferative activity but loses its hemagglutination and lymphoagglutination effects compared to the native protein. Notably, in vivo evaluation showed that mice administered with OsDp2Fve possessed an enhanced production of Der p 2-specific IgG antibodies without potentiating the production of Der p 2-specific IgE and Th2 effector cytokines in comparison with mice co administered with native Fve and Der p 2 proteins. These results suggest that the recombinant Der p 2-Fve fusion protein produced in rice suspension cell cultures has a great potential for allergy immunotherapy. PMID- 21556692 TI - Anion currents in yeast K+ transporters (TRK) characterize a structural homologue of ligand-gated ion channels. AB - Patch clamp studies of the potassium-transport proteins TRK1,2 in Saccharomyces cerevisiae have revealed large chloride efflux currents: at clamp voltages negative to -100 mV, and intracellular chloride concentrations >10 mM (J. Membr. Biol. 198:177, 2004). Stationary-state current-voltage analysis led to an in series two-barrier model for chloride activation: the lower barrier (alpha) being 10-13 kcal/mol located ~30% into the membrane from the cytoplasmic surface; and the higher one (beta) being 12-16 kcal/mol located at the outer surface. Measurements carried out with lyotrophic anions and osmoprotective solutes have now demonstrated the following new properties: (1) selectivity for highly permeant anions changes with extracellular pH; at pH(o)= 5.5: I(-)~ Br(-) >Cl(-) >SCN(-) >NO (3)(-) , and at pH(o) 7.5: I(-)~ Br(-) > SCN(-) > NO(3)(-) >Cl(-). (2) NO(2)(-) acts like "superchoride", possibly enhancing the channel's intrinsic permeability to Cl(-). (3) SCN(-) and NO(3)(-) block chloride permeability. (4) The order of selectivity for several slightly permeant anions (at pH(o)= 5.5 only) is formate>gluconate>acetate>>phosphate(-1). (5) All anion conductances are modulated (choked) by osmoprotective solutes. (6) The data and descriptive two barrier model evoke a hypothetical structure (Biophys. J. 77:789, 1999) consisting of an intramembrane homotetramer of fungal TRK molecules, arrayed radially around a central cluster of four single helices (TM7) from each monomer. (7) That tetrameric cluster would resemble the hydrophobic core of (pentameric) ligand-gated ion channels, and would suggest voltage-modulated hydrophobic gating to underlie anion permeation. PMID- 21556693 TI - Prevention of central line-associated bloodstream infections: a journey toward eliminating preventable harm. AB - Central line-associated blood stream infections (CLABSI) are among the most common, lethal, and costly health care-associated infections. Recent large collaborative quality improvement efforts have achieved unprecedented and sustained reductions in CLABSI rates and demonstrate that these infections are largely preventable, even for exceedingly ill patients. The broad acceptance that zero CLABSI rates are an achievable goal has motivated and stimulated diverse groups of stakeholders, including public and private groups to develop policy tools and to mobilize their local constituents toward achieving this goal. Nevertheless, attributing reductions in CLABSI rates achieved by multifaceted quality improvement efforts solely to the use of checklists to ensure adherence with appropriate infection control practices is an easily made but crucial mistake. National CLABSI prevention is a shared responsibility and creating novel partnerships between government agencies, health care industry, and consumers is critical to making and sustaining progress in achieving the goals toward eliminating CLABSI. PMID- 21556694 TI - Frontal theta power linked to neuroticism and avoidance. AB - Approach-avoidance conflict is thought to generate negative affective bias, mediated by theta rhythms. This process is distinct from, and adds to, the effects of simple aversive input. We assessed this distinction by holding gain constant and increasing loss value so that conflict and simple aversion peaked in the conflict (gain equals loss) and loss (net loss) conditions, respectively. Right frontal areas showed increases in both conflict- and loss-induced theta power. However, loss, but not conflict, power was correlated with avoidance and neuroticism, showing a Gender x Hemisphere interaction. We concluded that multiple aversive processes converge in lateral frontal networks and that individual differences in theta response in these networks may reflect differences in behavioural and emotional reactivity to aversive events. PMID- 21556695 TI - Working memory load reduces the late positive potential and this effect is attenuated with increasing anxiety. AB - Emotion regulation decreases the processing of arousing stimuli, as indexed by the late positive potential (LPP), an electrocortical component that varies in amplitude with emotional arousal. Emotion regulation increases activity in the prefrontal areas associated with cognitive control, including the dosolateral prefrontal cortex (DLPFC). The present study manipulated working memory load, known to activate the DLPFC, and recorded the LPP elicited by aversive and neutral IAPS pictures presented during the retention interval. The LPP was larger on low-load compared to high-load trials, and on trials with aversive compared to neutral pictures. These LPP data suggest that emotional content and working memory load have opposing effects on attention to distracting stimuli. State anxiety was associated with reduced modulation of the LPP by working memory load. Results are discussed in terms of competition for attention between emotion and cognition and suggest a relationship between DLPFC activation and the allocation of attentional resources to distracting visual stimuli-a relationship that may be disrupted with increasing anxiety. PMID- 21556696 TI - Longitudinal study of depressive symptoms and social support in adolescent mothers. AB - Previous studies have suggested that adolescent mothers with higher social support have lower depressive symptoms. This is a longitudinal study of adolescent mothers to examine the association of social support and depressive symptoms over one year postpartum. This was a prospective study of adolescent mothers (N at baseline = 120, N at 1 year = 89; age < 19 years) enrolled in a teen tot program. Participants completed the Center for Epidemiological Studies Depression Scale for children (CES-DC) and the Duke-UNC Functional Social Support Questionnaire at baseline, 12 weeks, and 1 year. A score of >= 16 on the CES-DC was suggestive of major depression. The mean CES-DC scores of the adolescent mothers were >= 16 points at all three time points (baseline: mean = 18.7 +/- 10.3; 53% >= 16; 12 weeks: mean = 18.4 +/- 11.4, 57% >= 16; one year: mean = 20.0 +/- 11.4; 57% >= 16). Social support had a significant, inverse association with depressive symptoms for all participants from baseline to 12 weeks with a stronger association for those with more depressive symptoms (score >= 16) at baseline (beta = -0.030 +/- 0.007; P < 0.001) than for those with fewer depressive symptoms (score < 16) at baseline (beta = -0.013 +/- 0.006; P = 0.021). From 12 weeks to one year, increased social support was only significantly associated with decreased depressive symptoms for those with a higher baseline level of depressive symptoms (beta = - 0.039 +/- 0.009; P < 0.001). Depressive symptoms were prevalent among adolescent mothers. For more depressed adolescent mothers, higher levels of social support were associated with less depressive symptoms over the 1 year follow-up. Effective long-term interventions are needed to lessen depression and enhance social support. PMID- 21556697 TI - Physical abuse around the time of pregnancy among women with disabilities. AB - Women with disabilities are at greater risk for physical abuse than women without disabilities. However, no previous population-based studies have examined physical abuse against women with disabilities around the time of pregnancy, a critical period for mother and child. The objective of this study was to describe the prevalence of physical abuse before and during pregnancy among a representative sample of Massachusetts women with and without disabilities. Data from the 2007-2008 Massachusetts Pregnancy Risk Assessment Monitoring System (PRAMS) were analyzed in 2010. Disability prevalence was 4.9% (95% CI = 3.9-6.2) among Massachusetts women giving birth during 2007-2008. The prevalence of physical abuse during the 12-months before pregnancy among women with disabilities was 13.6% (95% CI = 7.2-24.0) compared to 2.8% for women without disabilities (95% CI = 2.1-3.7). Similarly, 8.1% (95% CI = 4.0-15.7) of women with disabilities compared to 2.3% (95% CI = 1.7-3.1) of women without disabilities experienced physical abuse during pregnancy. Multivariate analyses indicated that women with disabilities were more likely to report physical abuse before pregnancy (OR = 4.3, 95% CI = 1.9-9.7), during pregnancy (OR = 2.8, 95% CI = 1.1-7.1), or during either time period (OR = 3.2, 95% CI = 1.4-7.1) than women without disabilities while controlling for maternal age, education, race/Hispanic ethnicity, marital status and household poverty status. No difference was observed by disability status in the likelihood of prenatal-care providers talking to women about physical abuse. These analyses reveal disproportionate prevalence of physical abuse before and during pregnancy among women with disabilities. Screening for physical abuse and timely referral of women in need of assistance are critical to optimize health outcomes for both mother and child. PMID- 21556698 TI - Three-dimensional evaluation of mandibular bone regenerated by bone transport distraction osteogenesis. AB - The purpose of this study was to evaluate the structure and material properties of native mandibular bone and those of early regenerate bone, produced by bone transport distraction osteogenesis. Ten adult foxhounds were divided into two groups of five animals each. In all animals, a 3- to 4-cm defect was created on one side of the mandible. A bone transport reconstruction plate, consisting of a reconstruction plate with an attached intraoral transport unit, was utilized to stabilize the mandible and regenerate bone at a rate of 1 mm/day. After the distraction period was finished, the animals were killed at 6 and 12 weeks of consolidation. Micro-computed tomography was used to assess the morphometric and structural indices of regenerate bone and matching bone from the unoperated contralateral side. Significant new bone was formed within the defect in the 6- and 12-week groups. Significant differences (P <= 0.05) between mandibular regenerated and native bone were found in regard to bone volume fraction, mineral density, bone surface ratio, trabecular thickness, trabecular separation, and connectivity density, which increased from 12 to 18 weeks of consolidation. We showed that regenerated bone is still mineralizing and that native bone appears denser because of a thick outer layer of cortical bone that is not yet formed in the regenerate. However, the regenerate showed a significantly higher number of thicker trabeculae. PMID- 21556699 TI - Temporal progression in migratory status and sexual maturation in European silver eels during downstream migration. AB - The onset of downstream migration of European eels is accompanied by a cessation of feeding and the start of sexual maturation which stresses the link between metabolism and sexual maturation, also suggesting an important role for exercise. Exercise has been tested with eels in swim tunnels and was found to stimulate the onset of sexual maturation. In this study, we have investigated the interplay between migration and maturation in the field during the downstream migration of female silver eels. Temporal changes in migratory status and sexual maturation among silver eels of the upstream Rhine River system over 3 months of the migration season (August, September and October) were determined in biometrical parameters, plasma 17beta-estradiol and calcium levels, oocyte histology and gonadal fat levels. Furthermore, the ecological relevant parameters age as determined by otolithometry and health aspects indicated by haematocrit, haemoglobin and swim-bladder parasite load were measured. Silver eels were estimated to be 14 years old. A strong temporal progression in migratory stage was shown over the months of downstream migration. Catches probably represented a mix of reproductive migrants and feeding migrants of which the ratio increased over time. Furthermore, this study confirmed our hypothesis linking the migratory stage to early maturation as indicated by enlargement of the eyes, oocyte growth and fat deposition in the oocytes, exactly the same changes as found induced by exercise but not ruling out environmental influences. Migrants show extensive fat uptake by the oocytes, probably stimulated by the swimming exercise. In addition, at least 83% of the silver eels in this spawning run may have suffered from negative effects of swim-bladder parasites on their swimming performance. PMID- 21556700 TI - Genetic analysis and QTL detection of reproductive period and post-flowering photoperiod responses in soybean. AB - Reproductive period (RP) is an important trait of soybean [Glycine max (L.) Merr.] It is closely related to yield, quality and tolerances to environmental stresses. To investigate the inheritance and photoperiod response of RP in soybean, the F(1), F(2), and F(2:3) populations derived from nine crosses were developed. The inheritance of RP was analyzed through the joint segregation analysis. It was shown that the RP was controlled by one major gene plus polygenes. 181 recombinant inbred lines (RILs) generated from the cross of Xuyong Hongdou * Baohexuan 3 were further used for QTL mapping of RP under normal conditions across 3 environments, using 127 SSR markers. Four QTLs, designated qRP-c-1, qRP-g-1, qRP-m-1 and qRP-m-2, were mapped on C1, G and M linkage groups, respectively. The QTL qRP-c-1 on the linkage group C1 showed stable effect across environments and explained 25.6, 27.5 and 21.4% of the phenotypic variance in Nanjing 2002, Beijing 2003 and Beijing 2004, respectively. Under photoperiod controlled conditions, qRP-c-1, and two different QTLs designated qRP-l-1 and qRP o-1, respectively, were mapped on the linkage groups L and O. qRP-o-1 was detected under SD condition and can explained 10.70% of the phenotypic variance. qRP-c-1 and qRP-l-1 were detected under LD condition and for photoperiod sensitivity. The two major-effect QTLs can explain 19.03 and 19.00% of the phenotypic variance, respectively, under LD condition and 16.25 and 14.12%, respectively, for photoperiod sensitivity. Comparative mapping suggested that the two major-effect QTLs, qRP-c-1 and qRP-l-1, might associate with E8 or GmCRY1a and the maturity gene E3 or GmPhyA3, respectively. These results could facilitate our understanding of the inheritance of RP and provide information on marker assisted breeding for high yield and wide adaptation in soybean. PMID- 21556701 TI - Progression of pre-hypertension. PMID- 21556702 TI - Pulmonary vasodilation in acute and chronic heart failure: empiricism and evidence. AB - Pulmonary hypertension in heart failure is associated with exercise intolerance and adverse outcomes. With the availability of multiple drugs that cause pulmonary vasodilation and decrease pulmonary arterial pressure, pulmonary hypertension becomes an attractive therapeutic target. Out of several classes of medications, oral phosphodiesterase inhibitors emerge as the most promising in terms of symptomatic improvement, hemodynamic benefits, reverse cardiac remodeling, and functional capacity. Future trials will show whether the use of these drugs translates to decreased morbidity and mortality in heart failure. PMID- 21556703 TI - The value of data collection within a palliative care program. AB - Collecting reliable and valid data is an increasing expectation within palliative care. Data remain the crux for demonstrating value and quality of care, which are the critical steps to program sustainability. Parallel goals of conducting research and performing quality assessment and improvement can also ensure program growth, financial health, and viability in an increasingly competitive environment. Mounting expectations by patients, hospitals, and payers and inevitable pay-for-performance paradigms have transitioned data collection procedures from novel projects to expected standard operation within usual palliative care delivery. We present types of data to collect, published guides for data collection, and how data can inform quality, value, and research within a palliative care organization. Our experiences with the Quality Data Collection Tool (QDACT) in the Carolinas Palliative Care Consortium to collect data on quality have led to valuable lessons learned in creating a data collection system. Suggested steps in forming data-sharing collaborations and building data collection procedures are shared. PMID- 21556704 TI - Prey behaviour across antipredator adaptation types: how does growth trajectory influence learning of predators? AB - Despite the fact that the ability of animals to avoid being consumed by predators is influenced by their behaviour, morphology and life history, very few studies have attempted to integrate prey responses across these adaptation types. Here, our goal was to address the link between life-history traits (size and growth trajectory) of tadpoles and behavioural responses to predators. Specifically, we wanted to determine whether information learned about predators was influenced by prey growth trajectory before and after learning. We manipulated the size/growth trajectory of tadpoles by raising them under different temperatures. Tadpoles raised on a slow-growth trajectory (under cold conditions) and taught to recognize a salamander subsequently showed stronger responses after 2 weeks than tadpoles that were raised on a fast-growth trajectory (under warm conditions). When we account for the effect of size (r (2)=0.22) on the responses of prey to predator cues, we find that the growth trajectory pre-learning but not post learning influences the learned responses of the tadpoles. The differences in responses to predators may reflect differential memory associated with the predator. To our knowledge, this is the first study that has attempted to link life-history traits (size and growth rate) with learning of predators. In order to gain a comprehensive understanding of antipredator responses of prey animals, we call for additional integrative studies that examine prey anti-predator responses across adaptation types. PMID- 21556705 TI - Discrimination of painting style and quality: pigeons use different strategies for different tasks. AB - Birds have visual cognition as well developed as humans. Sometimes, the birds show visual discrimination similar to humans, but the birds may use different cues. Previous reports suggest that global configuration cues are salient for humans, whereas local elemental cues are salient for pigeons. I analyzed the discriminative behavior of pigeons with scrambled images because scrambled images keep the local elemental cues of the original images but lose the global configuration cues. If pigeons use local elemental cues, then, they should show transfer of discrimination from the original images to their scrambled images and also transfer from the scrambled images to their original images. In Experiment I, I trained pigeons on painting style discrimination (Japanese paintings vs. Western impressionist paintings) using either the original or scrambled images and found that the pigeons showed bidirectional transfer. In Experiment II, I trained pigeons on discrimination of "good" versus "bad" paintings using children's paintings. The birds showed poor transfer from the original images to their scrambled images and vise versa. Thus, the pigeons discriminated good and bad paintings based mostly on global configuration cues in this case. These results suggest that the pigeons use different cues for different discriminations. PMID- 21556706 TI - Copper-induced oxidative damage, antioxidant response and genotoxicity in Lycopersicum esculentum Mill. and Cucumis sativus L. AB - Adequate copper (Cu(2+)) concentrations are required for plants; however, at higher concentrations it can also cause multiple toxic effects. In the present study, lipid peroxidation, hydrogen peroxide levels as well as ascorbate peroxidase (APX: EC 1/11/1/11) and catalase (CAT: EC 1.11.1.6) activities were determined in Lycopersicum esculentum Mill. and Cucumis sativus L. seedlings after 7-day exposure to copper sulfate. In addition, DNA damage in these two crops was assessed by measuring micronucleus (MN) frequency and tail moments (TM) as determined by Comet assay. Inhibitory copper concentrations (EC(50): 30 and 5.5 ppm for L. esculentum and C. sativus, respectively) were determined according to dose-dependent root inhibition curves, and EC(50) and 2*EC(50) were applied. Malondialdehyde (MDA) and H(2)O(2) levels significantly increased in all groups studied. CAT activity increased in treatment groups of C. sativus. APX activity increased in L. esculentum seedlings due to 2*EC(50) treatment. Reductions in mitotic indices (MI) represented Cu(2+)dependent root growth inhibition in all treatment groups studied. According to TMs and MN frequencies, copper exposure induced significant DNA damage (p < 0.05) in all study groups, whereas the DNA damage induced was dose dependent in C. sativus roots. In conclusion, Cu(2+)induced oxidative damage, elevations in H(2)O(2) levels and alterations in APX and CAT activities, as well as significant DNA damage in nuclei of both study groups. To our knowledge, this is the first comparative and comprehensive study demonstrating the effects of copper on two different plant species at relevant cytotoxic concentrations at both biochemical and genotoxicity levels with multiple end points. PMID- 21556707 TI - Different effects of night versus day high temperature on rice quality and accumulation profiling of rice grain proteins during grain filling. AB - High temperature has adverse effects on rice yield and quality. The different influences of night high temperature (NHT) and day high temperature (DHT) on rice quality and seed protein accumulation profiles during grain filling in indica rice '9311' were studied in this research. The treatment temperatures of the control, NHT, and DHT were 28 degrees C/20 degrees C, 27 degrees C/35 degrees C, and 35 degrees C/27 degrees C, respectively, and all the treatments were maintained for 20 days. The result of rice quality analysis indicated that compared with DHT, NHT exerted less effect on head rice rate and chalkiness, whereas greater effect on grain weight. Moreover, the dynamic accumulation change profiles of 61 protein spots, differentially accumulated and successfully identified under NHT and DHT conditions, were performed by proteomic approach. The results also showed that the different suppressed extent of accumulation amount of cyPPDKB might result in different grain chalkiness between NHT and DHT. Most identified isoforms of proteins, such as PPDK and pullulanase, displayed different accumulation change patterns between NHT and DHT. In addition, compared with DHT, NHT resulted in the unique accumulation patterns of stress and defense proteins. Taken together, the mechanisms of seed protein accumulation profiles induced by NHT and DHT during grain filling should be different in rice, and the potential molecular basis is discussed in this study. PMID- 21556708 TI - Endometriosis and headache. AB - Headache and endometriosis show some similarities in their clinical and epidemiological features that are probably due to the influence of female sexual hormones on both disorders. Epidemiological studies indicate that they are comorbid disorders. However, the nature of the comorbidity is not known with certainty, but a likely explanation may be common susceptibility genes. Another possibility is that, because they both are related to pain, increased pain sensitivity induced by one of the disorders may lead to a higher likelihood of developing the other, possibly mediated by nitrogen oxide or prostaglandins. A common link to the widespread use of estroprogestins may seem less probable. For physicians dealing with women with either of these disorders, awareness of the comorbidity may be helpful in the treatment of the patient. PMID- 21556709 TI - Epidemiology of cancer pain. AB - About half of cancer patients experience pain, most commonly due to their primary cancer. Pain severity is at least moderate for most patients experiencing cancer related pain. Pain may also persist in long-term cancer survivors. Cancer-related pain adds to mood disturbance and disability in cancer patients. Despite the frequent occurrence and substantial impact from cancer pain, both patient and provider barriers limit the identification and treatment of pain in cancer patients. PMID- 21556710 TI - Pain perception during menstrual cycle. AB - Sexual hormones influence complex brain function and pain perception. Many psychophysical studies attempted to establish pain perception changes across menstrual cycle in animal models and healthy women or those with chronic pain. General results are quite uncertain in regard to consistent menstrual-related fluctuations of pain perception. The few studies applying neurophysiological procedures to test pain-related changes during menstrual cycle suggested a fluctuation of central modulation of pain across phases, with a prevalence of excitatory versus inhibitory control in the premenstrual period, which may explain the cyclic worsening of many syndromes, such as migraine. Whatever is the relevance of menstrual cycle on individual painful symptoms, it should be accepted as one of the numerous factors influencing mechanisms of neuromodulation. PMID- 21556711 TI - Management of chronic pelvic pain. AB - Chronic pelvic pain is a complex condition that requires evaluation of the reproductive, gastrointestinal, urologic, musculoskeletal, psychological, and neurological systems. Usually, diagnosis and management entail identifying a network of disorders rather than a single cause of pain with a definitive cure. Only disorders that we commonly encounter in our practice will be discussed in this review. PMID- 21556714 TI - An infant with alternating metabolic acidosis and alkalosis: question. PMID- 21556713 TI - The demographics and costs of inpatient vesicoureteral reflux management in the USA. AB - This study evaluates the impact of vesicoureteral reflux (VUR) on the economy and inpatient healthcare utilization in the USA. A retrospective analysis was performed on children <= 18 years of age, hospitalized with the principal discharge diagnosis of VUR between 2000 and 2006, using the Healthcare Cost and Utilization Project Kids' Inpatient Database. The results are stratified as follows. First, by hospitalizations: between 2000 and 2006, 6,655 +/- 720 (standard error) children/year were hospitalized with VUR. Since 2003, both the length of each hospitalization and the number of hospitalizations have decreased. Second, by related procedures/diagnoses: ureteral reimplantation was the most common procedure, accounting for 89% of hospitalizations. Congenital genitourinary anomalies, disorders of the kidney/ureter/bladder, and urinary tract infections (UTI) were the most common related diagnoses. Thirdly, by hospital economics: since 2000, hospital charges for VUR increased despite decreased lengths of hospitalization. By 2006, hospital charges rose to $18,798/hospitalization, and aggregate national charges exceeded $100 million. Our results indicate that fewer children with VUR are requiring inpatient management. Children with VUR are often hospitalized for ureteral reimplantation or the management of related diagnoses. Since 2000, hospital charges for inpatient VUR management have increased. More efforts are needed to evaluate cost effective strategies for the evaluation and management of VUR. PMID- 21556715 TI - Parathyroid hormone levels in long-term renal transplant children and adolescents. AB - Secondary hyperparathyroidism is a common complication of chronic renal failure. Kidney transplantation corrects renal insufficiency and most metabolic abnormalities but hyperparathyroidism persists in 50% of children after transplantation. The aim of this study was to investigate parathyroid hormone (PTH) course and potential risk factors for hyperparathyroidism in children after renal transplant. We collected data from 145 transplanted children (mean follow up 4.7 years). Intact PTH level (iPTH) rapidly decreased in the first 6 months post-transplant and continued to decline in the following years. iPTH was above the normal range in 69.1% of the patients at the time of transplant and in 47% 1 year later, this improvement continuing thereafter. Hypercalcemia was present in 20.3% of the patients before transplant and in 6.3 and 4.1% of patients 6 months and 1 year after transplant, respectively. Hypophosphatemia was present in 5.5% of the patients at 6 months, and 45.5% of the patients needed phosphorus supplements during the first 6 months after transplant. Multivariate analysis indicated pre-transplant hyperparathyroidism, dialysis duration, creatinine clearance and hypophosphatemia as predictors of persistent hyperparathyroidism. In kidney transplanted children, serum iPTH normalized in the long term in the majority of cases. Thus, parathyroidectomy should be reserved for selected patients. PMID- 21556716 TI - Maintenance therapy with mycophenolate mofetil after rituximab in pediatric patients with steroid-dependent nephrotic syndrome. AB - Rituximab (RTX) has a significant steroid-sparing effect in children with steroid dependent nephrotic syndrome (SDNS). However, patients are likely to relapse with the recovery of CD20+ cells. We conducted a small prospective cohort study with a historical control to evaluate the effect of RTX infusion followed by mycophenolate mofetil (MMF) as a maintenance therapy. Nine patients with SDNS who stopped their steroid treatment but were treated with MMF after RTX infusion were prospectively observed (group A). Seven patients with SDNS who discontinued steroid and immunosuppressive agents after RTX administration served as a control (group B). During the first year after the administration of RTX, six patients in group A and one patient in group B did not suffer a relapse (p < 0.05). The number of patients who relapsed during the 1 year preceding RTX treatment did not differ between the two groups [4.1 (A) vs. 5.7 (B)], but it was significantly lower in the MMF-treated group 1 year after the RTX treatment [0.4 (A) vs. 2.3 (B), p < 0.005]. The daily amount of prednisolone after the RTX treatment was lower in group A than in group B (0.11 vs. 0.46 mg/kg/day, respectively; p < 0.05). Three patients in group A and five patients in group B relapsed to SDNS and needed additional RTX treatment(s) within 1 year (odds ratio 5.0). Based on these results, we conclude that maintenance therapy with MMF after RTX is a good clinical option. PMID- 21556717 TI - Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease associated with high morbidity and mortality. Most cases progress to end-stage renal failure. In approximately 50% of affected patients, mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway. This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells, particularly in the kidneys. Complement factor H (FH) heterozygosity induces unregulated activation of the membrane attack complex (MAC) C5b-9. Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis. Unfortunately, kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post-transplantation HUS recurrence, particularly in patients with FH mutation. Combined liver-kidney transplantation is also associated with poor outcome, mostly as a result of premature liver failure secondary to uncontrolled complement activation. Eculizumab is a complement C5 antibody that inhibits complement factor 5a (C5a) and the formation of the MAC. Thus, this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation. We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation. PMID- 21556718 TI - Posterior reversible encephalopathy syndrome in children with kidney diseases. AB - Posterior reversible encephalopathy syndrome (PRES) was originally used to describe a reversible, predominantly posterior leukoencephalopathy in patients who had renal insufficiency, hypertension, or who received immunosuppressive therapy. Since PRES is prevalent in children with kidney diseases, awareness and understanding of it is important for practicing pediatric nephrologists. A comprehensive approach to the diagnosis of PRES includes thorough determination of predisposing factors, clinical symptoms, and mandatory appropriate imaging. Unfortunately, the pathophysiology of PRES is still obscure and specificity of radiological examination has not yet been established. Two major predisposing factors, namely hypertension and calcineurin inhibitors, are well recognized. In addition, nephrotic syndrome is a common underlying condition for development of PRES. Frequent symptoms include altered consciousness (coma, stupor, lethargy, confusion), seizure, headache, and visual disturbance. Most of these symptoms usually develop abruptly and resolve within a few weeks after proper management. Cranial magnetic resonance (MR) imaging is the first-line modality of imaging studies for detecting PRES. Diffusion-weighted imaging with quantification of apparent diffusion coefficient (ADC) values by ADC mapping may provide more accurate and specific images in the future. PMID- 21556719 TI - Urinary MMP-9/NGAL complex in children with acute cystitis. AB - The matrix metalloproteinase-9 (MMP-9) and neutrophil gelatinase associated lipocalin (NGAL) are shown to increase in an inflammatory situation. Based on our previous reports that NGAL can be detected in the urine of children with urinary tract infection (UTI), we also asked whether MMP-9/NGAL complex could be detected in the urine of children with UTI. This multicenter, prospective study was conducted between October 2009 and October 2010. Seventy-one patients with symptomatic culture proven UTI, 37 asymptomatic children with contaminated urine and 37 healthy children were recruited. Mean uMMP-9/NGAL/Cr levels were significantly higher in the UTI group than in the control group (p < 0.0001). According to ROC analysis, the optimal cut-off level was 0.08 ng/mg to predict UTI. Using a cut-off value, sensitivity and specificity were 98.6 and 97.3%, respectively. The mean levels of uMMP-9/NGAL/cr in the UTI group were also significantly higher than those in the contamination group (p < 0.0001). There was no statistically significant difference between contamination group and the control group (p = 0.21). The mean uMMP-9/NGAL/Cr in the UTI group were significantly higher before treatment than after treatment (p < 0.0001). The area under the curve was 0.997 (SE: 0.002, 95% CI: 0.993 to 1.001) for uMMP-9/NGAL/Cr. Urinary MMP-9/NGAL/Cr level was also correlated with positive urine nitrite test, positive urine leukocyte esterase reaction and renal scarring (p = 0.0001, p = 0.0001, p = 0.04, respectively) whereas was not correlated to leukocytosis and positive CRP level in serum. Urine MMP-9/NGAL/cr can be used as a diagnostic biomarker for UTI in children. Identification of NGAL-MMP-9/cr levels in the urine of suspected UTI patients may also be useful to differentiate between contamination and infection and for monitoring of treatment response in children. PMID- 21556720 TI - Unmet psychosocial needs among cancer patients undergoing ambulatory care in Singapore. AB - PURPOSE: Previous studies have demonstrated high prevalence of unmet psychosocial needs among cancer patients, but few were conducted among Asians. In this cross sectional study, we investigated the prevalence of and factors associated with unmet psychosocial needs among cancer patients undergoing ambulatory care at a cancer centre in Singapore. METHOD: We conducted a cross-sectional study among 535 breast, gynaecological and colorectal cancer patients (response rate, 76%) using a modified version of the Cancer Survivors' Unmet Needs measure questionnaire, to assess the prevalence of patients' needs for disease information and social support, physical needs, financial needs and psychological needs, and the extent to which needs were met. Logistic regression analysis was used to identify demographic or disease characteristics associated with unmet needs. RESULTS: Seventy-five per cent of patients reported having any unmet needs, with disease information needs being most prevalent (61.5%) followed by financial (40.2%), social support (39.7%), psychological (27.3%) and physical (26.1%) needs. Factors independently associated with having high level of unmet needs were age below 60 years, ethnic minority, advanced disease and recent diagnosis. CONCLUSION: The prevalence of unmet psychosocial needs among cancer patients in ambulatory care is generally high. Young patients with disease recently diagnosed at advanced stage will benefit from additional support. PMID- 21556721 TI - Systematic review: malfunction of totally implantable venous access devices in cancer patients. AB - PURPOSE: Malfunction of totally implantable venous access devices is a common complication. The purpose was to identify definitions used to describe malfunction and to investigate the incidence of malfunction in different types of port and catheter designs. METHODS: Relevant studies were identified in PubMed that were published between January 1993 and February 2011. Empirical studies reporting functional outcomes in adults and where, at least 95% of the studied population consisted of onco-hematology patients with a newly inserted chest or arm port, were selected. The following data were extracted: patient and totally implantable venous access devices (TIVAD) characteristics, study design, definitions of malfunction, and functional outcomes. Two independent reviewers assessed the methodological quality of the series. RESULTS: Of the 4,886 potentially relevant articles, 57 were selected, involving 14,311 TIVADs. Twenty nine percent of the studies explicitly defined malfunction. Malfunction incidence rates were expressed in six different ways, including the proportion of affected devices per inserted devices (incidence 0-47%); the number of affected devices per 1,000 catheter days (incidence 0-2.24 per 1,000 catheter days); and the number of malfunctions over the total number of accessing attempts (incidence 0 26%). CONCLUSIONS: Heterogeneity in the definitions used to describe device malfunction was evident. A broad range in the reported incidence of malfunction and in the kind of calculation and reporting methods was also found. Methodological quality of the studies was often poor. Standardization of definitions and accurate outcome measurement is needed. Calculation and report of malfunction incidence should be based on prospective data collected at the moment of an accession attempt. PMID- 21556722 TI - A study of pipeline drugs in neuroendocrine tumors. AB - PURPOSE: Inhibition of neovessel development can stabilize tumor growth. A rapid in vitro method that can evaluate the effectiveness of anti-angiogenic drugs would aid in drug development. We tested a series of investigational agents to determine their ability to inhibit angiogenesis in our in vitro human angiogenesis model. METHODS: A total of 74 neuroendocrine tumors were tested with five therapeutic agents for anti-angiogenic activity. Angiogenic responses were assessed visually and the percent of tumor explants that developed an angiogenic response was determined. The extent of neovessel growth was rated using a validated semi-quantitative visual scale. Analysis of variance was used to compare treatment outcome results to control values for these angiogenic parameters. RESULTS: Vatalanib (2 * 10(-5) M) and patupilone (1 * 10(-8) M) were highly effective inhibitors of human tumor angiogenesis (mean overall angiogenic response for drug versus control 1.3 vs. 5.9 and 0.2 vs. 5.2, respectively) and were statistically significant at p <0.0001. Imatinib (2.5 * 10(-6) M) and everolimus (1 * 10(-8) M) were also effective (mean overall angiogenic response for drug versus control 2.2 vs. 5.9 and 4.5 vs. 5.9, respectively), and these were also statistically significant at p <0.0001. Pasireotide (1 * 10(-8) M) had no effect on angiogenesis (mean overall angiogenic response for drug vs. control 5.5 vs. 5.2). CONCLUSIONS: Significant differences in angiogenic response to test drugs were noted in this neuroendocrine patient population. In vitro screening of a large series of fresh human tumors may be a cost-effective way to select drugs for continued clinical development. PMID- 21556723 TI - Gastrointestinal Mantle Cell Lymphoma-A Tale of Two Endoscopies. AB - INTRODUCTION: A 52-year-old male with a 2-year history of typical gastroesophageal reflux symptoms and concomitant weight loss despite good appetite is presented in this paper. Endoscopy showed hypertrophic gastric folds and multiple antral ulcers which were considered benign both histologically and macroscopically. The diagnosis at the time of presentation was moderate chronic gastritis. Eighteen months later, the patient presents with overt adenopathy in all peripheral lymph nodes and was subsequently diagnosed with mantle cell lymphoma (MCL). DISCUSSION: On second presentation, the patient underwent a repeat endoscopy with biopsy and immunohistochemical (IHC) testing of gastrointestinal and lymph node tissue. The gastrointestinal endoscopy showed multiple polypoid nodules in the first and second parts of the duodenum and multiple sessile polypoid masses carpeting the colon. Gastric and lymph node biopsies were consistent with a diagnosis of MCL and MLP showing immunoperoxidase staining positive for cyclin D1, CD20 and bcl-2. A repeat IHC testing of the gastrointestinal tissue collected on initial endoscopy also showed a positive expression of the IHC markers consistent with MCL. In retrospect, an earlier detection of MCL was possible when the patient had first presented. PMID- 21556724 TI - Reversible posterior leukoencephalopathy syndrome associated with concurrent bevacizumab, gemcitabine, and oxaliplatin for cholangiocarcinoma. AB - INTRODUCTION: Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare disorder characterized by altered mental status, seizure, hypertension, and symmetrical white matter edema (leukoencephalopathy) typically in the posterior cerebral hemispheres on brain imaging. It is often linked to certain medication use, in particular, chemotherapeutic agents. Here, we present a case of chemotherapy-related RPLS and review the current literature on this topic. CASE REPORT: We report a case of RPLS associated with concurrent bevacizumab (Avastin), gemcitabine, and oxaliplatin use for unresectable intrahepatic cholangiocarcinoma. CONCLUSION: This is the first reported case of RPLS associated with bevacizumab, gemcitabine, and oxaliplatin combination chemotherapy. Concurrent use of multiple agents could significantly increase the risk of RPLS, a potentially fatal disease. Our case suggests that gradual progression of hypertension and proteinuria may be early warning signs before the onset of RPLS that should alarm clinicians. PMID- 21556725 TI - Localization of type III collagen in the lingual mucosa of rats during the morphogenesis of circumvallate papillae. AB - In an effort to identify a possible role for type III collagen in the morphogenesis of circumvallate papillae on the surface of the rat tongue, we examined its appearance by fluorescent immunostaining, in conjunction with differential interference contrast images and images obtained, after staining with toluidine blue, in the transmission mode by laser-scanning microscopy. We analyzed semi-ultrathin sections of epoxy resin-embedded samples of the lingual mucosa of embryonic and juvenile rats, 13 days after conception (E13) to day 21 after birth (P21). Immunoreactivity specific for type III collagen was recognized first in the mesenchymal connective tissue just beneath the circumvallate papilla placode in fetuses on E13. At this stage, most of the lingual epithelium with the exception of the circumvallate papilla placode was pseudostratified epithelium composed of one or two layers of cuboidal cells. However, the epithelium of the circumvallate papilla placode was composed of several layers of cuboidal cells. Immunoreactivity specific for type III collagen was detected mainly on the lamina propria just beneath the lingual epithelium of the rudiment of the circumvallate papilla and the developing circumvallate papilla in fetuses on E15 and E17, and slight immunostaining was detected on the lamina propria around the rudiment. In fetuses on E19, immunoreactivity specific for type III collagen was widely and densely distributed on the connective tissue around the developing circumvallate papillae and, also, on the connective tissue that surrounded the lingual muscle. However, the immunoreactivity specific for type III collagen was sparsely distributed on the lamina propria of each central papillar structure. After birth, from P0 to P14, morphogenesis of the circumvallate papillae advanced gradually with the increase in the total volume of the tongue. At these postnatal stages, the intensity of the fluorescence due to immunoreactivity specific for type III collagen was distinctively distributed on the lamina propria around each circumvallate papilla, on each central bulge and on the connective tissue that surrounded the lingual muscle. However, immunofluorescence was less distinct on the connective tissue that surrounded the lingual muscle. Thus, type III collagen appeared in conjunction with the morphogenesis of the circumvallate papillae, as well as in the connective tissue that surrounded the lingual muscle during myogenesis of the rat tongue. PMID- 21556726 TI - The characterization of dentin defects produced by air polishing. AB - The objective of this study is to characterize the defects in the dentin surface after air polishing for three types of polishing powders and five different nozzle distances. Human teeth were embedded in acrylic resin and then polished until the dentin surface became exposed. The nozzle of the polisher was fixed at a specified distance (2, 3, 4, 5, or 6 mm) and orientation (45 degrees ) with respect to the dentin surface. The three powders were CLASSIC (NaHCO(3), 65 MUm diameter), PERIO (glycine, 25 MUm diameter), and SOFT (glycine, 65 MUm diameter). With respect to nozzle distance, we find a significant difference in the mean defect depth only at 6 mm. The spray distance of 6 mm produced the shallowest defect depths. This variable had no effect on the defect volume. SOFT powder had significantly less depths and volumes of defects than the other two powders. The contact angle of the dentin increased significantly in all polishing tests, compared to an unpolished dentin surface (control). We find that spray distance of 6 mm from the nozzle of the polisher and orienting on 45 degrees angle produced less dentin surface defects than any other distance in all powder systems used. At this distance, SOFT powder produced statistically significant smaller depth and volume defects than the other two powder groups. PMID- 21556727 TI - Comparison of three strip-type tests and two laboratory methods for salivary buffering analysis. AB - This study evaluated the correlation between three strip-type, colorimetric tests and two laboratory methods with respect to the analysis of salivary buffering. The strip-type tests were saliva-check buffer, Dentobuff strip and CRT((r)) Buffer test. The laboratory methods included Ericsson's laboratory method and a monotone acid/base titration to create a reference scale for the salivary titratable acidity. Additionally, defined buffer solutions were prepared and tested to simulate the carbonate, phosphate and protein buffer systems of saliva. The correlation between the methods was analysed by the Spearman's rank test. Disagreement was detected between buffering capacity values obtained with three strip-type tests that was more pronounced in case of saliva samples with medium and low buffering capacities. All strip-type tests were able to assign the hydrogencarbonate, di-hydrogenphosphate and 0.1% protein buffer solutions to the correct buffer categories. However, at 0.6% total protein concentrations, none of the test systems worked accurately. Improvements are necessary for strip-type tests because of certain disagreement with the Ericsson's laboratory method and dependence on the protein content of saliva. PMID- 21556728 TI - Effect of the smear layer on a pulp proximity-indicating instrument. AB - The purpose of the study was to determine the effect of removing or modifying the smear layer on the indication provided by the Prepometer pulp proximity indicating instrument. Third molars were prepared to produce flat surfaces in the coronal dentine, and control Prepometer LED readings were made. Group E was treated with 18% EDTA and Group T with Tubulicid. Prepometer readings were repeated. Dentine was removed in 0.5 mm increments, and readings repeated until a red LED appeared, indicating a danger of pulp exposure. Distances to the pulp were measured. t test, Wilcoxon signed ranks test (WSR) and ordinal regression (OR) analysis were performed, together with SEM examination. There were significant differences between both test groups and their untreated controls. OR showed that a red LED appeared further from the pulp with EDTA treatment than with no treatment. A red LED appeared closer to the pulp with Tubulicid treatment than with no treatment. SEM showed smear removal in Group E and occlusion of tubules in Group T. Prepometer performance was significantly influenced by treatment with EDTA and Tubulicid. Practitioners would be required to learn to interpret the display of the Prepometer instrument in the context of the tooth under treatment and the surface condition of the cut dentine. PMID- 21556729 TI - Reviewer's comment concerning ''Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI'' (doi:10.1007/s00586-011 1776-8) by J. Domenech et al. PMID- 21556730 TI - Endoscope-assisted microsurgical transoral approach to the anterior craniovertebral junction compressive pathologies. AB - At the present time, an update to the classical microsurgical transoral decompression is strongly provided by the most recent literature dealing with the introduction of the endoscopy in spine surgery. In this paper, we present our experience on the endoscope-assisted microsurgical transoral approach to anterior craniovertebral junction (CVJ) compressive pathology. We analysed seven patients (3 paediatrics and 4 adults ranging from 6 to 78 years) operated on for CVJ decompressive procedures using an open access, microsurgical technique, neuronavigation and endoscopy. All techniques mentioned were simultaneously employed. Among the endoscopic routes described in the literature, we have preferred the transoral using 30 degrees endoscopes. In all the cases endoscopy allowed a radical decompression compared to the microsurgical technique alone, as confirmed intraoperatively with contrast medium fluoroscopy. In conclusion, endoscopy represents a useful complement to the standard microsurgical approach to the anterior CVJ; it provides information for a better decompression with no need for soft palate splitting, hard palate resection, or extended maxillotomy. Moreover, intraoperative fluoroscopy helps to recognize residual compression. Virtually, in normal anatomic conditions, no surgical limitations exist for endoscopically assisted transoral approach, compared with the pure endonasal and transcervical endoscopic approaches. In our opinion, the endoscope deserves a role as "support" to the standard transoral microsurgical approach since 30 degrees angulated endoscopy significantly increases the surgical area exposed at the level of the anterior CVJ. PMID- 21556731 TI - Somatosensory evoked potential from S1 nerve root stimulation. AB - The objective of this study was to detect cerebral potentials elicited by proximal stimulation of the first sacral (S1) nerve root at the S1 dorsal foramen and to investigate latency and amplitude of the first cerebral potential. Tibial nerve SEP and S1 nerve root SEP were obtained from 20 healthy subjects and 5 patients with unilateral sciatic nerve or tibial nerve injury. Stimulation of the S1 nerve root was performed by a needle electrode via the S1 dorsal foramen. Cerebral potentials were recorded twice to document reproducibility. Latencies and amplitudes of the first cerebral potentials were recorded. Reproducible cerebral evoked potentials were recorded and P20s were identified in 36 of 40 limbs in the healthy subjects. The mean latency of P20 was 19.8 +/- 1.6 ms. The mean amplitude of P20-N30 was 1.2 +/- 0.9 MUV. In the five patients, P40 of tibial nerve SEP was absent, while well-defined cerebral potentials of S1 nerve root SEP were recorded and P20 was identified from the involved side. This method may be useful in detecting S1 nerve root lesion and other disorders affecting the proximal portions of somatosensory pathway. Combined with tibial nerve SEP, it may provide useful information for diagnosis of lesions affecting the peripheral nerve versus the central portion of somatosensory pathway. PMID- 21556732 TI - Imaging signatures of molecular pathology in behavioral variant frontotemporal dementia. AB - Pathology underlying behavioral variant frontotemporal dementia (bvFTD) is heterogeneous, with the most common pathologies being Pick's disease (PiD), corticobasal degeneration (CBD), and FTLD-TDP type 1. Clinical features are unhelpful in differentiating these pathologies. We aimed to determine whether imaging atrophy patterns differ across these pathologies in bvFTD subjects. We identified 15 bvFTD subjects that had volumetric MRI during life and autopsy: five with PiD, five CBD, and five FTLD-TDP type 1. Voxel-based morphometry was used to assess atrophy patterns in each bvFTD group compared to 20 age- and gender-matched controls. All three pathological groups showed gray matter loss in frontal lobes, although specific patterns of atrophy differed across groups: PiD showed widespread loss in frontal lobes with additional involvement of anterior temporal lobes; CBD showed subtle patterns of loss involving posterior lateral and medial superior frontal lobe; and FTLD-TDP type 1 showed widespread loss in frontal, temporal, and parietal lobes. Greater parietal loss was observed in FTLD TDP type 1 compared to both other groups, and greater anterior temporal and medial frontal loss was observed in PiD compared to CBD. Imaging patterns of atrophy in bvFTD vary according to pathological diagnosis and may therefore be helpful in predicting these pathologies in bvFTD. PMID- 21556733 TI - Neuroprotection by NMDA preconditioning against glutamate cytotoxicity is mediated through activation of ERK 1/2, inactivation of JNK, and by prevention of glutamate-induced CREB inactivation. AB - N-methyl-D-aspartate (NMDA) preconditioning is a major endogenous brain protective mechanism, activated by sub-lethal stimulation of the NMDA glutamate receptors. Selective drug activation of this mechanism is considered to be a promising neuroprotective treatment against stroke and other traumatic brain insults. We have established an experimental in vitro model of NMDA preconditioning in primary rat neuronal cultures composed of three consecutive periods: preconditioning (NMDA 50 9M for 18 h), insult (glutamic acid 200 9M for 1 h), and reperfusion (regular medium for 24 h). The insulted neuronal cultures exhibited a 2.8-fold increase in LDH release into the media during the post insult reperfusion period, which was completely abolished in the preconditioned cultures. The alterations in the activity level of the pro-survival kinase extracellular signal-regulated kinase (ERK) 1/2, the death machine activator c Jun N-terminal kinase (JNK), and the pro-survival transcription factor cAMP responsive element binding (CREB) were monitored in preconditioned neuronal cultures in comparison to non-preconditioned cells during the three periods of the experimental model. The preconditioned neurons exhibited increased activity levels of ERK 1/2 and decreased activity levels of JNK during all periods of the model. In addition, the non-preconditioned neurons exhibited a marked reduction in the activity level of CREB during the insult period, which was totally prevented in the preconditioned cultures. These results suggest that the neuroprotection conferred by NMDA preconditioning against glutamate cytotoxicity is mediated (at least in part) through activation of ERK 1/2, inactivation of JNK and by prevention of glutamate-induced CREB inactivation. PMID- 21556734 TI - Effects of different copper sources and levels on plasma superoxide dismutase, lipid peroxidation, and copper status of lambs. AB - This study was performed to determine the effects of different copper (Cu) sources and levels on plasma superoxide dismutase (SOD), lipid peroxidation, and Cu status of lambs. Fifty Dorper * Mongolia wether lambs (approximately 3 month of age; average BW = 23.8 +/- 0.6 kg) were divided into five equal groups each with ten animals according to their weight. Treatments consisted of (1) control (no supplemental Cu), (2) 10 mg Cu/kg DM from Cu-lysine, (3) 20 mg Cu/kg DM from Cu-lysine, (4) 10 mg Cu/kg DM from tribasic copper chloride (Cu(2)(OH)(3)Cl; TBCC), and (5) 20 mg Cu/kg DM from TBCC. The Cu concentration was 6.74 mg/kg DM in the basal diet. Plasma copper concentrations and ceruloplasmin activities were not affected on day 30 by Cu supplementation. Copper supplementation increased plasma and liver copper concentrations and ceruloplasmin activities on day 60. Muscle Cu concentrations were not affected by Cu supplementation. There were no differences in plasma, liver, and muscle Cu concentrations and ceruloplasmin activities between Cu-lysine and TBCC. Liver copper concentrations and plasma ceruloplasmin activities were increased in lambs supplemented with 20 mg Cu/kg DM than in those supplemented with 10 mg Cu/kg DM on day 60. However, copper levels had no effects on Cu concentrations in plasma and muscle. Malondialdehyde (MDA) concentrations were decreased in plasma and liver tissues, but not affected in muscle by Cu supplementation. Plasma SOD activities were increased by Cu supplementation. There were no differences in plasma, liver, and muscle MDA concentrations and plasma SOD activities between Cu sources and levels. These results indicated that Cu supplementation increased plasma SOD activity, lipid oxidative stability, and copper status of lambs, but did not influence lipid oxidative stability in sheep muscle. Cu-lysine and TBCC were of similar availability when offered to finishing sheep. PMID- 21556735 TI - Farnesyltransferase inhibitor manumycin targets IL1beta-Ras-HIF-1alpha axis in tumor cells of diverse origin. AB - We have recently reported that Ras acts as an intermediate coactivator in IL 1beta-mediated hypoxia-inducible factor-1alpha (HIF-1alpha) activation in glioblastoma multiforme (GBM). Since HIF-1alpha plays a crucial role in linking inflammatory and oncogenic pathways, we investigated whether this IL1beta-Ras-HIF 1alpha signaling axis observed in GBM also exists in other tumors of diverse origin under normoxia. Treatment with IL-1beta induced Ras in non-GBM cell lines A549 (lung), HeLa (cervical), and HepG2 (liver), and inhibition of Ras activity attenuated HIF-1alpha activity. Our findings suggest that Ras links IL-1beta and HIF-1alpha in tumors of diverse origin. As we have previously reported that the farnesyltransferase inhibitor manumycin decreases Ras activity in glioma cells, we investigated whether manumycin could regulate IL-1beta-mediated HIF-1alpha activation. Manumycin abrogated IL-1beta-induced HIF-1alpha activation in both glioma and non-glioma tumor cells. In addition, manumycin also decreased IL-1beta induced pro-inflammatory responses in tumor cells. PMID- 21556736 TI - Evaluation of the inflammatory response to two different intensities of exercise in individuals with heart failure. AB - The aim of this study is to compare the response of interleukin-6 (IL-6) and soluble tumor necrosis factor alpha receptor 1 (s-TNFr1) to two submaximal intensities of exercise in individuals with heart failure (HF). Thirty-two HF individuals aged 45.53 +/- 9.41 years, classes II and III of the New York Heart Association (NYHA) classification underwent two sessions of exercise at low and moderate intensities with blood analysis at baseline, exercise and after exercise. The differences were evaluated by Friedman test and factorial ANOVA. Alpha = 5% was considered. No difference in IL-6 was detected for low intensity. At moderate intensity, there was a significant increase after exercise. The s TNFr1 increased in moderate-intensity exercise and went back to baseline levels after it. A session of moderate-intensity exercise is better than low-intensity exercise at promoting positive immediate inflammatory responses in individuals with HF class II and III of the NYHA. PMID- 21556737 TI - The role of Raf kinase inhibitor protein in rheumatoid fibroblast-like synoviocytes invasiveness and cytokine and matrix metalloproteinase expression. AB - Fibroblast-like synoviocytes (FLS) play an important role in the pathogenesis of rheumatoid arthritis. Raf kinase inhibitor protein (RKIP) negatively regulates the Raf/MEK/ERK and NF-kappaB pathway. The role of RKIP in rheumatoid FLS is unknown. The purpose of the present study was to investigate the function of RKIP in rheumatoid FLS. Rheumatoid FLS were transfected with either RKIP-expressing plasmids or RKIP small interfering RNA (siRNA). RKIP protein was detected in rheumatoid synovial tissue (ST) and FLS. RKIP overexpression significantly decreased IL-6 mRNA expression in TNF-alpha-stimulated rheumatoid FLS. RKIP overexpression also showed a decreased trend in IL-8, MMP-1, and MMP-3 mRNA expression in TNF-alpha-stimulated rheumatoid FLS. RKIP silencing resulted in significantly increased MMP-1 and MMP-3 mRNA expression in TNF-alpha-stimulated rheumatoid FLS. RKIP silencing also increased IL-6 and IL-8 mRNA expression in TNF-alpha-stimulated rheumatoid FLS, but this increase did not reach statistical significance. TNF-alpha-induced ERK and NF-kappaB activation was suppressed in FLS with RKIP overexpression. RKIP silencing resulted in a significantly higher invasion index in TNF-alpha-stimulated rheumatoid FLS compared to controls. These results suggest that RKIP might be a potential therapeutic target for rheumatoid arthritis. PMID- 21556738 TI - The evaluation of argyrophilic nucleolar organizing region proteins in fine needle aspiration samples of thyroid. AB - Argyrophilic nucleolar organizing region associated proteins (AgNORs) have been shown to be of interest in a variety of different diseases including thyroid disorders. Our aim was to distinguish benign thyroid lesions from papillary thyroid carcinoma (PTC) via AgNOR count and with a new approach, via AgNOR surface area/total nuclear surface area (NORa/TNa) proportions in the nuclei on fine-needle aspiration (FNA) materials. Thirty patients (eight men and 22 women) whose FNA was compatible with benign lesion and 26 patients (eight men and 18 women) whose FNA was compatible with PTC were included in the study. Fine-needle aspiration materials were stained for AgNOR detection according to a specific protocol. One hundred nuclei per individual have been evaluated, and AgNOR number and NORa/TNa proportions of individual cells were measured and calculated by using a computer program. Patients with PTC had significantly (p<0.001) higher AgNOR count (4.6 +/- 1.2%) than in the patients with benign lesions (2.0 +/- 0.5%). Additionally, patients with PTC had significantly (p<0.001) higher NORa/TNa (13.4 +/- 2.4) than in the patients with benign lesion (5.7 +/- 1.0). Modified method of AgNOR staining is an easy and reliable method for evaluating proliferation activity of cells in malignant and benign thyroid lesions and it may contribute to routine cytopathology in inconclusive situations. PMID- 21556739 TI - Classical and follicular variant papillary thyroid carcinoma: comparison of clinical, ultrasonographical, cytological, and histopathological features in 444 patients. AB - Follicular variant papillary thyroid carcinoma (FVPTC) is the most common variant of papillary thyroid carcinoma (PTC) after classical PTC (CPTC). In this study, we aimed to compare functional status, ultrasonographical features, cytological results, and histopathological characteristics of patients with CPTC and FVPTC. Preoperative thyroid functions, thyroid autoantibodies, ultrasonographical features, cytology, and histopathology results of 354 (79.9%) CPTC and 90 (20.3%) FVPTC patients were reviewed retrospectively. Sex distribution, mean age, thyroid autoantibody positivity, and thyroid dysfunctions were similar in two groups. Among 320 patients with preoperative ultrasonography (US) findings, a hypoechoic halo was observed more frequently (p=0.003), and marginal irregularity was observed less commonly (p=0.024) in FVPTC lesions. In CPTC, rate of malignant cytology (p=0.001), and in FVPTC, rate of suspicious cytology (p<0.001) were significantly higher. Histopathologically, mean tumor diameter was markedly higher in FVPTC compared to CPTC (16.89 +/- 13.86 vs 10.64 +/- 9.70 mm, p<0.001), while capsular invasion and extrathyroidal spread were significantly lower in patients with FVPTC (p=0.018 and p=0.039, respectively). FVPTC tend to have more benign features in US and less malignant results in cytology. Higher tumor size in FVPTC might be explained by the recognition of clinical importance of these lesions after reaching particular sizes due to benign US features. PMID- 21556740 TI - An unusual "thyroid cyst": intrathyroidal parathyroid cyst. PMID- 21556741 TI - Microfluidic array for three-dimensional perfusion culture of human mammary epithelial cells. AB - The ability to culture cells in three dimensional extracellular matrix (3D ECM) has proven to be an important tool for laboratory biology. Here, we demonstrate a microfluidic perfusion array on a 96-well plate format capable of long term 3D ECM culture within biomimetic microchambers. The array consists of 32 independent flow units, each with a 4 MUl open-top culture chamber, and 350 MUl inlet and outlet wells. Perfusion is generated using gravity and surface tension forces, allowing the array to be operated without any external pumps. MCF-10A mammary epithelial cells cultured in Matrigel in the microfluidic array exhibit acinus morphology over 9 days consistent with previous literature. We further demonstrated the application of the microfluidic array for in vitro anti-cancer drug screening. PMID- 21556742 TI - Velvet bean severe mosaic virus: a distinct begomovirus species causing severe mosaic in Mucuna pruriens (L.) DC. AB - Velvet bean [Mucuna pruriens (L.) DC] is one of the most important medicinal plants. It is used to treat many ailments, but is widely used for the treatment especially for Parkinson's disease because of the presence of 3,4 dihydroxyphenylalanine (L-dopa) in it. It was noticed in last 5 years that the plants in the field showed severe mosaic, downward curling of the leaves, stunting, etc. This is consistently observed over the years in India. The disease was transmitted by whiteflies and by grafting and the causal agent was found to be a bipartite begomovirus. The whole genome was amplified by rolling circle amplification (RCA) using phi-29 DNA polymerase and characterized. DNA-A and DNA B shared a 124-nucleotide (nt) long highly conserved (98%) common region (CR). Comparisons with other begomovirus showed that DNA-A sequence has highest identity (76%) with an isolate of Mungbean yellow mosaic India virus (MYMIV; AY937195) reported from India. This data suggested that the present isolate is a new species of genus Begomovirus for which the name "Velvet bean severe mosaic virus" (VbSMV) is proposed. DNA-B has a maximum sequence identity of 49% with an isolate of Horsegram yellow mosaic virus (HgYMV; AM932426) reported from India. Infectious clones consisting of a 1.7 mer partial tandem repeat of DNA-A and a dimer of DNB-B were constructed and agro-inoculated to Macuna pruriens (L.) DC plants, which showed field observed symptoms 24 days post-infiltration (dpi). In phylogenetic analysis, DNA-A and DNA-B of the present isolate grouped with DNA-A of different begomoviruses reported from fabaceous crops. The study presents first ever molecular evidence of any disease in velvet bean and whole genome analysis of the causative virus which is a distinct bipartite species of Begomovirus. PMID- 21556743 TI - Polymorphisms of the prion protein gene and their effects on litter size and risk evaluation for scrapie in Chinese Hu sheep. AB - It is well known that scrapie is a fatal, neurodegenerative disease in sheep and goat, which belongs to the group of transmissible spongiform encephalopathies (TSEs) or prion diseases. It has been confirmed that the polymorphisms of prion protein gene (PRNP) at codons 136, 154, and 171 have strong relationship with scrapie in sheep. In the present study, nine polymorphisms of PRNP at codons 136, 154, and 171 and other six loci (at codons 101, 112, 127, 137, 138, and 152) were detected in 180 Chinese Hu sheep. All the alleles at codons 136, 154, and 171 have been identified and resulted in three new genotypes. The frequencies of predominant alleles were 85% (A136), 99.40% (R154), and 37.78% (Q171), respectively. The predominant haplotype ARQ has a relatively high frequency of 57.77%. The frequencies of dominant genotypes of ARR/ARQ and ARQ/ARQ were 30 and 26.67%, respectively. Three new found genotypes named ARQ/TRK, ARQ/TRR, and TRR/TRQ had the same lower frequencies (0.56%). The relationship of PRNP genotype with scrapie risk and litter size showed that the predominant genotypes are corresponded to the risk score of R(1) (1.67%), R(2) (32.22%), and R(3) (42.22%). Just at the first parity, the individuals with ARH/ARH genotype had significantly larger litter size than the mean value and those with ARQ/ARQ and ARR/ARQ genotypes. In short, this study provided preliminary information about alleles and genotypes of PRNP in Chinese Hu sheep. It could be concluded that Hu sheep has a low susceptibility to natural scrapie, and the predominant PRNP genotype at least has no significant effect on litter size. PMID- 21556744 TI - A longitudinal study of motor performance and striatal [18F]fluorodopa uptake in Parkinson's disease. AB - Although [(18)F]fluoro-L: -dopa [FDOPA] positron emission tomography (PET) has been used as a surrogate outcome measure in Parkinson's disease therapeutic trials, this biomarker has not been proven to reflect clinical status longitudinally. We completed a retrospective analysis of relationships between computerized sampling of motor performance, FDOPA PET, and clinical outcome scales, repeated over 4 years, in 26 Parkinson's disease (PD) patients and 11 healthy controls. Mixed effects analyses showed that movement time and tongue strength best differentiated PD from control subjects. In the treated PD cohort, motor performance measures changed gradually in contrast to a steady decline in striatal FDOPA uptake. Prolonged reaction and movement time were related to lower caudate nucleus FDOPA uptake, and abnormalities in hand fine force control were related to mean striatal FDOPA uptake. These findings provide evidence that regional loss of nigrostriatal inputs to frontostriatal networks affects specific aspects of motor function. PMID- 21556745 TI - A few thoughts on brain ROIs. AB - Quantitative mapping of structural and functional connectivities in the human brain via non-invasive neuroimaging offers an exciting and unique opportunity to understand brain architecture. Because connectivity alterations are widely reported in a variety of brain diseases, assessment of structural and functional connectivities has emerged as a fundamental research area in clinical neuroscience. A fundamental question arises when attempting to map structural and functional connectivities: how to define and localize the best possible Regions of Interests (ROIs) for brain connectivity mapping? Essentially, when mapping brain connectivities, ROIs provide the structural substrates for measuring connectivities within individual brains and for pooling data across populations. Thus, identification of reliable, reproducible and accurate ROIs is critically important for the success of brain connectivity mapping. This paper discusses several major challenges in defining optimal brain ROIs from our perspective and presents a few thoughts on how to deal with those challenges based on recent research work done in our group. PMID- 21556746 TI - The effect of oral and parenteral vitamin D supplementation in the elderly: a prospective, double-blinded, randomized, placebo-controlled study. AB - Hypovitaminosis D in the elderly causes falls and fractures as a result of impaired neuromuscular functions and also may be a reason for nonspecific musculosceletal pain. The aim of this study is to investigate the benefits of a single dose per os or parenterally administrated vitamin D on increasing the quality of life and functional mobility and decreasing the pain in the elderly. The community-dwelling elderly subjects over 65 years age were included in the study. The subjects were given 300.000 IU Vitamin D via per os and parenteral route and assessed after 4 weeks. The serum creatinine, calcium, phosphorous, ALT, ALP, 24-h urine calcium excretion, PTH, and vitamin D levels, as well as VAS (visual analog scale) for pain assessment, functional mobility with TUG (timed up and go test) and quality of life with SF-36 before and after the treatment were evaluated. The serum vitamin D levels were measured by the RIA method. The subjects were divided into four groups each consisting of 30 subjects. The 1st group took i.m. vitamin D, the 2nd group took i.m. placebo, the 3rd group took p.o. vitamin D, and the 4th group took p.o. placebo. The mean age of all the participants was 70.1 +/- 4.3 years. There was no difference in the age and gender between the groups (P > 0.05). After treatment, the PTH level of first group was decreased (P = 0.0001) and the vitamin D level increased (P = 0.0001) significantly. In the third group, the PTH level of first group was decreased (P = 0.0001) and the vitamin D level increased (P = 0.004) and the 24-h calcium excretion in urine (P = 0.015) increased significantly. When the pain, the functional mobility, and the quality of life were evaluated, in the first group, the TUG (P = 0.0001) and the VAS (P = 0.0001) decreased significantly, whereas the SF-36 subtitles: physical functioning (P = 0.0001), role physical (0.006), bodily pain (P = 0.0001), general health (P = 0.007), social functioning (P = 0.05), and mental health (P = 0.048) increased significantly. In group two, the VAS (P = 0.001) decreased, the role physical (P = 0.009), and role emotional (P = 0.034) increased significantly; In group three, the TUG (P = 0.0001) and the VAS (P = 0.002) decreased, whereas the physical function (P = 0.0001) and role physical (0.001) increased significantly; In group four, the VAS (P = 0.007) decreased significantly. The megadose vitamin D administration increases quality of life, decreases pain, and improves functional mobility via po or im route in the elderly. PMID- 21556747 TI - A phase II trial of gemcitabine and capecitabine in patients with unresectable or metastatic gallbladder cancer or cholangiocarcinoma: Southwest Oncology Group study S0202. AB - PURPOSE: Patients with gallbladder cancer or cholangiocarcinoma were treated with the combination of gemcitabine 1,000 mg/m(2) IV over 100 min on days 1 and 8 and capecitabine 650 mg/m(2) BID PO on days 1-14, administered every 21 days. METHODS: The primary objective of this study was to assess the response rate (confirmed complete and partial responses) of gemcitabine and capecitabine used in advanced/metastatic biliary neoplasms. Secondary objectives included overall survival and toxicities. RESULTS: The study accrued 57 patients from September 2003 to April 2005. Three patients were ineligible, and two others received no treatment. Characteristics of analyzable patients: 35 (67%) cholangiocarcinoma, 17 (33%) gallbladder cancer; PS 0 (18 pts), 1 (26 pts), 2 (8 pts); 26 (50%) men; median age 58.8 years (29.5-85.6). Among 51 patients evaluated for toxicity, 6 experienced grade 4 toxicities. Among 52 patients, there were 7 confirmed partial responses for a confirmed response probability of 13% (95% CI: 6-26%). Six patients had an unconfirmed partial response for an overall response probability of 25% (95% CI: 14-39%). Twelve patients (23%) demonstrated stable disease. The 6 month overall survival was 55% (95% CI: 41-69%), and median survival was 7 months (95% CI: 5-8 months). CONCLUSIONS: The combination of gemcitabine and capecitabine is a well-tolerated regimen with activity in patients with advanced gallbladder cancer and cholangiocarcinoma. PMID- 21556748 TI - Functional histology of glioma vasculature by FTIR imaging. AB - Fourier-transform infrared (FTIR) imaging has been used to investigate brain tumor angiogenesis using a mice solid tumor model and bare-gold (? 25 nm) or BaSO(4) (? 500 nm) nanoparticles (NP) injected into blood vasculature. FTIR images of 20-MUm-thick tissue sections were used for chemical histology of healthy and tumor areas. Distribution of BaSO(4)-NP (using the 1,218-1,159 cm(-1) spectral interval) revealed clearly all details of blood vasculature with morphological abnormalities of tumor capillaries, while Au-NP (using the 1,046 1,002 cm(-1) spectral interval) revealed also diffusion properties of leaky blood vessels. Diffusion of Au-NP out of vascular space reached 64 +/- 29 MUm, showing the fenestration of "leaky" tumor blood vessels, which should allow small NP (<100 nm, as for Au-NP) to diffuse almost freely, while large NP should not (as for BaSO(4)-NP in this study). Therefore, we propose to develop FTIR imaging as a convenient tool for functional molecular histology imaging of brain tumor vasculature, both for identifying blood capillaries and for determining the extravascular diffusion space offered by vessel fenestration. PMID- 21556749 TI - Optimization of polymerization parameters for the sorption of oseltamivir onto molecularly imprinted polymers. AB - Molecularly imprinted polymers (MIPs) are tailor-made polymers with high selectivity for a given analyte, or group of structurally related compounds. The influence of the process parameters (the moles of functional monomer and cross linker, the selection of functional monomer and solvent) on the preparation of oseltamivir (OS)-imprinted polymers was investigated. A mathematical method for uniform design to optimize these selected parameters and to increase the MIP selectivity for template molecules was applied. The optimal conditions to synthesize MIP were 0.69 mmol 30% acrylamide (AA) + 70% 4-Vinylpyridine (4-VP) and 5.0 mmol ethylene glycol dimethacrylate (EGDMA) copolymerized in 5 ml toluene in the presence of 0.1 mmol OS. MIP showed high affinity and selectivity for separation of the template molecule from other compounds. In the present study, we have established an effective LC-MS/MS method to identify and quantify OS with good sensitivity, accuracy and precision. PMID- 21556750 TI - Development of an ultrasensitive immunochromatography test to detect nicotine metabolites in oral fluids. AB - Passive exposure to tobacco smoke causes a variety of illnesses ranging from allergic responses to cancer. Assessment of exposure to second-hand tobacco smoke (SHS), particularly among vulnerable populations enables intervention and prevention of future disease. A minimally invasive oral fluids-based onsite test to detect such exposure would create a valuable tool for researchers and clinicians. Here we describe the development of a test that uses an inexpensive reader that utilizes a CMOS image sensor to reliably quantify a reporter signal and determine nicotine exposure. The rapid lateral flow test consists of a nitrocellulose strip with a control line containing goat anti-rabbit IgG, used as an internal standard, and a test line containing BSA-cotinine conjugate. To run the test, diluted sample containing antibodies against cotinine, the major metabolite of nicotine, is mixed with protein A-gold nanoparticles and placed on the sample pad. As the sample runs up to the nitrocellulose pad, antibodies in the running buffer bind to available cotinine. If cotinine is absent, the antibodies will bind to the BSA-cotinine derivative immobilized on the test line, resulting in an intense purple-red band. The concentration of cotinine equivalents in the sample can be estimated from interpretation of the test line. In this article we describe the effect of different cotinine derivatives, oral fluid pretreatment, and application and running buffers on assay sensitivity. The test can reliably detect as little as 2 ng mL(-1) cotinine equivalents. The assay is sensitive, simple, rapid, inexpensive, and easily implementable in point-of care facilities to detect second-hand smoke exposure. PMID- 21556752 TI - Lipid analysis of flat-mounted eye tissue by imaging mass spectrometry with identification of contaminants in preservation. AB - Matrix-assisted laser desorption/ionization imaging mass spectrometry was used to analyze donor eye tissue specimens for phospholipid content to evaluate lipid distribution. Phosphatidylcholines and sphingomyelins were detected in the positive ion mode using 2,5-dihydroxybenzoic acid as the matrix. During this study, unknown ion signals in the lower m/z region (less than m/z 400) were detected, mainly in the far periphery of human flat-mounted tissue but not in age matched rhesus monkey tissue prepared in a similar manner. The unknown ion signals occurred at m/z 304, 332, 360, and 388. These ions were subjected to tandem mass spectrometry directly from the tissue sample, and exact mass measurements of extracts were prepared for further identification. These ions were identified as alkyl dimethylbenzylammonium surfactants (benzalkonium chlorides (BACs)). The classification of these species was verified by comparing an eye tissue extract to an over-the-counter eye-care product containing BACs. PMID- 21556751 TI - Lanthanide-based time-resolved luminescence immunoassays. AB - The sensitive and specific detection of analytes such as proteins in biological samples is critical for a variety of applications, for example disease diagnosis. In immunoassays a signal in response to the concentration of analyte present is generated by use of antibodies labeled with radioisotopes, luminophores, or enzymes. All immunoassays suffer to some extent from the problem of the background signal observed in the absence of analyte, which limits the sensitivity and dynamic range that can be achieved. This is especially the case for homogeneous immunoassays and surface measurements on tissue sections and membranes, which typically have a high background because of sample autofluorescence. One way of minimizing background in immunoassays involves the use of lanthanide chelate labels. Luminescent lanthanide complexes have exceedingly long-lived luminescence in comparison with conventional fluorophores, enabling the short-lived background interferences to be removed via time-gated acquisition and delivering greater assay sensitivity and a broader dynamic range. This review highlights the potential of using lanthanide luminescence to design sensitive and specific immunoassays. Techniques for labeling biomolecules with lanthanide chelate tags are discussed, with aspects of chelate design. Microtitre plate-based heterogeneous and homogeneous assays are reviewed and compared in terms of sensitivity, dynamic range, and convenience. The great potential of surface-based time-resolved imaging techniques for biomolecules on gels, membranes, and tissue sections using lanthanide tracers in proteomics applications is also emphasized. PMID- 21556753 TI - A new direct Fourier transform infrared analysis of free fatty acids in edible oils using spectral reconstitution. AB - A new transmission-based Fourier transform infrared (FTIR) spectroscopic method for the direct determination of free fatty acids (FFA) in edible oils has been developed using the developed spectral reconstitution (SR) technique. Conventional neat-oil and SR calibrations were devised by spiking hexanoic acid into FFA-free canola oil and measuring the response to added FFA at 1,712 cm(-1) referenced to a baseline at 1,600 cm(-1)(1,712 cm(-1)/1,600 cm(-1)). To compensate for the known oil dependency of such calibration equations resulting from variation of the triacylglycerol ester (C?O) absorption with differences in oil saponification number (SN), a correction equation was devised by recording the spectra of blends of two FFA-free oils (canola and coconut) differing substantially in SN and correlating the intensity of the ester (C?O) absorption at the FFA measurement location with the intensity of the first overtone of this vibration, measured at 3,471 cm(-1)/3,427 cm(-1). Further examination of the spectra of the oil blends by generalized 2D correlation spectroscopy revealed an additional strong correlation with an absorption in the near-infrared (NIR) combination band region, which led to the development of a second correction equation based on the absorbance at 4,258 cm(-1)/4,235 cm(-1). The NIR-based correction equation yielded superior results and was shown to completely eliminate biases due to variations in oil SN, thereby making a single FFA calibration generally applicable to oils, regardless of SN. FTIR methodology incorporating this correction equation and employing the SR technique has been automated. PMID- 21556754 TI - Unpredictability of metabolism--the key role of metabolomics science in combination with next-generation genome sequencing. AB - Next-generation sequencing provides technologies which sequence whole prokaryotic and eukaryotic genomes in days, perform genome-wide association studies, chromatin immunoprecipitation followed by sequencing and RNA sequencing for transcriptome studies. An exponentially growing volume of sequence data can be anticipated, yet functional interpretation does not keep pace with the amount of data produced. In principle, these data contain all the secrets of living systems, the genotype-phenotype relationship. Firstly, it is possible to derive the structure and connectivity of the metabolic network from the genotype of an organism in the form of the stoichiometric matrix N. This is, however, static information. Strategies for genome-scale measurement, modelling and predicting of dynamic metabolic networks need to be applied. Consequently, metabolomics science -the quantitative measurement of metabolism in conjunction with metabolic modelling--is a key discipline for the functional interpretation of whole genomes and especially for testing the numerical predictions of metabolism based on genome-scale metabolic network models. In this context, a systematic equation is derived based on metabolomics covariance data and the genome-scale stoichiometric matrix which describes the genotype-phenotype relationship. PMID- 21556755 TI - Chronic mechanical stress induces mucin 5AC expression in human bronchial epithelial cells through ERK dependent pathways. AB - Mucus hypersecretion is a common pathological change in chronic inflammatory diseases of the airway. These conditions are usually accompanied by chronic mechanical stress due to airway constriction. Our objective was to study the molecular mechanisms and physical effects of chronic mechanical stress on mucin 5AC (MUC5AC) expression in airway epithelial cells. We exposed normal human bronchial epithelial (NHBE) cells cultured at an air-liquid interface to different degrees of chronic compressive mechanical stress (10, 20, 30 cmH(2)O) for 7 days(1 h per day). MUC5AC protein content was detected by enzyme-linked immunosorbent assay (ELISA). MUC5AC mRNA expression was detected by reverse transcription PCR (RT-PCR) and real-time PCR. The effects of chronic mechanical stress on phosphorylated ERK1/2 (p-ERK1/2), phosphorylated JNK (p-JNK), phosphorylated P38 (p-P38), and phosphorylation of FAK at Tyr397 (p-FAK-Y397), were assessed by Western blot. We also assessed the impact of, an EGFR kinase inhibitor (AG1478), an ERK kinase inhibitor (PD-98059), and short interfering RNA (siRNA) targeted to FAK. We found that transcriptional and protein expression levels of MUC5AC were elevated significantly in the 30 cmH(2)O compressive stress group. p-ERK1/2 increased significantly in response to compressive stress and PD 98059 could attenuated stress-induced MUC5AC expression. p-FAK-Y397 increased significantly in response to compressive stress and FAK siRNA attenuated stress induced ERK activation strongly. AG1478 attenuated stress-induced ERK activation and MUC5AC expression significantly, but incompletely. Combination of FAK siRNA and AG1478 led to complete attenuation of ERK activation and MUC5AC expression. These results suggest that chronic mechanical stress can enhance MUC5AC expression in human bronchial epithelial cells through the ERK signal transduction pathway. Both FAK and EGFR mediate the mitogenic response induced by mechanical stress in human bronchial epithelial cells through an ERK signaling cascade. PMID- 21556756 TI - Identification of biotic and abiotic stress up-regulated ESTs in Gossypium arboreum. AB - Asiatic desi cotton (Gossypium arboreum) shows great potential against biotic and abiotic stresses. The stress resistant nature makes it a best source for the identification of biotic and abiotic stress resistant genes. As in many plants same set of genes show responding behavior against the various abiotic and biotic stresses. Thus in the present study the ESTs from the G. arboreum drought stressed leaves were subjected to find the up-regulated ESTs in abiotic and biotic stresses through homology and in-silico analysis. A cDNA library has been constructed from the drought stressed G. arboreum plant. 778 clones were randomly picked and sequenced. All these sequences were subjected to in-silico identification of biotic and abiotic up-regulated ESTs. Total 39 abiotic and biotic up-regulated ESTs were identified. The results were further validated by real-time PCR; by randomly selection of ten ESTs. These findings will help to develop stress resistant crop varieties for better yield and growth performance under stresses. PMID- 21556757 TI - An intronic polymorphism rs2237062 in the CXCL14 gene influences HBV-related HCC progression in Chinese population. AB - CXCL14 (C-X-C motif chemokine ligand 14) is a conserved member of chemokine family and functions as a chemoattractant for multiplicate immunocytes. CXCL14 expression is constitutive in normal tissues, but absent in wide range of epithelial tumors. Many reports have claimed its important role in tumorigenesis and vascularization. An association between rs2237062 polymorphism and hepatocellular carcinoma (HCC) susceptibility was found in patients with chronic HCV infection in Japanese population. Here we analyzed, by using a polymerase chain reaction-ligation detection reaction (PCR-LDR), the polymorphism in 202 non HCC patients with HBV infection, 361 HBV-related HCC patients and 407 healthy controls. The aim was to detect the possible association of this single nucleotide polymorphism (SNP) with HBV-related HCC susceptibility and progression. However, no association was found between rs2237062 polymorphism and susceptibility to HBV infection or HBV-related HCC. Intriguingly, our stratification analysis revealed that HBV-related HCC patients in advanced phase (TNM-II-IV stage) had significantly higher C allele frequency at this polymorphism than patients at early stage (TNM-I stage) (33.5% vs. 25.7%), and its odds ratio reached 1.47 (95% CI 1.06-2.04, P = 0.021). These results suggest that the rs2237062 polymorphism in the CXCL14 gene might influence HBV-related HCC progression in Chinese population. PMID- 21556758 TI - Type 17 T-helper cells might be a promising therapeutic target for osteoporosis. AB - Osteoporosis, a disease characterized by low bone mass and deterioration of bone tissue, is a pressing public health problem. Recent studies have suggested a possible role of T-helper (Th) cells in the pathogenesis of bone loss which occurs in systemic inflammatory diseases. However, there are contradictions in the published literature regarding the functional role of Th1/Th2 cells in the regulation of the differentiation of osteoclasts. These paradoxes have now been clarified by the recent discovery of Th17 cells, a novel subset of Th cells that selectively secrete several proinflammatory cytokines, mainly IL-17. It has been confirmed that Th17 cells have stimulatory effects on osteoclastogenesis and accelerate bone loss in animal models with inflammatory disorders. Targeting Th17 cells or IL-17 may inhibit the bone resorption with RA. Thus, we are led to suppose that Th17 cells might be promising therapeutic targets in osteoporosis. PMID- 21556759 TI - Polymorphisms and haplotypes in methylenetetrahydrofolate reductase gene and head and neck squamous cell carcinoma risk. AB - Functional polymorphisms in genes encoding enzymes involved in folate metabolism might modulate head and neck carcinoma risk because folate participates in DNA methylation and synthesis. We therefore conducted a case-control study of 853 individuals (322 head and neck cancer cases and 531 non-cancer controls) to investigate associations among MTHFR C677T and MTHFR A1298C polymorphisms and head and neck squamous cell carcinoma risk. Interactions between these two polymorphisms and risk factors and clinical histopathological parameters were also evaluated. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to genotype the polymorphisms and Chi square test and multiple logistic regression were used for statistical analyses. The variables age>=49 years, male gender, tobacco habits and alcohol consumption, MTHFR 1298 AC or CC genotypes, combined genotypes with two or more polymorphic alleles and 677T and 1298C polymorphic alleles were associated with increased risk for this disease (P<0.05). Furthermore, we found that 1298 AC or CC genotypes were associated with age>=49 years, tobacco and alcohol habits (P<0.05). Regarding clinical histopathological parameters, the A1298C polymorphism was more frequent in patients with oral cavity as primary site (P<0.05). MTHFR polymorphisms may contribute for increase risk for head and neck carcinoma and the variables age>=49 years, male gender, tobacco and alcohol habits were associated with MTHFR 1298AC or CC genotypes, confirming that individuals with these variables and MTHFR A1298C polymorphism has higher risk for this disease. PMID- 21556760 TI - The Ku70 -1310C/G promoter polymorphism is associated with breast cancer susceptibility in Chinese Han population. AB - Ku70 plays an important role in the DSBR (DNA double-strand breaks repair) and maintenance of genomic integrity. Genetic variations within human Ku70 have been demonstrated to be associated with increased risk of several types of cancers. In this hospital-based case-control study, we aimed to investigate whether a single nucleotide polymorphism (SNP) in the promoter region (rs2267437) of Ku70 gene is associated with susceptibility to breast cancer in Chinese Han population. A total of 293 patients with breast cancer and 301 age-matched healthy controls were enrolled in this study. The Ku70 -1310C/G polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. A significant difference in genotype distribution and allele frequency was observed between patients and controls. The CG or GG carries were at higher risk of breast cancer compared with the CC homozygotes (OR=1.43, 95% CI=1.02 2.00, P=0.038 and OR=3.53, 95% CI=1.60-7.80, P=0.002, respectively). Further stratification analysis revealed that G allele was associated with an increased risk of breast cancer among premenopausal women (OR=1.68, 95% CI=1.21-2.33, P=0.002), but not in postmenopausal women (OR=1.33, 5% CI=0.85-2.10, P=0.216). Our study suggests that the Ku70 -1310C/G promoter polymorphism may be a susceptibility factor for breast cancer in Chinese Han population. PMID- 21556761 TI - An upstream regulatory element confers orientation-independent enhancement of the TSG101 promoter activity in transformed cells. AB - Tumor susceptibility gene 101 (TSG101), a mammalian homologue of yeast vps23, is involved in protein sorting, vesicular trafficking and maintenance of genomic integrity. Upregulation of the TSG101 gene was found in human thyroid papillary and breast tumors. Here, we define the proximal promoter of human TSG101 at -1 to -436 by reporter assay. Intact Sp1 and MAZ binding sequences within this region are essential, and mutation of both sites eliminates proximal promoter activity implying cooperation between these two cis-elements. Chromatin immunoprecipitation and DNA affinity precipitation assay confirmed in vivo Sp1 binding on the GGGGCGGGTT sequence. MAZ protein was essential for TSG101 promoter activity because its knockdown using siRNA decreased reporter activity. An upstream regulatory element (URE) at the -1280 to -1757 region was identified to confer the orientation-independent enhancement of the promoter activity in transformed COS-1, ARO and WRO cell lines but not in a normal thyroid FRTL cell line. The sequence of this URE region contains putative binding sites for thyroid transcription factor 2 (TTF-2) and thyroid hormone receptor (T3R), which might be relevant to differential regulation of TSG101 promoter activity in transformed and primary cells. PMID- 21556762 TI - Human amniotic membrane derived-mesenchymal stem cells induce C6 glioma apoptosis in vivo through the Bcl-2/caspase pathways. AB - High-grade gliomas are difficult to treat. We examined the therapeutic effect of intratumoral administration of human amniotic membrane derived-mesenchymal stem cells (hAMCs) on the growth of gliomas. Tumor volume of the control group was 1632+/-316 mm3 on day 30, and the group treated with a single intratumoral dose of hAMCs had a tumor volume of 1128+/-269 mm3 (P<0.05). Thus, administration of hAMCs significantly reduced tumor size. In rat glioma tissues treated with single and multiple dosages of hAMCs, there was a reduction in tumor volume of approximately 30.9 and 49.5%, respectively. We further evaluated the glioma tissue using Western blotting analysis and observed that the expression of Bax, caspase-8 and caspase-3 were greatly increased and the expression of Bcl-2 was greatly decreased in tumors treated with hAMCs. Sections of nude mice treated with hAMCs clearly showed the presence of an increase in apoptotic cells. The data collected herein confirms for the first time that hAMCs can inhibit C6 glioma growth and induce apoptosis of C6 gliomas in vivo. This demonstrates that hAMCs are a potential new therapeutic agent for the treatment of gliomas. PMID- 21556763 TI - Cold stress in broiler: global gene expression analyses suggest a major role of CYP genes in cold responses. AB - To understand the exact mechanism of cold-stress in broilers depends heavily on identification of differentially expressed genes, rarely conducted so far, in the pituitary of 1 day pre- and post-cold-stress. Therefore, to identify such genes in the present study, gene expression profiling was performed using the pituitary as a model. The results showed that the expression of 15 genes were up-regulated and 15 down-regulated in the pituitary of cold stressed broilers compared with normal ones; and these differentially expressed genes belong to groups involved with catalytic activity, enzyme regulatory activity, signal transducer activity and transporter activity. Functional analysis revealed that cytochrome P450 (CYP) gene group, such as CYP7A1, CYP1A1, which are highly related to fat metabolism, involved in those biological activities. Furthermore, blood lipid levels of triglyceride, total cholesterol, low-density-lipoprotein and high-density lipoprotein were measured, and the decreased level of blood lipid after cold stress suggested that lipid could positively affect CYP7A1 gene expression in broilers. However, future study is required to quantify the CYP gene expression during cold stress. In conclusion, our findings will not only offer basic genetic information to identify candidate genes for chicken breeding of anti-cold stress broilers, but also provide new clues for deciphering mechanisms underlining cold stress in vertebrates. PMID- 21556764 TI - Analysis of differential transcriptional profiling in wheat infected by Blumeria graminis f. sp. tritici using GeneChip. AB - Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a devastating disease of wheat. The use of wheat cultivars resistant to powdery mildew provides an effective, economical, and environmentally friendly method to control the disease. Previously, we identified a dominant resistance gene, temporarily named Pmhym, from the wheat cultivar Hongyoumai. In order to screen differential transcripts related to Pmhym-mediated resistance, four F3 homozygous resistant and four susceptible progenies derived from the Hongyoumai/Yumai13 cross were selected to construct two different pools, respectively, representing an incompatible and compatible interaction with Bgt. Pre-inoculated control and the pathogen-inoculated treatments at 24 h post inoculation (hpi) were used. Three groups of differential genes were categorized from three comparisons as pre and post-induced, respectively, in two interactions, and post-induced between incompatible and compatible interaction. It was found that salicylic acid (SA), jasmonate (JA), and ethylene (ET) signaling-related genes were differentially expressed, thus suggesting that they are involved in the defensive response against Bgt infection. In compatible interactions, the genes involved in the abscisic acid (ABA) signaling pathway might be inhibitory to the above-mentioned three pathways, resulting in a susceptible reaction. Genes involved in disease/defense, signal transduction, and reactive oxygen species (ROS) metabolism were up-regulated in incompatible interactions, implying a role in resistant response. The results of qRT-PCR analysis on several candidate genes were consistent in their expression patterns as revealed by microarray analysis. The differential expression analyses in the present study are good candidates for further elucidation of wheat defensive response to powdery mildew. PMID- 21556765 TI - A miR-125b binding site polymorphism in bone morphogenetic protein membrane receptor type IB gene and prostate cancer risk in China. AB - Recently, a C>T polymorphism (rs1434536) in a miR-125b binding site in the 3' untranslated region (3'UTR) of bone morphogenetic protein membrane receptor type IB gene (BMPR1B) has been found to contribute to cancer susceptibility. To investigate whether it plays an important role in the development of prostate cancer in southern Chinese Han population, we performed a case-control study. 247 prostate cancer and 278 control subjects were included in the cancer association study and dual-luciferase reporter assay was used to test the binding ability of miR-125b to BMPR1B-C or -T vectors. The effect of CT/TT genotype on prostate cancer risk was found to be significant for localized disease (OR=1.60, 95% CI=1.01-2.53, P=0.044) and among subgroups of aged>70 years (OR=1.90, 95% CI=1.15 3.15, P=0.015) compared with CC genotype. Moreover, C-allele gave a reduced luciferase activity relative to T-allele in dual-luciferase reporter assay. Our findings show that rs1434536 in the 3'UTR of BMPR1B gene affects the binding ability of miR-125b to BMPR1B mRNA and contributes to the genetic predisposition to localized prostate cancer and patients aged>70 years. PMID- 21556766 TI - The 156KELK159 tetrapeptide of HIV-1 integrase is critical for lentiviral gene integration. AB - HIV-1 integrase (HIV-1 IN), a key element of HIV-1-derived lentiviral vectors, is crucial for the stable maintenance of the vector gene by inserting them into host genome. HIV-1 IN has been found to have functions other than integration, such as involving in virion morphology, viral DNA synthesis and viral DNA nuclear import. In our study, the yeast two-hybrid assay identified a tetrapeptide 156KELK159 in HIV-1 IN that was crucial for HIV-1 IN and Daxx interaction. To investigate the functions of the tetrapeptide 156KELK159 of the HIV-1 IN, both the wild type HIV 1 IN and a mutant without 156KELK159 were used to package the EGFP reporter gene contained lentivirus. p24 based titer assay revealed that deleting the tetrapeptide did not affect virus packaging. The result was verified by quantitative real time PCR with viral specific primers. But the 156KELK159 was crucial for lentiviral gene integration. Deleting the tetrapeptide made the percentage of cells expressing the reporter gene significantly decreased and did not affect the level of DNA entered into the cells or nucleus. Real time reverse transcription PCR and FACS were used to detect the lentiviral report gene expression in infection maintaining cells and revealed 156KELK159 did not affect lentiviral vector gene expression. Our results may shed light on the regulatory mechanism of gene integration of lentivirus. PMID- 21556767 TI - In silico characterization and expression analysis of the multigene family encoding the Bowman-Birk protease inhibitor in soybean. AB - The Bowman-Birk (BBI) protease inhibitors can be used as source of sulfur amino acids, can regulate endogenous protease activity during seed germination and during the defense response of plants to pathogens. In soybean this family has not been fully described. The goal of this work was to characterize in silico and analyze the expression of the members of this family in soybean. We identified 11 potential BBI genes in the soybean genome. In each one of them at least a characteristic BBI conserved domain was detected in addition to a potential signal peptide. The sequences have been positioned in the soybean physical map and the promoter regions were analyzed with respect to known regulatory elements. Elements related to seed-specific expression and also to response to biotic and abiotic stresses have been identified. Based on the in silico analysis and also on quantitative RT-PCR data it was concluded that BBI-A, BBI-CII and BBI-DII are expressed specifically in the seed. The expression profiles of these three genes are similar along seed development. Their expressions reach a maximum in the intermediate stages and decrease as the seed matures. The BBI-DII transcripts are the most abundant ones followed by those of BBI-A and BBI-CII. PMID- 21556768 TI - Decreased expression of Beclin-1 and LC3 in human lung cancer. AB - Autophagy, a conversed response to stress, has recently been studied in human cancers. Two important autophagic genes-Beclin-1 and LC3 are reported in several human cancers. However, the expressions of Beclin-1 and LC3 in lung cancer have not yet been investigated. In the present study, we investigated the expression of Beclin-1 and LC3, and the relationship between the expression profile and the clinical or pathological changes in human lung cancer. 40 primary lung cancer patients are involved in present study. mRNA expressions of Beclin-1 and LC3-II were detected by Real Time PCR and the protein levels were assessed by immunohistochemistry and western blot. Relative lower expressions of Beclin-1 and LC3-II mRNA were found in the lung cancer tissues compared to counterpart normal tissues. Consistently, the lower amount of Beclin-1 and LC3-II protein was found in lung cancer tissues. However, the expressions of Beclin-1 and LC3-II in lung cancer tissues were not affected by patients' age, gender, smoking, histological type, lymph node metastasis and tumor-node-metastasis (TNM) stage. Both mRNA and protein levels of Beclin-1 and LC3-II were significantly decreased in lung cancer tissues which suggested that autophagy may be involved in the pathogenesis of lung cancer. PMID- 21556769 TI - The radiosensitizing potential of glutaraldehyde on MCF7 breast cancer cells as quantified by means of the G2-chromosomal radiosensitivity assay. AB - Glutaraldehyde (GA) is a high production volume chemical that is very reactive with a wide spectrum of medical, scientific and industrial applications. Concerning the genotoxic and carcinogenic effect of GA, controversial results have been reported, while in humans no studies with positive carcinogenic results for GA have been published. However, our previous study concerning the combined effects of exposure to both GA and ionising radiation (IR) in peripheral blood lymphocytes of healthy donors has shown that non-genotoxic doses of the chemical induces a statistically significant increase in chromosomal radiosensitivity. The lack of information concerning the radiosensitizing potential of GA on cancerous cells triggered us to test the radiosensitizing effect of GA on breast cancer cells (MCF7). For this purpose the G2-chromosomal radiosensitivity assay (G2 assay) was used. The assay involves G2-phase irradiation and quantitation of the chromosomal fragility in the subsequent metaphase. The experimental data show that 48 h exposure to GA, at doses that are not clastogenic to MCF7 breast cancer cells enhances G2-chromosomal radiosensitivity of this cell line. In an effort to evaluate whether the observed increase in GAs-induced G2-chromosomal radiosensitization is linked to GA-induced alterations in the cell cycle and feedback control mechanism, Mitotic Index analysis was performed. The results have shown that such a mechanism cannot be directly related to the observed GA induced increase in G2-chromosomal radiosensitivity. Since increased G2 chromosomal radiosensitivity has been linked with cancer proneness, the radiosensitizing effect of GA at non-clastogenic doses highlights its potential carcinogenic profile. PMID- 21556770 TI - PNAS-4 expression and its relationship to p53 in colorectal cancer. AB - PNAS-4 is a novel pro-apoptotic protein activated during the early response to DNA damage; however, the molecular mechanisms and pathways regulating PNAS-4 expression in tumors are not well understood. We hypothesized that PNAS-4 is a p53 down-stream target gene and designed this study. We searched online for putative p53-binding sites in the entire PNAS-4 gene and did not find any corresponding information. In HCT116 colon cancer cells, after being transfected with small interfering RNA to silence p53, the expressions of PNAS-4 and other known p53 target gene (Apaf1, Bax, Fas and Dr5) were determined by real-time PCR. We found that PNAS-4 was up-regulated while Apaf1, Bax, Fas and Dr5 were down regulated. We then examined the expression of PNAS-4 and p53 mutation in colorectal cancer patients. PNAS-4 expressed both in colorectal cancers and normal tissues, but compared with paired control, PNAS-4 was up-regulated in cancers (P=0.018). PNAS-4 overexpression ratios were correlated to the p53 mutant status (P=0.001). The mean PNAS-4 expression levels of p53 mutant homozygote group and heterozygote group were higher than that of p53 wild type group (P=0.013). The expression ratios of PNAS-4 (every sample in relative to its paired normal mucosa) were different between negative lymph node metastasis (66% up-regulated, 34% down-regulated) and positive metastasis (42% up-regulated, 58% down-regulated). Taken together, these findings suggested that PNAS-4 was not a p53 target, but overexpression of PNAS-4 was correlated to p53 inactivity in colorectal cancer. PMID- 21556771 TI - The effect of aging on the DNA damage and repair capacity in 2BS cells undergoing oxidative stress. AB - Aging is associated with a reduction in the DNA repair capacity under oxidative stress. However, whether the DNA damage and repair capacity can be a biomarker of aging remains controversial. In this study, we demonstrated two cause-and-effect relationships, the one is between the DNA damage and repair capacity and the cellular age, another is between DNA damage and repair capacity and the level of oxidative stress in human embryonic lung fibroblasts (2BS) exposed to different doses of hydrogen peroxide (H2O2). To clarify the mechanisms of the age-related reduction in DNA damage and repair capacity, we preliminarily evaluated the expressions of six kinds of pivotal enzymes involved in the two classical DNA repair pathways. The DNA repair capacity was observed in human fibroblasts cells using the comet assay; the age-related DNA repair enzymes were selected by RT-PCR and then verified by Western blot in vitro. Results showed that the DNA repair capacity was negatively and linearly correlated with (i) cumulative population doubling (PD) levels only in the group of low concentration of hydrogen peroxide treatment, (ii) with the level of oxidative stress only in the group of young PD cells. The mRNA expression of DNA polymerase delta1 decreased substantially in senescent cells and showed negative linear-correlation with PD levels; the protein expression level was well consistent with the mRNA level. Taken together, DNA damage and repair capacity can be a biomarker of aging. Reduced expression of DNA polymerase delta1 may be responsible for the decrease of DNA repair capacity in senescent cells. PMID- 21556772 TI - Ethyl pyruvate reduces myocardial ischemia and reperfusion injury by inhibiting high mobility group box 1 protein in rats. AB - High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia and reperfusion (I/R) injury. Ethyl pyruvate (EP), a potent reactive oxygen species scavenger, has been reported to inhibit myocardial apoptosis and reduce myocardial I/R injury. The aim of this study was to investigate the mechanism by which EP reduces myocardial I/R injury in rats. Anesthetized male rats were once treated with EP (50 mg/kg, i.p.) before ischemia, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. Lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD) activity and infarct size were measured. HMGB1 expression was assessed by immunoblotting. The results showed that pretreatment of EP (50 mg/kg) could significantly reduce the infarct size and the levels of LDH and CK after 4 h reperfusion (all P<0.05). EP could also significantly inhibit the increase of the MDA level, the decrease of the SOD level (both P<0.05). Meanwhile, EP could significantly inhibit the expression of HMGB1 induced by I/R. The present study suggested that ethyl pyruvate could attenuate myocardial I/R injury by inhibiting HMGB1 expression. PMID- 21556773 TI - A meta-analysis of HLA-DR polymorphism and genetic susceptibility to idiopathic dilated cardiomyopathy. AB - Idiopathic dilated cardiomyopathy (IDC) has been hypothesized as a multifactorial disorder initiated by an environment trigger in individuals with predisposing human leukocyte antigen (HLA) alleles. Published data on the association between HLA-DR polymorphism and IDC risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 19 case control studies including 1,378 cases and 10,383 controls provided data on the association between HLA-DR polymorphism and genetic susceptibility to IDC. Overall, statistically elevated frequencies of HLA-DR4 (OR 1.58; 95% CI 1.21 2.07; P=0.0009) and HLA-DR5 (OR 1.35; 95% CI 1.05-1.73; P=0.02) alleles were found in patients with IDC compared with controls. Individuals with HLA-DR3 antigen have a protective effect against IDC (OR 0.72; 95% CI 0.58-0.90; P=0.004). In summary, this meta-analysis indicated that certain HLA-DR alleles may be genetic markers for susceptibility and resistance to IDC. PMID- 21556774 TI - AP-2beta enhances p53-mediated transcription of the alphaB-crystallin gene through stabilizing p53. AB - The alphaB-crystallin (CRYAB) is a member of the small heat shock protein family that can be induced by various stresses and pathological conditions. Aberrant expression of CRYAB has been shown to be associated with several neurological diseases and malignant neoplasms. To identify transcriptional regulators of CRYAB expression, we examined its promoter for binding sites of transcription factors and identified four potential AP-2 binding sites in addition to a p53 binding site reported previously. Although the CRYAB promoter contains four consensus binding sequences of AP-2 and can be activated by AP-2alpha either in the presence or absence of p53, the luciferase assay showed that AP-2beta alone does not regulate the activity of the CRYAB promoter in the absence of p53. However, in the presence of p53, AP-2beta can significantly increase the luciferase activities of both the CRYAB promoter and reporter vector pp53-TA-luc, which contains a p53-responsive element, but no AP-2 binding sites. These data suggest that AP-2beta enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2beta interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2beta up regulates the transcription of the CRYAB gene through stabilizing p53. PMID- 21556775 TI - STAT3/NF-kappaB interactions determine the level of haptoglobin expression in male rats exposed to dietary restriction and/or acute phase stimuli. AB - Haptoglobin is a constitutively expressed protein which is predominantly synthesized in the liver. During the acute-phase (AP) response haptoglobin is upregulated along with other AP proteins. Its upregulation during the AP response is mediated by cis-trans interactions between the hormone-responsive element (HRE) residing in the haptoglobin gene and inducible transcription factors STAT3 and C/EBP beta. In male rats that have been subjected to chronic 50% dietary restriction (DR), the basal haptoglobin serum level is decreased. The aim of this study was to characterize the trans-acting factor(s) responsible for the reduction of haptoglobin expression in male rats subjected to 50% DR for 6 weeks. Protein-DNA interactions between C/EBP and STAT families of transcription factors and the HRE region of the haptoglobin gene were examined in livers of male rats subjected to DR, as well as during the AP response that was induced by turpentine administration. In DR rats, we observed associations between the HRE and C/EBPalpha/beta, STAT5b and NF-kappaB p50, and the absence of interactions between STAT3 and NF-kB p65. Subsequent induction of the AP response in DR rats by turpentine administration elicited a normal, almost 2-fold increase in the serum haptoglobin level that was accompanied by HRE-binding of C/EBPbeta, STAT3/5b and NF-kB p65/p50, and the establishment of interaction between STAT3 and NF-kappaB p65. These results suggest that STAT3 and NF-kappaB p65 crosstalk plays a central role while C/EBPbeta acquires an accessory role in establishing the level of haptoglobin gene expression in male rats exposed to DR and AP stimuli. PMID- 21556776 TI - Genes with expression levels correlating to drip loss prove association of their polymorphism with water holding capacity of pork. AB - Six genes that were known to exhibit expression levels that are correlated to drip loss BVES, SLC3A2, ZDHHC5, CS, COQ9, and EGFR have been for candidate gene analysis. Based on in silico analysis SNPs were detected, confirmed by sequencing, and used for genotyping. The SNPs were genotyped in about 1,800 animals from six pig populations including commercial herds of Pietrain (PI) and German Landrace (DL), different commercial herds of Pietrain*(German Large White*German Landrace) (PIF1(a/b/c)), and one experimental F2-population Duroc*Pietrain (DUPI). Comparative and genetic mapping established the location of BVES on SSC1, of SLC3A2 and ZDHHC5 on SSC2, of CS on SSC5, of COQ9 on SSC6 and of EGFR on SSC9, respectively, coinciding with QTL regions for carcass and meat quality traits. BVES, SLC3A2, and CS revealed association at least with drip loss and with several other measures of water holding capacity (WHC). Moreover, COQ9 and EGFR were associated with several meat quality traits such as meat color and/or thawing loss. This study reveals statistic evidence in addition to the functional relationship of these genes to WHC previously evidenced by expression analysis. This study reveals positional and genetic statistical evidence for a link of genetic variation at these loci or close to them and promotes those six candidate genes as functional and/or positional candidate genes for meat quality traits. PMID- 21556777 TI - Interferon-gamma release assay in the diagnosis of latent tuberculosis infection in arthritis patients treated with tumor necrosis factor antagonists in Korea. AB - The aim of this study was to evaluate the usefulness of the interferon-gamma release assay (IGRA) for the diagnosis of latent tuberculosis infection (LTBI) in arthritis patients who received tumor necrosis factor (TNF) antagonist in Korea. The study involved 107 consecutive patients: 61 (57%) with ankylosing spondylitis and 46 (43%) with rheumatoid arthritis. Screening tests were performed including the tuberculin skin test (TST), the QuantiFERON-TB Gold In-Tube (QFT-IT) test, and chest radiography. A positive QFT-IT test result, regardless of TST results, was considered an indication for LTBI treatment. If the QFT-IT results were indeterminate, a positive TST was regarded as an indication for LTBI treatment. A Bacillus Calmette-Guerin (BCG) scar was found in 63 patients (59%). LTBI treatment was performed in 37 patients (35%), including 36 with positive QFT-IT results and one with indeterminate QFT-IT and positive TST results. No patients developed tuberculosis during a median of 18 months (range, 13-26 months) of TNF antagonist therapy. In 16 patients who had positive TST and negative QFT-IT results, TNF antagonists were given without LTBI treatment. Tuberculosis did not occur, even in these patients, during a median of 24.5 months (range, 15-33.5 months) of TNF antagonist therapy. IGRA may be used instead of TST for the diagnosis of LTBI in patients before starting TNF antagonists in countries where tuberculosis prevalence is intermediate and the BCG vaccination is mandatory at birth, such as in Korea. PMID- 21556778 TI - Relationship between radiological severity and clinical and psychological factors in knee osteoarthritis. AB - This study was designed to investigate the relationship between radiological severity and clinical and psychological factors in patients with knee osteoarthritis (OA). Patients with knee OA (n = 100) were included in the study. Radiographic staging was done using Kellgren-Lawrence (KL) radiological rating scale. Stage 1-2 changes according to KL were grouped as 'early' and stage 3-4 as 'late' radiological OA. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used for self-reported disability. Performance-based functional assessments were measured as time needed to walk 15 m and time needed to climb ten steps. Health-related quality of life was assessed by Nottingham Health Profile (NHP). Beck Depression Inventory (BDI) was used to assess the presence and severity of depression. Social isolation was assessed by a related NHP subscale. Significantly higher scores were found in the late stage group for NHP pain, physical mobility and social isolation subscales and all WOMAC subscales. Mean BDI score was significantly higher (p = 0.001) and performance-based functional score was significantly worse (p < 0.001) in the late stage group compared to the early stage. In logistic regression analysis, NHP social isolation subscore was found to be associated with WOMAC pain subscore (p = 0.013, odds ratio [OR] = 1.163; 95% confidence interval [CI], 1.032-1.309) and radiological severity (p = 0.018, OR = 2.924; 95% CI, 1.198-7.136). Radiological severity is an important indicative factor for pain, disability, depression and social isolation. We believe that assessment of psychological involvement in addition to pain and disability might provide benefit in the management of patients with advanced radiological knee OA. PMID- 21556779 TI - Tryptophan degradation and neopterin levels in treated rheumatoid arthritis patients. AB - Increased kynurenine/tryptophan-reflects trytophan degradation-and neopterin levels have been regarded as a biochemical marker of cell-mediated immune response and inflammation. This study was designed to evaluate the usefulness of tryptophan degradation and neopterin levels in active rheumatoid arthritis patients under therapy. In this case-control study, kynurenine and tryptophan levels were determined by HPLC; neopterin and tumor necrosis factor-alpha levels were measured with ELISA in 32 active rheumatoid arthritis patients and 20 healthy controls. Although mean values of tryptophan, kynurenine, ratio of kynurenine to tryptophan, neopterin, and tumor necrosis factor-alpha levels did not show statistically significant differences between patient and control groups, neopterin levels correlated positively with kynurenine (r = 0.582, p < 0.02), kynurenine/tryptophan (r = 0.486, p < 0.05), erythrocyte sedimentation rate (r = 0.472, p < 0.05) and RF (r = 0.478, p < 0.05) in the rheumatoid arthritis group. CRP levels of the patient group correlated with kynurenine levels (r = 0.524, p < 0.03). Determination of tryptophan degradation and neopterin levels in chronic inflammatory disease may provide a better understanding of progression of the disease. PMID- 21556780 TI - Evaluation of various endothelial biomarkers in ankylosing spondylitis. AB - Atherosclerosis has been shown to be increased in chronic inflammatory diseases including ankylosing spondylitis (AS). Impaired endothelial function, the first step in atherosclerosis, may be reflected by changes in various endothelial biomarkers of hemostasis and the release of several cellular adhesion molecules or cytokines. In this study, we investigated changes in the levels of various possible markers with regard to disease activity and treatment regimen with/without anti-TNF-alpha drugs. Fifty-six AS patients (44 males) and 27 controls (19 males) with no known cardiovascular risk factors were included in the study. Spinal mobility was assessed by the Bath Ankylosing Spondylitis Metrology Index, and patients were evaluated with the Bath Ankylosing Spondylitis Functional Index and the Bath Ankylosing Spondylitis Disease Activity Index. Cytokines and various endothelial biomarkers were measured in serum samples using commercially available ELISA kits. Age, sex, BMI, waist circumference, fasting glucose, MAP, lipids are all similar between patients and controls. von Willebrand factor (vWF), soluble thrombomodulin (sTM), and urotensin (UT-II) were found to be significantly higher in the sera of the patients compared to the controls. Treatment with anti-TNF-alpha compared to conventional therapy and disease activity in AS patients seemed to have no effect on the blood levels of UT-II, sTM, CD146, vWF, plasminogen activator inhibitor-1, tissue plasminogen activator, or the thrombin-antithrombin complex. The increased UT-II, sTM, and vWF in AS patient sera regardless of treatment and disease activity suggest an increased tendency for atherosclerosis. PMID- 21556781 TI - Phytoextraction potential of Prosopis juliflora (Sw.) DC. with specific reference to lead and cadmium. AB - Root and shoot samples of Prosopis juliflora were assessed for their heavy metal content to evaluate the species as a green solution to decontaminate soils contaminated with lead and cadmium. The highest uptake of both the metals was observed in plants from industrial sites. Sites with more anthropogenic disturbance exhibited reduced chlorophyll levels, stunted growth, delayed and shortened reproductive phase. The ratios of lead and cadmium in leaves to lead and cadmium in soil were in the range of 0.62-1.46 and 0.55-1.71, respectively. Strong correlation between the degree of contamination and concentrations of lead and cadmium in plant samples identifies P. juliflora as an effective heavy metal remediator coupled with environmental stress. PMID- 21556782 TI - Psychological morbidity of farmers and non-farming population: results from a UK survey. AB - The relatively high rate of suicide among UK farmers suggests that they may suffer greater mental health problems than the general population. This paper provides a comparison of the psychological morbidity of farmers and their partners/spouses with non-farmers. The General Health Questionnaire (GHQ-12) was administered using face-to-face interviews with 784 attendees of agricultural shows in the UK. Results show that GHQ-12 scores for farmers and their partners/spouses were significantly higher (P < 0.001) than those for the non farming population, indicating higher psychological morbidity among farmer families. Approximately 35% of farmers had scores 12 and higher (recommended cut off for psychiatric disorders), compared to 27% of non-farmers. Within the farmers group, male respondents, those aged from 45 to 64, self-employed or not in paid employment, having a non-supervisory position and living in a rural area were characterized by higher mean GHQ-12 scores compared to correspondent subgroups from the non-farming population. PMID- 21556783 TI - 'In sight, out of mind': the experiences of the compliantly engaged community psychiatric out-patient. AB - Research on engagement within community-based psychiatric services in the UK has mainly focussed on factors related to those 'at risk' of non-attendance or non compliance, with the tacit assumption that those in regular attendance are largely content and hence not a priority. The present study systematically explored the experiences and views of 25 people with severe and enduring mental illness who had regularly attended out-patient settings for more than 5 years. Regular attendance at consultations was not synonymous with satisfaction-in fact it masked varying levels of unmet needs and 'de-humanisation'. In order to establish and maintain non-coercive community services that prioritise 'recovery' above illness and 'risk' containment, it is essential that the experiences of people in established and apparently 'less troublesome' therapeutic relationships are also taken into account and integrated into policy and practice. PMID- 21556784 TI - Smoking reduction for persons with mental illnesses: 6-month results from community-based interventions. AB - Persons with mental illnesses use tobacco at significantly higher and heavier rates than the general population, and suffer greater tobacco- related morbidity and mortality. However, there are few existing tobacco cessation interventions for these individuals. This study examined two tobacco cessation interventions, a telephonic quitline intervention (counseling and nicotine replacement therapy) and a community-based group counseling intervention with adults currently receiving community mental health services. At 6-month follow-up, both groups demonstrated significantly reduced tobacco use, but participants who received both quitline services and the group counseling intervention were significantly more likely to have a 50% tobacco use reduction. Across groups, the overall intent-to-treat cessation rate was 7%. Tobacco dependence, depression symptoms, and psychotic symptoms decreased significantly for all treatment groups, while health and mental health functioning increased. Findings suggest that common community tobacco cessation services are effective for this population. PMID- 21556785 TI - The life situation of people with persistent mental illness visiting day centers: a comparative study. AB - This study compared the life situation of visitors of day centers (DC) for people with mental illness (N = 93) with a comparison group (N = 82) in respect of sociodemographic and clinical characteristics, care consumption, well-being and everyday activities. The response rate was 49%, and those who declined are believed to be those with the most severe psychiatric disabilities. Most individuals were single (81%/78%) and few had children (12%/18%). The DC group had less education than the comparison group but had a friend more often. Although having their need for daily activities met, the DC group had greater unmet needs in respect of daily living in general. They less frequently reported having a psychosis and had fewer negative and more depressive symptoms. They got more housing support and general outpatient care, while the comparison group used specialized psychiatric care more frequently. The samples were equally satisfied with their care, health and well-being and found their everyday activities equally meaningful. The DC visitors formed a vulnerable group, by living single, having a low level of education and having unmet needs, and were at risk of not getting specialized psychiatric care. PMID- 21556786 TI - The effects of assertive community treatment including integrated dual diagnosis treatment on nuisance acts and crimes in dual-diagnosis patients. AB - We investigated whether Assertive Community Treatment (ACT) combined with Integrated Dual Diagnosis Treatment (IDDT) is associated with a decrease in nuisance acts and crime convictions in dual-diagnosis repeated offenders. Forty three patients were monitored from 21 months before until 12 months after the start of ACT-IDDT, using police data and the Health of the Nation Outcome Scales (HoNOS). Results show that while nuisance acts and convictions increased in the 21 months before the start of ACT-IDDT, nuisance acts decreased and convictions stabilized during the next 12 months. The decrease in nuisance acts was associated with a decrease in substance abuse. PMID- 21556787 TI - Routine laboratory tests can predict in-hospital mortality in acute exacerbations of COPD. AB - Chronic obstructive pulmonary disease (COPD) has a rising global incidence and acute exacerbation of COPD (AECOPD) carries a high health-care economic burden. Classification and regression tree (CART) analysis is able to create decision trees to classify risk groups. We analysed routinely collected laboratory data to identify prognostic factors for inpatient mortality with AECOPD from our large district hospital. Data from 5,985 patients with 9,915 admissions for AECOPD over a 7-year period were examined. Randomly allocated training (n = 4,986) or validation (n = 4,929) data sets were developed and CART analysis was used to model the risk of all-cause death during admission. Inpatient mortality was 15.5%, mean age was 71.5 (+/-11.5) years, 56.2% were male, and mean length of stay was 9.2 (+/-12.2) days. Of 29 variables used, CART analysis identified three (serum albumin, urea, and arterial pCO(2)) to predict in-hospital mortality in five risk groups, with mortality ranging from 3.0 to 23.4%. C statistic indices were 0.734 and 0.701 on the training and validation sets, respectively, indicating good model performance. The highest-risk group (23.4% mortality) had serum urea >7.35 mmol/l, arterial pCO(2) >6.45 kPa, and normal serum albumin (>36.5 g/l). It is possible to develop clinically useful risk prediction models for mortality using laboratory data from the first 24 h of admission in AECOPD. PMID- 21556788 TI - Lack of association between the TGF-beta(1) gene and development of COPD in Asians: a case-control study and meta-analysis. AB - Abnormalities in the transforming growth factor-beta(1) (TGF-beta(1)) gene are thought to be linked to chronic obstructive pulmonary disease (COPD). We investigated the association between the single nuclear polymorphisms (SNPs) of TGF-beta(1) and the risk of COPD in a case-control study and meta-analysis. We genotyped 160 cases and 177 control subjects in a local hospital using the Mass Array(TM) Technology Platform and then tested the association of four SNPs in TGF beta(1) (rs6957, rs1800469, rs2241712, and rs2241718) with COPD. Plasma TGF beta(1) level measurement was performed later. A database covering all papers published up to October 30, 2010, was then reviewed. Statistical analysis was performed using Revman 5.0 and STATA 11.0 software. No association was found between TGF-beta(1) gene SNPs and an increased risk of COPD in Asians. By meta analysis, the link of two polymorphisms, rs1800469 and rs1982073, was investigated in seven and eight studies, respectively, involving 1,508 COPD patients and 2,608 control subjects. The results showed that there was no significant association between an increased risk of COPD in carriers of the T allele (TT+TC) versus the CC genotype in rs1800469 and rs1982073. In ethnic subgroup analysis, the risk of COPD associated with the rs1800469 T allele was not significantly elevated among Asians. TGF-beta(1) gene polymorphisms are not associated with an increased risk of COPD in the Asian population. PMID- 21556789 TI - Echocardiographic evidence of pulmonary hypertension is associated with increased 1-year mortality in patients admitted with chronic obstructive pulmonary disease. AB - Pulmonary hypertension (PH) is associated with decreased overall survival in patients with chronic lung disease. The purpose of this study was to determine the effect of echocardiographic evidence of PH on 1-year survival in patients hospitalized with acute exacerbations of chronic obstructive pulmonary disease (COPD). This is a retrospective study of patients admitted to a respiratory intermediate care unit with COPD exacerbation between October 1, 2002 and September 30, 2004. All patients who had 2D echocardiograms and pulmonary function tests done within 12 months prior to hospital admission or during the admission were examined. Charts were reviewed for the following outcomes: length of hospital stay, need for mechanical ventilation, survival at discharge, and mortality over the next year. Data were analyzed using multiple logistic regression and p values calculated using Fisher's exact test. Forty-three patients met study entry criteria, and PH, defined as systolic right ventricular pressure greater than 45 mmHg, was found in 23 (53%). Sixteen of the 23 patients (70%) with PH died during the 1-year follow-up period compared to 5 of 20 (25%) patients with no PH (p = 0.0058). The effect of PH on survival was independent of age, forced expiratory volume in 1 s (FEV(1)), arterial pH, pCO(2), or pO(2) (p < 0.01). Echocardiographic evidence of PH is associated with increased 1-year mortality in patients admitted with COPD exacerbation. Further studies are needed to determine if PH is a cause of increased mortality in this population or an indicator of other cardiovascular disease. PMID- 21556790 TI - A longitudinal analysis of intimacy processes and psychological distress among couples coping with head and neck or lung cancers. AB - Individuals diagnosed with lung and head and neck (HN) cancers and their spouses are at increased risk for distress. This study assessed whether the way couples communicate about cancer and their perceptions of relationship intimacy influenced both partners' adjustment. One-hundred thirty-nine patients and their spouses [For purposes of clarity, we refer to the patients' intimate partner as the spouse, regardless of actual marital status and we reserve the term partner to refer to the other person in the couple (i.e., the patient's partner is the spouse and the spouse's partner is the patient)] completed measures of spousal communication, intimacy, and distress at three time points over 6 months. Using multilevel modeling, an over-time actor-partner interdependence model was specified that examined whether intimacy mediated associations between one's own and one's partner's reports of communication at baseline and later distress. Patients and spouses who reported greater baseline distress reported more negative baseline communication as well as lower levels of intimacy and greater distress over time. Mediation analyses showed patients' and spouses' reports of positive spousal communication were associated with less subsequent distress largely through their effects on intimacy. Clinicians working with head and neck or lung cancer patients should assess communication and intimacy because both impact couples' distress. PMID- 21556791 TI - Problem gambling of Chinese college students: application of the theory of planned behavior. AB - The present study, using the theory of planned behavior (TPB), investigated psychological correlates of intention to gamble and problem gambling among Chinese college students. Nine hundred and thirty two Chinese college students (aged from 18 to 25 years) in Hong Kong and Macao were surveyed. The findings generally support the efficacy of the TPB in explaining gambling intention and problems among Chinese college students. Specifically, the results of the path analysis indicate gambling intention and perceived control over gambling as the most proximal predictors of problem gambling, whereas attitudes, subjective norms, and perceived control, which are TPB components, influence gambling intention. Thus, these three TPB components should make up the core contents of the prevention and intervention efforts against problem gambling for Chinese college students. PMID- 21556792 TI - Gambling-related cognitive biases and pathological gambling among youths, young adults, and mature adults in Chinese societies. AB - This study investigated the extent to which gambling-related cognitive biases would associate with various levels of gambling pathology among 2,835 youths, 934 young adults, and 162 mature adults in Chinese societies. Results showed that gambling cognitive biases, especially biases in perceived inability to stop gambling and positive gambling expectancy, were salient correlates of pathological gambling across the three age cohorts. Analyses of variances on total cognitive biases also showed a gambling pathology main effect and an age cohort * gambling pathology 2-way interaction effect. It was noted that the probable pathological gambling group had greater cognitive biases than the probable problem gambling group, which in turn had greater cognitive biases than the non-problem gambling group. In the non-problem gambling group, mature adults had greater cognitive biases than youths and young adults, but this pattern was reversed in the probable problem gambling group. In the probable pathological gambling group, youths had greater cognitive biases than young and mature adults. Specific categories of cognitive biases also varied according to gender and gambling pathology. While men as compared to women in the non-problem and probable problem gambling groups reported a greater bias in their perceived inability to stop gambling, no significant gender difference in this bias was found in the probable pathological gambling group. Men generally had greater perceived gambling expectancy bias than women. PMID- 21556794 TI - Cutting space-cutting body: the nature of the grotesque in umwelt. AB - We give psychological elaboration to some of Rayner's (2011) ideas. For the idea of a space and boundaries within it many psychological explanations are possible. We elaborate the boundaries as these occur in urban contexts as well as in the flow of irreversible time (between future and past). Shifting boundaries or any act of transforming them leads to changes in the understanding of the whole. Boundaries within space and between different fields-while having a physical existence-have also a symbolic component, which is specific to human beings. We reframe the dynamic concept of boundaries along the lines of Bergson's idea of duree, which allows us conceptualize boundaries between bodies and environments, as well as boundaries in the environment, as ever transforming in spaces of ambiguity and, following Bakhtin, grotesque. This opens way for treating the boundary phenomena as functionally emerging in person-environment-or, in von Uexkull's terms, organism-Umwelt relation. Following Heidegger, we conclude that through dynamic boundary-making we as species dwell in the world and make the world. PMID- 21556793 TI - Projections from the rat pedunculopontine and laterodorsal tegmental nuclei to the anterior thalamus and ventral tegmental area arise from largely separate populations of neurons. AB - Cholinergic and non-cholinergic neurons in the brainstem pedunculopontine (PPT) and laterodorsal tegmental (LDT) nuclei innervate diverse forebrain structures. The cholinergic neurons within these regions send heavy projections to thalamic nuclei and provide modulatory input as well to midbrain dopamine cells in the ventral tegmental area (VTA). Cholinergic PPT/LDT neurons are known to send collateralized projections to thalamic and non-thalamic targets, and previous studies have shown that many of the afferents to the VTA arise from neurons that also project to midline and intralaminar thalamic nuclei. However, whether cholinergic projections to the VTA and anterior thalamus (AT) are similarly collateralized is unknown. Ultrastructural work from our laboratory has demonstrated that cholinergic axon varicosities in these regions differ both morphologically and with respect to the expression and localization of the high affinity choline transporter. We therefore hypothesized that the cholinergic innervation to these regions is provided by separate sets of PPT/LDT neurons. Dual retrograde tract-tracing from the AT and VTA indicated that only a small percentage of the total afferent population to either region showed evidence of providing collateralized input to the other target. Cholinergic and non cholinergic cells displayed a similarly low percentage of collateralization. These results are contrasted to a control case in which retrograde labeling from the midline paratenial thalamic nucleus and the VTA resulted in higher percentages of cholinergic and non-cholinergic dual-tracer labeled cells. Our results indicate that functionally distinct limbic target regions receive primarily segregated signaling from PPT/LDT neurons. PMID- 21556795 TI - Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor 2 positive metastatic breast cancer. AB - BACKGROUND: Trastuzumab demonstrates significant clinical benefits in HER2 positive metastatic breast cancer (MBC), and recent clinical trials suggest that trastuzumab should be continued in combination with other chemotherapy beyond progression. There is an urgent need to assess if patients could substantially benefit from continuing trastuzumab-based therapy. METHODS: We reviewed 91 patients with HER2-positive MBC treated with trastuzumab and investigated correlations between survival and clinical response to first trastuzumab-based therapy and biological markers, time to first tumor progression (1st TTP), response rate (RR), estrogen receptor (ER), Ki-67, and p53 overexpression. RESULTS: With a median follow-up of 33 months, 76 patients had received two or more lines of consecutive trastuzumab-based therapy. Median 1st TTP was 8.6 months; patients who received trastuzumab with chemotherapy had a longer 1st TTP and better RR than those without chemotherapy. In terms of survival after first progression, patients with a longer 1st TTP (>= 8.6 months) had significantly better survival compared with those who had a shorter 1st TTP (24.3 months vs. 15.4 months, P = 0.024), and multivariate analysis revealed that 1st TTP was a significant prognostic factor (HR 0.44, 95% CI 0.23-0.82, P = 0.01). There were no correlations between survival and ER or Ki-67; however, there was a correlation with p53 overexpression (HR 1.92, 95% CI 1.01-3.64, P = 0.045). CONCLUSIONS: 1st TTP is a significant prognostic factor for patients who receive subsequent trastuzumab-based therapy. This factor should be considered when determining the efficacy of continuing trastuzumab or switching to another anti HER2 therapy beyond progression. PMID- 21556796 TI - The relationship between EGFR gain and VHL loss in lung adenocarcinoma and poor patient survival. AB - BACKGROUND: The prognosis of lung cancer remains poor and clinically applicable prognostic markers have not yet been satisfactory identified. Several chromosomal copy number alterations (CNAs) have been associated with metastasis, relapse, and survival of patients with lung cancer; however, no study has focused exclusively on identifying CNAs at a gene level. The aim of this study was to identify genes whose CNAs are associated with survival of patients with lung adenocarcinoma. METHODS: The CNA status of a panel of 48 genes was detected by high-resolution array comparative genomic hybridization in 56 lung adenocarcinoma samples. The follow-up time of these patients was 8.5-65.7 months. The gene CNAs were analyzed for their association with patient survival. RESULTS: Cox univariate regression analysis revealed that EGFR gain (hazard ratio (HR) 3.84, 95% confidence interval (CI) 1.62-9.10), VHL loss (HR 4.56, 95% CI 1.85-11.27) and WWOX loss (HR 4.14, 95% CI 1.60-10.69) were each associated with poor survival. Multivariate analyses including EGFR gain, VHL loss and WWOX loss, as well as the clinicopathological variables such as age, sex, tumor size, tumor differentiation and TNM stage showed that EGFR gain (HR 4.63, 95% CI 1.69-12.7) and VHL loss (HR 4.82, 95% CI 1.41-16.43) were independent prognostic factors for poor survival, whereas WWOX loss lost statistical significance. CONCLUSION: These findings suggest that EGFR gain and VHL loss are associated with poor overall survival for lung adenocarcinoma patients and may be used as prognostic markers. PMID- 21556797 TI - An early event of EGFR mutation in pleomorphic carcinoma of the lung. AB - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective in prolonging progression-free survival time of patients with non-small cell lung carcinoma, typically adenocarcinoma, bearing some active EGFR mutations in their tumors. However, the close relationship between the EGFR mutations and pleomorphic carcinoma of the lung, which is a very rare type of primary lung cancer, has never been elucidated. We present a 60-year-old Japanese woman with pleomorphic carcinoma of the lung that became resistant to cytotoxic chemotherapies including platinum-based chemotherapy, and her general condition seriously deteriorated. Thereafter, treatment with gefitinib was started and resulted in significant tumor shrinkage and a dramatic improvement in her general condition for up to 8.5 months. Analyses of the EGFR mutation in separately microdissected specimens from adenocarcinoma and spindle cell components revealed that both components possessed the L858R point mutation. These findings gave us some insight into the carcinogenesis of pleomorphic carcinoma of the lung in relation to EGFR gene alteration. Testing for EGFR mutation may be important in patients with advanced pleomorphic carcinoma including adenocarcinoma component that is usually chemoresistant. PMID- 21556798 TI - Histone deacetylase inhibitor augments anti-tumor effect of gemcitabine and pegylated interferon-alpha on pancreatic cancer cells. AB - BACKGROUND: Histone deacetylase (HDAC) is strongly associated with epigenetic regulation and carcinogenesis, and its inhibitor can induce the differentiation or apoptosis of cancer cells. METHODS: We investigated the anticancer effects of the HDAC inhibitor valproic acid (VPA) in combination with gemcitabine (GEM), an antimetabolic, and pegylated interferon-alpha2b (PEG-IFN-alpha2b) in a human pancreatic cancer cell line using a cell proliferation assay. The gene expressions of HDAC1, MTA1, p21(Waf1), and HIF-1 were evaluated by reverse transcription-PCR. RESULTS: Valproic acid at 0.5 mM when used alone did not suppress cell proliferation. PEG-IFN-alpha2b at 10(2 )E/ml weakly suppressed cell proliferation in both the BxPC3 (by 28%) and SUIT-2 (by 17%) human pancreatic cancer cell lines. GEM at 5 nM when used alone suppressed cell proliferation by 36 and 61% in the BxPC3 and SUIT-2 cell lines, respectively. The combination treatment of GEM + PEG-IFN-alpha2b strongly suppressed cell proliferation in the SUIT-2 (82%) and BxPC3 (51%) cell lines, which was further reinforced by the addition of VPA up to 88 and 67%, respectively. The combination treatment of GEM + PEG-IFN-alpha2b enhanced the expression of p21(Waf1), which was also reinforced by VPA. CONCLUSION: VPA augmented the inhibitory effects of PEG-IFN-alpha2b alone or in combination with PEG-IFN-alpha2b and GEM on cell proliferation. Such inhibitory effects may be due to the up-regulation of p21(Waf1) expression. PMID- 21556799 TI - The role of lymph node dissection in the management of prostate cancer. AB - Lymph node dissection is a standard procedure for treatment of several cancers, but its role in prostate cancer (PCa) as an adjunct of radical prostatectomy is still debated and controversial. Pelvic lymph node dissection (PLND) is currently the most reliable means of diagnosis of lymph node metastases. A uniform PLND surgical template cannot be determined, but recent evidence shows that extended PLND provides more lymph nodes, increases the accuracy of detection of lymph node metastases, and affects decision making with regard to adjuvant therapy. Several nomograms have been developed to predict those who may need more extensive PLND, while sparing the rest. Importantly, no prospective data indicate that extension of PLND improves cancer control or benefits survival. A well designed prospective randomized study is needed to resolve these issues. We present a comprehensive literature review and critical discussion of the diagnostic and therapeutic role of PLND in PCa. PMID- 21556800 TI - Pulmonary metastasectomy in patients with renal cell carcinoma: a single institution experience. AB - BACKGROUND: Pulmonary metastasectomy in patients with renal cell carcinoma (RCC) remains controversial. The purpose of our analysis was to explore the outcome of patients with RCC who underwent pulmonary metastasectomy at our institution. METHODS: We reviewed data on 25 patients who underwent resection of lung metastasis from 1998 to 2008 at our institution. RESULTS: All patients were treated by radical nephrectomy for primary RCC. Progression-free survival (PFS) ranged from 0.3 to 198.8 months (median 7.4 months), and overall survival (OS) ranged from 2.4 to 198.8 months (median 33.9 months). The 5-year PFS rate was 24.9%, and the OS rate was 35.5%. Although differences in the resectability of the metastasectomy and OS were not significant in univariate or multivariate analyses, the relationship between PFS and the radicality of pulmonary metastasectomy was significant in both the univariate and multivariate analyses (P = 0.004, 0.012, respectively). CONCLUSIONS: The results of pulmonary metastasectomy for patients with RCC at our institution indicate that pulmonary metastasectomy should be performed only when the pulmonary metastasis can be completely resected. Additional studies are therefore necessary to evaluate the prognostic factors and to determine the selection criteria for pulmonary metastasectomy in the new era of molecular-targeted agents. PMID- 21556801 TI - A prospective clinical trial of lenalidomide with topotecan in women with advanced epithelial ovarian carcinoma. AB - BACKGROUND: Lenalidomide is an anti-angiogenic IMiD((r)) immunomodulatory drug. The objective of this study was to determine the maximum tolerated dose (MTD), overall safety profile, and activity of oral lenalidomide in combination with topotecan in women with advanced epithelial ovarian or primary peritoneal carcinoma. METHODS: In this Phase I/II open-label, dose-escalation study, patients with histologically or cytologically confirmed advanced ovarian or primary peritoneal carcinoma with disease progression or recurrence following first-line therapy with a platinum agent and paclitaxel were eligible. The Phase I trial utilized a standard dose-escalation design to define the MTD and evaluate the safety profile of lenalidomide and topotecan. The starting doses were lenalidomide 5 mg, days 1-14, and intravenous topotecan 1.25 mg/m(2), days 1-5 of a 21-day cycle. Only the lenalidomide dose was escalated, in 5-mg increments up to 25 mg. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The Phase II portion was designed to evaluate the antitumor activity based on objective response rate of lenalidomide and topotecan. RESULTS: Five women with advanced epithelial ovarian carcinoma were enrolled, each receiving 5 mg oral lenalidomide and 1.25 mg/m(2) topotecan. Four patients discontinued because of dose-limiting toxicity, most commonly grade 4 neutropenia (n = 3). One patient discontinued because of lack of therapeutic effect. The study was terminated early for reasons of toxicity. CONCLUSION: The addition of lenalidomide to topotecan is not a feasible drug combination in women with advanced epithelial ovarian carcinoma because of dose-limiting toxicity. PMID- 21556802 TI - Co-transcriptional architecture in a Y loop in Drosophila melanogaster. AB - The Y loops of Drosophila spermatocytes are formed by the expression of huge individual transcription units on the Y chromosome and their large size provides a unique system for the investigation of the organisation of transcription in intact nuclei. By labelling ribonucleo-protein (RNP) components, the loop chromatin and nascent transcripts in Y loop C, we reveal a highly structured organisation of RNP domains associated with nascent transcripts. We distinguish two types of RNP domain, a proximal domain that runs alongside the chromatin of loop C and a distal RNP domain that wraps around the proximal domain and the loop chromatin. The proximal domain is marked by the Pasilla protein, and separate distal subdomains are marked by the S5 antigen and Boule. We discuss the implications of this highly structured co-transcriptional architecture for the organisation of the process of transcription. PMID- 21556803 TI - Effects of low-dose D-serine on recognition and working memory in mice. AB - RATIONALE: D -Serine is an endogenous co-agonist of the N-methyl-D: -aspartate (NMDA) receptor and has been suggested to improve cognitive deficits in schizophrenia. OBJECTIVES: The present study investigates the effects of treatment with D -serine in mice on tasks that require recognition learning and working memory, two cognitive domains that are impaired in schizophrenia. METHODS: We studied the effects of various regimens of systemic administration of D -serine (50 mg/kg/day) on BALB/c mice performing object recognition, T-maze alternation, and open-field exploration tasks. For the object recognition task, we also contrasted the effects of D -serine and D -cycloserine and investigated whether D -serine could reverse alterations induced by subchronic injections of the NMDA antagonist MK-801. D -Serine levels after injections were measured by high-performance liquid chromatography. RESULTS: In the object recognition task, pre-training treatment with D -serine or D -cycloserine significantly enhanced recognition memory 24 h after training. A single administration of D -serine 30 min (but not 6 h) after training produced similar enhancement, suggesting an effect on memory consolidation. Daily treatment with D: -serine enhanced both object recognition and T-maze performance over multiple days and improved short term memory in MK-801-treated mice. D -Serine treatment did not alter open-field exploration. Behavioral effects were accompanied by increased levels of D -serine in the hippocampus of treated animals. CONCLUSIONS: Our results show that treatment with D -serine can improve performance in tasks related to recognition learning and working memory, suggesting that this agent can be useful for the treatment of disorders involving declines in these cognitive domains. PMID- 21556805 TI - Central serotonergic activity correlates with salivary cortisol after waking in depressed patients. PMID- 21556804 TI - Intermittent ethanol exposure increases long-lasting behavioral and neurochemical effects of MDMA in adolescent mice. AB - RATIONALE: Heavy binge drinking is increasingly frequent among adolescents, while ethanol (EtOH) is often used in combination with 3,4 methylenedioxymethamphetamine (MDMA). OBJECTIVES: The long-lasting effects of intermittent exposure to EtOH and MDMA during adolescence on motor activity, anxiety, and social behavior were evaluated in adult mice. The concentration of brain monoamines in the striatum, cortex, and hippocampus was measured following the behavioral test. METHODS: Adolescent OF1 mice were exposed to ethanol (1.25 g/kg) on two consecutive days at 48-h intervals over a 14-day period (from PND 29 to 42). A total of eight injections of MDMA (10 or 20 mg/kg) were administered twice daily at 4-h intervals over two consecutive days, and this schedule was repeated 6 days later (PND 33, 34, 41, and 42). Behavioral tests and analysis of brain monoamines took place on PND 64 to 67. RESULTS: Exposure to MDMA during adolescence increased the anxiogenic response in the elevated plus maze, with adult mice spending less time in the open arms of the maze and exhibiting lower concentrations of DA in the striatum. A pattern of ethanol administration modeling binge drinking during adolescence enhanced these effects and undermined the hyperthermic response induced by MDMA. Passive avoidance was affected only when EtOH was administered alone. CONCLUSIONS: Juvenile administration of MDMA and alcohol was found to cause a decrease in monoamine levels in adulthood, as well as changes in social interaction behaviors, locomotor activity, increase measures of anxiety in the elevated plus maze (EPM), and decrease step-through latencies in passive avoidance test. PMID- 21556806 TI - Variation in saliva cotinine as a function of self-reported attempts to reduce cigarette consumption. AB - RATIONALE: Cotinine is an accurate objective marker of nicotine intake. There is very little information on its stability over time or as a function of self reported attempts at smoking reduction. OBJECTIVES: This study aimed to assess the stability of saliva cotinine concentrations over a 3-month period, as a function of self-reported attempts to reduce cigarette consumption, using data from a general population sample of English smokers. METHODS: Six-hundred and ninety-one smokers from a population sample of English smokers provided saliva samples for cotinine analysis on two occasions 3 months apart. Data on cigarette consumption, whether smokers reported that they were attempting to cut down consumption and concurrent use of nicotine replacement therapy (NRT), were also collected on both occasions. RESULTS: The 'test-retest' measure of cotinine stability was 0.76, and the simple correlation was 0.73. Smokers not using NRT who reported cutting down on one occasion but not the other showed a small reduction in cigarette consumption at the time they were cutting down (1.1 cig per day, p = 0.013) but no significant difference in saliva cotinine concentrations (mean reduction = 13.4 ng/ml, p = 0.39). CONCLUSIONS: Saliva cotinine concentrations show moderate-to-high stability within subjects over a 3 month period. Smokers' reports of attempting to cut down their smoking are associated with small daily cigarette consumption decreases but no detectable change in nicotine intake. PMID- 21556807 TI - Evidence-based statin prescription for cardiovascular protection in renal impairment. AB - Dyslipidemia is a well-known risk factor for cardiovascular disease in the general population, and the cardioprotective role of statins is well established. However, although cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease (CKD), the role of statin therapy is still under investigation. In CKD the atherosclerotic burden is high and pathophysiology of dyslipidemia is complex; however, the majority of large-scale statin trials excluded patients with CKD. Statins could have different effects in the different stages of CKD. Two large trials involving haemodialysis patients showed unfavourable results, whereas in renal transplant subjects as well as in early CKD subjects, statins reduced cardiovascular risk. The studies involving early CKD patients are post-hoc analyses of large trials and they showed that statins are more effective in secondary than in primary prevention. The aim of this study was to evaluate the effectiveness of statins for prevention of cardiovascular events by calculating the number of patients needed to be treated in different interventional trials. We conclude that dyslipidemia is a modifiable cardiovascular risk and statins appear to be an effective treatment especially in the early stages of CKD. Patients on renal replacement therapy could obtain an advantage from this treatment; however, the patient's clinical prognosis should be taken into account when evaluating treatment. PMID- 21556808 TI - Assimilation and contrast: the two sides of specific interference between action and perception. AB - Perception and action have long been treated as relatively independent and serial processes. More recent views, however, consider perception and action as relying on a common set of processes and/or representations. The present paper will focus on a variety of specific (content-based) perception-action interactions that have been taken as support for such views. In particular, the following aspects will be considered: direction of influence (perception on action vs. action on perception), temporal type (concurrent vs. non-concurrent), functional relation (related/unrelated), and type of movements (biological vs. non-biological). Different extant models of the perception-action interface are discussed and a classification schema proposed that tries to explain when contrast and when assimilation effects will arise. PMID- 21556809 TI - The motor side of emotions: investigating the relationship between hemispheres, motor reactions and emotional stimuli. AB - The aim of the present study was to analyze if the left hemisphere preferentially controls flexion responses toward positive stimuli, while the right hemisphere is specialized toward extensor responses to negative pictures. To this end, right handed subjects had to pull or push a joystick subsequent to seeing a positive or a negative stimulus in their left or right hemifield. Flexion responses were faster for positive stimuli, while negative stimuli were associated with faster extensions responses. Overall, performance was fastest when emotional stimuli were presented to the left visual hemifield. This right hemisphere superiority was especially clear for negative stimuli, while reaction times toward positive pictures showed no hemispheric difference. We did not find any interaction between hemifield and response type. Neither was there a triple interaction between valence, hemifield and response type. We suppose that response dichotomies in humans are not as tightly linked to a hemisphere- and valence bound reaction type as previously assumed. PMID- 21556810 TI - Animal models and molecular imaging tools to investigate lymph node metastases. AB - Lymph node metastasis is a strong predictor of poor outcome in cancer patients. Animal studies of lymph node metastasis are constrained by difficulties in the establishment of appropriate animal models, limitations in the noninvasive monitoring of lymph node metastasis progression, and challenges in the pathologic confirmation of lymph node metastases. In this comprehensive review, we summarize available preclinical animal cancer models for noninvasive imaging and identification of lymph node metastases of non-hematogenous cancers. Furthermore, we discuss the strengths and weaknesses of common noninvasive imaging modalities used to identify tumor-bearing lymph nodes and provide guidelines for their pathological confirmation. PMID- 21556811 TI - Development of genetically engineered CD4+ and CD8+ T cells expressing TCRs specific for a M. tuberculosis 38-kDa antigen. AB - Cell-mediated immunity is critical to the clearance of Mycobacterium tuberculosis due to the primarily intracellular niche of this pathogen. Adoptive transfer of M. tuberculosis-specific effector T cells has been shown to confer immunity to M. tuberculosis-infected recipients resulting in M. tuberculosis clearance. However, it is difficult to generate sufficient numbers of M. tuberculosis antigen specific T cells in a short time. Recent studies have developed T cell receptor (TCR) gene-modified T cells that allow for the rapid generation of large numbers of antigen-specific T cells. Many TCRs that target various tumor and viral antigens have now been isolated and shown to have functional activity. Nevertheless, TCRs specific for intracellular bacterial antigens (including M. tuberculosis antigens) have yet to be isolated and their functionality confirmed. We isolated M. tuberculosis 38-kDa antigen-specific HLA class I and class II restricted TCRs and modified the TCR gene C regions by substituting nine amino acids with their murine TCR homologs (minimal murinization). Results showed that both wild-type and minimal murinized TCR genes were successfully cloned into retroviral vectors and transduced into primary CD4(+) and CD8(+) T cells and displayed anti-M. tuberculosis activity. As expected, minimal murinized TCRs displayed higher cell surface expression levels and stronger anti-M. tuberculosis activity than wild-type TCRs. To the best of our knowledge, this is the first report describing TCRs targeting M. tuberculosis antigens and this investigation provides the basis for future TCR gene-based immunotherapies that can be designed for the treatment of immunocompromised M. tuberculosis-infected patients. PMID- 21556812 TI - Acute cortisol release during stereotactic fractionated radiotherapy to an ACTH secreting pituitary macroadenoma. AB - A 33-year old male was diagnosed with Cushing's disease due to a large and invasive ACTH-secreting macroadenoma. After surgical failure ketoconazole therapy was initiated to control cortisol hypersecretion and his symptoms. He was referred to radiotherapy, and fractionated stereotactic radiotherapy in 30 fractions was delivered. After 12 daily fractions of radiotherapy the urinary cortisol release increased abruptly together with clinical deterioration. The daily ketoconazole dose was increased, and 10 days after concluding radiotherapy his urinary cortisol returned to normal values. Hormonal remission was observed less than 1 year following radiotherapy. PMID- 21556813 TI - Medical suppression of hypercortisolemia in Cushing's syndrome with particular consideration of etomidate. AB - Cushing's syndrome is associated with excessive cortisol secretion by the adrenal gland or ectopic tumours and may result in diabetes, hypertension, and life threatening infections with high mortality rates especially in the case of surgical resection. Although surgical resection is the treatment of choice, patients may benefit from preceding medical therapy. This may especially be useful as an adjunctive approach in emergency settings, if patients cannot undergo surgery, if surgery or radiotherapy fails, or if the tumour recurs. Medical therapy can be categorized in three different groups-inhibition of steroidogenesis, suppression of adrenocorticotropic hormone, and antagonism of the glucocorticoid receptor. However, the majority of common drugs are not available for parenteral administration, which may evoke a management problem in emergency settings or in patients unable to tolerate oral medication. The carboxylated imidazole etomidate is a well known parenteral induction agent for general anaesthesia. Besides its hypnotic properties, etomidate also has alpha adrenergic characteristics and inhibits the enzyme 11-deoxycortisol beta hydroxylase, which catalyzes the final step of the conversion of cholesterol to cortisol. Adverse outcomes have been reported when used for sedation in septic or trauma patients probably by its interference with steroid homeostasis. However, its capability of inhibition of the 11-deoxycortisol beta-hydroxylase leads to suppression of cortisol secretion which has been demonstrated to be a useful tool in severe and complicated hypercortisolemia. Within this article, we review the data concerning different pharmacological approaches with particular consideration of etomidate in order to suppress steroidogenesis in patients with Cushing's syndrome. PMID- 21556814 TI - Continuous blood pressure measurement by using the pulse transit time: comparison to a cuff-based method. AB - Pulse transit time (PTT) and pulse wave velocity (PWV), respectively, were shown to have a correlation with systolic blood pressure (SBP) and have been reported to be suitable for indirect BP measurements. The aim of this study was to create a function between SBP and PWV, and to test its reliability for the determination of absolute SBP using a non-linear algorithm and a one-point calibration. 63 volunteers performed exercise to induce rises in BP. Arterial PTT was measured between the R-spike of the ECG and the plethysmographic curve of finger pulse oximetry. The reference BP was measured using a cuff-based sphygmomanometric aneroid device. Data from 13 of the 63 volunteers served for the detection of the PWV-BP relationship. The created non-linear function was used to calculate BP values after individual correction for the BP offset in a group of 50 volunteers. Individual correlation coefficients for SBP measured by PTT (SBP(PTT)) and by cuff (SBP(CUFF)) varied between r = 0.69 and r = 0.99. Taking all data together, we found r = 0.83 (276 measurements in 50 volunteers). In the Bland-Altman plot, the limits of agreement were [Formula: see text]+/- 19.8 mmHg. In conclusion, comparing SBP values using the PTT-based method and those measured by cuff resulted in a significant correlation. However, the Bland-Altman plot shows relevant differences between both methods, which are partly due to greater variability of the SBP(PTT) measurement during intensified exercise. Results suggest that PTT can be used for measuring absolute SBP when performing an individual correction for the offset of the BP-PWV relation. PMID- 21556815 TI - Influence of moderate hypoxia on tolerance to high-intensity exercise. AB - It remains uncertain as how the reduction in systemic oxygen transport limits high-intensity exercise tolerance. 11 participants (5 males; age 35 +/- 10 years; peak [Formula: see text] 3.5 +/- 0.4 L min(-1)) performed cycle ergometry to the limit of tolerance: (1) a ramp test to determine ventilatory threshold (VT) and peak [Formula: see text]; (2) three to four constant-load tests in order to model the linear P-t (-1) relationship for estimation of intercept (critical power; CP) and slope (AWC). All tests were performed in a random order under moderate hypoxia (FiO(2) = 0.15) and normoxia. The linearity of the P-t (-1) relationship was retained under hypoxia, with a systematic reduction in CP (220 +/- 25 W vs. 190 +/- 28 W; P < 0.01) but no significant difference in AWC (11.7 +/- 5.5 kJ vs. 12.1 +/- 4.4 kJ; P > 0.05). However, large individual variations in the change of the latter were observed (-36 to +66%). A significant relationship was found between the % change in CP (r = 0.80, P < 0.01) and both peak [Formula: see text] (CP: r = -0.65, P < 0.05) and VT values recorded under normoxia (CP: r = -0.65, P < 0.05). The present study demonstrates the aerobic nature of the intercept of the P-t (-1) relationship, i.e. CP. However, the extreme within-individual changes in AWC do not support the original assumption that AWC reflects a finite energy store. Lower hypoxia-induced decrements in CP were observed in aerobically fitter participants. This study also demonstrates the greater ability these participants have to exercise at supra-CP but close to CP workloads under moderate hypoxia. PMID- 21556816 TI - South Pacific Islanders resist type 2 diabetes: comparison of aerobic and resistance training. AB - The purpose of this study was to evaluate the effectiveness of two exercise modalities for improving glycosylated hemoglobin (HbA1c) and associated clinical outcomes in Polynesian adults diagnosed with type 2 diabetes and visceral obesity. Twenty-six adults were randomized to receive resistance training or aerobic training, 3*/week, for 16 weeks. Dependent variables collected before and after intervention included: diabetes markers including HbA1c, blood lipids, relevant cytokines (C-reactive protein, adiponectin), and anthropometric and hemodynamic indices. Eighteen participants (72% female; age: 49.3 +/- 5.3 years; waist circumference: 128.7 +/- 18.7 cm) completed the intervention and follow-up assessments. Body mass index in the whole cohort at baseline indicated Class III (morbid) obesity (43.8 +/- 9.5 kg/m(2)). Compliance to training was 73 +/- 19 and 67 +/- 18% in the aerobic and resistance training groups, respectively. HbA1c remained elevated in both groups after training. Aerobic training reduced systolic and diastolic blood pressure and increased serum triglycerides (all P < 0.05). No other exercise-induced adaptations were noted within or between groups. Post hoc analysis using pooled data indicated that higher adherence to training (>=75% attendance, n = 8) significantly reduced waist circumference (P < 0.001) and tended to reduce body weight and fasting insulin (all P <= 0.11) versus lower adherence (<75% attendance, n = 10). In conclusion, this study did not demonstrate an improvement in HbA1c with exercise in morbidly obese Polynesian people. Future investigations involving exercise regimens that are more practicable and which involve greater frequency and duration of training may be required to induce significant and clinically meaningful adaptations in this unique diabetes population. PMID- 21556817 TI - Alterations in peripheral muscle contractile characteristics following high and low intensity bouts of exercise. AB - The aim of this study was to monitor muscle contractile performance in vivo, using an electrical stimulation protocol, immediately following an acute high and low intensity exercise session conducted at the same average intensity performed on a cycle ergometer. Eighteen healthy males (25.1 +/- 4.5 years, 81.6 +/- 9.8 kg, 1.83 +/- 0.06 m; mean +/- SD) participated in the study. On two occasions, separated by 1 week, subjects completed a high and low intensity exercise session in a random order on a cycle ergometer, performing equal total work in each. At the end of each test, a muscle performance test using electrical stimulation was performed within 120 s. Post-exercise muscle data were compared to the subjects' rested muscle. We found a reduction in muscle contractile performance following both high and low intensity exercise protocols but a greater reduction in maximal voluntary contraction (MVC) (P < 0.01), rate of torque development (RTD) (P < 0.001), rate of relaxation (RR(1/2)), (P < 0.001) the 60 s slope of the fatigue protocol (P < 0.01) and torque frequency response (P < 0.05) following the high intensity bout. Importantly muscle performance remained reduced 1 h following high intensity exercise but was recovered following low intensity exercise. Muscle function was significantly reduced following higher intensity intermittent exercise in comparison to lower intensity exercise even when the average overall intensity was the same. This study is the first to demonstrate the sensitivity of muscle contractile characteristics to different exercise intensities and the impact of higher intensity bursts on muscle performance. PMID- 21556818 TI - A computational study of multisensory maturation in the superior colliculus (SC). AB - Multisensory neurons in cat SC exhibit significant postnatal maturation. The first multisensory neurons to appear have large receptive fields (RFs) and cannot integrate information across sensory modalities. During the first several months of postnatal life RFs contract, responses become more robust and neurons develop the capacity for multisensory integration. Recent data suggest that these changes depend on both sensory experience and active inputs from association cortex. Here, we extend a computational model we developed (Cuppini et al. in Front Integr Neurosci 22: 4-6, 2010) using a limited set of biologically realistic assumptions to describe how this maturational process might take place. The model assumes that during early life, cortical-SC synapses are present but not active and that responses are driven by non-cortical inputs with very large RFs. Sensory experience is modeled by a "training phase" in which the network is repeatedly exposed to modality-specific and cross-modal stimuli at different locations. Cortical-SC synaptic weights are modified during this period as a result of Hebbian rules of potentiation and depression. The result is that RFs are reduced in size and neurons become capable of responding in adult-like fashion to modality-specific and cross-modal stimuli. PMID- 21556819 TI - Facilitation and interference components in the joint Simon task. AB - Two experiments were conducted to assess whether the joint Simon effect is composed of facilitation and interference and whether facilitation is increased by a joint spatially compatible practice performed before performing the joint Simon task. In both experiments, participants were required to perform a Simon task along another person. Trials could be corresponding, non-corresponding, and neutral. In Experiment 1, participants performed only the Simon task. In Experiment 2, participants first practiced on a joint spatial compatibility task with a compatible mapping and, after a 5-min delay, transferred to a joint Simon task. Results indicated that the joint Simon effect consisted primarily of interference, which was significantly increased by a spatially compatible practice performed jointly. These results allow us to better define in what ways the presence of the other influences performance, in showing that when participants perform a task along with another individual, they display a disadvantage (i.e., slower RTs) when they have to respond to stimuli appearing on the other agent's side. PMID- 21556820 TI - Making oneself predictable: reduced temporal variability facilitates joint action coordination. AB - Performing joint actions often requires precise temporal coordination of individual actions. The present study investigated how people coordinate their actions at discrete points in time when continuous or rhythmic information about others' actions is not available. In particular, we tested the hypothesis that making oneself predictable is used as a coordination strategy. Pairs of participants were instructed to coordinate key presses in a two-choice reaction time task, either responding in synchrony (Experiments 1 and 2) or in close temporal succession (Experiment 3). Across all experiments, we found that coactors reduced the variability of their actions in the joint context compared with the same task performed individually. Correlation analyses indicated that the less variable the actions were, the better was interpersonal coordination. The relation between reduced variability and improved coordination performance was not observed when pairs of participants performed independent tasks next to each other without intending to coordinate. These findings support the claim that reducing variability is used as a coordination strategy to achieve predictability. Identifying coordination strategies contributes to the understanding of the mechanisms involved in real-time coordination. PMID- 21556822 TI - A rare case of thymoma in a 15-month-old girl. AB - We report a case of thymoma in a 15-month-old girl successfully treated with thymectomy. This case is unique due to the very young age of the child and a family history of thymoma in the father, who was treated with resection at age 10. Radiographic and CT findings mimicked thymic hyperplasia, and highlight the difficulty of distinguishing between these two conditions, since the latter is more common in children. The case is followed by a discussion of thymic hyperplasia and thymoma. PMID- 21556821 TI - Alpe d'HuZes cancer rehabilitation (A-CaRe) research: four randomized controlled exercise trials and economic evaluations in cancer patients and survivors. AB - BACKGROUND: Previous studies showed that exercise in cancer patients is feasible and may reduce fatigue and improve physical fitness and quality of life. However, many previous studies had methodological weaknesses related to trial design, sample size, comparison group, outcome measures, short follow-up durations and programme content. PURPOSE: This paper aims to present the rationale and design of the clinical research subprogramme of the Alpe d'HuZes Cancer Rehabilitation (A-CaRe) programme. METHOD: A-CaRe Clinical Research includes four randomized controlled trials in patients: (a) after chemotherapy, (b) during chemotherapy, (c) after stem cell transplantation and (d) during childhood cancer. These trials compare high-intensity resistance and endurance exercise interventions with usual care or a waiting list control group. In two studies, a second intervention arm consisting of low-to-moderate intensity exercise is included. All four A-CaRe trials use similar methods. RESULTS: Outcome measures are carefully chosen based on the International Classification of Functioning Disability and Health model. Measurements will be performed prior to randomization (T0), after completion of the intervention (T1) and at follow-up (T2). The primary outcome measures are cardiorespiratory fitness, muscle strength and fatigue. Secondary outcome measures include health-related quality of life and psychosocial functioning. Furthermore, cost-effectiveness and cost-utility analyses are performed from a societal perspective. CONCLUSION: We hypothesize that exercise is more effective at improving physical fitness and thereby reducing fatigue and more cost effective compared with usual care or a waiting list control group. If so, the programmes will be implemented in the Dutch clinical practice. PMID- 21556823 TI - Protection by endogenous FGF-2 against isoproterenol-induced cardiac dysfunction is attenuated by cyclosporine A. AB - Fibroblast growth factor-2 (FGF-2) is implicated in cardioprotection. However, previously we found that chronic elevation in cardiac FGF-2 levels in transgenic mice was associated with exaggerated, cyclosporine A-preventable, cellular infiltration after isoproterenol-induced injury, suggestive of an adverse outcome, although this was not examined with functional studies. We have now used highly sensitive tissue Doppler imaging (TDI) to evaluate cardiac functional parameters after isoproterenol administration in transgenic mice overexpressing the 18 kDa FGF-2 in the heart in vivo. Cardiac function was assessed in conscious FGF-2 transgenic and non-transgenic mice at 24 h as well as 2 and 4 weeks after isoproterenol administration, and in the absence or presence of either cyclosporine A or anti-CD3epsilon treatments. Isoproterenol decreased left ventricular endocardial velocity and strain rate by 47-51% at 24 h in non transgenic mice, but to a significantly lesser extent (by 24%) in transgenic mice. While additional decreases were seen in non-transgenic mice at 2 weeks, there was no further reduction in ventricular endocardial velocity or strain rate up to 4 weeks post-treatment in FGF-2 transgenic mice. Functional improvement at 2 and 4 weeks post-isoproterenol was reduced significantly by treatment with cyclosporine A but not anti-CD3epsilon; the latter targets T lymphocyte activation more specifically. TDI values in the presence of chronic FGF-2 overexpression are prognostic of an improved cardiac outcome and protection from isoproterenol induced cardiac dysfunction in vivo. Our data also suggest that cyclosporine A-sensitive infiltrating cell population(s) may contribute to the sustained beneficial effect of FGF-2 in vivo. PMID- 21556824 TI - Diet-induced obesity suppresses ghrelin in rat gastrointestinal tract and serum. AB - The aims of the present study were to examine ghrelin expression in serum and gastrointestinal tract (GIT) tissues, and to measure tissue ghrelin levels and obesity-related alterations in some serum biochemical variables in rats with diet induced obesity (DIO). The study included 12 male rats, 60 days old. The rats were randomly allocated to two groups (n = 6). Rats in the DIO group were fed a cafeteria-style diet to induce obesity, while those in the control group were fed on standard rat pellets. After a 12 week diet program including an adaptation period all rats were decapitated, tissues were individually fixed, ghrelin expression was examined by immunohistochemistry , and tissue and serum ghrelin levels were measured by radioimmunoassay. Serum biochemical variables were measured using an autoanalyzer. When the baseline and week 12 body mass index and GIT ghrelin expression were compared between DIO and control rats, BMI had increased and ghrelin expression decreased due to obesity. The RIA results were consistent with these findings. Serum glucose, LDL cholesterol, and total cholesterol levels were elevated and HDL cholesterol significantly decreased in the DIO group. A comparison of GIT tissues between the control and obese groups demonstrated that ghrelin was decreased in all tissues of the latter. This decrease was brought about a decline in the circulating ghrelin pool. This suggests that rather than being associated with a change in a single tissue, obesity is a pathological condition in which ghrelin expression is changed in all tissues. PMID- 21556825 TI - Surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries. AB - PURPOSE: Although various surgical procedures have attempted to restore valgus stability in medial knee injuries, so far none has achieved satisfactory results. The purpose of this study was to assess clinical outcome for patients with grade 3 valgus instability who were treated according to our surgical management strategy. METHODS: Eighteen patients with both acute and chronic grade 3 medial knee injuries, all of which had combined cruciate ligament injuries, were treated with a proximal advancement of both the superficial medial collateral ligament (MCL) and posterior oblique ligament together with underlying deep MCL and joint capsule, in conjunction with cruciate ligament reconstructions in chronic phase. Augmentation with doubled semitendinosus tendon was added in 7 patients whose medial knee stability had been considered to be insufficient with only the proximal advancement procedure. They were evaluated preoperatively and at final follow-up. RESULTS: Manual valgus laxities at 0 degrees and 30 degrees , as well as side-to-side difference in medial joint opening in stress radiograph, were significantly improved at final follow-up. The Lysholm knee scale was also significantly improved. Median values of the subjective evaluations of the patients' satisfaction, stability and sports performance level measured with visual analogue scale at final follow-up were 82 (60-100), 94 (71-100) and 88 (60 100), respectively. CONCLUSIONS: Clinical outcomes of our surgical management strategy were reasonable in terms of restoring medial knee stability. This treatment protocol can help determine the surgical management of grade 3 medial knee injuries combined with cruciate ligament injuries. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 21556826 TI - Arthroscopic lateral collagen meniscus implant in a professional soccer player. AB - A case of an arthroscopically implanted lateral Collagen Meniscus Implant in a 24 year-old professional soccer player is reported. This meniscal scaffold was able to improve knee function and reduce pain in this symptomatic meniscectomized young athlete at 36-month follow-up. This is the first case of an arthroscopic lateral collagen meniscal scaffold implanted in a high-level soccer player described in literature. PMID- 21556827 TI - Double-layered lateral meniscus. AB - A case of double-layered lateral meniscus in which an accessory proximal hemimeniscus was overlying the body and posterior horn of the lateral meniscus is here reported. The accessory hemimeniscus lays marginal and parallel to the normal lateral meniscus with its periphery dissociated from the capsule and was significantly thinner and more mobile than its underlying counterpart. It was resected arthroscopically, and the patient's symptoms were significantly improved. This case demonstrates an interesting and extremely rare anatomical abnormality of the lateral meniscus. PMID- 21556828 TI - Biomechanical comparison of four double-row speed-bridging rotator cuff repair techniques with or without medial or lateral row enhancement. AB - BACKGROUND: Biomechanical comparison of four different Speed-Bridge configurations with or without medial or lateral row reinforcement. Reinforcement of the knotless Speed-Bridge double-row repair technique with additional medial mattress- or lateral single-stitches was hypothesized to improve biomechanical repair stability at time zero. METHODS: Controlled laboratory study: In 36 porcine fresh-frozen shoulders, the infraspinatus tendons were dissected and shoulders were randomized to four groups: (1) Speed-Bridge technique with single tendon perforation per anchor (STP); (2) Speed-Bridge technique with double tendon perforation per anchor (DTP); (3) Speed-Bridge technique with medial mattress-stitch reinforcement (MMS); (4) Speed-Bridge technique with lateral single-stitch reinforcement (LSS). All repairs were cyclically loaded from 10-60 N up to 10-200 N (20 N stepwise increase) using a material testing device. Forces at 3 and 5 mm gap formation, mode of failure and maximum load to failure were recorded. RESULTS: The MMS-technique with double tendon perforation showed significantly higher ultimate tensile strength (338.9 +/- 90.0 N) than DTP (228.3 +/- 99.9 N), LSS (188.9 +/- 62.5 N) and STP-technique (122.2 +/- 33.8 N). Furthermore, the MMS-technique provided increased maximal force resistance until 3 and 5 mm gap formation (3 mm: 77.8 +/- 18.6 N; 5 mm: 113.3 +/- 36.1 N) compared with LSS, DTP and STP (P < 0.05 for each 3 and 5 mm gap formation). Failure mode was medial row defect by tendon sawing first, then laterally. No anchor pullout occurred. CONCLUSION: Double tendon perforation per anchor and additional medial mattress stitches significantly enhance biomechanical construct stability at time zero in this ex vivo model when compared with the all-knotless Speed-Bridge rotator cuff repair. PMID- 21556829 TI - Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients. AB - BACKGROUND/AIMS: Anemia is commonly observed as a side effect in a treatment with protease inhibitors combined with peginterferon alpha and ribavirin for hepatitis C virus infection. This study assessed the safety, tolerability, viral kinetics, and selection of variants in telaprevir monotherapy for 24 weeks, and outcomes of the off-study treatment with peginterferon alpha-2b and ribavirin among Japanese female patients at a median age of 54 years who were difficult to treat with the standard therapy (peginterferon alpha-2b and ribavirin) alone in Japan. METHODS: Four treatment-naive patients with chronic hepatitis C virus subtype 1b infection received telaprevir (750 mg every 8 h) alone for 24 weeks. All patients then started the off-study treatment with peginterferon alpha-2b and ribavirin. Safety, tolerability, hepatitis C virus RNA levels, and emergence of telaprevir resistant variants were monitored. RESULTS: During the 24 weeks of telaprevir monotherapy, there was no discontinuation due to adverse events, but 2 patients stopped the intake at weeks 6 and 15 because of viral breakthrough. Emergence of telaprevir-resistant variants was observed in 3 patients who showed viral breakthrough. These variants were eliminated by the off-study treatment, and sustained virological response was achieved in all patients. CONCLUSIONS: Anemia was manageable by carefully adjusting the ribavirin dosage in the standard therapy that followed telaprevir monotherapy. This sequential regimen seems to be safer and more tolerable than the triple combination of telaprevir, peginterferon alpha, and ribavirin, especially among elderly females with low baseline hemoglobin. PMID- 21556830 TI - Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low dose aspirin users: a pilot randomized controlled study. AB - BACKGROUND: Few studies have investigated measures to prevent small bowel injuries induced by aspirin. Our aim was to evaluate the effect of probiotic treatment on the small bowel injuries induced by chronic low-dose aspirin use. METHODS: Thirty-five patients who took low-dose enteric-coated aspirin 100 mg daily (for more than 3 months) plus omeprazole 20 mg daily and were diagnosed as having unexplained iron deficiency anemia participated in this prospective randomized controlled trial. We assigned the patients to receive probiotic treatment with Lactobacillus casei for 3 months (L. casei group) or not receive the probiotic (control group). Patients underwent capsule endoscopy (CE) before and after treatment. RESULTS: Twenty-five patients, including 13 in the L. casei group and 12 in the control group, underwent the full analysis. Significant decreases in the number of mucosal breaks and the CE score were observed at the 3 month evaluation in the L. casei group as compared with the results in the control group (P = 0.039). The change from the baseline in the median number of mucosal breaks in the L. casei group was -2, as compared with 0.5 in the control group. The change from the baseline in the median CE score in the L. casei group was -228 compared with -4 in the control group (P = 0.026). CONCLUSIONS: Co administration of L. casei is effective for the treatment of aspirin-associated small bowel injury. PMID- 21556831 TI - Parent-reported benefits of flupirtine in juvenile neuronal ceroid lipofuscinosis (Batten disease; CLN3) are not supported by quantitative data. AB - Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood that typically presents at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. No therapy has been shown to slow the progression of disease in JNCL patients, and all current treatments are symptomatic. Flupirtine has been shown in vitro to reduce apoptosis in CLN3 lymphocytes. Based on that preclinical study, several children with JNCL were given flupirtine by their parents. The purpose of this study was to determine if there was evidence of attenuated disease progression in any JNCL symptom domain. We administered a survey to parents of JNCL children to qualitatively assess flupirtine efficacy. We used the Unified Batten Disease Rating Scale (UBDRS) to determine specific aspects of disease progression and investigated three age-related factors: loss of independent ambulation, loss of intelligible speech, and loss of ability to perform independent activities of daily living. The median scores for the UBDRS physical, behavior, and capability subscales were determined in flupirtine-exposed subjects and compared to age-, sex-, and genotype-matched subjects who had never taken flupirtine. Twenty-one percent of survey responders reported administering flupirtine to their JNCL child, and 56% of these families perceived beneficial changes that they attributed to flupirtine. However, our quantitative, prospectively obtained data did not show any change in JNCL disease progression that could be attributed to flupirtine. This study highlights the need for prospective experimental therapeutic research. PMID- 21556832 TI - Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect. AB - The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated (1)H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H(1)-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age related decline in IQ subscales in boys affected with the CRTR defect. PMID- 21556833 TI - Genistein supplementation in patients affected by Sanfilippo disease. AB - BACKGROUND: Mucopolysaccharidosis type III (Sanfilippo syndrome) is a group of autosomal recessive disorders caused by a deficiency in one of the four enzymes involved in the lysosomal degradation of heparan sulfate. Genistein supplementation has been proposed as a potential therapy for the reduction of substrates in patients with these disorders. OBJECTIVE: The aim of this study was to assess the effectiveness and potential side effects of genistein supplementation in MPS III patients. METHODS: Open-label study, with 19 children (10 males and 9 females) enrolled with confirmed diagnosis of MPS III (age range 2.8-19 years). Patients were supplemented with genistein (5 mg kg(-1) day(-1)) for 1 year. Clinical evaluation, hair morphology, urinary glycosaminoglycan analysis, study of nutritional parameters, and other routine biochemical tests were performed. RESULTS: We did not observe an improvement in the disability scale; after genistein treatment, in most patients there was an increased disability score or it remained unchanged. There was a relative decrease in the recurrence of infections and gastrointestinal symptoms, as well as improvement in skin texture and hair morphology. Glycosaminoglycan levels were above normal at all control points and showed great variability in their elimination. CONCLUSION: Our results suggest that genistein supplementation at 5 mg kg(-1) day(-1) did not improve disability estimated by using a particular scale. PMID- 21556834 TI - Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content. AB - We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin stimulated glucose uptake was measured with positron emission tomography using 2- [(18)F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ~50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes. PMID- 21556835 TI - The use of continuous glucose monitoring in the practical management of glycogen storage disorders. AB - Continuous glucose monitoring systems (CGMS) are now in widespread use in diabetes management with an increasing evidence base. There are few reports of their use in GSD. Liver glycogen storage disorders (GSDs) are most often managed by intensive dietary regimens. Risks of over and under-treatment remain. We describe our use of CGMS in a cohort of GSD patients, the results obtained and the frequency of complications. Our experience is that CGM is a reliable, well accepted and valid tool in the monitoring of GSD patients and allows for assessment of blood sugar control in the 'real-life' setting, unlike hospital admissions. Combining CGM with urine ketone and / or blood lactate measurements, again at home, improves the investigation yet further. It is possible to perform CGM for periods including both schooldays and weekends, and also to change the dietary regimen during the period of monitoring to reduce the frequency of assessments. Risks of decreased reliability in the low range of blood sugars may be outweighed by the increased validity of the patient being in the home environment, with a normal diet and activity schedule. PMID- 21556836 TI - Correlation of age-specific phenylalanine levels with intellectual outcome in patients with phenylketonuria. AB - Patients with treated phenylketonuria (PKU) can have subtle deficits in intellect, academic skills, and executive functioning. This study evaluates the relationship between intellectual outcome and concentration/variation in blood phenylalanine (Phe) during specific developmental periods (0-6 years, 7-12 years, >12 years) in our patients with PKU. Verbal comprehension, perceptual reasoning, and processing speed were used as measures of intelligence. Data were collected from 55 patients receiving treatment at the University of Utah Metabolic Clinic. Yearly median Phe levels increased and mean number of blood Phe samples decreased as patients aged. Yearly median blood Phe from 0-6 and 7-12 years were inversely associated with perceptual reasoning abilities using linear regression. Additionally, increased blood Phe concentration negatively impacted specific areas of verbal comprehension abilities for those 0-6 years of age (p = 0.001). Variation of Phe levels around the mean (assessed as standard deviation) in each patient was associated with diagnostic (highest pretreatment) Phe levels and yearly median Phe levels (p < 0.001 for both), but did not significantly impact intelligence in our group of patients. Frequent blood Phe monitoring from 7-12 years significantly reduced the probability of yearly median Phe exceeding 360 MUM (p = 0.005). Our data show that compliance with treatment in patients with PKU affects both the concentration and variation of blood Phe levels, and may have a greater impact on verbal comprehension and perceptual reasoning skills during the first 12 years of life when compared the influence beyond 12 years. PMID- 21556837 TI - Neck and shoulder complaints in computer workers and associated easy to assess occupational factors--a large-scale cross-sectional multivariate study. AB - PURPOSE: The aim of this study was to identify easy to assess occupational factors that are associated with the presence of neck and shoulder complaints (NSC) in computer workers. METHODS: A total of 5,630 computer workers filled out a standardised questionnaire at the occasion of their periodical health examination. The dependent outcome variable was the one-year prevalence of neck and/or shoulder complaints. Following independent variables were considered in the analyses: age, gender, number of hours of computer work per week (both at work and at home), average time of uninterrupted computer work, screen position, position of documents, computer mouse use, forearm and separate wrist support, user friendly software and occupational psychosocial factors. Stepwise multivariate logistic regression analysis was used to identify those variables that contributed to the presence of NSC. RESULTS: Apart from gender and three psychosocial factors, following occupational factors were associated with NSC in computer workers: 25 h or more computer work per week, working more than 1 h on a computer without interruption, use of the computer mouse during half or more of the working time, reaching far for the computer mouse, insufficient space for the computer mouse, insufficient forearm support (less than 2/3 on table or no support) and the use of a separate wrist support. CONCLUSIONS: The study enabled to identify several easy to assess occupational factors that were associated with NSC, providing clear cut-off points concerning duration of computer work. Use of the computer mouse, both duration and relative position, and forearm support were also important factors. PMID- 21556838 TI - Psychosocial work environment among immigrant and Danish cleaners. AB - INTRODUCTION: Non-Western cleaners have been shown to have poorer health than their Danish colleagues. One reason could be a poorer psychosocial work environment. However, it is unknown if differences in self-reported psychosocial work environment exist between non-Western and Danish workers within the same social class. The aim of this study was to investigate such differences among cleaners with the hypothesis that the non-Western compared with Danish cleaners would report a generally poorer psychosocial work environment. METHODS: Two hundred and eighty-five cleaners (148 Danes and 137 non-Western immigrants) from 9 workplaces in Denmark participated in this cross-sectional study. The cleaners' immigrant status was tested for association with psychosocial work environment scales from the short version of the Copenhagen Psychosocial Questionnaire (COPSOQ) using ordinal logistic regression. RESULTS: Models adjusted for age, sex, BMI, smoking, workplace, and perceived physical work exertion showed that non-Western cleaners compared with Danish cleaners reported significantly higher scores with regard to Predictability (OR = 3.97), Recognition (OR = 1.92), Quality of Leadership (OR = 1.81), Trust Regarding Management (OR = 1.72), and Justice (OR = 2.14). CONCLUSIONS: This study showed that non-Western immigrant cleaners reported a statistically significantly better psychosocial work environment than Danish cleaners on a number of scales. Therefore, the hypothesis of non-Western immigrants reporting worse psychosocial work environment than their Danish colleagues was not supported. PMID- 21556839 TI - (Therapy-related?) large bowel acute ischemia in thalidomide-treated patient. PMID- 21556840 TI - Polypoid adenocarcinoma of small bowel in a patient with hereditary nonpolyposis colorectal cancer: does an adjacent gastrojejunostomy have any influence on its development? PMID- 21556841 TI - Long-term survival benefits of adjuvant chemotherapy by decreasing incidence of tumor recurrence without delaying relapse in stage III colorectal cancer. AB - BACKGROUNDS AND AIMS: To elucidate the survival benefits of adjuvant chemotherapy by decreasing incidence or by delaying time of tumor recurrence, we reported the long-term results of a nonrandomized prospective study comparing the adjuvant chemotherapy to no chemotherapy in stage III colorectal cancer. PATIENTS: From 1991 to 1995, 463 patients with stage III colorectal cancer were divided to three groups which were no chemotherapy, weekly chemotherapy, and monthly chemotherapy (5-FU plus levamisole). RESULTS: The recurrent incidence was significantly decreased in patients with chemotherapy (47.8% vs. 63.9% of no chemotherapy, P = 0.001), resulting into better survival. The 10-year cancer-specific and overall survival rates of patients with chemotherapy vs. no chemotherapy were 52.1% vs. 37.8% and 46.9% vs. 29.9%, respectively (P < 0.001). Weekly chemotherapy had better survival than monthly chemotherapy (P < 0.05). There was no significant difference in recurrent time or types between the patients with and without chemotherapy. The percentages of patients with recurrence happened within 3 years were 85.2% and 84.6% of those with and without chemotherapy, respectively. Patients with advanced stage of T4b invasion depth, N2, and central node invasion had no significant survival benefits by adjuvant chemotherapy. CONCLUSIONS: Long term survival benefits achieved by adjuvant chemotherapy is through decreasing recurrent incidence, not through postponing tumor recurrent time. That means adjuvant chemotherapy indeed cures some patients by eradicating occult tumor. In adjuvant setting, more powerful regimen for eradicating occult tumor is the keystone to improve long-term survival of stage III colorectal cancer. PMID- 21556842 TI - Involvement of spinal serotonin receptors in electroacupuncture anti-hyperalgesia in an inflammatory pain rat model. AB - We previously showed that electroacupuncture (EA) activates medulla-spinal serotonin-containing neurons. The present study investigated the effects of intrathecal 5,7-dihydroxytryptamine creatinine sulfate, a selective neurotoxin for serotonergic terminals, the 5-hydroxytryptamine 1A receptor (5-HT1AR) antagonist NAN-190 hydrobromide and the 5-HT2C receptor (5-HT2CR) antagonist SB 242,084 on EA anti-hyperalgesia. EA was given twice at acupoint GB30 after complete Freund's adjuvant (CFA) injection into hind paw. CFA-induced hyperalgesia was measured by assessing hind paw withdrawal latency (PWL) to a noxious thermal stimulus 30 min post-EA. Serotonin depletion and the 5-HT1AR antagonist blocked EA anti-hyperalgesia; the 5-HT2CR antagonist did not. Immunohistochemical staining showed that spinal 5-HT1AR was expressed and that 5 HT2CR was absent in naive and CFA-injected animals 2.5 h post-CFA. These results show a correlation between EA anti-hyperalgesia and receptor expression. Collectively, the data show that EA activates supraspinal serotonin neurons to release 5-HT, which acts on spinal 5-HT1AR to inhibit hyperalgesia. PMID- 21556843 TI - The neuroprotective effect of propofol against brain ischemia mediated by the glutamatergic signaling pathway in rats. AB - Several mechanisms are involved in the neuroprotection of propofol against ischemia, but influences of propofol on the binding properties of glutamate receptors and the uptake of glutamate in brain ischemia are not known. The present study was undertaken to investigate these issues in rat global brain ischemic model using methods of neuropathological evaluation, radioligand binding assay with and uptake test for L-(3)H-glutamate. It was shown that propofol used in anesthetic doses protected pyramidal neurons in the hippocampal CA1 subfield against delayed neuronal death normally induced by global brain ischemia. Simultaneously, the propofol decreased the value of maximal number of binding sites (Bmax), increased the value of equilibrium dissociation constant (Kd), and increased the glutamate uptake in the CA1 subfield. These findings indicate that it is, at least partly, via modulating the binding properties of glutamate receptors and the uptake of glutamate that propofol protects neurons against ischemic injury. PMID- 21556844 TI - Review of the use of ultrasound for the diagnosis and monitoring of enthesitis in psoriatic arthritis. AB - Musculoskeletal ultrasound is rapidly advancing, with contemporary machines offering exquisite high-resolution pictures of superficial structures such as tendons, ligaments, bursae, and joints. It is a useful tool that maybe used to evaluate patients with psoriasis and psoriatic arthritis. High-resolution transducers readily depict ultrastructural changes in the entheses and surrounding structures, while Doppler modalities elicit signs of increased blood flow, suggesting inflammation. Some of the findings seen at the entheses of psoriatic patients maybe viewed in an alternative framework of an enthesis organ concept. There are limited studies that search for the presence of enthesopathy in patients with psoriatic arthritis. Most of these examine lower extremity entheses with heterogeneous scoring methods. Similar indices have been used to examine patients with psoriasis to elucidate signs of early or occult psoriatic enthesitis. Although ultrastructural differences have been noted compared with control groups, longitudinal data are lacking with regard to placing these changes in the context of future development of psoriatic arthritis or functional outcome. PMID- 21556845 TI - Development of SCAR marker specific to non-toxic Jatropha curcas L. and designing a novel multiplexing PCR along with nrDNA ITS primers to circumvent the false negative detection. AB - Jatropha curcas L., a multipurpose shrub, has acquired significant economic importance for its seed oil which can be converted to biodiesel an emerging alternative to petro-diesel. In addition to the commercial value, it is also having medicinal and even high nutritional value to use as animal fodder which is limited due to the toxicity. Development of molecular marker will enable to differentiate non-toxic from toxic variety of J. curcas in a mixed population and also for quality control since the toxic components of J. curcas has deleterious effect on animals. In the present study, the efforts were made to generate the specific SCAR marker for toxic and/or non-toxic J. curcas from RAPD markers. Among the markers specific for toxic and non-toxic varieties, four were selected, purified, cloned, sequenced, and designed primers out of which one set of primers NT-JC/SCAR I/OPQ15-F and R could able to discriminate the non-toxic with toxic Jatropha by giving expected 430 bp size amplification in non-toxic variety. Furthermore, novel multiplex PCR was designed using the nrDNA ITS primers to overcome the false negatives. Present work also demonstrates utility of the conserved regions of nrDNA coding genes in ruling out the artifacts in PCR-like false negatives frequently occur in SCAR due to various reasons. The specific SCAR markers generated in the present investigation will help to distinguish non toxic from toxic varieties of J. curcas or vice versa, and isolated marker along with designed multiplex protocol has applications in quality control for selective cultivation of non-toxic variety and will also assist in breeding and molecular mapping studies. PMID- 21556846 TI - Doses from beta radiation in sensitive layers of human lung and dose conversion factors due to 222Rn/220Rn progeny. AB - Great deal of work has been devoted to determine doses from alpha particles emitted by (222)Rn and (220)Rn progeny. In contrast, contribution of beta particles to total dose has been neglected by most of the authors. The present work describes a study of the detriment of (222)Rn and (220)Rn progeny to the human lung due to beta particles. The dose conversion factor (DCF) was introduced to relate effective dose and exposure to radon progeny; it is defined as effective dose per unit exposure to inhaled radon or thoron progeny. Doses and DCFs were determined for beta radiation in sensitive layers of bronchi (BB) and bronchioles (bb), taking into account inhaled (222)Rn and (220)Rn progeny deposited in mucus and cilia layer. The nuclei columnar secretory and short basal cells were considered to be sensitive target layers. For dose calculation, electron-absorbed fractions (AFs) in the sensitive layers of the BB and bb regions were used. Activities in the fast and slow mucus of the BB and bb regions were obtained using the LUNGDOSE software developed earlier. Calculated DCFs due to beta radiation were 0.21 mSv/WLM for (222)Rn and 0.06 mSv/WLM for (220)Rn progeny. In addition, the influence of Jacobi room parameters on DCFs was investigated, and it was shown that DCFs vary with these parameters by up to 50%. PMID- 21556847 TI - Scanning irradiation device for mice in vivo with pulsed and continuous proton beams. AB - A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 * 100 MUm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed. PMID- 21556848 TI - The performance of automated case-mix adjustment regression model building methods in a health outcome prediction setting. AB - We have previously described a system for monitoring a number of healthcare outcomes using case-mix adjustment models. It is desirable to automate the model fitting process in such a system if monitoring covers a large number of outcome measures or subgroup analyses. Our aim was to compare the performance of three different variable selection strategies: "manual", "automated" backward elimination and re-categorisation, and including all variables at once, irrespective of their apparent importance, with automated re-categorisation. Logistic regression models for predicting in-hospital mortality and emergency readmission within 28 days were fitted to an administrative database for 78 diagnosis groups and 126 procedures from 1996 to 2006 for National Health Services hospital trusts in England. The performance of models was assessed with Receiver Operating Characteristic (ROC) c statistics, (measuring discrimination) and Brier score (assessing the average of the predictive accuracy). Overall, discrimination was similar for diagnoses and procedures and consistently better for mortality than for emergency readmission. Brier scores were generally low overall (showing higher accuracy) and were lower for procedures than diagnoses, with a few exceptions for emergency readmission within 28 days. Among the three variable selection strategies, the automated procedure had similar performance to the manual method in almost all cases except low-risk groups with few outcome events. For the rapid generation of multiple case-mix models we suggest applying automated modelling to reduce the time required, in particular when examining different outcomes of large numbers of procedures and diseases in routinely collected administrative health data. PMID- 21556849 TI - Association between severity of body mass index and periodontal condition in women. AB - This study evaluated the association between body mass index (BMI) and periodontal condition in a population of Brazilian women. A hospital convenience sample of 594 eligible women was recruited from a women's health reference center of Belo Horizonte, Brazil. Four groups were formed considering BMI levels: BMI normal group (n = 352), overweight (n = 54), obesity level I (n = 48), obesity level II (n = 56), and obesity level III (n = 74). Full-mouth periodontal examination was performed and biological, demographic, and behavioral risk variables were evaluated. Obese and overweight women showed statistically significant differences in bleeding on probing, probing depth and clinical attachment level >= 4 mm, and frequency of periodontitis (p < 0.05) compared to women showing normal BMI. The final multivariate model for the occurrence of periodontitis revealed that obesity groups were significantly associated with periodontitis. In addition, age (25-45), smoking, diabetes, and hypertension remained significantly associated with the occurrence of periodontitis (p < 0.05). Periodontitis was positively associated with obesity, and this association was more evident as obesity levels increases. These findings indicate the need for early diagnosis and the inclusion of periodontal care in health care programs for obese women. PMID- 21556850 TI - [Status and prospects of recent university history]. PMID- 21556851 TI - Comparison of target coverage and dose to organs at risk between simultaneous integrated-boost whole-field intensity-modulated radiation therapy and junctioned intensity-modulated radiation therapy with a conventional radiotherapy field in treatment of nasopharyngeal carcinoma. AB - We have retrospectively investigated 15 nasopharyngeal carcinoma patients treated at our institution between March 2007 and August 2009. We used simultaneous integrated-boost whole field intensity-modulated radiation therapy (SIB WF-IMRT) to treat the entire planning target volume in the head and neck cancer. All of the SIB WF-IMRT plans were replanned by use of the junctioned intensity modulated radiation therapy (J-IMRT) technique for comparison. The effect on target coverage and sparing of organs at risk, including laryngeal sparing in the optimal SIB WF-IMRT plan was compared with that achieved with use of the J-IMRT technique. The mean larynx dose and standard deviation was 25.2 +/- 5.8 Gy for SIB WF-IMRT and 19.8 +/- 16.8 Gy for J-IMRT. A comparison between SIB WF-IMRT and the J-IMRT technique demonstrated that the larynx dose was increased in SIB WF IMRT. However, when the strong dose constraint was applied to the larynx and the pseudo-volume was used for a steep dose fall-off immediately outside the target, the SIB WF-IMRT technique would have led to a larynx dose comparable to that achieved with J-IMRT. Therefore, in our current practice we use the SIB WF-IMRT technique, which does not have the problem of setup error at the match line for treatment of nasopharyngeal carcinoma. PMID- 21556853 TI - Complicated evolution of the caprellid (Crustacea: Malacostraca: Peracarida: Amphipoda) body plan, reacquisition or multiple losses of the thoracic limbs and pleons. AB - The Caprellidea (Crustacea) have undergone an interesting morphological evolution from their ancestral gammarid-like form. Although most caprellid families have markedly reduced third and fourth pereopods (the walking thoracic limbs) and pleons (the posterior body parts), one family, Caprogammaridae, has developed pleon with swimming appendages (pleopods), whereas another family, Phtisicidae, possesses well-developed functional third and fourth pereopods. The unique character status of these families implies that there has been reacquisition or multiple losses of both pereopods and the pleon within the Caprellidea lineages. Although the Caprellidea are fascinating animals for the study of morphological evolution, the phylogenetic relationships among the Caprellidea are poorly understood. One obstacle to studying the evolution of the Caprellidea is the difficulty of collecting samples of caprogammarid species. In this study, we obtained live samples of a Caprogammaridae species and confirmed that its pleon and pleopods could perform similar locomotive functions and swimming movements as observed in gammarids. From the phylogenetic analyses on 18S ribosomal RNA gene sequences, we identified three distinct clades of Caprellidea. The ancestral state reconstruction based on the obtained phylogeny suggested that once lost, the third and fourth pereopods were regained in the Phtisicidae, while the pleon was regained in the Caprogammaridae, while we could not exclude the possibility of independent losses. In either case, the caprellid lineage underwent a quite complicated morphological evolution, and possibly the Caprellidea may be an exception to Dollo's law. PMID- 21556852 TI - Astrocyte-like glia associated with the embryonic development of the central complex in the grasshopper Schistocerca gregaria. AB - In this study we employed the expression of the astrocyte-specific enzyme glutamine synthetase, in addition to the glia-specific marker Repo, to characterize glia cell types associated with the embryonic development of the central complex in the grasshopper Schistocerca gregaria. Double labeling experiments reveal that all glutamine synthetase-positive cells associated with the central complex are also Repo-positive and horseradish peroxidase-negative, confirming they are glia. Early in embryogenesis, prior to development of the central complex, glia form a continuous population extending from the pars intercerebralis into the region of the commissural fascicles. Subsequently, these glia redisperse to envelop each of the modules of the central complex. No glial somata are found within the central complex neuropils themselves. Since glutamine synthetase is expressed cortically in glia, it allows their processes as well as their soma locations to be visualized. Single cell reconstructions reveal one population of glia as directing extensive ensheathing processes around central complex neuropils such as the central body, while another population projects columnar-like arborizations within the central body. Such arborizations are only seen in central complex modules after their neuroarchitecture has been established suggesting that the glial arborizations project onto a prior scaffold of neurons or tracheae. PMID- 21556854 TI - Expansion of the Ago gene family in the teleost clade. AB - AGO proteins are universal effectors of eukaryotic small RNA-directed regulatory pathways. In this study, we used a comparative genomics approach to explore the AGO sub-family in the teleost clade. We identified five Ago homologues in teleost genomes, one more than encoded in other vertebrate clades. The additional teleost homologue was preserved most likely due to the differential retention of regulatory elements following the fish-specific genome duplication event that occurred approximately 350 million years ago. Analysis of all five Ago genomic loci in teleosts revealed that orthologues contain specific, conserved sequence elements in non-coding regions indicating that the teleost Ago paralogues are differentially regulated. This was supported by qRT-PCR analysis that showed differential expression of the zebrafish homologues across development and between adult tissues indicating stage and tissue-specific function of individual AGO proteins. Multiple sequence alignments showed not only that all teleost homologues possess critical residues for AGO function, but also that teleost homologues contain multiple orthologue-specific features, indicative of structural diversification. Notably, these are retained throughout the vertebrate lineage arguing these may be important for orthologue-specific functions. PMID- 21556855 TI - Expression analysis of epb41l4a during Xenopus laevis embryogenesis. AB - Epbl41l4a (erythrocyte protein band 4.1-like 4a, also named Nbl4) is a member of the band 4.1/Nbl4 (novel band 4.1-like protein 4) group of the FERM (4.1, ezrin, radixin, moesin) protein superfamily. Proteins encoded by this gene family are involved in many cellular processes such as organization of epithelial cells and signal transduction. On a molecular level, band 4.1/Nbl4 proteins have been shown to link membrane-associated proteins and lipids to the actin cytoskeleton. Epbl41l4a has also recently been identified as a target gene of the Wnt/beta catenin pathway. Here, we describe for the first time the spatio-temporal expression of epbl41l4a using Xenopus laevis as a model system. We observed a strong and specific expression of epb41l4a in the developing somites, in particular during segmentation as well as in the nasal and cranial placodes, pronephros, and neural tube. Thus, epbl41l4a is expressed in tissues undergoing morphogenetic movements, suggesting a functional role of epbl41l4a during these processes. PMID- 21556856 TI - A novel tissue in an established model system: the Drosophila pupal midgut. AB - The Drosophila larval and adult midguts are derived from two populations of endodermal progenitors that separate from each other in the early embryo. As larval midgut cells differentiate into an epithelial layer, adult midgut progenitors (AMPs) remain as small clusters of proliferating, undifferentiated cells attached to the basal surface of the larval gut epithelium. During the first few hours of metamorphosis, AMPs merge into a continuous epithelial tube that overgrows the larval layer and differentiates into the adult midgut; at the same time, the larval midgut degenerates. As shown in this paper, there is a second, transient pupal midgut that develops from the AMPs at the beginning of metamorphosis and that intercalates between the adult and larval midgut epithelia. Cells of the transient pupal midgut form a multilayered tube that exhibits signs of differentiation, in the form of septate junctions and rudimentary apical microvilli. Some cells of the pupal midgut develop as endocrine cells. The pupal midgut remains closely attached to the degenerating larval midgut cells. Along with these cells, pupal midgut cells are sequestered into the lumen where they form the compact "yellow body." The formation of a pupal midgut has been reported from several other species and may represent a general feature of intestinal metamorphosis in insects. PMID- 21556857 TI - Possible functions of Dpp in gastropod shell formation and shell coiling. AB - We examined dpp expression patterns in the pulmonate snail Lymnaea stagnalis and analyzed the functions of dpp using the Dpp signal inhibitor dorsomorphin in order to understand developmental mechanisms and evolution of shell formation in gastropods. The dpp gene is expressed in the right half of the circular area around the shell gland at the trochophore stage and at the right-hand side of the mantle at the veliger stage in the dextral snails. Two types of shell malformations were observed when the Dpp signals were inhibited by dorsomorphin. When the embryos were treated with dorsomorphin at the 2-cell and blastula stages before the shell gland is formed, the juvenile shells grew imperfectly and were not mineralized. On the other hand, when treated at the trochophore and veliger stage after the shell gland formation, juvenile shells grew to show a cone-like form rather than a normal coiled form. These results indicated that dpp plays important roles in the formation and coiling of the shell in this gastropod species. PMID- 21556858 TI - Diversity of killer cell immunoglobulin-like receptor genes in four ethnic groups in China. AB - Killer cell immunoglobulin-like receptors (KIRs) show extensive variation in terms of gene content and allelic polymorphisms among different populations. The aim of this study was to analyze the distribution of KIR genes in the Bulang, Nu, Yugu, and Zhuang ethnic groups, which belong to four different language families in China, and thus to provide basic KIR gene and genotype data for these Chinese ethnic groups. Genotyping of 16 KIR genes was performed in 425 unrelated individuals using the polymerase chain reaction-sequence-specific oligonucleotide probe method with the Luminex MultiAnalyte Profiling System. The four framework KIR genes were detected in all four ethnic groups. The activating KIR genes as well as the inhibitory KIR genes showed extreme diversity among these four populations. A total of 35 distinct KIR genotypes were identified, one of which was previously unknown. The four most common genotypes were identified in all four populations and comprised 66.1~91.1% of all the genotypes. The group A haplotype occurred more frequently than the group B haplotype in the Nu, Yugu, and Zhuang populations, as in other East Asian populations. In contrast, the group A and group B haplotypes occurred equally in the Bulang population. The results of the present study suggested that the KIR genes and genotypes are diverse in these four ethnic groups, and each ethnic group has its own characteristic KIR distribution. The findings with respect to KIR gene diversity in these four populations should provide relevant genomic diversity data for the future study of viral infections, autoimmune diseases, and reproductive fitness. PMID- 21556859 TI - Screening and confirmatory testing of MHC class I alleles in pig-tailed macaques. AB - Pig-tailed macaques (Macaca nemestrina) are a commonly studied primate model of human AIDS. The Mane-A1*084:01 MHC class I allele (previously named Mane-A*10) is important for the control of SIV infection by CD8+ T cells in this model. Validated methods to detect this allele in large numbers of macaques are lacking. We studied this MHC allele using sequence-specific PCRs in 217 pig-tailed macaques and identified 75 (35%) positive animals. We then performed massively parallel pyrosequencing with a universal 568-bp MHC class I cDNA-PCR amplicon for 50 of these 75 macaques. All 50 animals expressed Mane-A1*084:01 or closely related variants of the Mane-A1*084 lineage. Mane-A1*084 transcripts accounted for an average of 20.9% of all class I sequences identified per animal. SIV infection of a subset of these macaques resulted in the induction of SIV-specific CD8+ T cell responses detected by Mane-A1*084:01 tetramers. An average of 19 distinct class I transcripts were identified per animal by pyrosequencing. This analysis revealed 89 new Mane class I sequences as well as 32 previously described sequences that were extended with the longer amplicons employed in the current study. In addition, multiple Mane class I haplotypes that had been inferred previously based on shared transcript profiles between unrelated animals were confirmed for a subset of animals where pedigree information was available. We conclude that sequence-specific PCR is useful to screen pig-tailed macaques for Mane-A1*084:01, although pyrosequencing permits a much broader identification of the repertoire of MHC class I sequences and haplotypes expressed by individual animals. PMID- 21556860 TI - Genetics of rheumatoid arthritis: what have we learned? AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5-1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70-74 of the DRbeta1 chain are associated with the disease. The HLA molecules carrying these "shared epitope" sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA. PMID- 21556861 TI - Letter to the editor: Multimodal treatment of co-existent callosal cavernous malformation and anterior communicating artery aneurysm associated with an infraoptic anterior cerebral artery. PMID- 21556862 TI - Endovascular embolization for symptomatic perimedullary AVF and intramedullary AVM: a series and a literature review. AB - INTRODUCTION: Perimedullary arteriovenous fistula (AVF) has shunt on the spinal cord surface and it can be treated with surgery, or endovascular embolization. Intramedullary arteriovenous malformation (AVM) has its nidus in the cord and is difficult to treat either by surgery or endovascular technique. We report our experience with endovascular embolization in the treatment of perimedullary AVF and intramedullary AVM. METHODS: Four consecutive cases of spinal perimedullary AVF and six intramedullary AVM were retrospectively reviewed. These cases were evaluated and treated at Beijing Tiantan Hospital, China, over a 2-year period. A review of previously reported cases was also performed. RESULTS: There was no significant difference in the presentations (P = 0.348), level of lesions (P = 0.350), arterial suppliers (P = 0.801), and associated vascular anomalies between perimedullary AVF and intramedullary AVM, except for age (P = 0.014) and treatment modalities (P = 0.003). The patients with perimedullary AVFs were younger in our cases; the age at onset of symptoms averaged 25.8 years compared to 31.7 years for intramedullary AVMs. There was a significant male predominance for both lesions, and a significantly higher incidence of subarachnoid hemorrhage than in spinal dural AVFs. Regarding treatment, endovascular coil embolization is frequently used in perimedullary AVF and liquid embolic agent is an effective therapeutic choice in intramedullary AVM. CONCLUSION: Perimedullary AVF and intramedullary AVM are dissimilar with dural AVF in clinical characteristics. Our experience suggests that the endovascular treatment of spine perimedullary AVFs and intramedullary AVMs is feasible and effective. Endovascular treatment for intramedullary AVMs is still challenging, the main problem is acute ischemia injury of the spinal cord. PMID- 21556863 TI - Fractional anisotropy and mean diffusivity in the corpus callosum of patients with multiple sclerosis: the effect of physiotherapy. AB - INTRODUCTION: Modulation of neurodegeneration by physical activity is an active topic in contemporary research. The purpose of this study was to investigate changes in the brain's microstructure in multiple sclerosis (MS) after facilitation physiotherapy. METHODS: Eleven patients with MS were examined using motor and neuropsychological testing and multimodal MRI at the beginning of the study, with second baseline measurement after 1 month without any therapy, and after a 2-month period of facilitation physiotherapy. Eleven healthy controls were examined at the beginning of the study and after 1 month. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda (ax)), and radial diffusivity (lambda (rad)) were calculated for the whole corpus callosum (CC) in the midsagittal slice of T1W 3D MPRAGE spatially normalized images. Data were analyzed using linear mixed-effect models, paired, and two-sample tests. RESULTS: At the baseline, patients with MS showed significantly lower values in FA (p < 0.001), and significantly higher values in MD (p < 0.001), lambda (ax) (p = 0.003), and lambda (rad) (p < 0.001) compared to control subjects. The FA, MD, lambda (ax), and lambda (rad) did not change between the first and second baseline examinations in either group. Differences 2 months after initiating facilitation physiotherapy were in FA, MD, and in lambda (rad) significantly higher than differences in healthy controls (p < 0.001 for FA, p = 0.02 for MD, and p = 0.002 for lambda (rad)). In MS patients, FA in the CC significantly increased (p < 0.001), MD and lambda (rad) significantly decreased (p = 0.014 and p = 0.002), and thus approached the values in healthy controls. CONCLUSION: The results of the study show that facilitation physiotherapy influences brain microstructure measured by DTI. PMID- 21556864 TI - Inflammatory myopathy in a patient with postural and kinetik tremor. AB - Essential tremor (ET) is a common neurological disease of unknown etiopathogenesis, possibly neurodegenerative, characterized by kinetic tremor at the arms. Here we reported the case of an HCV-positive patient with inflammatory myopathy, who did not develop typical neuromuscular signs or symptoms during at least 7 years of hyperCKemia, in whom kinetic tremor of the arms was the prominent clinical feature, suggesting a possible diagnosis of ET. After 3 months of treatment with corticosteroids/methotrexate, creatine kinase (CK) levels were nearly normal and the tremor was remarkably improved. To our knowledge, similar cases have not been previously reported. Postural tremor can be present in muscular diseases, but only very rarely tremor has been reported as a major clinical feature. Because inflammatory myopathies are potentially treatable conditions it is very important to consider this diagnosis. Our case suggests that in patients with isolated postural and kinetic tremor routine laboratory assays should include CK blood screening. PMID- 21556865 TI - Acute encephalopathy associated with Campylobacter jejuni enteritis. AB - We present for the first time a case of acute encephalopathy in an adult patient induced by Campylobacter jejuni enteritis. Possible pathogenic mechanisms and importance of neuropsychological testing in the assessment of infection-related encephalopathy are discussed. PMID- 21556866 TI - Steroid-responsive Hashimoto encephalopathy mimicking Creutzfeldt-Jakob disease. AB - Hashimoto's encephalopathy (HE) is a rare neurological disorder with a heterogeneous group of neurological symptoms associated with high titres of anti thyroid antibodies. Clinical manifestations may include encephalopathic features such as seizures, behavioural and psychiatric manifestations, movement disorders and coma. The objective of this presentation is to describe a patient with this rare and controversial clinical syndrome mimicking Creutzfeldt-Jakob disease, associated with a Hashimoto euthyroid thyroiditis and with a significant response to high dose intravenous prednisone. The responsiveness of this syndrome to steroids suggests that this disorder involves immune pathogenic mechanisms, as previous reviews reported. PMID- 21556867 TI - Wallenberg's syndrome with extradural-extracranial origin of the posterior inferior cerebellar artery. AB - We report a case of lateral medullary syndrome (LMS) with extradural origin of the posterior inferior cerebellar artery (PICA). A 45-year-old construction worker presented with acute signs and symptoms of typical LMS. Prolonged work related neck extension was reported just prior to the onset of symptoms. Cerebral angiography revealed a patent vertebrobasilar tree with an extradural origin of an otherwise normal appearing PICA ipsilaterally. Workup did not show evidence for cardioembolic or atheroembolic source. The presence of an extradural origin of PICA may be considered a predisposing factor for non-traumatic LMS associated with head and neck movement. PMID- 21556868 TI - Can triptans safely be used for airplane headache? AB - A few cases of airplane headache (AH) have been reported in the literature. Treatment strategies of AHs are also controversial. We followed-up five patients with AH. They were symptom-free during the daytime. Their physical, neurological, and ear-nose-throat examinations were all normal. Blood chemistries, cerebral magnetic resonance imaging, cerebral magnetic resonance imaging angiography, and paranasal sinus tomography studies of the patients were also normal. We preferred triptans because of the possible effect on the mechanism of AH. Patients were recommended to use single-dose of their drugs half an hour prior to flights. All of the patients had a good response to single dose triptan treatment and became headache-free during flights. This is the first study which puts forward the usefulness of the triptans as a safe treatment choice for airplane AH. PMID- 21556869 TI - Head tremor secondary to MS resolved with rituximab. AB - We describe the case of a 33-year-old woman who presented with a 2-month history of worsening head tremor. The medical evaluation led to the new diagnosis of MS and the MRI of brain demonstrated prominently active disease. Intravenous rituximab was started according to the HERMES trial, and significant improvement was noted. She has received additional rituximab dosing approximately every 6 months, and at the 2-year follow-up the tremor has not recurred. The resolution of head tremor likely resulted from the complete suppression of MS disease activity, which must have allowed restoration of normal neural circuitry. In agreement with a growing body of evidence that supports early control of MS disease activity to prevent accumulation of fixed disability, this case advocates for aggressive immunological therapy at the onset of tremor in MS patients. PMID- 21556870 TI - Bickerstaff's brainstem encephalitis: case report and Tc99m brain SPECT findings. AB - A 21-year-old healthy female suffered from an upper respiratory tract infection and 2 days later developed diplopia, unsteady gait, dysarthria and a profound disturbance of consciousness with rapid development of coma. Brain MRI and Tc99m brain perfusion SPECT, EEG, neurophysiological tests and CSF analysis results were unspecific. The detection of serum anti-GQ1b IgG autoantibodies at high titre led to the diagnosis of Bickerstaff's brainstem encephalitis (BBE). Clinical symptoms resolved after treatment with plasma exchange and the outcome was good. Brain MRI was normal, and Tc99m brain perfusion SPECT demonstrated hypoperfusion of the whole cerebral hemispheres and basal ganglia with relative sparing of the thalami and the brainstem. Similar to brain MRI, the sensitivity of Tc99m brain perfusion SPECT in detecting brainstem lesions in typical BBE patients seems to be low. PMID- 21556871 TI - Reversible posterior leukoencephalopathy syndrome after spinal anesthesia. PMID- 21556872 TI - A puzzling visual field defect and the missing knee. PMID- 21556874 TI - Hunter syndrome and new onset idiopathic thrombocytopenic purpura in a young patient. PMID- 21556873 TI - Carboxysomes: cyanobacterial RubisCO comes in small packages. AB - Cyanobacteria (as well as many chemoautotrophs) actively pump inorganic carbon (in the form of HCO(3)(-)) into the cytosol in order to enhance the overall efficiency of carbon fixation. The success of this approach is dependent upon the presence of carboxysomes-large, polyhedral, cytosolic bodies which sequester ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and carbonic anhydrase. Carboxysomes seem to function by allowing ready passage of HCO(3)(-) into the body, but hindering the escape of evolved CO(2), promoting the accumulation of CO(2) in the vicinity of RubisCO and, consequently, efficient carbon fixation. This selectivity is mediated by a thin shell of protein, which envelops the carboxysome's enzymatic core and uses narrow pores to control the passage of small molecules. In this review, we summarize recent advances in understanding the organization and functioning of these intriguing, and ecologically very important molecular machines. PMID- 21556875 TI - Risk factors for infection and treatment outcome of extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae bacteremia in patients with hematologic malignancy. AB - This study was performed to evaluate the impact of extended-spectrum beta lactamase (ESBL)-producing bacteremia on outcome in patients with hematologic malignancy. We collected and analyzed data on 156 hematologic malignancy patients with Escherichia coli or Klebsiella pneumoniae bacteremia from the database of nationwide surveillance studies for bacteremia. Thirty-seven of the 156 patients (23.7%) harbored ESBL-producing bacteremia. No significant differences in underlying diseases were found in either group. The multivariate analysis showed that significant factors associated with ESBL-producing bacteremia were ICU care (OR = 7.03, 95% CI = 1.79-27.6) and nosocomial acquisition (OR = 5.66, 95% CI = 1.60-20.23). There was an association between prior receipt of cephalosporins and ESBL-producing bacteremia, although this association was not statistically significant (OR = 2.27, 95% CI = 0.99-5.23). The overall 30-day mortality rate of the study population was 20.4% (29/142), and the 30-day mortality rate for the ESBL group was significantly higher than that for the non-ESBL group (44.8% vs. 14.2%, P < 0.001). Multivariate analysis showed that ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality (OR, 5.64; 95% CI, 1.91-16.67), along with ICU care (OR = 4.35, 95% CI = 1.16-16.26) and higher Pitt bacteremia score (per 1-point increment) (OR = 1.50, 95% CI = 1.18 1.92). In conclusion, ESBL-producing bacteremia was the most important risk factor associated with 30-day mortality in patients with hematologic malignancy, along with ICU care and higher Pitt bacteremia score. Our data suggest that determining the optimal empiric antimicrobial therapy in patients with hematologic malignancy is now becoming a challenge for clinicians in the era of multidrug-resistant Gram-negative bacilli. PMID- 21556876 TI - Altered patterns of cortical activation in ALS patients during attention and cognitive response inhibition tasks. AB - Since amyotrophic lateral sclerosis (ALS) can be accompanied by executive dysfunction, it is hypothesised that ALS patients will have impaired performance on tests of cognitive inhibition. We predicted that ALS patients would show patterns of abnormal activation in extramotor regions when performing tests requiring the inhibition of prepotent responses (the Stroop effect) and the inhibition of prior negatively primed responses (the negative priming effect) when compared to healthy controls. Functional magnetic resonance imaging was used to measure activation during a sparse sequence block design paradigm investigating the Stroop and negative priming effects in 14 ALS patients and 8 healthy age- and IQ-matched controls. Behavioural measures of performance were collected. Both groups' reaction times (RTs) reflected the Stroop effect during scanning. The ALS and control groups did not differ significantly for any of the behavioural measures but did show significant differences in cerebral activation during both tasks. The ALS group showed increased activation predominantly in the left middle temporal gyrus (BA 20/21), left superior temporal gyrus (BA 22) and left anterior cingulate gyrus (BA 32). Neither group's RT data showed clear evidence of a negative priming effect. However the ALS group showed decreased activation, relative to controls, particularly in the left cingulate gyrus (BA 23/24), left precentral gyrus (BA 4/6) and left medial frontal gyrus (BA 6). Greater cerebral activation in the ALS group accompanying the performance of the Stroop effect and areas of decreased activation during the negative priming comparison suggest altered inhibitory processing in ALS, consistent with other evidence of executive dysfunction in ALS. The current findings require further exploration in a larger study. PMID- 21556877 TI - Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease. AB - Segawa disease is a rare dystonia due to autosomal dominant guanosine triphosphate cyclohydrolase I (adGTPCH) deficiency, affecting dopamine and serotonin biosynthesis. Recently, the clinical phenotype was expanded to include psychiatric manifestations, such as depression, anxiety, obsessive-compulsive disorder, and sleep disturbances. Although cognitive and neuropsychiatric symptoms may be attributable to dopamine deficiency in the prefrontal cortex and frontostriatal circuitry, intelligence is considered normal in Segawa disease. Our aim was to investigate neuropsychiatric symptoms and intelligence quotients (IQ) in a series of individuals with adGTPCH deficiency. The assessment included a structured clinical interview following the DSM-IV-TR's guidelines, Beck's Depression Inventory, the State-Trait Anxiety Inventory, the Maudsley Obsessive Compulsive Questionnaire, the Barratt Impulsiveness Scale-11 (BIS-11), the Oviedo Sleep Questionnaire, the Pittsburgh Sleep Quality Index, and the Wechsler Adult Intelligence Scale-Third Edition. Equivalent tests were applied to pediatric patients as appropriate for their age group. Fourteen patients with adGTPCH deficiency were evaluated (seven adult and seven pediatric patients). Depression, anxiety, and obsessive-compulsive symptoms were not more common than expected in the general population. However, the seven adults showed impulsivity in the BIS 11; nine individuals had an IQ in the range of borderline intellectual functioning to mild mental retardation, and sleep disturbances were found in four individuals. We found no differences between these results and the motor impairment. In conclusion, our findings would suggest that cognitive impairment, and impulsivity in adults, may be associated with Segawa disease. PMID- 21556878 TI - Three cases of CLIPPERS: a serial clinical, laboratory and MRI follow-up study. AB - The aim of the study was to further determine the pathophysiology, clinical course, MRI-features and response to therapy of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), which has recently been proposed as a rare chronic inflammatory central nervous system disorder responsive to immunosuppressive therapy. Three patients with this rare entity underwent serial clinical and bimonthly MRI follow-up over a period of up to 16 months. Extensive laboratory work-up and brain biopsy were performed. Intravenous methylprednisolone or oral dexamethasone was administered as treatment, additionally cyclophosphamide in one patient. Clinically, diplopia, nystagmus, ataxia and facial paresthesia were the cardinal symptoms. Magnetic resonance imaging (MRI) disclosed patchy spot-like gadolinium enhancement in a "salt-and-pepper like appearance" in the pons, midbrain and cerebellum, in two cases with thalamic and in the other with spinal involvement. Brain biopsies demonstrated a predominantly angiocentric but also diffuse infiltration pattern by small mature lymphocytes. Treatment with steroids led to rapid clinical improvement and marked resolution of MRI lesions. As discontinuation of steroids led to clinical relapse, one patient was treated with a further course of steroids and the other with steroids and cyclophosphamide as immunosuppressive therapy. This led to stable remission with only mild clinical residue and normalization of MRI. Extensive laboratory and radiological work-up could not identify any other cause of the disease. Of note, in two cases a marked elevation of IgE in serum was found initially and throughout the course. CLIPPERS seems to be a distinct inflammatory central nervous system disorder. It shows characteristic MRI core features. Extrapontine involvement seems to be frequent. Histologically it is characterised by predominantly angiocentric infiltration by small mature lymphocytes. A pathogenetic relationship between the elevated IgE levels and the perivascular infiltrates can be presumed. It is responsive to immunosuppressive therapy and can require prolonged or maintenance treatment. PMID- 21556879 TI - LGI1 related limbic encephalitis and response to immunosuppressive therapy. PMID- 21556880 TI - Anal avulsion caused by abdominal crush injury. AB - We report the case of a pelvic and lower abdomen crushing trauma in 37-year-old male patient. The patient had an open lumbar wound, laceration of the psoas muscle, pelvic fracture, a ruptured urogenital diaphragm, and extensive urogenital lacerations. An emergency laparotomy was performed with debridment, urethral reconstruction, and osteosynthesis of the pubic bone. The mobilization of the patient revealed a deep gap, about 8 * 8 cm, in the perineum, with the anus and rectum displaced from their original site. Anal reimplantation was performed, suturing the median raphe, inserting two pelvic drainage tubes, and fashioning a loop transverse colostomy. Closed rectal traumas account for only 4 11% of all rectal traumas. Crushing of the pelvis causes a sudden reduction in its anteroposterior diameter and a corresponding increase in its latero-lateral diameter, together with an abrupt rise in intra-abdominal pressure. The anus is pushed out of the perineal plane due to the divarication of the levator muscles. As suggested in the literature, the standard treatment is wound debridement with immediate or deferred repair, fashioning a diversion colostomy, and repair of the rectum, wherever possible. PMID- 21556881 TI - Immunologic similarities between selected autoimmune diseases and peanut allergy: possible new therapeutic approaches. AB - Food allergies are an important medical problem in Westernized countries. Allergy to peanuts is a dramatic example of a food allergy that tends to be particularly severe and long-lived. This article examines food allergy-specifically peanut allergy-from the perspective that tolerance to foods is a normal state, just as tolerance to self-proteins is a normal state. From this vantage point, loss of tolerance to foods in food-allergic individuals can be viewed as parallel to the loss of tolerance to self-proteins in those with autoimmune diseases. Although our knowledge base is far from satisfactory, there are important similarities in the immunologic abnormalities that are characteristic of both peanut allergy and several autoimmune diseases. Delineation of these similarities may open the door to new therapeutic approaches for the treatment of severe food allergies. PMID- 21556882 TI - Extraction parameters significantly influence the quantity and the profile of PLFAs extracted from soils. AB - Phospholipid fatty acid (PLFA) analysis is a robust method for characterizing soil microbial communities. We determined the effects of extraction solvent (chloroform vs dichloromethane) and buffer (phosphate vs citrate) on the yield and the profile of PLFAs extracted from an acidic (pH 5.5) and an alkaline (pH 8.6) soil following two 2-h sequential extractions. The yield and the profile of the PLFAs obtained separately by the first and the second 2-h extraction were compared to identify the impact of sequential extractions on the PLFA extraction efficiency. Chloroform-citrate and a 2 * 2-h extraction maximized PLFA yields in both soils. Multivariate analysis of the data showed that the choice of the extraction mixture did not significantly influence the profile of the PLFAs obtained by the first 2-h extraction, whereas it had a profound effect on the profile of the PLFAs obtained by the second 2-h extraction. Most PLFAs were extracted during the first extraction except 18:2omega6,9 and 22:0 which were almost equally extracted by the two sequential extractions. The choice of organic solvent significantly influenced the profile of the PLFAs extracted; their yield increased with chloroform with the exception of 18:2omega6,9 and 22:0 which were favored by dichloromethane. Overall, a 2 * 2-h extraction with chloroform/methanol/citrate is expected to provide maximum PLFA yields. PMID- 21556883 TI - A single-cell analysis of virioplankton adsorption, infection, and intracellular abundance in different bacterioplankton physiologic categories. AB - Culture studies of phage-host systems have shown that phage proliferation strongly depends on the physiological state of the host, but it is still unclear to what extent this holds true within aquatic ecosystems. We used a combination of flow sorting and electron microscopy to explore how the frequency of bacterial cells with attached viruses (FCAV), of visibly infected cells, and the number of intracellular viruses are distributed within five physiologic categories: cells with high (HNA) and low (LNA) nucleic acid content, with a compromised membrane, in division, and with an intact-looking morphology. FCAV was not different between the cellular physiologic categories, suggesting low influence of host physiology on viral adsorption. Infected cells were found within all the physiologic categories, besides the dividing cells, but showed different levels of new virion production, with the abundance of intracellular viruses ranked as follows: HNA > intact-looking cells > LNA > compromised membrane cells. These results favor the physiological control hypothesis of viral progeny production. The calculation of viral production rate of the HNA and LNA cells show that viral infection of HNA cells likely accounts for the majority of viral production. It also show that cells considered as less active can still act as resources for phages, although they contain much less intracellular phage particles. PMID- 21556884 TI - Influence of deglaciation on microbial communities in marine sediments off the coast of Svalbard, Arctic Circle. AB - Increases in global temperatures have been shown to enhance glacier melting in the Arctic region. Here, we have evaluated the effects of meltwater runoff on the microbial communities of coastal marine sediment located along a transect of Temelfjorden, in Svalbard. As close to the glacier front, the sediment properties were clearly influenced by deglaciation. Denaturing gradient gel electrophoresis profiles showed that the sediment microbial communities of the stations of glacier front (stations 188-178) were distinguishable from that of outer fjord region (station 176). Canonical correspondence analysis indicated that total carbon and calcium carbonate in sediment and chlorophyll a in bottom water were key factors driving the change of microbial communities. Analysis of 16S rRNA gene clone libraries suggested that microbial diversity was higher within the glacier-proximal zone (station 188) directly affected by the runoffs than in the outer fjord region. While the crenarchaeotal group I.1a dominated at station 176 (62%), Marine Benthic Group-B and other Crenarchaeota groups were proportionally abundant. With regard to the bacterial community, alpha-Proteobacteria and Flavobacteria lineages prevailed (60%) at station 188, whereas delta Proteobacteria (largely sulfate-reducers) predominated (32%) at station 176. Considering no clone sequences related to sulfate-reducers, station 188 may be more oxic compared to station 176. The distance-wise compositional variation in the microbial communities is attributable to their adaptations to the sediment environments which are differentially affected by melting glaciers. PMID- 21556885 TI - Bacterial communities in central European bumblebees: low diversity and high specificity. AB - Recent studies on the microbial flora of the honeybee gut have revealed an apparently highly specific community of resident bacteria that might play a role in immune defence and food preservation for their hosts. However, at present, very little is known about the diversity and ecology of bacteria occurring in non domesticated bees like bumblebees, which are of similar importance as honeybees for the pollination of agricultural and wild flowers. To fill this gap in knowledge, we examined six of the most common bumblebee species in Central Europe from three locations in Germany and Switzerland for their bacterial communities. We used a culture-independent molecular approach based on sequencing the 16S rRNA gene from a selection of individuals and examining a larger number of samples by terminal restriction fragment length polymorphism profiles. The gut flora was dominated by very few and mostly undescribed groups of bacteria belonging to the Proteobacteria, Bacteroidetes, Firmicutes and Actinobacteria. This core set of bacteria was present in all of the examined bumblebee species. These bacteria are similar to, but distinct from, bacteria previously described from the honeybee gut. Significant differences were observed between the communities of bacteria in the different bumblebee species; the effect of sampling location was less strong. A novel group of Betaproteobacteria additionally shows evidence for host species specific genotypes. The gut flora of bumblebees therefore is apparently composed of relatively few highly specialized bacteria, indicating a strong interaction and possibly important functions with their hosts. PMID- 21556886 TI - A spatially extended model for macroscopic spike-wave discharges. AB - Spike-wave discharges are a distinctive feature of epileptic seizures. So far, they have not been reported in spatially extended neural field models. We study a space-independent version of the Amari neural field model with two competing inhibitory populations. We show that this competition leads to robust spike-wave dynamics if the inhibitory populations operate on different time-scales. The spike-wave oscillations present a fold/homoclinic type bursting. From this result we predict parameters of the extended Amari system where spike-wave oscillations produce a spatially homogeneous pattern. We propose this mechanism as a prototype of macroscopic epileptic spike-wave discharges. To our knowledge this is the first example of robust spike-wave patterns in a spatially extended neural field model. PMID- 21556887 TI - Physiological uncoupling of mitochondrial oxidative phosphorylation. Studies in different yeast species. AB - Under non-phosphorylating conditions a high proton transmembrane gradient inhibits the rate of oxygen consumption mediated by the mitochondrial respiratory chain (state IV). Slow electron transit leads to production of reactive oxygen species (ROS) capable of participating in deleterious side reactions. In order to avoid overproducing ROS, mitochondria maintain a high rate of O(2) consumption by activating different exquisitely controlled uncoupling pathways. Different yeast species possess one or more uncoupling systems that work through one of two possible mechanisms: i) Proton sinks and ii) Non-pumping redox enzymes. Proton sinks are exemplified by mitochondrial unspecific channels (MUC) and by uncoupling proteins (UCP). Saccharomyces. cerevisiae and Debaryomyces hansenii express highly regulated MUCs. Also, a UCP was described in Yarrowia lipolytica which promotes uncoupled O(2) consumption. Non-pumping alternative oxido reductases may substitute for a pump, as in S. cerevisiae or may coexist with a complete set of pumps as in the branched respiratory chains from Y. lipolytica or D. hansenii. In addition, pumps may suffer intrinsic uncoupling (slipping). Promising models for study are unicellular parasites which can turn off their aerobic metabolism completely. The variety of energy dissipating systems in eukaryote species is probably designed to control ROS production in the different environments where each species lives. PMID- 21556888 TI - Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types. AB - Non-metastatic 23 [NM23/nucleoside diphosphate kinases (NDPK)] genes are the first discovered metastasis suppressor genes. More than two decades of research has demonstrated their roles in a variety of biological processes with NME1 and NME2 being most studied in the context of metastasis suppression. Although NME1 and NME2 share >85% homology at amino acid level, they show redundant as well as unique molecular functions. Phenotypic analyses of knockout (KO) mice for NM23 members (NDPK-A, B) and compound KO (A as well as B) showed requirement of both proteins in hematopoiesis suggesting shared functions in development disease. Several reviews have discussed NME1, however the role of NME2 appears to be relatively less understood in the context of metastasis suppression. Here, we focus on NME2 and by meta-analysis of gene expression from multiple tumor types, and survey of in vivo and vitro studies, suggest the possibility that NME2 may be one of the key factors in metastasis. This along with the relevance of normal physiological functions of NME2 in the context of metastasis is discussed. We further examined the genetic and epigenetic features of NME2 and NME1 gene promoters and found aspects of transcription control that could be unique to NME2/NME1. Findings on signaling pathways and small molecules which regulate the expression of NME2 that could be therapeutically important are also discussed. PMID- 21556889 TI - Controversies in IVM. AB - PURPOSE: To explore four areas of controversy: the benefits of gonadotropin priming, benefits and timing of hCG trigger as well as the ideal protocols for endometrial preparation and luteal support. METHODS: A literature review was performed to explore the current evidence RESULTS: Current evidence suggests that Gonadotropin priming in combination with hCG prior to collection benefits patients with normal ovaries. In PCOS patients 10,000 IU hCG 38 h before retrieval increases the total number and rate of oocyte maturation. Gonadotropin priming may also benefit PCOS patients. The ideal timing of hCG trigger appears to be when the leading follicle is 10-12 mm. Sparse data exists regarding luteal support protocols. CONCLUSIONS: There is still a need for well-designed studies to establish ideal methods for oocyte priming, timing of retrieval, endometrial preparation and luteal support. Further studies must incorporate both clinical and basic science principles of ovarian, follicular and endometrial physiology. PMID- 21556890 TI - Study of GT-repeat expansion in Heme oxygenase-1 gene promoter as genetic cause of male infertility. AB - PURPOSE: The length of GT-repeats polymorphic region in the promoter of human Heme oxygenase-1 gene (HO-1) alters the level of its transcriptional activity in response to oxidative stresses. Decreased level of HO-1 protein in the seminal plasma has been reported to be associated with oligospermia and azoospermia in male infertility. This is the first study to investigate the association between GT-repeats expansion in the promoter of the HO-1 gene and male infertility. METHODS: The frequencies of different GT-repeats alleles in the promoter of HO-1 gene were determined in 100 cases and 100 normal controls using PCR-PAGE, ABI fragment analysis genotyping and sequencing analysis. RESULTS: All alleles were classified into S and L alleles. S alleles were specified as number 0 to 3 with <27 GT-repeats and L alleles were specified as number 4 to 6 with >27 repeats. The L allele frequency was significantly higher among case group (54.5%) than that was obtained in the normal control group (37.5%). Statistical analysis provided a significant relationship between L allele and male infertility (P < 0.001). CONCLUSIONS: This study shows for the first time that GT-repeats expansion in promoter of the HO-1 gene is associated with oligospermia and azoospermia among Iranian infertile cases. PMID- 21556891 TI - An association study of SPO11 gene single nucleotide polymorphisms with idiopathic male infertility in Chinese Han population. AB - PURPOSE: To investigate the incidence of single nucleotide polymorphisms in SPO11 and its influence in idiopathic male infertility in China. METHODS: Infertility factors such as anatomical, immunological and infectious disorders were examined in selecting patients with idiopathic male infertility. Routine semen analysis was performed. DNA was isolated from peripheral blood of the selected patients and control group, and five SNP loci of SPO11 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Furthermore, nucleotide sequences were sequenced. RESULTS: SNP5 (rs28368082) in the exon7 of SPO11 was identified to be associated with idiopathic male infertility (P = 0.037 for differences across genotypes). A transversion (C5679T) was detected in eight patients (11.0%), which led arginine change into tryptophan. And this variant was not found in the remaining patients and controls. CONCLUSION: A SPO11 SNP was associated with idiopathic male reproduction, suggested that SPO11 might has an effect on premorbid functioning, which increase susceptibility for idiopathic male reproduction. Further research on this issue is still necessary. PMID- 21556892 TI - Severe septic arthritis of the shoulder with an axillary nerve lesion in a 4-year old child. PMID- 21556893 TI - Necrotizing fasciitis caused by emphysematous pyelonephritis through iliopsoas abscess. PMID- 21556894 TI - Primary aneurysmal bone cyst of the proximal tibia crossing the open physis. PMID- 21556895 TI - Comparative transcription profiling analyses of maize reveals candidate defensive genes for seedling resistance against corn earworm. AB - As maize seedlings germinate into the soil, they encounter an environment teeming with insects seeking rich sources of nutrition. Maize presumably has developed a number of molecular mechanisms to ensure survival at the beginning of its life cycle. Comparative transcription analysis using microarrays was utilized to document the expression of a number of genes with potential defensive functions in seedling tissue. In addition to elevated levels of the genes involved in the biosynthesis of DIMBOA (2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one), an anti insect resistance molecule, other highly expressed genes in the seedling encode the following putative defensive proteins: defensin, hydroxyproline and proline rich protein, thaumatin-like protein, lipase, cystatin, protease inhibitor, and a variety of proteases. The potential resistance genes identified occurred mainly on chromosomes 1 and 5 in the B73 genome. Analysis of promoters of seven DIMBOA biosynthetic genes identified three transcription factor binding sites that are possibly involved in regulation of the DIMBOA biosynthetic pathway. The results indicate that maize employs a wide variety of potential resistance mechanisms in seedling tissue to resist a possible insect attack. PMID- 21556896 TI - Kinase gene expression and subcellular protein expression pattern of protein kinase C isoforms in curcumin-treated human hepatocellular carcinoma Hep 3B cells. AB - Curcumin, a yellow component of turmeric or curry powder, has been demonstrated to exhibit anti-carcinogenic effects in vitro, in vivo, and in human clinical trials. One of its molecular targets is protein kinase C (PKC) which has been reported to play essential roles in apoptosis, cell proliferation, and carcinogenesis. In this study, PKC mRNA expression was significantly inhibited in curcumin-treated human hepatocellular carcinoma (HCC) Hep 3B cells identified using a kinase cDNA microarray. Furthermore, curcumin decreased total protein expression of all PKCs in a time-related manner by immunoblotting of whole cell lysates, nuclear, membrane, and cytosolic fractions. In cytosolic fraction, the expression of PKC-alpha was totally inhibited by curcumin. In contrast, the expression levels of PKC-zeta and -MU were dramatically increased. Increases in expression of PKC-delta and PKC-zeta in the membrane and nucleus, and PKC-iota in the membrane were detected. In summary, the changes in expression and distribution of subcellular PKC isoforms in curcumin-treated Hep 3B cells suggest possible PKC-associated anti-tumor mechanisms of curcumin and provide alternative therapies for human HCC. PMID- 21556897 TI - A reliable user authentication and key agreement scheme for Web-based Hospital acquired Infection Surveillance Information System. AB - With the rapid development of the Internet, both digitization and electronic orientation are required on various applications in the daily life. For hospital acquired infection control, a Web-based Hospital-acquired Infection Surveillance System was implemented. Clinical data from different hospitals and systems were collected and analyzed. The hospital-acquired infection screening rules in this system utilized this information to detect different patterns of defined hospital acquired infection. Moreover, these data were integrated into the user interface of a signal entry point to assist physicians and healthcare providers in making decisions. Based on Service-Oriented Architecture, web-service techniques which were suitable for integrating heterogeneous platforms, protocols, and applications, were used. In summary, this system simplifies the workflow of hospital infection control and improves the healthcare quality. However, it is probable for attackers to intercept the process of data transmission or access to the user interface. To tackle the illegal access and to prevent the information from being stolen during transmission over the insecure Internet, a password based user authentication scheme is proposed for information integrity. PMID- 21556898 TI - Comparison of artificial neural networks with logistic regression for detection of obesity. AB - Obesity is a common problem in nutrition, both in the developed and developing countries. The aim of this study was to classify obesity by artificial neural networks and logistic regression. This cross-sectional study comprised of 414 healthy military personnel in southern Iran. All subjects completed questionnaires on their socio-economic status and their anthropometric measures were measured by a trained nurse. Classification of obesity was done by artificial neural networks and logistic regression. The mean age+/-SD of participants was 34.4 +/- 7.5 years. A total of 187 (45.2%) were obese. In regard to logistic regression and neural networks the respective values were 80.2% and 81.2% when correctly classified, 80.2 and 79.7 for sensitivity and 81.9 and 83.7 for specificity; while the area under Receiver-Operating Characteristic (ROC) curve were 0.888 and 0.884 and the Kappa statistic were 0.600 and 0.629 for logistic regression and neural networks model respectively. We conclude that the neural networks and logistic regression both were good classifier for obesity detection but they were not significantly different in classification. PMID- 21556899 TI - [A physician can do what he can--even outside his specialty: the German Federal Constitutional Court opens up medical specialty borders]. PMID- 21556900 TI - Epigenetic inactivation of hMLH1 in the malignant transformation of ovarian endometriosis. AB - PURPOSE: To investigate the role of epigenetic inactivation of hMLH1 during the malignant transformation of ovarian endometriosis (EMs), and to explore the relationship between the epigenetic inactivation of hMLH1 in eutopic endometria and the malignant transformation of ovarian EMs. METHODS: The target tissue from 29 cases of the endometriosis-associated ovarian carcinoma (EAOC) group, 20 cases of EMs group and 16 cases of control endometrium (CEs) group was obtained by laser capture microdissection (LCM). The methylation statue of hMLH1 promoter was determined by methylation-specific PCR (MSP) and the protein expression of hMLH1 was analysed by immunohistochemistry. RESULTS: The frequency of promoter hypermethylation of hMLH1 in the neoplastic tissue or ectopic endometria of the EAOC group was higher than that of the EMs group (p < 0.05), and the frequency of promoter hypermethylation of hMLH1 in eutopic endometria of the EAOC group was higher than that of the EMs and CEs groups (p < 0.05). In addition, the protein expression of hMLH1 in eutopic endometria of the EAOC group was lower than that of the EMs and CEs group (p < 0.05), and absence of hMLH1 protein expression was significantly correlated with promoter hypermethylation of the gene. CONCLUSIONS: Epigenetic inactivation of hMLH1 was an early event in the malignant transformation of ovarian EMs. Epigenetic inactivation of hMLH1 in eutopic endometria was synchronous with that in ectopic endometria and the epigenetic inactivation of hMLH1 in eutopic endometria of EMs might be a potential molecular tool for early diagnosis of the malignant transformation of ovarian EMs. PMID- 21556901 TI - Differential effects of cold exposure on gene expression profiles in white versus brown adipose tissue. AB - The thermogenic function of brown adipose tissue (BAT) is known to be markedly elevated when animals are exposed to the cold, and intensive studies have been carried out to understand the molecular basis enabling effective thermogenesis in cold-exposed animals. In this study, we used microarray analysis to examine the effects of cold exposure of animals on their gene expression profiles in white adipose tissue (WAT), which seems to function as a counterpart tissue of BAT. The results indicate that the effects of cold exposure on the gene expression profiles of WAT were much more moderate than the effects on those of BAT. Possible reasons for the different responses of BAT and WAT to cold exposure are discussed. PMID- 21556902 TI - Three powerful research tools from single cells into single molecules: AFM, laser tweezers, and Raman spectroscopy. AB - By using three physical techniques (atomic force microscopy (AFM), laser tweezers, and Raman spectroscopy), many excellent works in single-cell/molecule research have been accomplished. In this review, we present a brief introduction to the principles of these three techniques, and their capabilities toward single cell/molecule research are highlighted. Afterward, the advances in single cell/molecule research that have been facilitated by these three techniques are described. Following this, their complementary assets for single-cell/molecule research are analyzed, and the necessity of integrating the functions of these three techniques into one instrument is proposed. PMID- 21556903 TI - Effect of training data size and noise level on support vector machines virtual screening of genotoxic compounds from large compound libraries. AB - Various in vitro and in-silico methods have been used for drug genotoxicity tests, which show limited genotoxicity (GT+) and non-genotoxicity (GT-) identification rates. New methods and combinatorial approaches have been explored for enhanced collective identification capability. The rates of in-silco methods may be further improved by significantly diversified training data enriched by the large number of recently reported GT+ and GT- compounds, but a major concern is the increased noise levels arising from high false-positive rates of in vitro data. In this work, we evaluated the effect of training data size and noise level on the performance of support vector machines (SVM) method known to tolerate high noise levels in training data. Two SVMs of different diversity/noise levels were developed and tested. H-SVM trained by higher diversity higher noise data (GT+ in any in vivo or in vitro test) outperforms L-SVM trained by lower noise lower diversity data (GT+ in in vivo or Ames test only). H-SVM trained by 4,763 GT+ compounds reported before 2008 and 8,232 GT- compounds excluding clinical trial drugs correctly identified 81.6% of the 38 GT+ compounds reported since 2008, predicted 83.1% of the 2,008 clinical trial drugs as GT-, and 23.96% of 168 K MDDR and 27.23% of 17.86M PubChem compounds as GT+. These are comparable to the 43.1-51.9% GT+ and 75-93% GT- rates of existing in-silico methods, 58.8% GT+ and 79% GT- rates of Ames method, and the estimated percentages of 23% in vivo and 31 33% in vitro GT+ compounds in the "universe of chemicals". There is a substantial level of agreement between H-SVM and L-SVM predicted GT+ and GT- MDDR compounds and the prediction from TOPKAT. SVM showed good potential in identifying GT+ compounds from large compound libraries based on higher diversity and higher noise training data. PMID- 21556904 TI - [Knowledge transfer between research and practice]. PMID- 21556905 TI - [Treatment of massive bleeding: summary of the updated European guidelines]. AB - Despite improved strategies in the treatment of polytraumatized patients the mortality rate of severely injured patients remains high. Thus, worldwide 5 million patients die due to trauma or trauma-related complications each year. As the majority of early trauma-related deaths are attributed to or caused by exsanguination the prevention and treatment of coagulopathy is of paramount significance. With the aim of developing guidelines and improve strategies to treat polytraumatized patients the multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2005. Under consideration of new clinical studies, an updated version of the original publication from 2007 has recently been published. Based on a systematic review of published literature the recommendations were formed according to "Grading of Recommendations Assessment, Development and Evaluation" (GRADE). This publication summarizes the main recommendations with a special emphasis on revisions and new aspects. PMID- 21556906 TI - [Painful hip arthroplasty: a diagnostic algorithm]. AB - The number of implantations of hip prostheses in Germany is now approximately 190,000 per year. By improving the implants and the development of modern surgical techniques and instruments the revision rate has been significantly reduced. The survival rate of the implants could be further increased in recent years, however, up to 22% of patients complain about persistent pain after hip arthroplasty. The diagnosis of existing pain after total joint replacement of the hip joint to achieve a causal therapy needs a systematic approach because of the heterogeneity of the symptoms and diseases. The etiology of the pain can be joint associated and also hip joint independent. Often the causes of pain are multifactorial so that a standardized assessment should be conducted using an algorithm. The clarification of pain begins with the history, inspection and palpation followed by a clinical examination. It is then useful to perform radiological imaging followed by invasive procedures if necessary. The exploratory revision is nowadays considered to be obsolete in the literature. PMID- 21556907 TI - The value of dual-energy CTA for control of surgically clipped aneurysms. AB - OBJECTIVE: Comparison of image quality in DE-CTA with and without automatic head bone removal (BR) versus CTA with 16-detectors as a tool in postoperative evaluation of patients after neurosurgical clipping. METHODS: In this study 30 aneurysms that had undergone neurosurgical clipping were included: 18 with DE-CTA and 12 with conventional CTA. The images were further processed using the volume rendering technique (VRT) and BR. Two experienced neuroradiologists reviewed the images regarding the severity of artefacts surrounding the clip, visibility of the vessels and remnant necks. The results were compared with DSA images, if performed. RESULTS: Significantly fewer disturbances by artefacts were observed in DE-CTA versus CTA in a 16-row system. Visibility of the surrounding vessels was satisfying in both techniques and there were comparable results with DSA with only one exception. All images produced with 140 kV provided fewer artefacts than those with 80 kV. CONCLUSION: DE-CTA provides better image quality with fewer disturbances by clip artefact, a satisfying evaluation of remnant aneurysm necks and the surrounding vessels. As this method is easily performed and readily accessible with fast image post-processing using BR it provides an opportunity to avoid invasive DSA in the evaluation of suspected aneurysm rests. PMID- 21556908 TI - Improved detection of in-stent restenosis by blood pool agent-enhanced, high resolution, steady-state magnetic resonance angiography. AB - OBJECTIVE: The aim of this study was to assess whether visualisation of in-stent changes can be improved with high-resolution, steady-state, blood pool contrast enhanced MR angiography compared with first-pass MR angiography. Intra-arterial digital subtraction angiography (DSA) served as the reference standard. METHODS: Twenty patients after stent placement in the superficial femoral artery (SFA) underwent MRA prior to reintervention. MRA of the SFA includes first-pass MRA as well as 3D high-resolution MRA in the steady state (SS-MRA) after injection of Gadofosveset trisodium. Sensitivity and specificity values for the detection of significant in-stent lesions by means of SS-MRA were calculated at the proximal, middle and distal stent segments in comparison to DSA. Kappa statistics were used to determine agreement between the two techniques. RESULTS: Sensitivity and specificity values for the detection of significant stenosis with SS-MRA reached 95% in the proximal, 100% in the middle and 100% in the distal stent segment. Kappa coefficients between SS-MRA and DSA were 0.789, 0.797 and 0.859 for the proximal, middle and distal segments, whereas the Kappa coefficients for FP-MRA were 0,211, 0,200 and 0,594 in these segments, respectively. CONCLUSION: Detection of in stent stenosis is significantly improved using SS MRA, in comparison to state-of-the-art FP-MRA. PMID- 21556909 TI - The use of MR imaging and spectroscopy of the brain in children investigated for developmental delay: what is the most appropriate imaging strategy? AB - OBJECTIVES: Developmental delay is a common problem in paediatric practice and many children with developmental delay are referred for MR imaging. Our study was performed as part of a continuing audit process to optimise our MR protocol and case selection. MATERIALS AND METHODS: We performed MR imaging and spectroscopy protocol on 157 children with developmental delay. We analysed the effect of these interventions by looking at the overall detection rate of relevant pathology and in particular subgroups of the children. RESULTS: 71% of the children had normal MR imaging, 10% had non-specific findings and 19% had specific abnormalities on MR imaging. The overall risk of having a specific structural abnormality with isolated developmental was 7.5% but if other neurological symptoms/signs were present the risk was 28%. Two children had abnormal spectroscopic findings, one with tuberous sclerosis and the other with absent brain creatine. CONCLUSION: Case selection for MR imaging is important in children with developmental delay. The best strategies for selecting children for MR are either; not performing MR with developmental delay in one domain only or performing MR with developmental delay in three or four domains or if there are other neurological features. PMID- 21556910 TI - Ultrasound features of malignancy in the preoperative diagnosis of parathyroid cancer: a retrospective analysis of parathyroid tumours larger than 15 mm. AB - OBJECTIVE: Nearly all reported parathyroid cancers are >15 mm at presentation. The objective was to identify ultrasound criteria of malignancy in parathyroid lesions of >15 mm in size. MATERIALS AND METHODS: This study was approved by a local ethics committee. A retrospective review of patients identified from a database from 2004-2009 was performed. All patients underwent ultrasound imaging according to the protocol. Two trained observers categorized findings using the pre-determined features: shape, calcification, pattern of vascularity, local infiltration and internal lesion gray scale appearances. RESULTS: Sixty-nine patients (mean age 54.3 years, range 19-79 years; male = 16, female = 53) fulfilled the criteria of a parathyroid lesion >15 mm; 8/69 (11.6%) with parathyroid cancer and 61/69 (88.4%) with benign solitary parathyroid adenoma. A high positive predictive value (PPV) for cancer was identified for infiltration (PPV 100%) and calcification (PPV 100%), whilst a high negative predictive value (NPV) was found for the absence of suspicious vascularity (NPV 97.6%), a thick capsule (NPV 96.7) and inhomogeneity (NPV 100%). CONCLUSION: In lesions >15 mm systematic ultrasound assessment of specific features provides a valuable tool to identify parathyroid cancers before surgery. PMID- 21556911 TI - 64-section multidetector CT of the upper abdomen: optimization of a saline chaser injection protocol for improved vascular and parenchymal contrast enhancement. AB - OBJECTIVES: To prospectively investigate the effect of varying the injection flow rates of a saline chaser on vascular and parenchymal contrast enhancement during abdominal MDCT. METHODS: 100 consecutive patients were randomly assigned to four injection protocols. A fixed dose of contrast medium was administered followed by no saline (Protocol A) or 50 mL of saline at 2, 4, or 8 mL/s (Protocols B, C, and D). Peak, time-to-peak, and duration of 90% peak enhancement were determined for aorta, pancreas, and liver. RESULTS: Aortic peak enhancement was significantly higher for Protocol D (369.5 HU) compared with Protocols A and B (332.9 HU and 326.0 HU, respectively; P < 0.05). Pancreatic peak enhancement was significantly higher for Protocols C and D (110.6 HU and 110.9 HU, respectively) compared to Protocol A (92.5 HU; P < 0.05). Aortic and pancreatic time-to-peak enhancement occurred significantly later for Protocol D compared with Protocol A (42.8 s vs. 36.1 s [P < 0.001] and 49.7 s vs. 45.3 s [P = 0.003]). CONCLUSIONS: Injecting a saline chaser at high flow rates yields significantly higher peak aortic and pancreatic enhancement, with a slight longer time-to-peak enhancement. PMID- 21556912 TI - The HyPRP gene EARLI1 has an auxiliary role for germinability and early seedling development under low temperature and salt stress conditions in Arabidopsis thaliana. AB - The effect of the hybrid proline-rich protein (HyPRP) gene EARLI1 on the rate of germination (germinability) of Arabidopsis seeds and seedling growth under low temperature and salt stress conditions was investigated. EARLI1 was induced during germination in embryonic tissues, and was strongly expressed in certain parts of young seedlings. Comparisons of control, overexpressing (OX), and knockout (KO) lines indicated that higher than wild type levels of EARLI1 improved germinability, root elongation, and reduction of sodium accumulation in leaves under salt stress, as well as germinability under low-temperature stress. Abscisic acid (ABA) contents were relatively low after prolonged salt stress, suggesting that EARLI1 has an ABA-independent effect on germinability under these conditions. Overexpression of EARLI1 during germination enhanced the sensitivity of seeds to exogenously applied ABA, suggesting that EARLI1 has an ABA-dependent negative effect on seed germinability under high ABA stress conditions. Well known stress response marker genes such as COR15a, KIN1, P5SC1, and RD29 were unaffected whereas P5SC2, RD22, or RAB18 were only slightly affected in OX and KO plants. The pleiotropic effects of EARLI1 during stress and an absence of strong regulatory effects on stress marker genes suggest that this HyPRP gene has an auxiliary role for various stress protection responses in Arabidopsis. PMID- 21556913 TI - Dehydration-mediated activation of the xanthophyll cycle in darkness: is it related to desiccation tolerance? AB - The development of desiccation tolerance by vegetative tissues was an important step in the plants' conquest of land. To counteract the oxidative stress generated under these conditions the xanthophyll cycle plays a key role. Recent reports have shown that desiccation itself induces de-epoxidation of xanthophyll cycle pigments, even in darkness. The aim of the present work was to study whether this trait is a common response of all desiccation-tolerant plants. The xanthophyll cycle activity and the maximal photochemical efficiency of PS II (F(v)/F(m)) as well as beta-carotene and alpha-tocopherol contents were compared during slow and rapid desiccation and subsequent rehydration in six species pairs (with one desiccation-sensitive and one desiccation-tolerant species each) belonging to different taxa. Xanthophyll cycle pigments were de-epoxidised in darkness concomitantly with a decrease in F(v)/F(m) during slow dehydration in all the desiccation-tolerant species and in most of the desiccation-sensitive ones. De-epoxidation was reverted in darkness by re-watering in parallel with the recovery of the initial F(v)/F(m). The stability of the beta-carotene pool confirmed that its hydroxylation did not contribute to zeaxanthin formation. The alpha-tocopherol content of most of the species did not change during dehydration. Because it is a common mechanism present in all the desiccation tolerant taxa and in some desiccation-sensitive species, and considering its role in antioxidant processes and in excess energy dissipation, the induction of the de-epoxidation of xanthophyll cycle pigments upon dehydration in the dark could be understood as a desiccation tolerance-related response maintained from the ancestral clades in the initial steps of land occupation by plants. PMID- 21556914 TI - Transthoracic echocardiography may show saddle pulmonary embolism. PMID- 21556916 TI - LPS pretreatment ameliorates multiple organ injuries and improves survival in a murine model of polymicrobial sepsis. AB - OBJECTIVE: The endotoxin tolerance phenotype is characterized with decreased inflammation and increased phagocytosis. We hypothesized that endotoxin tolerance would provide protective effects on experimental sepsis with multiple organ injuries induced by cecal ligation and puncture (CLP). METHODS: Endotoxin tolerance was induced in male Sprague-Dawley rats with daily intraperitoneal injection of either 0.6 mg/kg of lipopolysaccharide (LPS) or vehicle for four consecutive days before subsequent CLP. Biochemical parameters, histological changes, inflammatory cytokine production, and lung tissue nuclear factor-kappaB (NF-kappaB) activation were assessed post-CLP. In a separate experiment, survival rate was monitored for 7 days after CLP. RESULTS: In vehicle-treated animals, CLP caused multiple organ injuries confirmed by the biochemical variables and histological examination. This was accompanied by an early activation of NF kappaB in the lung and a substantial increase in plasma levels of tumor necrosis factor-alpha, interleukin-6, and interleukin-10. In contrast, pretreatment with LPS not only alleviated the development of multiple organ injuries after CLP, but also decreased sepsis-induced activation of pulmonary NF-kappaB and reduced plasma cytokines production. In addition, LPS pretreatment improved the survival in rats subjected to CLP. CONCLUSIONS: The beneficial effects of endotoxin tolerance indicate the potential of immunomodulatory strategies in the management of severe sepsis. PMID- 21556917 TI - Simultaneous cadmium removal and 2,4-dichlorophenol degradation from aqueous solutions by Phanerochaete chrysosporium. AB - Phanerochaete chrysosporium has been recognised as an effective bioremediation agent due to its unique degradation to xenobiotic and biosorption ability to heavy metals. However, few studies have focused on the simultaneous removal of heavy metals and organic pollutants. The aim of this work was to study the feasibility of simultaneous cadmium removal and 2,4-dichlorophenol (2,4-DCP) degradation in P. chrysosporium liquid cultures. The removal efficiencies were pH dependent and the maximum removal efficiencies were observed at pH 6.5 under an initial cadmium concentration of 5 mg/L and an initial 2,4-DCP concentration of 20 mg/L. The removal efficiencies for cadmium and 2,4-DCP reached 63.62% and 83.90%, respectively, under the optimum conditions. The high production levels of lignin peroxidase (7.35 U/mL) and manganese peroxidase (8.30 U/mL) resulted in an increase in 2,4-DCP degradation. The protein content decreased with increasing cadmium concentration. The surface characteristics and functional groups of the biomass were studied by scanning electron microscopy and a Fourier-transformed infrared spectrometer. The results showed that the use of P. chrysosporium is promising for the simultaneous removal of cadmium and 2,4-DCP from liquid media. PMID- 21556918 TI - Enhancing Jatropha oil extraction yield from the kernels assisted by a xylan degrading bacterium to preserve protein structure. AB - We investigated the use of bacterial cells isolated from paddy crab for the extraction of oil from Jatropha seed kernels in aqueous media while simultaneously preserving the protein structures of this protein-rich endosperm. A bacterial strain-which was marked as MB4 and identified by means of 16S rDNA sequencing and physiological characterization as either Bacillus pumilus or Bacillus altitudinis-enhanced the extraction yield of Jatropha oil. The incubation of an MB4 starter culture with preheated kernel slurry in aqueous media with the initial pH of 5.5 at 37 degrees C for 6 h liberated 73% w/w of the Jatropha oil. Since MB4 produces xylanases, it is suggested that strain MB4 facilitates oil liberation via degradation of hemicelluloses which form the oil containing cell wall structure of the kernel. After MB4 assisted oil extraction, SDS-PAGE analysis showed that the majority of Jatropha proteins were preserved in the solid phase of the extraction residues. The advantages offered by this process are: protein in the residue can be further processed for other applications, no purified enzyme preparation is needed, and the resulting oil can be used for biodiesel production. PMID- 21556919 TI - Identification of novel genes responsible for ethanol and/or thermotolerance by transposon mutagenesis in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae strains tolerant to ethanol and heat stresses are important for industrial ethanol production. In this study, five strains (Tn 1-5) tolerant to up to 15% ethanol were isolated by screening a transposon-mediated mutant library. Two of them displayed tolerance to heat (42 degrees C). The determination of transposon insertion sites and Northern blot analysis identified seven putative genes (CMP2, IMD4, SSK2, PPG1, DLD3, PAM1, and MSN2) and revealed simultaneous down-regulations of CMP2 and IMD4, and SSK2 and PPG1, down regulation of DLD3, and disruptions of the open reading frame of PAM1 and MSN2, indicating that ethanol and/or heat tolerance can be conferred. Knockout mutants of these seven individual genes were ethanol tolerant and three of them (SSK2, PPG1, and PAM1) were tolerant to heat. Such tolerant phenotypes reverted to sensitive phenotypes by the autologous or overexpression of each gene. Five transposon mutants showed higher ethanol production and grew faster than the control strain when cultured in rich media containing 30% glucose and initial 6% ethanol at 30 degrees C. Of those, two thermotolerant transposon mutants (Tn 2 and Tn 3) exhibited significantly enhanced growth and ethanol production compared to the control at 42 degrees C. The genes identified in this study may provide a basis for the application in developing industrial yeast strains. PMID- 21556920 TI - Improved expression of secretory and trimeric proteins in mammalian cells via the introduction of a new trimer motif and a mutant of the tPA signal sequence. AB - Ideal immunogenicity in antigens is a prerequisite to eliciting a sufficiently strong immune and memory response via either DNA or protein vaccines. To improve immunogenicity, efforts have focused on high-level expression of target proteins and on maintaining their natural conformations. In the present work, two trimer motifs (MTQ and MTI) were designed and introduced into a plasmid vector with the tissue plasminogen activator signal peptide (tPA-SP). Next, we examined the efficacy and the efficiency of the two motifs as well as the introduction of tPA SP and its mutant forms, 22P/A and 22P/G, in facilitating the secretory expression of trimeric proteins in mammalian cells. We found that both trimer motifs could produce the target protein in a trimeric form at a high level. Introduction of tPA-SP 22P/A markedly increased the secretory expression level. The combination of the trimer motif, MTQ, and the signal peptide, 22P/A, may serve as a universal mammalian vector for producing trimeric proteins in vaccine development. PMID- 21556921 TI - Basidiomycete Clitocybe nebularis is rich in lectins with insecticidal activities. AB - Basidiomycete mushrooms are a rich source of unique substances, including lectins, that could potentially be useful in biotechnology or biomedical applications. Lectins are a group of carbohydrate-binding proteins with diverse biological activities and functions. Here, we demonstrate the presence of a number of lectins in the basidiomycete mushroom Clitocybe nebularis. Glucose-, galactose-, sucrose-, lactose-, and Sepharose-binding lectins were isolated from fruiting bodies using affinity chromatography on Sepharose-immobilized sugars or on Sepharose. The lectins were characterized biochemically and their binding specificities examined by agglutination and agglutination inhibition assays. In addition, insecticidal and anti-nutritional properties of the lectins were studied against a model organism, fruit fly (Drosophila melanogaster), and Colorado potato beetle (Leptinotarsa decemlineata). Of the several basidiomycete mushrooms screened, C. nebularis extract showed the most potent insecticidal activity. Sucrose-binding lectin showed the strongest activity against D. melanogaster, followed by lactose- and galactose-binding lectins. Feeding bioassays with Colorado potato beetle revealed that C. nebularis extract exhibited high anti-nutritional activity against the insect; and of those tested, only lactose-binding lectin, named CNL showed the effect. Mushroom C. nebularis is shown to be rich in a variety of lectins with versatile biological activities, including insecticidal and anti-nutritional effects. C. nebularis lectins could thus have potential for use as natural insecticides. PMID- 21556922 TI - The influence of nanoscopically thin silver films on bacterial viability and attachment. AB - The physicochemical and bactericidal properties of thin silver films have been analysed. Silver films of 3 and 150 nm thicknesses were fabricated using a magnetron sputtering thin-film deposition system. X-ray photoelectron and energy dispersive X-ray spectroscopy and atomic force microscopy analyses confirmed that the resulting surfaces were homogeneous, and that silver was the most abundant element present on both surfaces, being 45 and 53 at.% on the 3- and 150-nm films, respectively. Inductively coupled plasma time of flight mass spectroscopy (ICP-TOF-MS) was used to measure the concentration of silver ions released from these films. Concentrations of 0.9 and 5.2 ppb were detected for the 3- and 150 nm films, respectively. The surface wettability of the films remained nearly identical for both film thicknesses, displaying a static water contact angle of 95 degrees , while the surface free energy of the 150-nm film was found to be slightly greater than that of the 3-nm film, being 28.8 and 23.9 mN m(-1), respectively. The two silver film thicknesses exhibited statistically significant differences in surface topographic profiles on the nanoscopic scale, with R (a), R (q) and R (max) values of 1.4, 1.8 and 15.4 nm for the 3-nm film and 0.8, 1.2 and 10.7 nm for the 150-nm film over a 5 * 5 MUm scanning area. Confocal scanning laser microscopy and scanning electron microscopy revealed that the bactericidal activity of the 3-nm silver film was not significant, whereas the nanoscopically smoother 150-nm silver film exhibited appreciable bactericidal activity towards Pseudomonas aeruginosa ATCC 9027 cells and Staphylococcus aureus CIP 65.8 cells, obtaining up to 75% and 27% sterilisation effect, respectively. PMID- 21556923 TI - In brief: Standard deviation and standard error. PMID- 21556924 TI - Correlation between light transmission and permeability of human dentin. AB - The influence of dentin permeability on transdentinal LED light propagation should be evaluated since this kind of phototherapy may further be clinically used to stimulate the metabolism of pulp cells, improving the healing of damaged pulps. This study evaluated the influence of the dentin permeability on the transdentinal LED light (630 nm) transmission. Forty-five 0.5-mm-thick dentin disks were prepared from the coronal dentin of extracted sound human molars. An initial measurement of transdentinal LED light transmission was carried out by illuminating the discs in the occlusal-to-pulpal direction onto a light power sensor to determine light attenuation. The discs were treated with EDTA for smear layer removal, subjected to analysis of hydraulic conductance, and a new measurement of transdentinal LED light transmission was taken. Spearman's correlation coefficient was used for analysis of data and showed a weak correlation between dentin permeability and light attenuation (coefficient = 0.19). This result indicates that higher or lower dentin permeability does not reflect the transdentinal propagation of LED light. Significantly greater transdentinal propagation of light was observed after treatment of dentin surface with EDTA (Wilcoxon test, p < 0.05). According to the experimental conditions of this in vitro study, it may be concluded that dentin permeability does not interfere in the transdentinal LED light transmission, and that smear layer removal facilitates this propagation. PMID- 21556925 TI - Optical absorption and scattering of bovine cornea, lens, and retina in the near infrared region. AB - The optical properties of bovine ocular tissues have been determined at laser wavelengths in the near-infrared (NIR) region. The inverse adding doubling (IAD), Kubelka-Munk (KM), and inverse Monte Carlo (IMC) methods were applied to the measured values of the total diffuse transmission, total diffuse reflection, and collimated transmission to determine the optical absorption and scattering coefficients of the bovine cornea, lens and retina from 750 to 1,000 nm using a CW Ti:sapphire laser. The optical properties obtained from these three methods have been compared and are discussed. PMID- 21556926 TI - Low-level infrared laser effect on plasmid DNA. AB - Low-level laser therapy is used in the treatment of many diseases based on its biostimulative effect. However, the photobiological basis for its mechanism of action and adverse effects are not well understood. The aim of this study, using experimental models, was to evaluate the effects of laser on bacterial plasmids in alkaline agarose gel electrophoresis and Escherichia coli cultures. The electrophoretic profile of bacterial plasmids in alkaline agarose gels were used for studying lesions in DNA exposed to infrared laser. Transformation efficiency and survival of Escherichia coli AB1157 (wild-type), BH20 (fpg/mutM(-)), BW9091 (xth(-)), and DH5alphaF'Iq (recA(-)) cells harboring pBSK plasmids were used as experimental models to assess the effect of laser on plasmid DNA outside and inside of cells. Data indicate low-level laser: (1) altered the electrophoretic profile of plasmids in alkaline gels at 2,500-Hz pulsed-emission mode but did not alter at continuous wave, 2.5- and 250-Hz pulsed-emission mode; (2) altered the transformation efficiency of plasmids in wild-type and fpg/mutM(-) E. coli cells; (3) altered the survival fpg/mutM(-), xthA(-) and recA(-) E. coli cultures harboring pBSK plasmids. Low-level infrared laser with therapeutic fluencies at high frequency in pulsed-emission modes have effects on bacterial plasmids. Infrared laser action can differently affect the survival of plasmids in E. coli cells proficient and deficient in DNA repair mechanisms, therefore, laser therapy protocol should take into account fluencies, frequencies and wavelength of laser, as well as tissue conditions and genetic characteristics of cells before beginning treatment. PMID- 21556927 TI - No evidence of volatile chemicals regulating reproduction in a multiple queen ant. AB - Efficient cooperation in eusocial insect colonies requires effective communication, and there is abundant evidence of non-volatile chemicals playing a role in regulating reproduction within colonies. In contrast, there have been fewer studies investigating the role of volatile chemicals. This study investigated the potential role of volatile chemicals in regulating queen reproduction either by directly inhibiting queen reproduction or by honestly signalling queen fecundity to workers. We tested this using multiple queen colonies of the ant (Leptothorax acervorum) from a functionally monogynous population where one queen monopolizes all reproduction. Nine colonies, each with an established laying queen, were split to produce two colony fragments-one containing the reproducing queen (group 1) and one containing only previously non reproducing queens (group 2). Each group was separated by a fine wire mesh preventing physical contact, but allowing volatile chemical contact. In each group 2 fragment, we found that a single formerly non-reproductive queen commenced reproduction and that the rate of egg laying and maximum number of eggs recorded did not significantly differ between groups 1 and 2, results that do not support volatile chemicals as playing a role in regulating queen reproduction. Instead, our findings suggest that physical contact is necessary to maintain functional monogyny. PMID- 21556928 TI - Expression of the H+-ATPase AHA10 proton pump is associated with citric acid accumulation in lemon juice sac cells. AB - The sour taste of lemons (Citrus limon (L.) Burm.) is determined by the amount of citric acid in vacuoles of juice sac cells. Faris is a "sweet" lemon variety since it accumulates low levels of citric acid. The University of California Riverside Citrus Variety Collection includes a Faris tree that produces sweet (Faris non-acid; FNA) and sour fruit (Faris acid; FA) on different branches; it is apparently a graft chimera with layer L1 derived from Millsweet limetta and layer L2 from a standard lemon. The transcription profiles of Faris sweet lemon were compared with Faris acid lemon and Frost Lisbon (L), which is a standard sour lemon genetically indistinguishable from Faris in prior work with SSR markers. Analysis of microarray data revealed that the transcriptomes of the two sour lemon genotypes were nearly identical. In contrast, the transcriptome of Faris sweet lemon was very different from those of both sour lemons. Among about 1,000 FNA-specific, presumably pH-related genes, the homolog of Arabidopsis H(+) ATPase proton pump AHA10 was not expressed in FNA, but highly expressed in FA and L. Since Arabidopsis AHA10 is involved in biosynthesis and acidification of vacuoles, the lack of expression of the AHA10 citrus homolog represents a very conspicuous molecular feature of the FNA sweet phenotype. In addition, high expression of several 2-oxoglutarate degradation-related genes in FNA suggests activation of the GABA shunt and degradation of valine and tyrosine as components of the mechanism that reduces the level of citric acid in sweet lemon. PMID- 21556929 TI - Distribution of mefloquine in the blood of Thai patients with acute uncomplicated falciparum malaria following administration of therapeutic doses of artesunate. AB - PURPOSE: The study objectives to investigate the distribution of the antimalarial drug mefloquine (MQ) in cellular and fluid blood compartments when given at therapeutic dosage with artesunate and to investigate an eventual association with the occurrence of treatment-related adverse events in Thai patients with acute uncomplicated falciparum malaria. METHODS: MQ distribution following administration of standard therapeutic doses (1,250 mg MQ in split dose) with artesunate to 20 Thai patients with acute uncomplicated falciparum malaria was assessed in whole blood, serum, plasma, red blood cells (RBC), white blood cells (WBC), and platelets using high -performance liquid chromatography. RESULTS: All patients responded to treatment without reappearance of parasitemia during the 42 day follow-up period. There was no significant gender difference in MQ levels. The chronological change in MQ levels in all blood components, including ratios of plasma to serum, whole blood, RBC, platelets or WBC were similar and parallel in both genders. MQ concentrations at 14 and 168 h, in descending order, in both male and female patients were as follow: WBC > platelets > plasma > serum > whole blood > RBC. Gender-specific whole blood, serum, and RBC concentrations were similar at all time points, with median ratios of plasma:whole blood, plasma:serum, and plasma:RBC of 0.84:1.21, 1.09:1.64, and 1.59:3.79, respectively. Plasma vs whole blood and plasma vs RBC MQ concentrations showed a highly significant correlation, with r = 0.923 and 0.867, respectively. No association between occurrence of treatment-related adverse events and MQ concentrations in various blood components/fluids was observed in either gender. CONCLUSIONS: Based on these observations, gender-specific therapeutic MQ dose adjustment is obviously not required. PMID- 21556930 TI - Gastric leakage after sleeve gastrectomy-clinical presentation and therapeutic options. AB - OBJECTIVE: To analyze gastric leakage following sleeve gastrectomy depending on its point of detection and localization in order to evaluate therapeutic strategies. METHOD: From Dec 2006 until June 2010, data of all patients undergoing bariatric surgery were entered into a prospectively documented database. Evaluation contained patient's gender, age, body mass index (BMI), type of surgery, clinical symptoms, diagnostics, onset and localization of leakage, type of therapy, length of stay (LOS), and clinical outcome. RESULTS: Forty-five of 196 bariatric patients underwent sleeve gastrectomy, 22 male and 23 female with mean age 43 +/- 9.7 years and mean BMI 54.9 +/- 10 kg/m(2). Four patients developed a gastric leak (8.9%)-three proximal leaks and one distal leak. Leakage was detected by upper gastrointestinal (UGI) radiography in two cases, by gastroscopy in one case, and by abdominal computed tomographic (CT) scan in another case. In two cases, CT scan was not feasible because of patient's conditions. Three patients underwent relaparoscopy with re-suture of staple line, abdominal lavage, and placement of an intraabdominal drain. Both patients with proximal leaks required stent graft application as leakage reoccurred within 5 days after relaparoscopy. LOS varied between 30 and 120 days. None of the patients died. CONCLUSION: The location of leakage, and the presence or absence of an intraabdominal drain are determining factors for its treatment. UGI radiography with contrast media and gastroscopy are comparable and superior to standard CT scan. Stent graft application is a promising therapy in case of proximal leakage; re-suture or resection of the staple line are possible solutions in case of a distal leak. PMID- 21556931 TI - The effect of prophylactic lamivudine on hepatitis B virus reactivation in HBsAg positive patients with diffuse large B-cell lymphoma undergoing prolonged rituximab therapy. AB - The association of prolonged rituximab therapy and hepatitis B virus (HBV) reactivation in diffuse large B-cell lymphoma (DLBCL) and the role of lamivudine prophylaxis remain undefined. The prevalence and mortality of HBV reactivation in HBsAg-positive patients with DLBCL undergoing rituximab-based treatment, who received prophylactic treatment with or without lamivudine, were retrospectively analyzed. From January 2003 to December 2009, there were 50 patients enrolled in the study, among of which 30 received the prophylactic treatment of lamivudine and 20 without prophylactic treatment of lamivudine. Among of the 50 patients, seven patients received further rituximab maintenance, once every 3 months for 2 years. Compared with lamivudine treatment group, it showed that there was significantly higher prevalence of HBV reactivation (60.0% vs 13.3%, P = .001), severe hepatitis (45.0% vs 6.7%, P = .004), and mortality (25.0% vs 3.3%, P = .032) in non-lamivudine prophylactic group; however, there was no statistically significant difference in the HBV DNA levels at reactivation (3.94 * 10(6) vs 8.30 * 10(5) copies/ml, P = .47) and the time from first dose of rituximab to HBV reactivation(207 vs 386 days, P = .28). For patients undergoing further rituximab maintanence treatment, the prevalence and mortality of HBV reactivation were 71.4 and 28.6%, respectively. The prevalence and mortality of HBV reactivation are 66.7% vs 75.0% (P = 1.00) and 0 vs 50.0% (P = .43) in lamivudine prophylactic and non-lamivudine prophylactic groups, respectively. The effect of lamivudine prophylaxis on preventing HBV reactivation was found to be less in patients undergoing longer duration of rituximab treatment. A longer duration of rituximab treatment contributed to higher morbidity and mortality of HBV reactivation in HbsAg-positive patients with DLBCL. Further study is warranted for the optimal management of hepatitis caused by HBV reactivation. PMID- 21556932 TI - Expression of GPC3 protein and its significance in lung squamous cell carcinoma. AB - The purpose of this study was to investigate GPC3 gene expression in lung squamous cell carcinoma tissue and its correlation with clinical and tumor characteristics. Using RT-PCR, the presence of GPC3 gene expression was detected in cancer tissue and adjacent normal tissue in 66 cases of lung squamous cell carcinoma and positive rates were calculated. Using Western blot, changes in GPC3 protein expression were detected in lung squamous cell carcinoma and adjacent normal tissues. The percentage of tissue samples expressing GPC3 mRNA was significantly higher in lung squamous cell carcinoma than in adjacent normal tissue (P < 0.05). This percentage was also significantly higher for cases with lymph node metastasis than for those without lymph node metastasis (P < 0.05). Further, the percentage of samples expressing GPC3 mRNA was higher with lowering degrees of tumor differentiation (P < 0.05). Rates of GPC3 expression were, however, independent of patient gender, age, and tumor size (P > 0.05). The expression of GPC3 protein in lung squamous cell carcinoma was significantly higher than that in adjacent normal tissues (P < 0.05). The expression in cases with lymph node metastasis was significantly higher than in those without lymph node metastasis (P < 0.05), and GPC3 protein expression increased with lowering degrees of tumor differentiation (P < 0.05). Further investigation is warranted for the association of initiation, development, invasion, and metastasis of disease. PMID- 21556933 TI - Clinical significance of vascular endothelial growth factor and endostatin levels in the differential diagnosis of malignant and benign ascites. AB - The aim of this study is to evaluate the performance of VEGF and endostatin levels in the differential diagnosis of malignant and benign ascites. The study included 101 consecutive patients with malignant ascites (55.2 +/- 15.8 years, 63 men and 38 women) and 81 patients with benign ascites (53.0 +/- 17.2 years, 51 men and 30 women). VEGF and endostatin levels in serum and ascites were determined by a sandwich enzyme immunoassay technique using a commercially available assay kit. The serum VEGF, ascites VEGF, and ascites endostatin levels of patients with malignant ascites were significantly higher than those in patients with benign ascites (P < 0.001), but there was no difference in serum endostatin levels between the two groups (P = 0.267). Ascites endostatin levels correlated positively with ascites VEGF (r = 0.5193, P < 0.01), and serum endostatin showed a low correlation with serum VEGF (r = 0.3291, P < 0.01) in patients with malignant ascites. Areas under the ROC curves of ascites VEGF, ascites endostatin, serum VEGF, and serum endostatin were 0.890, 0.815, 0.694, and 0.552, respectively. The combination of ascites VEGF and endostatin improved the sensitivity up to 90.1%, the specificity up to 87.7%, and the accuracy up to 89.0% in the differential diagnosis of malignant and benign ascites. VEGF and endostatin levels in ascites appear to be suitable for differentiating between malignant and benign ascites, which can be applied to clinical examination. PMID- 21556934 TI - The biological behavior of SDF-1/CXCR4 in patients with myelodysplastic syndrome. AB - The purpose of this investigation is to evaluate the biological behavior of stromal cell-derived factor-l (SDF-1) in migration, adhesion, and apoptosis as well as the related signaling transduction pathways in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We chose 22 patients with MDS, 7 patients with de novo AML, and 8 patients with non-clonal cytopenia diseases. We performed flow cytometric analysis of CD34(+) cells apoptosis using annexinV-FITC, which binds to exposed phosphatidylserine on apoptotic cells. The cell adhesion capability was detected by CCK-8 assay. The migration ability of the cell was checked by transwell assay. Furthermore, we measured SDF-1 levels in BM plasma from patients by enzyme-linked immunosorbent assay (ELISA). Our results indicated that the apoptosis of CD34(+) cell was significantly increased in the Low-grade MDS (IPSS score <= 1.0) patients compared with the high-grade MDS (IPSS score >= 1.5) (21.33% vs. 7.27%, P < 0.001) and patients with de novo AML (21.33% vs. 7.53%, P < 0.001). SDF-1 promoted CXCR4 high expression cells adhesion to the stroma cells (MSC) and induced these cells migration. SDF-1 could trigger the occurrence of polarized morphology of the cells that expressed CXCR4 high. After addition of wortmannin or PTX, the ability of adhesion and migration of the cells that expressed CXCR4 high decreased. But in the patient's cells that expressed CXCR4 low, there was no above-mentioned phenomenon. So we can suppose that the signaling pathway of SDF 1/CXCR4 axis is PI3K pathway, and we should do more things about this pathway and may find out the target treatment of MDS. PMID- 21556935 TI - Effective control of aquatic invasive species in tropical Australia. AB - Often ecologists and natural resource managers can easily access data on invasive species occurrence across a region. Yet, collecting species abundance data over a large area is arguably more important for decision making, but inherently costly, so methods which can provide robust information at low-cost are particularly valuable. Studies of species distribution often use occurrence data to build models of the environmental niche. Environmental suitability derived from such models may be used to predict the potential distributions of species. The ability of such models to predict spatial patterns in abundance have recently been demonstrated. Here we tested the relationship of environmental suitability with local abundance of an aquatic invasive species, olive hymenachne (Hymenachne amplexicaulis) in the Wet Tropics of Australia. Ordinary least squares and quantile regressions revealed a positive relationship between environmental suitability and local abundance of olive hymenachne. We expand on this and use the relationship between environmental suitability and local abundance to quantify the effectiveness of management (reduction in local abundance) under four different management investments. We show that the upper limit of abundance can be used to evaluate management effectiveness based on varying investments, and that ongoing management is the most effective at reducing local abundance. We discuss implications of this in addressing important problems in invasive species management. PMID- 21556936 TI - Incorporating agroforestry approaches into commodity value chains. AB - The productivity of tropical agricultural commodities is affected by the health of the ecosystem. Shade tolerant crops such as coffee and cocoa benefit from environmental services provided by forested landscapes, enabling landscape design that meets biodiversity conservation and economic needs. What can motivate farmers to apply and maintain such landscape approaches? Rather than rely on a proliferation of externally funded projects new opportunities are emerging through the international market that buys these commodities. As part of their growing commitment to sustainable supply chains, major companies are supporting agroforestry approaches and requiring producers and traders to demonstrate that the source of their commodities complies with a set of principles that conserves forested landscapes and improves local livelihoods. The paper presents examples of international companies that are moving in this direction, analyzes why and how they are doing it and discusses the impact that has been measured in coffee and cocoa communities in Latin America and Africa. It particularly considers the role of standards and certification systems as a driver of this commitment to promote profitable operations, environmental conservation and social responsibility throughout the coffee and cocoa value chains. Such approaches are already being taken to scale and are no longer operating only in small niches of the market but the paper also considers the limitations to growth in this market based approach. PMID- 21556937 TI - Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. AB - BACKGROUND: T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled. MATERIALS AND METHODS: CD4(+)IFNgamma(-)IL17( )IL-22(+) T cells (Th22 cells), CD4(+)IFNgamma(-)IL-22(-)IL17(+) T cells (pure Th17 cells), CD4(+)IL17(+) T cells (Th17 cells), and CD4(+)IFNgamma(+) T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay. RESULTS: Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score. CONCLUSION: Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA. PMID- 21556938 TI - Choroidal thickness measurement in healthy Japanese subjects by three-dimensional high-penetration optical coherence tomography. AB - BACKGROUND: We performed retinal and choroidal thickness mapping by three dimensional high-penetration optical coherence tomography (OCT) and evaluated the choroidal thickness distribution throughout the macula in healthy eyes. METHODS: Forty-three eyes of 43 healthy Japanese volunteers were evaluated by 1060-nm swept-source OCT. The eyes were scanned with a three-dimensional raster scanning protocol, and the mean retinal and choroidal thicknesses of the posterior sectors were obtained. The sectors were defined by the Early Treatment Diabetic Study (ETDRS) layout. These data were compared by age (23-56 years), spherical equivalent refractive error (between +0.9 D and -10.3 D), and axial length (22.9 27.6 mm). RESULTS: The mean retinal and choroidal thicknesses of the ETDRS area were 284 +/- 14 MUm and 348 +/- 63 MUm respectively. The mean regional choroidal thicknesses in the nasal inner macula and nasal outer macula were significantly smaller than those in all other sectors. The mean regional choroidal thickness in most sectors showed a significant negative correlation with axial length and a significant positive correlation with refractive error. In eyes with a long axial length (>25.0 mm), the mean regional choroidal thickness of five sectors showed a significant negative correlation with age. The coefficient of variation of choroidal thickness between sectors showed a significant negative correlation with axial length, and a positive correlation with refractive error. The mean retinal thickness in each sector was not significantly correlated with the mean choroidal thickness, age, axial length, or refractive error. CONCLUSIONS: The choroidal thickness map showed a distribution entirely different from the retinal thickness map. Choroidal thickness varies significantly with location, axial length, refractive error, and age. These variations should be considered when evaluating choroidal thickness. PMID- 21556939 TI - Insights into pathology of cuticular drusen from integrated confocal scanning laser ophthalmoscopy imaging and corresponding spectral domain optical coherence tomography. AB - BACKGROUND: To analyze the integrated confocal scanning laser ophthalmoscopy (cSLO) fundus and angiographic imaging and corresponding spectral domain optical coherence tomography (SD-OCT) features of cuticular drusen. METHODS: Twenty-one consecutive patients with cuticular drusen were submitted to cSLO fundus and angiographic imaging [infrared reflectance (IR), fundus autofluorescence (FAF), near-infrared autofluorescence (NIA), fluorescein angiography (FA), and indocyanine green angiography (ICGA)) and "eye-tracked" SD-OCT. RESULTS: A total of 42 eyes were included for analysis. BCVA ranged from 20/20 to 20/400. In 5/42 eyes, cSLO imaging and corresponding SD-OCT showed coincident vitelliform macular detachment, and in 9/42 eyes showed coincident geographic atrophy (GA). The "typical" cuticular drusen, intensely staining on early FA phase ("stars-in-the sky" appearance in the fundus), appeared as "sawtooth" retinal pigment epithelium (RPE) elevation on SD-OCT. Some "atypical" cuticular drusen appeared, on early FA and ICGA frames, as hyper-fluoresecent lesions surrounded by faint hypo fluoresecent halos. These lesions, which became intensely hyper-fluorescent in the late FA and ICGA phases, appeared, on SD-OCT, as small, confluent "dome shaped" RPE elevations. Interestingly, some less intensely staining cuticular drusen (FA and ICGA) appeared as irregular slight thickening of RPE/Bruch's membrane complex on SD-OCT scans. CONCLUSION: Integrated imaging makes it possible to highlight different features within cuticular drusen-containing regions, and gives insights into pathology. We suggest that "typical" cuticular drusen may represent a continuous layer of early basal laminar deposit (BLamD) associated with membranous debris accumulation. As early BLamD thicken, the lesions become richer in solid lipid particles, and "atypical" cuticular drusen may develop. PMID- 21556940 TI - Implementation of a fast-track clinical pathway decreases postoperative length of stay and hospital charges for liver resection. AB - A fast-track clinical pathway is designed to streamline patient care delivery and maximize cost effectiveness. It has decreased postoperative length of stay (LOS) and hospital charges for many surgical procedures. However, data on clinical pathways after liver surgery are sparse. This study examined whether use of a fast-track clinical pathway for patients undergoing elective liver resection affected postoperative LOS and hospital charges. A fast-track clinical pathway was developed and implemented by a multidisciplinary team for patients undergoing liver resection. Between July, 2007 and May, 2008, a total of 117 patients underwent elective liver resection: the fast-track clinical pathway (education of patients and families, earlier oral feeding, earlier discontinuation of intravenous fluid, no drains or nasogastric tubes, early ambulation, use of a urinary catheter for less than 24 h and planned discharge 6 days after surgery) was studied prospectively in 56 patients (postpathway group). These patients were compared with the remainder who had usual care (prepathway group). Outcome measures were postoperative LOS, perioperative hospital charges, intraoperative and postoperative complications, mortality, and readmission rate. Among all patients, 69 (59%) had complicating diseases and/or a history of surgery and 24 patients belonged to American Society of Anesthesiologists grade III-IV. Compared with the prepathway group, the postpathway group had a significantly shorter postoperative LOS (7 vs. 11 days, P < 0.01). The average perioperative hospital charges were RMB 26,626 for patients in the prepathway group and only RMB 21,004 for those in the postpathway group (P < 0.05), with no differences in intraoperative and postoperative complications (P = 0.814), mortality (P = 0.606), and readmission rate (P = 0.424). Implementation of the fast-track clinical pathway is an effective and safe method for reducing postoperative LOS and hospital charges for high-risk patients undergoing elective liver resection. The result supports the further development of fast-track clinical pathways for liver surgical procedures. PMID- 21556941 TI - Investigation of siRNA-loaded polyethylenimine-coated human serum albumin nanoparticle complexes for the treatment of breast cancer. AB - Small interfering RNA (siRNA) molecules have great potential for developing into a future therapy for breast cancer. To overcome the issues related to rapid degradation and low transfection of naked siRNA, polyethylenimine (PEI)-coated human serum albumin (HSA) nanoparticles have been characterized and studied here for efficient siRNA delivery to the MCF-7 breast cancer cell line. The optimized nanoparticles were ~90 nm in size, carrying a surface charge of +26 mV and a polydispersity index (PDI) less than 0.25. The shape and morphology of the particles was studied using electron microscopy. A cytotoxicity assessment of the nanoparticles showed no correlation of cytotoxicity with HSA concentration, while using high molecular weight PEI (MW of 70 against 25 kDa) showed higher cytotoxicity. The optimal transfection achieved of fluorescin-tagged siRNA loaded into PEI-coated HSA nanoparticles was 61.66 +/- 6.8%, prepared with 6.25 MUg of PEI (25 kDa) added per mg of HSA and 20 mg/ml HSA, indicating that this nonviral vector may serve as a promising gene delivery system. PMID- 21556942 TI - Effect of atorvastatin (Lipitor) on myocardial apoptosis and caspase-8 activation following coronary microembolization. AB - We determined the effect of atorvastatin on myocardial apoptosis and caspase-8 activation following coronary microembolization (CME) in a rat model. For this, 50 rats were randomly and equally divided into CME; sham-operated (control); atorvastatin lavage; gastric lavage control; and caspase-8 inhibitor (CHO) groups. In CME animals, a microembolization ball was injected through the left ventricle. Sham animals were injected with normal saline (NS). Atorvastatin group received atorvastatin gastric lavage once-a-day, 1 week before surgery. Gastric lavage controls had similar lavage with NS. CHO group was i.p-injected (CHO: 10 mg/kg) 30 min before surgery. Cardiac indices in each group were determined by echocardiography 6-h postoperatively. TUNEL assay and western blot were used for myocardial apoptosis and expression of caspases-3/-8, respectively. Echocardiography data show that left ventricular ejection fraction (LVEF) in CME group was significantly decreased (P < 0.05) compared with sham controls. Besides, left ventricular fractional shortening (FS) and cardiac output (CO) were also decreased with an increase in left ventricular end-diastolic dimension (LVEDd). Atorvastatin and CHO animals had significantly improved (P < 0.05) cardiac function compared with CME group. Myocardial apoptosis and activation levels of caspases-3/-8 were significantly increased (P < 0.05) compared with sham; myocardial apoptosis and activation levels of caspases-3/-8 were significantly decreased (P < 0.05) in atorvastatin and CHO groups compared with CME group. In conclusion, atorvastatin pretreatment suppressed post-CME myocardial apoptosis and improved cardiac function through the blockade of a myocardial death receptor-mediated apoptotic pathway. PMID- 21556943 TI - Among-population variation in costs of reproduction in the long-lived orchid Gymnadenia conopsea: an experimental study. AB - A cost of reproduction in terms of reduced future performance underlies all life history models, yet costs have been difficult to detect in short-term experiments with long-lived plants. The likelihood of detecting costs should depend on the range of variation in reproductive effort that can be induced, and also on the shape of the cost function across this range, which should be affected by resource availability. Here, we experimentally examined the effects of both reduced and increased fruit production in two populations of the long-lived orchid Gymnadenia conopsea located at sites that differ in length of the growing season. Plants that were prevented from fruiting produced more flowers in the population with a longer growing season, had higher survival in the other population, and grew larger compared to control plants in both populations. Fruit production was pollen-limited in both populations, and increased reproductive investment after supplemental hand-pollination was associated with reduced fecundity the following year. The results demonstrate that the shape of the cost function varies among fitness components, and that costs can be differentially expressed in different populations. They are consistent with the hypothesis that differences in temporal overlap between allocation to reproduction and other functions will induce among-population variation in reproductive costs. PMID- 21556944 TI - Breaking the rules: sex roles and genetic mating system of the pheasant coucal. AB - Generally in birds, the classic sex roles of male competition and female choice result in females providing most offspring care while males face uncertain parentage. In less than 5% of species, however, reversed courtship sex roles lead to predominantly male care and low extra-pair paternity. These role-reversed species usually have reversed sexual size dimorphism and polyandry, confirming that sexual selection acts most strongly on the sex with the smaller parental investment and accordingly higher potential reproductive rate. We used parentage analyses and observations from three field seasons to establish the social and genetic mating system of pheasant coucals, Centropus phasianinus, a tropical nesting cuckoo, where males are much smaller than females and provide most parental care. Pheasant coucals are socially monogamous and in this study males produced about 80% of calls in the dawn chorus, implying greater male sexual competition. Despite the substantial male investments, extra-pair paternity was unusually high for a socially monogamous, duetting species. Using two or more mismatches to determine extra-pair parentage, we found that 11 of 59 young (18.6%) in 10 of 21 broods (47.6%) were not sired by their putative father. Male incubation, starting early in the laying sequence, may give the female opportunity and reason to seek these extra-pair copulations. Monogamy, rather than the polyandry and sex-role reversal typical of its congener, C. grillii, may be the result of the large territory size, which could prevent females from monopolising multiple males. The pheasant coucal's exceptional combination of classic sex-roles and male-biased care for extra-pair young is hard to reconcile with current sexual selection theory, but may represent an intermediate stage in the evolution of polyandry or an evolutionary remnant of polyandry. PMID- 21556945 TI - Can we prevent or treat renal dysfunction in acute heart failure? AB - Most patients with heart failure (HF) already have or develop renal dysfunction; this might contribute to their poor outcome. Current treatment for HF can also contribute to worsen renal function. High furosemide doses are traditionally associated with worsening renal function (WRF), but patients with fluid overload may benefit of aggressive fluid removal. Unfortunately, promising therapies like vasopressin antagonists and adenosine antagonists have not been demonstrated to improve outcomes. Likewise, correction of low renal blood flow through dopamine, inotropic agents, or vasodilators does not seem to be associated with a clear benefit. However, transient WRF associated with acute HF treatment may not necessarily portend a poor prognosis. In this review, we focus on the strategies to detect renal dysfunction in acute HF, the underlying pathophysiological mechanisms, and the potential treatments. PMID- 21556947 TI - Rapid microfluidic perfusion enabling kinetic studies of lipid ion channels in a bilayer lipid membrane chip. AB - There is growing recognition that lipids play key roles in ion channel physiology, both through the dynamic formation and dissolution of lipid ion channels and by indirect regulation of protein ion channels. Because existing technologies cannot rapidly modulate the local (bio)chemical conditions at artificial bilayer lipid membranes used in ion channel studies, the ability to elucidate the dynamics of these lipid-lipid and lipid-protein interactions has been limited. Here we demonstrate a microfluidic system supporting exceptionally rapid perfusion of reagents to an on-chip bilayer lipid membrane, enabling the responses of lipid ion channels to dynamic changes in membrane boundary conditions to be probed. The thermoplastic microfluidic system allows initial perfusion of reagents to the membrane in less than 1 s, and enables kinetic behaviors with time constants below 10 s to be directly measured. Application of the platform is demonstrated toward kinetic studies of ceramide, a biologically important lipid known to self-assemble into transmembrane ion channels, in response to dynamic treatments of small ions (La(3+)) and proteins (Bcl-x(L) mutant). The results reveal the broader potential of the technology for studies of membrane biophysics, including lipid ion channel dynamics, lipid-protein interactions, and the regulation of protein ion channels by lipid micro domains. PMID- 21556948 TI - Integrin beta4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF. AB - Prior studies have indicated that the beta4 integrin promotes mammary tumor invasion and metastasis by combining with ErbB2 and amplifying its signaling capacity. However, the effector pathways and cellular functions by which the beta4 integrin exerts these effects are incompletely understood. To examine if beta4 signaling plays a role during mammary tumor cell adhesion to microvascular endothelium, we have examined ErbB2-transformed mammary tumor cells expressing either a wild-type (WT) or a signaling-defective form of beta4 (1355T). We report that WT cells adhere to brain microvascular endothelium in vitro to a significantly larger extent as compared to 1355T cells. Interestingly, integrin beta4 signaling does not exert a direct effect on adhesion to the endothelium or the underlying basement membrane. Rather, it enhances ErbB2-dependent expression of VEGF by tumor cells. VEGF in turn disrupts the tight and adherens junctions of endothelial monolayers, enabling the exposure of underlying basement membrane and increasing the adhesion of tumor cells to the intercellular junctions of endothelium. Inhibition of ErbB2 on tumor cells or the VEGFR-2 on endothelial cells suppresses mammary tumor cell adhesion to microvascular endothelium. Our results indicate that beta4 signaling regulates VEGF expression by the mammary tumor cells thereby enhancing their adhesion to microvascular endothelium. PMID- 21556949 TI - Class III nerve-sparing radical hysterectomy versus standard class III radical hysterectomy: an observational study. AB - BACKGROUND: The purpose of this observational study was to evaluate disease-free survival, overall survival, local recurrence rate, and morbidities in patients submitted to class III nerve-sparing radical hysterectomy (NSRH) compared with standard radical hysterectomy (RH) in cervical cancer (CC). This was a comparative study in the context of multimodal therapies. MATERIALS AND METHODS: We investigated patients with CC admitted to the National Cancer Institute of Milan between January 4, 2001, and September 29, 2009, treated with NSRH. We compared patients operated with RH between March 20, 1980, and December 28, 1995. A total of 496 patients were enrolled. The median follow-up was 93 months (42 and 159 months for the NSRH and RH groups, respectively). RESULTS: The overall number of relapses was 30 out of 185 and 60 out of 311 for NSRH and RH, respectively. Five-year disease-free survival estimate was 78.9% (95% confidence interval [CI] 72.0-85.7) in NSRH and 79.8% (95% CI 75.3-84.3) in RH (P=0.519). Five-year overall survival estimate was 90.8% (95% CI 85.9-95.6) in NSRH and 84.1% (95% CI 8.0-88.3) in RH (P=0.192). Rates of postoperative serious complications were 9.7% and 19.6% for NSRH and RH, respectively (P=0.004). Positive pelvic lymph node and vagina status were significant (P<0.01) independent predictors by multivariable analyses. CONCLUSIONS: The oncologic results were comparable between NSRH and conventional class III RH in the context of two multimodal treatments. Bladder function and postoperative complications rate are improved by nerve-sparing technique. The nerve-sparing technique should be considered in all CC patients addressed to surgery because it improves functional outcome and preserves radicality without compromising overall survival. PMID- 21556950 TI - Oral vitamin B12 replacement: an effective treatment for vitamin B12 deficiency after total gastrectomy in gastric cancer patients. AB - BACKGROUND: Vitamin B12 deficiency is a common long-term sequelae after total gastrectomy. Intramuscular injection of vitamin B12 is the only known treatment. We investigated the efficacy and safety of oral vitamin B12 replacement for gastric cancer patients with vitamin B12 deficiency after total gastrectomy. METHODS: We performed a single-arm, open-label, fixed-drug dosage, prospective study (NCT00699478) involving gastric cancer patients who underwent total gastrectomy. Vitamin B12-deficient (<200 pg/ml) patients (n = 30) received daily oral vitamin B12 (dosage: 1500 MUg mecobalamin) administration for 3 months. The primary outcome measurement was serum vitamin B12. The secondary outcome measurements were improvement of neurologic symptoms and hematologic findings (serum folate, homocysteine, ferritin, iron, total iron binding capacity, transferrin, and mean corpuscular volume). For comparison, another group of vitamin B12 deficient patients (n = 30) received intramuscular vitamin B12 injections (dosage: 1000 MUg cyanocobalamin) weekly for 5 weeks and monthly thereafter for a total of 3 months in a separate study period. RESULTS: In both groups, mean serum vitamin B12 increased after 30 days of treatment and was maintained up to 90 days. No adverse effects related to oral or intramuscular vitamin B12 replacements were noted. Both groups showed decreased homocysteine levels. Before treatment, 29 patients in the oral vitamin B12 group had neurologic symptoms related to vitamin B12 deficiency. After oral vitamin B12 treatment, 28 patients experienced symptom relief, and 16 patients were symptom free. CONCLUSIONS: Oral vitamin B12 replacement is an effective and safe treatment for vitamin B12 deficiency in gastric cancer patients after total gastrectomy. PMID- 21556951 TI - Quality assurance parameters and predictors of outcome for ilioinguinal and inguinal dissection in a contemporary melanoma patient population. AB - BACKGROUND: Regional lymph node dissection (RLND) is currently the most effective therapy for metastatic melanoma in groin lymph nodes. With thorough surgery, RLND lymph node (LN) retrieval numbers have a predictable distribution. Whether patients have inguinal or ilioinguinal dissection varies between institutions. This study was designed to provide LN retrieval parameters for inguinal and ilioinguinal LN dissections, and secondarily, to analyze known predictors for survival outcomes, including LN ratio, i.e., involved/total number LN removed. METHODS: A prospective database was used to identify 189 patients who had 200 groin dissections between July 2002 and February 2008 to derive parameters of LN retrieval. A subgroup of 177 patients who had one RLND was assessed for predictors of survival outcome. RESULTS: Inguinal dissection had median LN retrieval of 11 (interquartile range, 10-14); 8 LN or more were retrieved in 90% of cases, and 38% of cases had 10 LN or less. Ilioinguinal dissection had median LN retrieval of 21.5 (interquartile range, 17-25); 14 LN or more were retrieved in 90% of cases, and 0 cases had 10 LN or less. The strongest predictors of survival on multivariate analysis were LN ratio, macroscopic LN disease, and ulceration of the primary melanoma. Overall 39% of ilioinguinal dissections had positive pelvic LNs, but only 9.3% of those completed after positive sentinel node biopsy. CONCLUSIONS: Thorough groin RLNDs have a predictable LN yield. LN ratio is the strongest predictor of outcome. Because pelvic LNs are frequently positive ilioinguinal dissection should be considered for all patients, especially those with macroscopic metastases to groin LNs. PMID- 21556952 TI - Nodal metastasis from locally advanced esophageal cancer: how neoadjuvant therapy modifies their frequency and distribution. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (CT-RT) before esophagectomy seems to affect the number of nodal metastasis and to alter the distribution of those that remain. The aim of this study was to define how neoadjuvant chemoradiotherapy changes nodal metastasis patterns in locally advanced esophageal cancer. METHODS: A total of 402 consecutive patients with cancer of the esophagus or esophagogastric junction (181 adenocarcinoma [AC] and 221 squamous cell carcinoma [SCC]) (evaluated at clinical stage T1N1, T2N1, T3N0, or T3N1 and pathological stage M0) presenting in our Department between 1992 and 2007 and who underwent complete resection (R0) were included in this retrospective study on a prospectively collected database. All dissected lymph nodes were retrieved and microscopically analyzed. Nodal metastasis patterns in patients who underwent chemotherapy (CT) or chemoradiotherapy (CT-RT) neoadjuvant therapy were compared with those in patients who underwent surgery alone. RESULTS: Almost 30% of the adenocarcinoma patients and approximately 40% of the SCC patients showed effective tumor downstaging after neoadjuvant therapy. There were fewer paracardial node metastases (P = .002) in the AC patients who underwent CT-RT neoadjuvant therapy. There were, likewise, significantly fewer paraesophageal, paracardial, and subcarinal node metastases in the SCC patients in whom the perigastric nodes became the second-most frequent site of metastasis. CONCLUSION: Not only was frequency of lymph node metastases decreased after neoadjuvant therapy, but nodal localization and pattern were also significantly modified. PMID- 21556953 TI - Prognostic significance of stromal microinvasion in the intestinal type of ovarian mucinous adenocarcinoma. AB - BACKGROUND: The purpose of this study was to assess clinical outcomes with respect to the extent of stromal invasion in patients with stage I ovarian mucinous adenocarcinoma (MAC) of the intestinal type. METHODS: We retrospectively reviewed the medical records and pathologic slides of 113 patients with stage I ovarian MACs who were treated at the Asan Medical Center from January 1994 to July 2009. According to the recent histopathologic criteria, MACs were classified into 3 groups: intraepithelial carcinoma without invasion (IEC), intraepithelial carcinoma with microinvasion (IECMI), and mucinous adenocarcinoma with extensive invasion (MACEI). Stromal invasion was confined to the tumors showing severe cytologic atypia in the invasive foci. Therefore, cases showing mucin granulomas composed only of macrophages without malignant cells were excluded from the definition of invasion. RESULTS: Of the 113 patients, 54 (47.8%) had IEC, 15 (13.3%) had IECMI, and 44 (38.9%) had MACEI. There were no differences among groups in age, menopausal status, CA-125 level, surgical procedures, stage, capsular and lymphovascular space invasion. The 5-year disease-free-survival rates in the IEC, IECMI, and MACEI groups were 97.7%, 77.3%, and 79.9%, respectively (IEC vs IECMI, P=0.004; IEC vs MACEI, P=0.012; IECMI vs MACEI, P=0.555). Prognosis was significantly poorer for patients with IECMI than for those with IEC, but not different between patients with IECMI and MACEI. CONCLUSIONS: Stromal microinvasion in ovarian MAC is a significant prognostic factor. Therefore, diligent search for "stromal microinvasion" with adequate sampling of tumor tissue are important at the time of histopathologic diagnosis, and patients with IECMI should no longer be treated identically to those with IEC. PMID- 21556954 TI - Comparative analysis of the N-genome in diploid and polyploid Aegilops species. AB - The genetic classification for the N-genome chromosomes has been developed on the basis of C-banding analysis on the set of Triticum aestivum * Aegilops uniaristata single chromosome addition lines and examination of A. uniaristata (2n = 2 * = 14, NN), Aegilops ventricosa (2n = 4 * = 28, DDNN) and Aegilops recta (2n = 6 * = 42, UUX(n)X(n)NN) accessions carrying intergenomic translocations using fluorescence in situ hybridisation with probes for three repetitive DNA sequences as well as the 5S and 45S rDNA families. The N-genome chromosomes of the tetraploid A. ventricosa show significant changes relative to the diploid progenitor species, while those of the hexaploid A. recta are similar to A. uniaristata with regard to the distribution of C-bands, 45S and 5S rDNA loci and hybridisation sites of all the three families of tandem repeats. The possible mechanisms of N-genome evolution are discussed. PMID- 21556955 TI - Initial experience with combined endoscopic third ventriculostomy and choroid plexus cauterization for post-hemorrhagic hydrocephalus of prematurity: the importance of prepontine cistern status and the predictive value of FIESTA MRI imaging. AB - PURPOSE: Post-hemorrhagic hydrocephalus of prematurity (PHHP) is among the most common causes of infant hydrocephalus in developed nations. This population has a high incidence of shunt failure, infection, and slit ventricle syndrome. Although effective for other etiologies of infant hydrocephalus, the efficacy of combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) in PHHP has not been investigated. This pilot study reports the initial experience. METHODS: Ten patients (four grade III and six grade IV intraventricular hemorrhage) requiring definitive treatment for PHHP underwent ETV/CPC within 6 months of birth. Seven had a prior ventriculo-subgaleal shunt. Mean age at birth was -12.8 weeks, or 25.2 weeks gestation (24-28 weeks), and at surgery was -1.6 weeks (-11 to +11 weeks). Mean weight at surgery was 3.3 (1.0-5.5 kg). Each patient had preoperative magnetic resonance imaging (MRI) with fast imaging employing steady-state acquisition (FIESTA). RESULTS: Four of ten (40%) required no further operations related to hydrocephalus (mean follow-up, 29.7 months). Six required another procedure (five ultimately shunted). Prepontine cistern status correlated with outcome (p = 0.033). Procedures in all infants with unobstructed cisterns were successful but failed in six of seven with cisternal obstruction, with the one success having an alternative lamina terminalis endoscopic third ventriculostomy. Preoperative MRI FIESTA images correlated well with intraoperative assessment of the cistern. CONCLUSIONS: Results from this small homogenous cohort suggest cistern status is an important determinant of outcome. FIESTA imaging correlated with endoscopic observation. Preliminary analysis suggests ETV/CPC as an effective treatment for PHHP, but only when the cistern is unscarred. This information should guide patient selection for future study protocols. PMID- 21556956 TI - Computational analysis of nanoparticle adhesion to endothelium: effects of kinetic rate constants and wall shear rates. AB - Various nanoparticles have been developed as imaging probes and drug carriers, and their selectivity in binding to target cells determines the efficacy of these functionalized nanoparticles. Since target cells in different arterial segments experience different hemodynamic environments, we study the effects of wall shear rate waveforms on particle binding. We also explore the effects of the kinetic rate constant, which is determined by particle design parameters, on particle binding. A transport and reaction model is used to evaluate nanoparticle binding to the substrate in a laminar flow chamber. Flow and particle concentration fields are solved by using a computational fluid dynamics. The particle binding rate increases as the mean value of wall shear increases, and the amplitudes of sinusoidal shear waveform do not affect the bound particle density profiles significantly. Particle binding rates increase with the rate constant of attachment (k(A)), and are more sensitively affected by low k(A) values and less by k(A) values higher than 1 * 10-6 m s-1. Since binding selectivity is affected by k(A) and the wall shear rate, the results of this study can be used for designing functionalized nanoparticles targeting for the specific cells that experience a specific shear rate. PMID- 21556957 TI - Do navigators' estimates of navigation intensity predict navigation time for cancer care? AB - Patient navigation requires that patient load be equitably distributed. We examined whether navigators could predict the relative amount of time needed by different patients for navigation. Analysis of 139 breast and colorectal cancer patients randomized to the navigation arm of a trial evaluating the effectiveness of navigation. Navigators completed a one-item scale estimating how much navigation time patients were likely to require. Participants were mostly females (89.2%) with breast cancer (83.4%); barriers to cancer care were insurance difficulties (26.6%), social support (18.0%), and transportation (14.4%). Navigator baseline estimates of navigation intensity predicted total navigation time, independent of patient characteristics. The total number of barriers, rather than any specific type of barrier, predicted increased navigator time, with a 16% increase for each barrier. Navigators' estimate of intensity independently predicts navigation time for cancer patients. Findings have implications for assigning navigator case loads. PMID- 21556958 TI - Osteopontin enhances HIV replication and is increased in the brain and cerebrospinal fluid of HIV-infected individuals. AB - Despite effective and widely available suppressive anti-HIV therapy, the prevalence of mild neurocognitive dysfunction continues to increase. HIV associated neurocognitive disorder (HAND) is a multifactorial disease with sustained central nervous system inflammation and immune activation as prominent features. Inflammatory macrophages, HIV-infected and uninfected, play a central role in the development of HIV dementia. There is a critical need to identify biomarkers and to better understand the molecular mechanisms leading to cognitive dysfunction in HAND. In this regard, we identified through a subtractive hybridization strategy osteopontin (OPN, SPP1, gene) an inflammatory marker, as an upregulated gene in HIV-infected primary human monocyte-derived macrophages. Knockdown of OPN in primary macrophages resulted in a threefold decrease in HIV-1 replication. Ectopic expression of OPN in the TZM-bl cell line significantly enhanced HIV infectivity and replication. A significant increase in the degradation of the NF-kappaB inhibitor, IkappaBalpha and an increase in the nuclear-to-cytoplasmic ratio of NF-kappaB were found in HIV-infected cells expressing OPN compared to controls. Moreover, mutation of the NF-kappaB binding domain in the HIV-LTR abrogated enhanced promoter activity stimulated by OPN. Interestingly, compared to cerebrospinal fluid from normal and multiple sclerosis controls, OPN levels were significantly higher in HIV-infected individuals both with and without neurocognitive disorder. OPN levels were highest in HIV-infected individuals with moderate to severe cognitive impairment. Moreover, OPN was significantly elevated in brain tissue from HIV-infected individuals with cognitive disorder versus those without impairment. Collectively, these data suggest that OPN stimulates HIV-1 replication and that high levels of OPN are present in the CNS compartment of HIV-infected individuals, reflecting ongoing inflammatory processes at this site despite anti-HIV therapy. PMID- 21556959 TI - Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. AB - To begin to unravel the complexity of HIV-associated changes in the brain, broader, multifaceted analyses of cerebrospinal fluid (CSF) are needed that examine a wide range of proteins reflecting different functions. To provide the first broad profiles of protein changes in the CSF of HIV-infected patients, we used antibody arrays to measure 120 cytokines, chemokines, growth factors, and other proteins. CSF from HIV-infected patients with a range of cognitive deficits was compared to CSF from uninfected, cognitively normal patients to begin to identify protein changes associated with HIV infection and neurological disease progression. Uninfected patients showed relatively consistent patterns of protein expression. Highly expressed proteins in CSF included monocyte chemotactic protein-1, tissue inhibitors of metalloproteases, granulocyte colony-stimulating factor, adiponectin, soluble tumor necrosis factor receptor-1, urokinase-type plasminogen activator receptor, and insulin-like growth factor binding protein-2. Inflammatory and anti-inflammatory cytokines were expressed at low levels. HIV infected patients showed increases in inflammatory proteins (interferon-gamma, tumor necrosis factor-alpha), anti-inflammatory proteins (IL-13), and chemokines but these correlated poorly with neurological status. The strongest correlation with increasing severity of neurological disease was a decline in growth factors, particularly, brain-derived neurotrophic factor and NT-3. These studies illustrate that HIV infection is associated with parallel changes in both inflammatory and neuroprotective proteins in the CSF. The inverse relationship between growth factors and neurological disease severity suggests that a loss of growth factor neuroprotection may contribute to the development of neural damage and may provide useful markers of disease progression. PMID- 21556960 TI - Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies. AB - Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted. PMID- 21556961 TI - A review of morphological characteristics relating to the production and reproduction of fat-tailed sheep breeds. AB - The purpose of this study is to survey the literature pertinent to some morphological traits which are related with the production and reproduction of fat-tailed sheep breeds. The fat-tailed breeds were identified according to Food and Agriculture Organization databases. Articles referring to all these sheep breeds were evaluated. The morphology of udders and their measurable variables were collected and described. The particularities of pelt and fleece features which are important from an economic point of view were summarized. Linear, planar, and spatial parameters of body, slaughter, and carcass factors were compared at various ages of breeding. Testicular dimensions and semen characteristics were recorded. Their relationships with productive and reproductive performance were discussed. The pattern of ovarian follicle development and the involution of the genital tract were assessed from the anatomical point of view in normal and untreated animals. The data presented here provide useful baseline information on the normal morphological aspects which are important in the animal production of these breeds. PMID- 21556962 TI - [Current therapy of non-melanoma skin cancer]. AB - Basal cell carcinoma, actinic keratosis as a carcinoma in situ and squamous cell carcinoma are classified as non-melanoma epithelial skin cancers. These forms of skin cancer are thought to be the most common cancers worldwide with rising incidences. In the past years new insights into the pathogenesis of non-melanoma skin cancers have been gained. Through knowledge of the pathologic pathways, new treatment options have become available. This review summarizes the recent advantages of treatment options of non-melanoma skin cancer. PMID- 21556966 TI - Substantial problems with measuring brain mitochondrial dysfunction in autism spectrum disorder using magnetic resonance spectroscopy. PMID- 21556967 TI - Autism Parenting Stress Index: initial psychometric evidence. AB - Data validating the Autism Parenting Stress Index (APSI) is presented for 274 children under age six. Cronbach's alpha was .827. As a measure of parenting stress specific to core and co-morbid symptoms of autism, the APSI is unique. It is intended for use by clinicians to identify areas where parents need support with parenting skills, and to assess the effect of intervention on parenting stress. Mean parenting stress in the autism group was four times that of the typical group and double that of the other developmental delay group [F(2,272) = 153; p < 001]. An exploratory factor analysis suggested three factors impacting parenting stress: one relating to core deficits, one to co-morbid behavioral symptoms, and one to co-morbid physical symptoms. PMID- 21556968 TI - Food variety as a predictor of nutritional status among children with autism. AB - The frequency of selective eating and nutritional deficiency was studied among 22 children with autism and an age matched typically developing control group. Children with autism ate fewer foods on average than typically developing children. (33.5 vs. 54.5 foods, P < .001) As compared to typical controls, children with autism had a higher average intake of magnesium, and lower average intake of protein, calcium, vitamin B12, and vitamin D. Selective eaters were significantly more likely than typical controls to be at risk for at least one serious nutrient deficiency (P < .001). PMID- 21556969 TI - Measures of cortical grey matter structure and development in children with autism spectrum disorder. AB - The current study examined group differences in cortical volume, surface area, and thickness with age, in a group of typically developing children and a group of children with ASD aged 6-15 years. Results showed evidence of age by group interactions, suggesting atypicalities in the relation between these measures and age in the ASD group. Additional vertex-based analyses of cortical thickness revealed that specific regions in the left inferior frontal gyrus (BA 44) and left precuneus showed thicker cortex for the ASD group at younger ages only. These data support the hypothesis of an abnormal developmental trajectory of the cortex in ASD, which could have profound effects on other aspects of neural development in children with ASD. PMID- 21556970 TI - The Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia and the Fibromyalgia Symptom Scale: reliability and validity. AB - The aim of this study was to investigate the reliability and the validity of the Japanese version of the 2010 American College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia (ACR 2010-J), and its quantification scale, the Fibromyalgia Symptom Scale (FS-J). In this study, we divided patients with chronic pain without psychiatric disorders other than depression into two groups according to the 1990 ACR Diagnostic Criteria for Fibromyalgia, a fibromyalgia group and a non-fibromyalgia group (rheumatoid arthritis, osteoarthritis, and gout). Patients in both groups were assessed using the ACR 2010-J and FS-J. Seventy-seven of 94 (82%) patients in the fibromyalgia group met the ACR 2010-J, whereas 9% (4/43) of the non-fibromyalgia group did so, with a sensitivity of 82%, specificity of 91%, positive predictive value of 95%, negative predictive value of 70%, and positive likelihood ratio of 8.8. Mean total scores on the FS-J significantly differentiated the fibromyalgia from the non-fibromyalgia group. The scale had high inter-rater reliability and high internal consistency. With a cutoff score of 10, the positive likelihood ratio was 10.1. Our findings indicate that the ACR 2010-J and FS-J have high reliability and validity, and are useful for assessing fibromyalgia in Japanese populations with chronic pain. As regards the positive likelihood ratio, that of the FS-J might be suitable as a positive test. PMID- 21556971 TI - GEANT4 simulation of the effects of Doppler energy broadening in Compton imaging. AB - A Monte Carlo approach was used to study the effects of Doppler energy broadening on Compton camera performance. The GEANT4 simulation toolkit was used to model the radiation transport and interactions with matter in a simulated Compton camera. The low energy electromagnetic physics model of GEANT4 incorporating Doppler broadening developed by Longo et al. was used in the simulations. The camera had a 9 * 9 cm scatterer and a 10 * 10 cm absorber with a scatterer to absorber separation of 5 cm. Modelling was done such that only the effects of Doppler broadening were taken into consideration and effects of scatterer and absorber thickness and pixelation were not taken into account, thus a 'perfect' Compton camera was assumed. Scatterer materials were either silicon or germanium and the absorber material was cadmium zinc telluride. Simulations were done for point sources 10 cm in front of the scatterer. The results of the simulations validated the use of the low energy model of GEANT4. As expected, Doppler broadening was found to degrade the Compton camera imaging resolution. For a 140.5 keV source the resulting full-width-at-half-maximum (FWHM) of the point source image without accounting for Doppler broadening and using a silicon scatterer was 0.58 mm. This degraded to 7.1 mm when Doppler broadening was introduced and degraded further to 12.3 mm when a germanium scatterer was used instead of silicon. But for a 511 keV source, the FWHM was better than for a 140 keV source. The FWHM improved to 2.4 mm for a silicon scatterer and 4.6 mm for a germanium scatterer. Our result for silicon at 140.5 keV is in very good agreement with that published by An et al. PMID- 21556972 TI - Hypotensive effect of the water extract of the leaves of Pseuderanthemum palatiferum. AB - The cardiovascular effects of the water extract from fresh leaves of P. palatiferum (PP) were evaluated in rats in both in vivo and in vitro models. The PP extract consisted of alkaloids, coumarins and sterols. The extract (5-25 mg/kg, I.V.) decreased both the mean arterial blood pressure and heart rate of normotensive and L: -N-(omega)-nitro-arginine methyl ester (L: -NAME)-induced hypertensive anesthetized rats. The extract caused relaxation of the norepinephrine-contracted endothelium-intact aorta ring (EC(50) = 81.0 MUg/mL). Functional removal of the endothelium attenuated the vasodilatation effect of the extract (EC(50) = 136.4 MUg/mL). Pretreatment with L: -NAME or atropine did not alter the vasodilation effect of the extract. Pre-incubation with atropine did not alter bradycardic effect of the extract on isolated rat atrium. The effects of isoproterenol on isolated atrium were attenuated by the extract (2.5-5 mg/mL). In conclusion, the water extract from fresh leaves of P. palatiferum possessed hypotensive and bradycardic effects. The vasorelaxant effect of the extract was dependent partly on the vascular endothelium but was not dependent on the synthesis of nitric oxide and did not act through activation of the muscarinic receptor. PMID- 21556973 TI - Anemia and community-acquired pneumococcal pneumonia. PMID- 21556974 TI - Optimal medical therapy, lifestyle intervention, and secondary prevention strategies for cardiovascular event reduction in ischemic heart disease. AB - Medical and lifestyle secondary prevention strategies are essential components for reducing cardiovascular risk, irrespective of whether revascularization is performed. In patients with coronary artery disease (CAD), recent clinical trials have further clarified the management of lipid optimization, renin-angiotensin aldosterone system inhibition, antiplatelet therapy, and diabetes. Still, many questions remain with regard to optimal secondary prevention strategies in patients with CAD. Despite the significant reductions in cardiovascular morbidity and mortality with secondary prevention therapies demonstrated in clinical trials, long-term adherence to these interventions remains relatively low, with reasons being multifactorial. One promising method to improve compliance is the use of trained nurses/case managers to routinely follow medications, and provide both lifestyle and behavioral counseling. Implementation of this strategy led to significant improvements in medication compliance and risk factor optimization, although these results require confirmation in a randomized clinical study. Given that poor compliance has been associated with worsening cardiovascular outcomes, effective CAD management should include strategies for improving patient adherence to therapies that have proven benefits. PMID- 21556975 TI - Extruded collagen fibres for tissue engineering applications: effect of crosslinking method on mechanical and biological properties. AB - Reconstituted collagen fibres are promising candidates for tendon and ligament tissue regeneration. The crosslinking procedure determines the fibres' mechanical properties, degradation rate, and cell-fibre interactions. We aimed to compare mechanical and biological properties of collagen fibres resulting from two different types of crosslinking chemistry based on 1-ethyl-3-(3 dimethyllaminopropyl)carbodiimide (EDC). Fibres were crosslinked with either EDC or with EDC and ethylene-glycol-diglycidyl-ether (EDC/EGDE). Single fibres were mechanically tested to failure and bundles of fibres were seeded with tendon fibroblasts (TFs) and cell attachment and proliferation were determined over 14 days in culture. Collagen type I and tenascin-C production were assessed by immunohistochemistry and dot-blotting. EDC chemistry resulted in fibres with average mechanical properties but the highest cell proliferation rate and matrix protein production. EDC/EGDE chemistry resulted in fibres with improved mechanical properties but with a lower biocompatibility profile. Both chemistries may provide useful structures for scaffolding regeneration of tendon and ligament tissue and will be evaluated for in vivo tendon regeneration in future experiments. PMID- 21556976 TI - In vivo evaluation of a novel dexamethasone-heparin-double-coated stent for inhibition of artery restenosis and thrombosis. AB - To evaluate the efficacy and safety of dexamethasone-heparin-double-coated stent (DHDCS) on inhibition of artery lumen reduction and neointimal hyperplasia in porcine model we carried out this study. Bare mental stents (BMS, n = 12), protein-coated stents (PCS, n = 12), heparin microballoon-coated stents (HMCS, n = 12), and DHDCS (n = 12), prepared by the spray drying method, were implanted into the selected internal iliac artery, external iliac artery, sacrococcygeal artery, and femoral artery of each of the selected pigs (n = 12), which were randomly divided into four groups on average. Thirty days and ninety days after the implantation, aorta angiography was performed on all the 12 mini-pigs to evaluate the artery lumen reduction. Subsequently, in order to analyze their histological appearance, the pigs were killed, and their arteries with the stents inside were taken out, embedded in plastic for hard histological section and hematoxylin-eosin (H.E.) staining, and examined by light microscopy and scanning electron microscopy (SEM). The artery lumen reduction and average neointimal hyperplasia in the group of DHDCS were significantly lesser than those in the other three groups of BMS, PCS, and HMCS. This study shows that DHDCS is capable of inhibiting the proliferation of intima and lumen area reduction of the target artery within stents, and effectively and safely reducing the incidence of regional thrombosis and restenosis for a short term. PMID- 21556977 TI - Antimicrobial activity of gentamicin palmitate against high concentrations of Staphylococcus aureus. AB - The reduction of implant related infections plays a pivotal role in orthopaedic surgery as an increasing number of people require implants (up to 200,000 per year in the United States (source: Joint Implant Surgery & Research Foundation 2010)). The aim of the current study is to prevent and thus decrease the number of bacterial infections. Both pre and post operative systemic antibiotic treatment and gentamicin containing bone cements (polymethylmethacrylate, PMMA) are commonly used strategies to overcome infections. In this study, the antimicrobial efficacy of gentamicin sulfate loaded bone cement was compared with titan discs coated with a new form of gentamicin, gentamicin palmitate. Adherence prevention, killing rates and killing kinetics were compared in an in vitro model, using Staphylococcus aureus (S. aureus), which together with Staphylococcus epidermidis (S. epidermidis) represents 60% of bacteria found responsible for hip implant infections (An and Friedman, 1996, J Hosp Infect 33(2):93-108). In our experiments gentamicin, which was applied as gentamicin palmitate on the surface of the implants, showed a high efficacy in eliminating bacteria. In contrast to gentamicin sulfate containing bone cements, gentamicin palmitate is released over a shorter period of time thus not inducing antibiotic resistance. Another benefit for clinical application is that it achieves high local levels of active ingredient which fight early infections and minimize toxic side effects. Furthermore, the short term hydrophobic effect of gentamicin palmitate can successfully impede biofilm formation. Thus, the use of self adhesive antibiotic fatty acid complexes like gentamicin palmitate represents a new option for the anti-infective coating of cementless titan implants. PMID- 21556978 TI - Silicate and borate glasses as composite fillers: a bioactivity and biocompatibility study. AB - Composites filled with a silicate glass (CSi) and a new borate glass (CB) were developed and compared in terms of their in vitro behaviour both in acellular and cellular media. Acellular tests were carried out in SBF and the composites were characterized by SEM-EDS, XRD and ICP. Biocompatibility studies were investigated by in vitro cell culture with MG-63 osteoblast-like and human bone marrow cells. The growth of spherical calcium phosphate aggregates was observed in acellular medium on all composite surfaces indicating that these materials became potentially bioactive. The biological assessment resulted in a dissimilar behavior of the composites. The CSi demonstrated an inductive effect on the proliferation of cells. The cells showed a normal morphology and high growth rate when compared to standard culture plates. Contrarily, inhibition of cell proliferation occurred in the CB probably due to its high degradation rate, leading to high B and Mg ionic concentration in the cell culture medium. PMID- 21556979 TI - Assessment of antimicrobial effect of Biosilicate(r) against anaerobic, microaerophilic and facultative anaerobic microorganisms. AB - This study assessed the antimicrobial activity of a new bioactive glass-ceramic (Biosilicate(r)) against anaerobic, microaerophilic, and facultative anaerobic microorganisms. Evaluation of the antimicrobial activity was carried out by three methods, namely agar diffusion, direct contact, and minimal inhibitory concentration (MIC). For the agar diffusion technique, bio glass-ceramic activity was observed against various microorganisms, with inhibition haloes ranging from 9.0 +/- 1.0 to 22.3 +/- 2.1 mm. For the direct contact technique, Biosilicate(r) displayed activity against all the microorganisms, except for S. aureus. In the first 10 min of contact between the microorganisms and Biosilicate(r), there was a drastic reduction in the number of viable cells. Confirming the latter results, MIC showed that the Biosilicate(r) inhibited the growth of microorganisms, with variations between <= 2.5 and 20 mg/ml. The lowest MIC values (7.5 to <= 2.5 mg/ml) were obtained for oral microorganisms. In conclusion, Biosilicate(r) exhibits a wide spectrum of antimicrobial properties, including anaerobic bacteria. PMID- 21556980 TI - Effects of thermal treatments on protein adsorption of Co-Cr-Mo ASTM-F75 alloys. AB - Post-manufacturing thermal treatments are commonly employed in the production of hip replacements to reduce shrinkage voids which can occur in cast components. Several studies have investigated the consequences of these treatments upon the alloy microstructure and tribological properties but none have determined if there are any biological ramifications. In this study the adsorption of proteins from foetal bovine serum (FBS) on three Co-Cr-Mo ASTM-F75 alloy samples with different metallurgical histories, has been studied as a function of protein concentration. Adsorption isotherms have been plotted using the surface concentration of nitrogen as a diagnostic of protein uptake as measured by X-ray photoelectron spectroscopy. The data was a good fit to the Langmuir adsorption isotherm up to the concentration at which critical protein saturation occurred. Differences in protein adsorption on each alloy have been observed. This suggests that development of the tissue/implant interface, although similar, may differ between as-cast (AC) and heat treated samples. PMID- 21556981 TI - Transverse mechanical properties of collagen fibers from nanoindentation. AB - The mechanical properties of collagenous tissues, such as tendon and ligaments, are of particular interest as they are found extensively in the human body. In the present study the transverse mechanical properties of collagen fibers are reported for the first time. The elastic modulus was found to be 63 +/- 4 MPa, while the viscosity was estimated to be 14 GPa <= eta <= 56 GPa s. Comparison with similar data in the literature, for bulk tendon and collagen fibrils, suggests that the apparent modulus of a network of interconnected building blocks is reduced as compared to the modulus of the individual building blocks; in particular E (tendon) < E (fiber) < E (fibril); this is due to the fact that as the scale of the microstructure increases (i) slippage and sliding between the respective building blocks (fibrils or fibers) increases, (ii) the volume fraction of the stiff collagen proteins decreases. PMID- 21556982 TI - The role of surgical treatment in orbital vascular anomalies. AB - BACKGROUND: The details of the surgical treatment of orbital vascular anomalies (OVAs) are not fully defined in the literature. METHODS: Two hundred forty-nine patients who underwent surgical treatment of OVAs at our institution between January 1995 and December 2005 were included in a consecutive-series study. Each patient's clinical data, technique details, and clinical outcomes were prospectively collected. The aesthetic results were analyzed according to clinical features and treatment by using the chi (2) association test or Fisher's exact test. RESULTS: Thirty-seven percent of the patients had OVAs involving the upper eyelid, 23% the lower lid, and 40% both eyelids. A complete resection was performed in 65.9% of the patients. A total of 379 surgeries were performed to achieve the final result. The majority of patients (98.3%) had no complaints about surgical scars. The majority of patients had no clinical treatment prior to the surgery. One or more clinical deformities were identified in association with the OVA. Those deformities included ptosis, scar sequelae due to ulceration/infection, eyelash or tarsal/ligament distortions, fibroadipose tissue residues, proptosis, or strabism. Bone deformities were present in 11.3% of the patients. A complete functional and aesthetic restoration was achieved in 66.6% of the patients. CONCLUSIONS: Outcomes with a significant relationship to not obtain complete functional and aesthetic restoration included involvement of both eyelids, upper-eyelid involvement, older age, bilateral involvement, diffuse facial pattern OVAs, and OVAs with dimensions greater than one third of the orbit dimension. PMID- 21556983 TI - Lid loading for treatment of paralytic lagophthalmos. AB - Lagophthalmos secondary to facial palsy is a most clinically important condition that requires effective and early treatment because prolonged corneal exposure may cause corneal lesions, ranging from corneal spots to corneal ulceration and finally blindness. Lid loading is the therapy used most commonly to treat the condition. This method was first described in 1950, modified in 1966, and popularized in 1974. Since its inception, only several reviews have referred to the technology, but they talked about only parts of this technology and did not provide information on the technology overall. This review discusses lid loading in detail. This method now often uses gold and platinum as the material for the implant and should be done as early as possible in those patients whose paralytic lagophthalmos has little chance of being reversed. This method has shown good clinical results and given patients a better perspective. Of course, this method has its intrinsic complications such as allergic reactions, extrusion, and migration. However, with modification of the implant and the surgical procedure, the complication rate has decreased. In conclusion, although lid loading cannot solve all the problems associated with the paralyzed eyelid, it is a simple, reversible, and effective way to treat paralytic lagophthalmos. PMID- 21556984 TI - Correction of severely inverted nipple with telescope method. AB - For female patients, an inverted nipple can result in functional problems, such as difficulty breast feeding, and emotional difficulties because of self consciousness about the condition. Numerous surgical techniques for inverted nipple correction have been proposed, but none of the methods provides a reliable outcome. Most methods involve releasing retractile ducts and fibrous bands and adding bulk at the base of nipple; however, these techniques can cause injury to normal lactiferous ducts and sensory dysfunction. Herein we describe a "telescope method," performed under local anesthesia, which consists of making a circumferential incision, pulling out the nipple, and tightening the nipple base. With this technique, most lactiferous ducts and parallel sensory nerves that travel through the nipple base are not injured, and the procedure is associated with a less visible scar and nipple deformity than other methods. We report on 23 nipples of 17 patients that were successfully treated with this method. There was no recurrence of nipple inversion or sensory disturbance in the follow-up period. This technique is a simple, safe, and reliable method for the correction of severely inverted nipples. PMID- 21556985 TI - Vaginismus: review of current concepts and treatment using botox injections, bupivacaine injections, and progressive dilation with the patient under anesthesia. AB - Vaginismus is a poorly understood condition affecting approximately 1-7% of females worldwide. This article aims to bring attention to this disorder and to review the use of Botox injections to treat these patients. Vaginismus, also known as vaginal penetration disorder, is an aversion to any form of vaginal penetration as a result of painful attempts and a fear of anticipated pain. It is involuntary and uncontrolled and functions much the same as any reflex to avoid injury. It is the most common reason for unconsummated marriages. The etiology is thought to be unknown. Numerous papers note a history of religious or strict sexual upbringing or aversion to penetration because of perceived pain and bleeding with first-time intercourse. Sexual molestation may be more prevalent in this group of patients. The Lamont classification is very helpful in stratifying these patients for treatment. Lamont grade 5 vaginismus is introduced. Vaginal Botox injections for the treatment of vaginismus has received increasing attention since the technique was first described in a 1997 case report. Plastic surgeons worldwide with their experience using Botox are well positioned to learn more about this relatively unknown entity and render treatment. PMID- 21556986 TI - Preliminary experience using oncoplastic techniques of reduction mammaplasty and intraoperative radiotherapy: report of 2 cases. AB - BACKGROUND: Since 2004 in the Department of Oncological Integrated Surgery at the National Institute for Cancer Research of Genoa, we have applied different techniques of reduction mammaplasty for a subgroup of 26 patients with medium- to large-sized and ptotic breasts who are candidates for conservative surgery. METHODS: In this series of patients, the choice between different techniques of breast reduction (superior or inferior pedicled or with free areola-nipple graft) depended only on cancer position. The chosen technique minimized reshaping and displacement of residual glandular flaps. In September 2009, the radiotherapists at the Institute began to apply intraoperative radiotherapy (IORT) to early breast cancer, and at the time of this report, more than 200 patients have been treated. RESULTS: This report describes two cases of reduction mammaplasty associated with this new and easily performed radiotherapy option (IORT) and discusses its advantages and cautions. CONCLUSIONS: Close collaboration between surgical oncologist, plastic surgeon, and radiotherapist is essential before and during surgery to obtain adequate tumor resection and good aesthetic results and to minimize postoperative complications. PMID- 21556987 TI - Correction of liposuction sequelae by autologous fat transplantation. AB - BACKGROUND: In many countries, liposuction is the most frequently performed aesthetic procedure. Although liposuction has been considered a safe surgical procedure, reports indicate that it can have significant sequelae. Irregularities ranging from "oversuctioning" to bumpy skin and asymmetries result from inadequate experience of the surgeon. METHODS: A total of 57 consecutive female patients were operated on from June 2005 to June 2007. The age distribution of the patients ranged from 22 to 53 years, with a mean of 34.2 years. All the patients that were included in the study had undergone from one to three liposuction procedures. Overall satisfaction with the body appearance after autologous fat transplantation for correction of postliposuction irregularities was rated on a scale of 1-5, where 1 is poor, 2 is fair, 3 is good, 4 is very good, and 5 is excellent. RESULTS: The total amount of clean adipose tissue transplanted varied from 14 to 120 ml. There were no cases of liponecrosis, which developed in the grafted area, and no liponecrotic lumps were palpated on postoperative evaluation on any operated cases. There were no cases of cellulitis at the donor or grafted area, no deep vein thrombosis, and no pulmonary embolism. There were nine cases that needed one additional session of fat grafting of 5-35 ml. Seven of those cases needed further fat grafting on the abdominal area and the remaining two needed further grafting of the infragluteal depressions. At 12 months, 68% reported that their appearance after autologous fat grafting was "very good" to "excellent" and 23% responded that their appearance was "good." Only 9% of patients thought their appearance was less than good. CONCLUSION: With the overall acceptance of aesthetic surgery increasing and the number of patients undergoing liposuction increasing, it is likely that plastic surgeons will see more patients requesting secondary contour surgery in the future. The key to successful autologous fat grafting is familiarity with the technique, recognizing its limitations, and understanding the goals of the patient. This study has shown that the patient satisfaction rate observed after autologous fat transplantation produces aesthetically acceptable results in correcting post liposuction deformities. PMID- 21556988 TI - Analysis of the strength of the abdominal fascia in different sutures used in abdominoplasties. AB - BACKGROUND: Protrusion of the abdominal wall secondary to abdominoplasty may occur in patients with weakness of the aponeurotic structures. The anterior layer of the rectus abdominis muscle consists of fibers that are transverse rather than vertical. Based on this anatomical feature, vertical sutures are suggested for the correction of diastasis recti, since they include a greater amount of fascial fibers and thus would be more resistant to tensile strength than horizontal ones. METHODS: The anterior layers of the rectus abdominis muscles of 15 fresh cadavers were dissected. Two vertical lines were marked on each side of the linea alba, corresponding to the site where plication is usually performed in abdominoplasties. Three abdominal levels were evaluated: the supraumbilical, umbilical, and infraumbilical levels. A simple suture was placed in the vertical direction in one group and in the horizontal direction in the other group, at each of the three levels previously described. These sutures were connected to a dynamometer, which was pulled medially toward the linea alba until rupture of the aponeurosis occurred. RESULTS: The mean strength required to rupture the aponeurotic structures in which the vertical sutures had been placed was greater than for the horizontal ones (p < 0.0001). CONCLUSION: The vertical suture of the rectus abdominis sheaths was stronger than the horizontal suture because of the more transversal arrangement of its aponeurotic fibers. Thus, routine use of the vertical suture in plications of the aponeurosis of the rectus abdominis muscles is suggested. PMID- 21556989 TI - Reply to: re "Single incision laparoscopic cholecystectomy: is it more than a challenge?" ((2010)24:68-71). PMID- 21556990 TI - Assessment of a simple, novel endoluminal method for gastrotomy closure in NOTES. AB - BACKGROUND: A reliable method for gastrotomy closure in NOTES will be essential for NOTES to become viable clinically. However, methods using existing and widely available endoscopic accessories have been ineffective. The objective of this study was to evaluate the feasibility and safety of a new simple method for gastric closure (retracted clip-assisted loop closure) that uses existing endoscopic accessories with minor modifications. METHODS: The retracted clip assisted loop closure technique involves deploying 3-4 Resolution((r)) clips (modified by attaching a 90-cm length of suture to the end of each clip) along the margin of the gastrotomy with one jaw on the serosal surface and the other jaw on the mucosal surface. The suture strings are threaded through an endoloop. Traction is then applied to the strings causing the gastric wall to tent. The endoloop is secured below the tip of the clips, completing a full-thickness gastrotomy closure. The main outcome measures were feasibility, efficacy, and safety of the new retracted clip-assisted loop closure technique for NOTES gastrotomy closure. RESULTS: An air-tight seal was achieved in 100% (n = 9) of stomachs. The mean leak pressure was 116.3 (+/-19.4) mmHg. CONCLUSIONS: The retracted clip-assisted loop closure technique can be used to perform NOTES gastrotomy closure by using existing endoscopic accessories with minor modifications. PMID- 21556991 TI - Preoperative symptoms of irritable bowel syndrome predict poor outcome after laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the accepted treatment for symptomatic cholelithiasis. This study examines the effect LC has on quality of life (QOL) and gastrointestinal (GI) symptoms and determines whether patients with symptoms of irritable bowel syndrome (IBS) gain the same benefit as those without. METHODS: A total of 158 patients who underwent LC for symptomatic gallstones were recruited to this prospective observational study. IBS Manning scores were calculated and QOL was measured using the Gastrointestinal Quality of Life Index (GIQLI) preoperatively, at 6 weeks, 3 months, and 2 years postoperatively. Linear regression analysis was used to identify preoperative symptoms that predict outcome. RESULTS: One hundred twelve patients had sufficient data sets for inclusion. Patient's GIQLI scores were calculated for the four time points in the study. The mean preoperative score was 88.8 +/- 1.3 (61.7% of 144, the highest score possible) and improved 6 weeks after surgery to 105.5 +/- 1.3 (p < 0.001). This improvement was maintained at 3 months, but at 2 years analysis showed regression toward the baseline of 7.6 +/- 2.3 (p = 0.003) points. There was a negative correlation of -5.2 +/- 1.29 (p < 0.001) points between each Manning symptom and QOL scores. The largest effect was seen in patients describing loose bowel movement with the onset of pain. Patients with this symptom had a -17.3 +/- 4.6 (p < 0.001) lower global QOL score. CONCLUSIONS: Patients with symptoms of IBS indicated by the Manning criteria show less improvement in quality of life after laparoscopic cholecystectomy for gallstones. PMID- 21556992 TI - Laparoscopic versus open sigmoid resection for diverticulitis: long-term results of a prospective, randomized trial. AB - BACKGROUND: Elective laparoscopic sigmoid resection for diverticulitis has proven short-term benefits, but little data are available from prospective randomized trials regarding long-term outcome, quality of life, and functional results. METHODS: Of 113 patients randomized to undergo laparoscopic (LAP) versus open (OP) sigmoid resection for diverticulitis, 105 (93%, LAP = 54, OP = 51) patients were examined and answered the Gastrointestinal Quality of Life Index (GIQLI) questionnaire, with a median follow-up of 30 (range, 9-63) months after surgery. RESULTS: Incisional hernias were detected in five (9.8%) patients in the OP group versus seven (12.9%) in the LAP group, P = 0.84). Overall satisfaction with the operation on a scale of 0 (very poor) to 10 (excellent) was 9 (range, 2-10) in the OP group versus 9 (range, 2-10) in the LAP group (P = 0.78). Median GIQLI score was 115 (range, 57-144) in the OP group versus 110 (range, 61-134) in the LAP group (P = 0.17). Overall satisfaction with the cosmetic aspect of the scar on a scale of 0 (very poor) to 10 (excellent) was 8 (range, 1-10) in the OP group versus 9 (range, 0-10) in the LAP group (P = 0.01). Finally, median hospital cost (including reoperations for hernias) was 11,606 (5,230-147,982) CHF in the LAP group versus 12,138 (6,098-39,786) CHF in the OP group (P = 0.47). CONCLUSIONS: Both open and laparoscopic approaches for sigmoid resection achieve good long term results in terms of gastrointestinal function, quality of life, and patients' satisfaction. Significant long-term benefits of laparoscopic surgery are restricted to cosmetic (ClinicalTrials.gov protocol #NCT00453830). PMID- 21556993 TI - Single-center experience of laparoscopic left pancreatic resection in 359 consecutive patients: changing the surgical paradigm of left pancreatic resection. AB - BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is increasingly performed for lesions of the body and tail of the pancreas. We analyzed the clinical characteristics of the largest series of patients to date who underwent LDP at a single center, as well as their outcomes, to reassess the surgical paradigm for left pancreatic resection. METHODS: We retrospectively reviewed the records of 359 patients who underwent LDP at Asan Medical Center, Seoul, Korea, for pancreatic neoplasms between March 2005 and December 2010. RESULTS: Of the 359 patients, 323 (90%) had benign or low-grade malignant neoplasms and 36 (10%) had malignancies. The most common diagnosis was intraductal papillary mucinous neoplasm (IPMN) in 72 patients (21.2%). There were 24 patients (6.7%) with pancreatic ductal adenocarcinoma (PDAC). We found that 178 patients (49.6%) underwent spleen-preserving LDP (SP-LDP): 150 (84.3%) by main splenic vessel preservation, and 28 (15.7%) supported by short gastric and gastroepiploic vessels (Warshaw technique). Postoperative complications occurred in 43 (12%) patients, including 25 (7%) with pancreatic fistula (ISGPF grade B, C), but there was no death. Median operative time was 195 (range, 78-480) min, and median postoperative hospital stay was 8 (range, 4-37) days. The proportion of patients with pancreatic lesions who underwent LDP increased from 8.6% in 2005 to 66.9% in 2010. Kaplan-Meier analysis showed that the 1- and 2-year overall survival rates in the 24 patients with PDAC were 85.2% each. CONCLUSIONS: LDP is feasible, safe, and effective for the treatment of benign and low-grade malignant lesions of the pancreas. The increased use of LDP for left-sided pancreatic lesions, including malignant lesions, represents a paradigm shift from open distal pancreatectomy. PMID- 21556994 TI - A natural orifice transrectal approach for oncologic resection of the rectosigmoid: an experimental study and comparison with conventional laparoscopy. AB - BACKGROUND: A transrectal (TR) approach for natural orifice translumenal endoscopic surgery (NOTES) makes sense for colorectal surgery because the colotomy can be incorporated into subsequent anastomosis. Because cancer is a primary indication for left-sided colon resection, oncologic standards will have to be met by a NOTES procedure. This study aimed to assess whether pure TR rectosigmoidectomy can be performed with strict adherence to oncologic principles compared with a conventional laparoscopically assisted approach (LAP). METHODS: Human male cadavers were allocated to either TR (n = 4) or LAP (n = 2). A simulated sigmoid lesion was created at 25 cm. Transrectal retrograde mobilization of the rectosigmoid was performed using conventional transanal endoscopic microsurgery (TEM) instrumentation. After ligation of the superior hemorrhoidal artery and further mobilization, the specimen was delivered transanally and divided extracorporeally. Using a circular stapler, NOTES colorectal anastomosis was performed. Lymph node yield, adequate resection margins, and operative time were compared with LAP. RESULTS: Transrectal retrograde rectosigmoid dissection was achieved in all attempts (4/4) and showed numbers of lymph nodes (median, 5; range, 3-6) similar to the LAP group (median, 4.5; range, 2-7). One pure TR approach failed to resect the lesion. Three TR procedures required additional mobilization via an abdominal approach to provide adequate margins. The mean length of TR specimens was 16 +/- 4 cm compared with 31 +/- 9 cm achieved by LAP (p < 0.01). The TR operative time was significantly longer (247 +/- 15 vs 110 +/- 14 min). CONCLUSION: Lymph node yield during TR rectosigmoidectomy was similar to that achieved by the LAP approach. However, conventional TEM instrumentation alone did not permit adequate colon mobilization. This indicates a need for flexible instrumentation or other technical solutions to perform true NOTES colectomies. PMID- 21556995 TI - Laparoscopic repair of intrathoracic liver herniation after traumatic rupture of the diaphragm. AB - Right diaphragmatic hernia after abdominal trauma is a rare injury. Most patients can be asymptomatic, and the diagnosis may be delayed for several years. The treatment of choice involves surgical repair via laparotomy. The authors treated a young patient with transdiaphragmatic herniation of the right hepatic lobe and delayed diagnosis using a laparoscopic approach and accomplished a successful complete repair. The 6-month radiologic follow-up assessment confirmed good results. PMID- 21556996 TI - Laparoscopic extended lateral pelvic node dissection following total mesorectal excision for advanced rectal cancer: initial clinical experience. AB - AIM: To evaluate the technical feasibility, safety, and oncological outcomes of laparoscopic extended lateral pelvic lymph node dissection (LPLD) following total mesorectal excision (TME) in patients with advanced low rectal cancer. STUDY DESIGN: A review of a prospectively collected database at Kyungpook National University Hospital from May 2003 to September 2009 revealed a series of 16 consecutive laparoscopic TME with LPLD patients with preoperative diagnosis of lateral node metastasis. Data regarding patient demographics, operating time, perioperative blood loss, surgical morbidity, lateral lymph node status, functional outcome, and mid-term oncologic result were analyzed. RESULTS: In all 16 patients, the procedures were completed without conversion to open surgery. During the study period, robot-assisted laparoscopic LPLD was performed in two patients. Mean operative time was 321.9 min (range 220-510 min). The mean number of lateral lymph nodes harvested was 9.1 (range 3-19), and a total of nine patients (56.2%) had lymph node metastases. Postoperative mortality and morbidity were 0 and 31.2%, respectively. Recovery after the procedure was rapid, and mean hospital stay was 9.9 days (range 7-14 days). With median follow-up of 38 months, among nine patients who were lateral pelvic node positive, one patient experienced pelvic side-wall local recurrence (11.2%). CONCLUSIONS: Laparoscopic TME with LPLD is safe and feasible, with the advantage of a minimally invasive approach. Prospective controlled study comparing laparoscopy and conventional open surgery with long-term follow-up evaluation is needed to confirm the authors' initial experience. PMID- 21556997 TI - Video: laparoscopic right hepatectomy and partial resection of the diaphragm for liver metastases. AB - BACKGROUND: Indications for minimally invasive major hepatectomies have been increasing as experience with these techniques grows. Invasion into the diaphragm is considered a contraindication to the laparoscopic approach. At their institution, the authors have begun approaching all tumors laparoscopically. This report presents the techniques necessary to perform right hepatectomy, partial diaphragm resection, and repair using totally laparoscopic techniques. METHODS: Five trocars are placed in a semilunar fashion approximately one handbreadth apart along a line one handbreadth below the right subcostal margin. The hepatic inflow is taken extraparenchymally before transection of the hepatic parenchyma in an anterior-to-posterior fashion. The hepatic inflow then is transected, and the involved portion of diaphragm is transected with ultrasonic shears. Next, the diaphragm is repaired primarily and buttressed with an absorbable material to decrease the incidence of recurrent diaphragmatic hernia. RESULTS: Laparoscopic treatment was attempted for ten patients and successfully completed for nine of these patients (90%). All 10 patients had secondary liver tumors. Three patients required concomitant partial diaphragm resection. The median estimated blood loss (EBL) was 500 ml (range, 300-3,000 ml). All margins were negative, and the average hospital stay was 8 days (range, 5-17 days). Two patients (20%) experienced complications, which consisted of biliary leaks, which were treated with percutaneous drainage. One of these patients underwent conversion to an open procedure due to an inferior vena cava injury. No mortality occurred at 30 or 90 days of follow-up evaluation. CONCLUSION: The minimally invasive approach to secondary tumors requiring right hepatectomy is feasible and safe even when there is diaphragmatic involvement. Larger series with long-term follow-up evaluation are needed to determine whether these short-term results translate into durable benefits. PMID- 21556998 TI - Video: two novel endoscopic esophageal lengthening and reconstruction techniques. AB - BACKGROUND: Esophageal reconstruction presents a significant clinical challenge in patients ranging from neonates with long-gap esophageal atresia to adults after esophageal resection. Both gastric and colonic replacement conduits carry significant morbidity. As emerging organ-sparring techniques become established for early stage esophageal tumors, less morbid reconstruction techniques are warranted. We present two novel endoscopic approaches for esophageal lengthening and reconstruction in a porcine model. METHODS: Two models of esophageal defects were created in pigs (30-35 kg) under general anesthesia and subsequently reconstructed with the novel techniques. The first model was a segmental defect of the esophagus created by thoracoscopically transecting the esophagus above the gastroesophageal (GE) junction. The first reconstruction technique involved bilateral submucosal endoscopic lengthening myotomies (BSELM) with a magnetic compression anastomosis (MAGNAMOSISTM). The second model was a wedge defect in the anterior esophagus created above the GE junction through a laparotomy. The second reconstruction technique involved an inverted mucosal-submucosal sleeve transposition graft (IMSTG) that crossed the esophageal gap and was secured in place with a self-expandable covered esophageal stent. RESULTS: Both techniques were feasible in the pig model. The BSELM approach lengthened the esophagus 1 cm for every 2 cm length of myotomy. The myotomy targeted only the inner circular fibers of the esophagus, with preservation of the longitudinal layer to protect against long-term dilation and pouching. The IMSTG approach generated a vascularized mucosal graft almost as long as the esophagus itself. CONCLUSIONS: Emerging endoscopic capabilities are enabling complex endoluminal esophageal procedures. BSELM and IMSTG are two novel and technically feasible approaches to esophageal lengthening and reconstruction. Further survival studies are needed to establish the safety and efficacy of these techniques. PMID- 21556999 TI - Video: temporary gastric electrical stimulation for gastroparesis: endoscopic placement of electrodes (ENDOstim). AB - BACKGROUND: Studies have shown high-frequency, low-energy gastric electrical stimulation (GES) to be an effective management strategy for patients with medication refractory gastroparesis. However, placement of a permanent GES device requires surgery and has considerable cost considerations. More importantly, however, this mode of therapy may not be successful for all patients. Patients likely to benefit from such an invasive and expensive procedure could be selected on the basis of their response to temporary GES. Electrodes for the purpose of temporary GES usually are placed percutaneously or through a percutaneous endoscopic gastrostomy (PEG) tube (PEGStim). This study demonstrated an easier and less cumbersome placement of these electrodes endoscopically [1-3]. METHODS: The current case involved a 32-year-old man with diabetic gastroparesis. The endoscopic methods and protocol were approved by the Institutional Review Board at the University of Mississippi, Jackson, Mississippi. Informed consent was obtained before the procedure. Standard upper endoscopy was performed initially. A temporary cardiac pacing lead (Model 6414-200; Medtronic, Minneapolis, MN, USA) was used as the electrode. The video demonstrates an innovative technique of endoscopic placement of electrodes for temporary GES. The external stimulation device used was the standard GES device (Enterra; Medtronic). RESULTS: Temporary GES produced a rapid and marked improvement in the patient's intractable symptoms, improvement in his health-related quality-of-life score, electrogastrography parameters, and gastric emptying. Although the temporary electrodes could have been removed easily by gentle traction in a counterclockwise direction, the patient desired that the electrodes be left in place until permanent electrode placement. CONCLUSION: For patients such as the man in the current case, who do not have a preexisting PEG tube, the authors demonstrated that endoscopic placement of electrodes is technically feasible. The reported patient likely will benefit from surgical placement of a permanent GES device. Thus, the authors propose ENDOStim as the preferred method for placement of electrodes for temporary GES. PMID- 21557000 TI - Sentinel lymph node and prognostic factors in gastric cancer. PMID- 21557001 TI - Overweight and its impact on the health-related quality of life in children and adolescents: results from the European KIDSCREEN survey. AB - PURPOSE: To analyse the impact of overweight on HRQoL in a European sample of children and adolescents. METHODS: Analyses were conducted using data on 17,159 children and adolescents aged 8-18 from 10 European countries (Germany, Spain, France, Netherlands, Austria, United Kingdom, Switzerland, Hungary, Czech Republic and Poland) participating in the KIDSCREEN Health Interview Survey. In the studied sample (N = 13,041), there were slightly more girls (52.6%) than boys (47.4%). Gender- and age-specific cut-offs of Cole et al. (BMJ 320:1240, 2000) were used to define overweight and obesity. The two groups were collapsed into one 'overweight' category. HRQoL was assessed on 10 dimensions using the KIDSCREEN-52. Univariate analysis of covariance (ANCOVA) was performed for group comparisons (normal weight vs. overweight). Partial eta squared (eta (p) (2) ) was used as a measure of effect strength. RESULTS: Overall, 14.2% (N = 1,849) of the sample was overweight, with prevalence rates ranging between 9.4% in France and 17.6% in Spain. Across all countries, overweight children and adolescents had lower mean HRQoL scores than normal weight children and adolescents. The strongest HRQoL impairments emerged on the physical well-being (eta (p) (2) = 0.012) and self-perception dimensions (eta (p) (2) = 0.021), both P < 0.001. CONCLUSIONS: This is one of the first studies comparing the impact of HRQoL at European level using a generic and internationally valid HRQoL instrument, and the results show that, irrespective of national background, overweight children and adolescents are significantly impaired on their HRQoL, in particular on the physical well-being and the self-perception domain. PMID- 21557002 TI - Adults' and children's monitoring of story events in the service of comprehension. AB - When reading narratives, adults monitor shifts in time, space, characters, goals, and causation. Shifts in any of these dimensions affect both moment-by-moment reading and memory organization. The extant developmental literature suggests that middle school children have relatively sophisticated understandings of each of these dimensions but does not indicate whether they spontaneously monitor these dimensions during reading experiences. In four experiments, we examined the processing of event shifts by adults and children, using both an explicit verb clustering task and a reading time task. The results indicate that middle school children's and adults' post-reading memory is organized using these dimensions but that children do not monitor dimensions during moment-by-moment reading in the same manner as adults. These differences were not a function of differentially difficult texts for children and adults, or between-group differences. The findings have implications for models of adult and child text processing and for understanding children's developing narrative comprehension. PMID- 21557003 TI - Effects of aging on interference control in selective attention and working memory. AB - Working memory decay in advanced age has been attributed to a concurrent decrease in the ability to control interference. The present study contrasted a form of interference control in selective attention that acts upon the perception of external stimuli (access) with another form that operates on internal representations in working memory (deletion), in order to determine both of their effects on working memory efficiency in younger and older adults. Additionally, we compared memory performance under these access and deletion functions to performance in their respective control conditions. The results indicated that memory accuracy improved in both age groups from the access functions, but that only young adults benefited from the deletion functions. In addition, intrusion effects in the deletion condition were larger in older than in younger adults. The ability to control the irrelevant perception- and memory-elicited interference did not decline in general with advancing age; rather, the control mechanisms that operate on internal memory representations declined specifically. PMID- 21557004 TI - Lack of color integration in visual short-term memory binding. AB - Bicolored objects are retained in visual short-term memory (VSTM) less efficiently than unicolored objects. This is unlike shape-color combinations, whose retention in VSTM does not differ from that observed for shapes only. It is debated whether this is due to a lack of color integration and whether this may reflect the function of separate memory mechanisms. Participants judged whether the colors of bicolored objects (each with an external and an internalcolor) were the same or different across two consecutive screens. Colors had to be remembered either individually or in combination. In Experiment 1, external colors in the combined colors condition were remembered better than the internal colors, and performance for both was worse than that in the individual colors condition. The lack of color integration observed in Experiment 1 was further supported by a reduced capacity of VSTM to retain color combinations, relative to individual colors (Experiment 2). An additional account was found in Experiment 3, which showed spared color-color binding in the presence of impaired shape-color binding in a brain-damaged patient, thus suggesting that these two memory mechanisms are different. PMID- 21557005 TI - Prospective memory and aging: preserved spontaneous retrieval, but impaired deactivation, in older adults. AB - Prospective remembering is partially supported by cue-driven spontaneous retrieval processes. We investigated spontaneous retrieval processes in younger and older adults by presenting prospective memory target cues during a lexical decision task following instructions that the prospective memory task was finished. Spontaneous retrieval was inferred from slowed lexical decision responses to target cues (i.e., intention interference). When the intention was finished, younger adults efficiently deactivated their intention, but the older adults continued to retrieve their intentions. Levels of inhibitory functioning were negatively associated with intention interference in the older adult group, but not in the younger adult group. These results indicate that normal aging might not compromise spontaneous retrieval processes but that the ability to deactivate completed intentions is impaired. PMID- 21557006 TI - Entropy, semantic relatedness and proximity. AB - Although word co-occurrences within a document have been demonstrated to be semantically useful, word interactions over a local range have been largely neglected by psychologists due to practical challenges. Shannon's (Bell Systems Technical Journal, 27, 379-423, 623-665, 1948) conceptualization of information theory suggests that these interactions should be useful for understanding communication. Computational advances make an examination of local word-word interactions possible for a large text corpus. We used Brants and Franz's (2006) dataset to generate conditional probabilities for 62,474 word pairs and entropy calculations for 9,917 words in Nelson, McEvoy, and Schreiber's (Behavior Research Methods, Instruments, & Computers, 36, 402-407, 2004) free association norms. Semantic associativity correlated moderately with the probabilities and was stronger when the two words were not adjacent. The number of semantic associates for a word and the entropy of a word were also correlated. Finally, language entropy decreases from 11 bits for single words to 6 bits per word for four-word sequences. The probabilities and entropies discussed here are included in the supplemental materials for the article. PMID- 21557007 TI - Mantra: an open method for object and movement tracking. AB - Mantra is a free and open-source software package for object tracking. It is specifically designed to be used as a tool for response collection in psychological experiments and requires only a computer and a camera (a webcam is sufficient). Mantra is compatible with widely used software for creating psychological experiments. In Experiments 1 and 2, we validated the spatial and temporal precision of Mantra in realistic experimental settings. In Experiments 3 and 4, we validated the spatial precision and accuracy of Mantra more rigorously by tracking a computer controlled physical stimulus and stimuli presented on a computer screen. PMID- 21557008 TI - A method for quantifying focused versus overview behavior in AOI sequences. AB - We present a new measure for evaluating focused versus overview eye movement behavior in a stimulus divided by areas of interest. The measure can be used for overall data, as well as data over time. Using data from an ongoing project with mathematical problem solving, we describe how to calculate the measure and how to carry out a statistical evaluation of the results. PMID- 21557009 TI - The nature of orthographic-phonological and orthographic-semantic relationships for Japanese kana and kanji words. AB - It is generally assumed that orthographic-phonological (O-P) consistencies are higher for Japanese kana words than for kanji words and that orthographic semantic (O-S) consistencies are higher for kanji words than for kana words. In order to examine the validity of these assumptions, we attempted to measure the O P and O-S consistencies for 339 kana words and 775 kanji words. Orthographic neighbors were first generated for each of these words. In order to measure the O P consistencies of the words, their neighbors were then classified as phonological friends or enemies, based on whether the characters shared with the original word were pronounced the same in the two words. In order to measure the O-S consistencies, the similarity in meaning of each of the neighbors to the original word was rated on a 7-point scale. Based on the ratings, the neighbors were classified as semantic friends or enemies. The results indicated that both the O-P consistencies for kanji words and the O-S consistencies for kana words were greater than previously assumed and that the two scripts were actually quite similar on both types of consistency measures. The implications for the nature of the reading processes for kana and kanji words are discussed. PMID- 21557010 TI - Personalized cancer approach: using RNA interference technology. AB - Normal cellular survival is dependent on the cooperative expression of genes' signaling through a broad array of DNA patterns. Cancer, however, has an Achilles' heel. Its altered cellular survival is dependent on a limited subset of signals through mutated DNA, possibly as few as three. Identification and control of these signals through the use of RNA interference (RNAi) technology may provide a unique clinical opportunity for the management of cancer that employs genomic-proteomic profiling to provide a molecular characterization of the cancer, leading to targeted therapy customized to an individual cancer signal. Such an approach has been described as "personalized therapy." The present review identifies unique developing technology that employs RNAi as a method to target, and therefore block, signaling from mutated DNA and describes a clinical pathway toward its development in cancer therapy. PMID- 21557011 TI - Glycogen synthase kinase 3 beta positively regulates Notch signaling in vascular smooth muscle cells: role in cell proliferation and survival. AB - The role of glycogen synthase kinase 3 beta (GSK-3beta) in modulating Notch control of vascular smooth muscle cell (vSMC) growth (proliferation and apoptosis) was examined in vitro under varying conditions of cyclic strain and validated in vivo following changes in medial tension and stress. Modulation of GSK-3beta in vSMC following ectopic expression of constitutively active GSK 3beta, siRNA knockdown and pharmacological inhibition with SB-216763 demonstrated that GSK-3beta positively regulates Notch intracellular domain expression, CBF 1/RBP-Jkappa transactivation and downstream target gene mRNA levels, while concomitantly promoting vSMC proliferation and inhibiting apoptosis. In contrast, inhibition of GSK-3beta attenuated Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to cyclic strain environments in vitro using both a FlexercellTM Tension system and a novel SylgardTM phantom vessel following bare metal stent implantation revealed that cyclic strain inhibits GSK-3beta activity independent of p42/p44 MAPK and p38 activation concomitant with reduced Notch signaling and decreased vSMC proliferation and survival. Exposure of vSMC to changes in medial strain microenvironments in vivo following carotid artery ligation revealed that enhanced GSK-3beta activity was predominantly localized to medial and neointimal vSMC concomitant with increased Notch signaling, proliferating nuclear antigen and decreased Bax expression, respectively, as vascular remodeling progressed. GSK-3beta is an important modulator of Notch signaling leading to altered vSMC cell growth where low strain/tension microenvironments prevail. PMID- 21557012 TI - Intra-abdominal pressure and abdominal perfusion pressure: which is a better marker of severity in patients with severe acute pancreatitis. AB - BACKGROUND: Intra-abdominal hypertension is common in patients with severe acute pancreatitis. The aim of this study was to assess the clinical relevance of intra abdominal pressure and abdominal perfusion pressure in the first 72 h after admission during severe acute pancreatitis. METHODS: From January 2009 to February 2011, 50 patients admitted for severe acute pancreatitis were included in this prospective, observational study. The intra-abdominal pressure and abdominal perfusion pressure level were repeatedly measured every 12 h during the first 72 h. The maximum and the mean values of intra-abdominal pressure and the minimum and mean values of abdominal perfusion pressure were used for analysis. RESULTS: Both the maximum and mean levels of intra-abdominal pressure were significantly different between patients with or without kinds of clinical variables. But for abdominal perfusion pressure, difference could only be detected in terms of need of vasoactive drugs. Besides that, different from abdominal perfusion pressure, intra-abdominal pressure is associated with high incidence rates of MODS and secondary infection. CONCLUSION: Compared with abdominal perfusion pressure, intra-abdominal pressure is much more valuable as an early marker of the evolution and complications of severe acute pancreatitis. PMID- 21557013 TI - Improvement in insulin sensitivity and beta-cell function following ileal interposition with sleeve gastrectomy in type 2 diabetic patients: potential mechanisms. AB - INTRODUCTION: Bariatric surgery in morbidly obese type 2 diabetic (T2DM) patients is associated with high rates of diabetes remission. We investigated the mechanisms of the anti-diabetic effect of the laparoscopic ileal interposition with sleeve gastrectomy (LII-SG) in normal weight (NW), overweight (OW) and obese (OB) T2DM patients. METHODS: Ninety-four patients (aged 54 +/- 8 years) with long standing (median 10 years), treated diabetes (median HbA(1c) = 8.6%), who were NW (15), OW (64) or OB (15) based on BMI, underwent LII-SG. Insulin sensitivity and parameters of beta-cell function were measured from an Oral Glycaemic Tolerance Test pre- and post-operatively. RESULTS: At a median of 13.4 months post operatively, weight loss averaged 9.4 +/- 1.3, 16.8 +/- 0.8 and 23.2 +/- 1.7 kg in NW, OW and OB subjects, respectively (p < 0.0001). Insulin sensitivity was fully restored (395 [108] vs 208 [99] ml min-1 m-2), fasting insulin secretion rate decreased (68 [52] vs 146 [120] pmol min-1 m-2) and total insulin output increased (52 [26] vs 39 [28] nmol m-2, all p <= 0.001). beta-cell glucose sensitivity doubled (37 [33] vs 18 [24] mol min-1 m-2 mM-1, p < 0.0001). The only parameter predicting remission of diabetes was a lower baseline insulin sensitivity (p = 0.005). CONCLUSIONS: LII-SG induced changes on T2DM by mechanisms in part distinct from weight loss, principally involving restoration of insulin sensitivity and improvement of beta-cell function. PMID- 21557014 TI - A meta-analysis of the short- and long-term results of randomized controlled trials that compared laparoscopy-assisted and conventional open surgery for rectal cancer. AB - PURPOSE: We conducted a meta-analysis to evaluate and compare the short- and long term results of laparoscopy-assisted and open rectal surgery for the treatment of patients with rectal cancer. METHODS: We searched MEDLINE, EMBASE, Science Citation Index, and the Cochrane Controlled Trial Register for relevant papers published between January 1990 and April 2011 by using the search terms "laparoscopy," "laparoscopy assisted," "surgery," "rectal cancer," and "randomized controlled trials." We analyzed outcomes over short- and long-term periods. RESULTS: We identified 12 papers reporting results from randomized controlled trials that compared laparoscopic surgery with open surgery for rectal cancer. Our meta-analysis included 2,095 patients with rectal cancer; 1,096 had undergone laparoscopic surgery, and 999 had undergone open surgery. In the short term period, 13 outcome variables were examined. In the long-term period, eight oncologic variables, as well as late morbidity, urinary function, and sexual function were analyzed. Laparoscopic surgery for rectal cancer was associated with a reduction in intraoperative blood loss and the number of transfused patients, earlier resumption of oral intake, and a shorter duration of hospital stay over the short-term, but with similar short-term and long-term oncologic outcomes compared to conventional open surgery. CONCLUSIONS: Laparoscopic surgery may be an acceptable alternative treatment option to conventional open surgery for rectal cancer. PMID- 21557015 TI - Diagnosis and management of anastomotic leaks after esophagectomy. AB - INTRODUCTION: Complications following esophagectomy significantly affect outcomes, including perioperative mortality, costs, and survival. Anastomotic leak remains one of the most serious complications, and early recognition and appropriate initial treatment are essential. METHODS: Mortality associated with esophageal leaks is decreasing, due in part to the increased use of CT scans and endoscopy for diagnosis. Endoscopic and interventional radiology techniques are being increasingly applied, but appropriate patient selection is important. Removable esophageal stents can be utilized successfully in a significant proportion of patients with limited anastomotic defects. RESULTS AND CONCLUSION: It is critically important to differentiate between leaks and conduit necrosis. Endoscopic examination is the best method for making this assessment. Surgeons should become familiar with the expanding options for endoscopic assessment and treatment of esophageal anastomotic leaks. PMID- 21557016 TI - A comparison of pre-operative comorbidities and post-operative outcomes among patients undergoing laparoscopic nissen fundoplication at high- and low-volume centers. AB - INTRODUCTION: Commonly cited data promoting laparoscopic Nissen fundoplication (LNF) as safe and efficacious are typically published by single centers, affiliated with teaching institutions with a high volume of cases, but LNF is not universally performed at these hospitals. The purpose of this study is to assess where these procedures are being done and to compare pre-operative comorbidities and post-operative outcomes between high-and low-volume centers using a state wide inpatient database. METHODS: This is a retrospective study using data from the North Carolina Hospital Association Patient Data System. Selected patients include adults (>17 years old) that have undergone laparoscopic Nissen fundoplication for gastroesophageal reflux disease as an inpatient from 2005 to 2008. Patients that underwent operative management for emergent purposes or had associated diagnoses of esophageal cancer or achalasia were excluded from the study. High-volume centers were defined as institutions that performed ten or more LNFs per year averaged over a period of 4 years. Comparative statistics were performed on comorbidities and complications between high- and low-volume centers. RESULTS: A total of 1,019 patients underwent LNF for GERD in North Carolina between 2005 and 2008 in the inpatient setting. High-volume centers performed 530 LNFs (52%) while low-volume centers performed 489 LNFs (48%). Patients at high-volume centers were older (median 52.5 years old vs. 49.0 years old, p = 0.019), had a higher incidence of diabetes (13.4% vs. 8.8%, p = 0.026), chronic obstructive pulmonary disease (5.1% vs. 2.0 %, p = 0.015), hyperlipidemia (9.6% vs. 4.7%, p = 0.004), and cystic fibrosis (2.8% vs. 0.8%, p = 0.03). Patients with a history of transplantation were also more likely to undergo LNF at a high-volume center (15.8% vs. 1.6%, p < 0.0001). There were no deaths among the two groups and also no difference between median length of stay (2.7 days for high-volume center vs. 2.6 days for low-volume center). Low-volume centers had a higher incidence of intraoperative accidental puncture or laceration (3.3% vs. 0.9%, p = 0.017) while high-volume centers had a higher incidence of atelectasis (5.3% vs. 2.5%, p = 0.031). CONCLUSION: A significant proportion of the LNFs in North Carolina are performed at low-volume centers. High-volume centers perform LNF on older patients with more comorbidities. Low-volume centers have three times more accidental perforations, yet there is no detectable difference in mortality or median length of stay. It is impossible to tell if these perforations are managed at these low-volume centers or transferred to facilities with a higher level of care. These findings argue for regionalization of LNF and for a reevaluation of the global safety of this operation. PMID- 21557017 TI - Three-step esophagojejunal anastomosis with atraumatic anvil insertion technique after laparoscopic total gastrectomy. AB - BACKGROUND: Esophagojejunostomy during laparoscopic total gastrectomy (LATG) using a circular stapler is a difficult procedure for which there remains no widely accepted standard technique. Based upon our experience with esophagogastrostomy during laparoscopic proximal gastrectomy, we have applied a modified lift-up method to LATG. MATERIAL AND METHODS: Esophagojejunostomy using a modified lift-up method was performed during LATG in 41 patients with early gastric cancer, from July 2005 to June 2010. The lift-up technique comprises three steps, which together reduce the difficulty of anvil insertion by lifting up the nasogastric tube connected to the anvil head. RESULTS: During the early stages of the present study, some patients who underwent LATG with the modified lift-up method developed anastomotic leakage, with stenosis occurring in two cases (4.9%) and three cases (7.3%), respectively. All patients who developed complications showed improvement following conservative treatment with no surgical procedure. The anastomotic leaks occurred during the later periods of the study. There was no mortality in the present study. CONCLUSIONS: Our modified lift-up technique facilitates circular-stapled esophagojejunostomy in LATG and could provide a more feasible and safe option for an established procedure, especially for preventing anastomotic leak. PMID- 21557018 TI - Mesenteric Castleman's disease in a 12-year-old girl. AB - INTRODUCTION: Castleman's disease is a rare disorder characterized by proliferation of the lymphoid tissue usually presenting as an asymptomatic mediastinal mass in children. The location of the disease in the mesentery is rare. DISCUSSION: We report a case of a 12-year-old girl with an isolated mass of mesenteric root presenting with vague abdominal pain. The surgical resection of the mass revealed the hyaline-vascular type of Castleman's disease. The patient had an uneventful postoperative course. PMID- 21557019 TI - Characteristics of perforated appendicitis: effect of delay is confounded by age and gender. AB - INTRODUCTION: The effect of age and gender on time to perforation in acute appendicitis has not been well characterized. This study examined the relationship between duration of disease and appendiceal perforation in different subgroups of age and gender. METHODS: This study is a retrospective analysis of 380 patients who underwent an appendectomy from January 2000 to June 2005 at a rural teaching hospital. RESULTS: Factors associated with perforated appendicitis included age, symptom duration, CT scan, and distance from the hospital. Factors associated with increased patient time included age, temperature >101.5 F, and referral from an outside institution. Factors associated with shorter system time included right lower quadrant tenderness, classic or severe presentation, and leading diagnosis of acute appendicitis. Preoperative CT scan increased system time by approximately 3 h. Analyzing symptom duration and time to perforation, males have a higher prevalence of perforated appendicitis compared to females with similar duration of symptoms. In patients older than 55 years of age, 29% had perforated appendicitis at 36 h of symptoms and 67% at 36 to 48 h of symptoms. In a multivariate regression analysis, age greater than 55 years (odds ratio (OR) 3.0, P value 0.007), fever (OR 4.3, P 0.007), and symptom duration more than 24 h (OR 4.1, P 0.001) were significant predictors of perforated appendicitis. CONCLUSIONS: There is an early risk of perforated appendicitis even within the first 36 h of symptoms. This risk appears to be higher in males and patients older than 55 years, a quarter of whom are perforated within the first 36 h of symptom duration. Additionally, perforation in acute appendicitis may be more of a continuous phenomena worsening exponentially with duration of symptoms rather than a threshold phenomenon. PMID- 21557020 TI - Appropriate treatment strategy for intrahepatic recurrence after curative hepatectomy for hepatocellular carcinoma. AB - INTRODUCTION: The aim of this study is to evaluate the appropriate treatment for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma (HCC). METHODS: Of 151 patients who underwent initial hepatectomy for HCC, 82 had intrahepatic recurrence and were divided into two groups: group A, <=2 tumors, each 3 cm in size; and group B, beyond the group A. Survival and treatment in each group were analyzed retrospectively to determine the best therapeutic modality for intrahepatic recurrence. RESULTS: The 5-year overall survival and recurrence rate were 65% and 58%, respectively. Overall 1-, 3-, and 5-year survival rates after recurrence were better in group A (100%, 76%, and 54%) than in group B (74%, 23%, and 5.8%; p < 0.001). The clinical backgrounds were not different for each modality. Of the 43 patients in group A, 10 underwent hepatectomy, 21 ablation therapy, and 12 transcatheter arterial chemoembolization (TACE). The survival rate of hepatectomy was similar to that of ablation therapy and significantly better than that of TACE (p = 0.0248). Of the 39 patients in group B, the results of TACE were similar to other therapies after recurrence. CONCLUSIONS: Repeat hepatectomy and ablation therapy were more effective than TACE in the group with <=2 tumors up to 3 cm in size at recurrence, while any treatment modality was more effective than best supportive care, but the outcome was poorer in the group with >=3 tumors or tumor size >=3 cm at recurrence. PMID- 21557021 TI - Use of intraoperative ablation as an adjunct to surgical resection in the treatment of recurrent colorectal liver metastases. AB - OBJECTIVE: To evaluate the role of intraoperative ablation as an adjunct to resection in patients with recurrent colorectal liver metastases (rCLM). METHODS: All patients undergoing curative-intent reoperative surgery for rCLM from 1992 to 2009 at a tertiary cancer center were included. Overall survival (OS) and recurrence-free survival (RFS) were compared between patients treated with resection alone or in combination with ablation. RESULTS: A total of 112 reoperative hepatectomies were performed, of which 16 were combined with ablation. The proportion of patients treated with resection and ablation increased from 0% to 41%. Patients undergoing resection and ablation had a greater tumor burden (median, 4 vs. 1, p < 0.0001) and higher baseline clinical risk scores (median, 3 vs. 2, p = 0.065) than patients undergoing resection alone. Patients undergoing resection and ablation had lower intraoperative blood loss than patients undergoing resection alone (344 vs. 877 ml, p = 0.018). Five year OS from the time of surgery was 48.6%. In multivariable analysis, there was no significant difference in OS or RFS based on the treatment modality. CONCLUSION: In patients with rCLM, the use of intraoperative ablation can extend the limits of surgical resection in patients with disease that might otherwise not be amenable to complete resection. PMID- 21557022 TI - [Contrast-enhanced sonography. Therapy control of radiofrequency ablation and transarterial chemoembolization of hepatocellular carcinoma]. AB - Due to the imaging of dynamic perfusion, hepatocellular carcinoma can be detected with a sensitivity of >90% using contrast-enhanced sonography. The characterization of liver tumors with contrast-enhanced sonography is comparable to the diagnostic accuracy of contrast-enhanced computed tomography. The dynamic detection of microvascularization with contrast-enhanced sonography allows the differentiation between vascularized tumors and non-vascularized necrotic lesions before, during and after transarterial chemoembolization or percutaneous radiofrequency ablation. Image fusion with volume navigation can be useful in the followup control. PMID- 21557023 TI - [Summary of technical principles of contrast sonography and future perspectives]. AB - Ultrasound contrast agents have considerably expanded the range of ultrasound diagnostics. Up to date ultrasound machines with contrast-specific software allow the selective demonstration and quantification of contrast agents in real-time based on the specific signal signature of oscillating contrast agent microbubbles. After intravenous injection the microbubbles are transported with the bloodstream and distributed purely intravascularly. This allows an artefact free representation of the vascular architecture and delineation of the vascular lumen, independent of blood flow velocity and with high spatial resolution. Traumatic lesions and active bleeding can be detected with high sensitivity. Blood volume in vessels and organs can be assessed qualitatively and quantitatively. The possibility of short-term destruction of microbubbles within the ultrasound field allows the measurement of blood flow velocity during replenishment and based on that the assessment of perfusion in parenchymal tissue. Target-specific microbubbles for imaging of molecular surface structures as well as drug-loaded microbubbles for local ultrasound-mediated therapy are under development. PMID- 21557024 TI - Clinical significance of serum autoantibodies in patients with NAFLD: results from the nonalcoholic steatohepatitis clinical research network. AB - PURPOSE: Some studies have suggested that autoantibodies might define a subcategory and phenotype of nonalcoholic fatty liver disease (NAFLD) associated with advanced histological features. We evaluated the relationship between the presence of serum autoantibodies and liver histology in a large cohort of well characterized patients with NAFLD. METHODS: A total of 864 NAFLD patients participating in two prospective multicentre clinical studies underwent testing for serum autoantibodies within 24 months of a liver biopsy. Liver histology was compared between the patients with and without ANA >= 1:160 or ASMA >= 1:40 or both. RESULTS: Autoantibodies were present in 182 patients (21%). There was no difference in age, gender, race, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), or history of diabetes between the two groups. Biopsies in subjects with autoantibodies were less likely to have moderate-to-severe steatosis (i.e., >33%) compared to controls (57.1 vs. 43.0%, P value = 0.0006). Lobular inflammation (46.7 vs. 47.5%), ballooning degeneration (38.5 vs. 42.5%), and advanced fibrosis (33.2 vs. 29.3%) were not different between the two groups. Histologic evidence of 'definite' NASH did not differ significantly between the two groups (55.5 vs. 58.9%). After adjusting for age, gender, BMI, race, and diabetes, the presence of autoantibodies was independently associated with lower prevalence of moderate-to-severe steatosis [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.41-0.82; P = 0.01]. CONCLUSION: Autoantibodies are frequently positive in NAFLD in the absence of autoimmune hepatitis and their occurrence is not associated with more advanced histologic features. PMID- 21557025 TI - Effects of chronic metal exposure on wild fish populations revealed by high throughput cDNA sequencing. AB - Given the inherent variability of aquatic systems, predicting the in situ effects of contaminants on such ecosystems still represents a major challenge for ecotoxicology. In this context, transcriptomic tools can help identify and investigate the mechanisms of toxicity beyond the traditional morphometric, physiological and population-level endpoints. In this study, we used the 454 sequencing technology to examine the in situ effects of chronic metal (Cd, Cu) exposure on the yellow perch (Perca flavescens) transcriptome. Total hepatic mRNA from fish sampled along a polymetallic gradient was extracted, reverse transcribed, labeled with unique barcode sequences and sequenced. This approach allowed us to identify correlations between the transcription level of single genes and the hepatic concentrations of individual metals; 71% of the correlations established were negative. Chronic metal exposure was thus associated with a decrease in the transcription levels of numerous genes involved in protein biosynthesis, in the immune system, and in lipid and energy metabolism. Our results suggest that this marked decrease could result from an impairment of bile acid metabolism by Cd and energy restriction but also from the recruitment of several genes involved in epigenetic modifications of histones and DNA that lead to gene silencing. PMID- 21557026 TI - The influence of number of syllables on word skipping during reading. AB - In an eye-tracking experiment, participants read sentences containing a monosyllabic (e.g., grain) or a disyllabic (e.g., cargo) five-letter word. Monosyllabic target words were skipped more often than disyllabic target words, indicating that syllabic structure was extracted from the parafovea early enough to influence the decision of saccade target selection. Fixation times on the target word when it was fixated did not show an influence of number of syllables, demonstrating that number of syllables differentially impacts skipping rates and fixation durations during reading. [corrected] PMID- 21557027 TI - Words can slow down category learning. AB - Words have been shown to influence many cognitive tasks, including category learning. Most demonstrations of these effects have focused on instances in which words facilitate performance. One possibility is that words augment representations, predicting an across the-board benefit of words during category learning. We propose that words shift attention to dimensions that have been historically predictive in similar contexts. Under this account, there should be cases in which words are detrimental to performance. The results from two experiments show that words impair learning of object categories under some conditions. Experiment 1 shows that words hurt performance when learning to categorize by texture. Experiment 2 shows that words also hurt when learning to categorize by brightness, leading to selectively attending to shape when both shape and hue could be used to correctly categorize stimuli. We suggest that both the positive and negative effects of words have developmental origins in the history of word usage while learning categories. [corrected] PMID- 21557028 TI - Adaptive memory: fitness relevant stimuli show a memory advantage in a game of pelmanism. AB - A pelmanism (matched-pairs) game was used in order to test the hypothesis that survival-relevant stimuli that are likely to have been present during human evolution (e.g., a snake in attack position) enjoy a memory advantage over other survival-relevant (but "modern") stimuli (e.g., a threatening image of a gunman). Survival-relevant stimuli were matched for arousal and presented in one of two 5 x 4 grids, along with filler items. Participants were asked to match the pairs in the grids by clicking on successive squares to reveal stimuli. Participants made significantly fewer errors when matching evolutionarily relevant survival stimuli than when matching the other stimuli. Additionally, on incorrect trials, the attempted matches were significantly closer to the actual locations of evolutionarily relevant targets than to those of other stimuli. The results suggest that objects that likely posed a consistent threat throughout human evolutionary history are better remembered than other, equally arousing and survival-relevant, stimuli. [corrected] PMID- 21557029 TI - Effect of glucocorticoids pretreatment on steroidogenic capacity of adrenocortical cells isolated from Meishan piglets. AB - The present in vitro experiment was designed to test whether 48 h of pretreatment with glucocorticoids, cortisol, or dexamethasone (DEX), would affect basal and corticotrophin (ACTH) stimulated (24 h) cortisol secretion from primary cultures of pig adrenocortical cells. Cells were divided into six groups: control pretreatment with or without ACTH challenge, cortisol pretreatment with or without ACTH challenge, and DEX pretreatment with or without ACTH. The culture medium and cells were collected at the end of treatment. Cortisol concentration in medium was measured by radioimmunoassay, and protein content of glucocorticoid receptor (GR) and key regulatory factors for steroidogenesis, including melanocortin type 2 receptor (MC2R), steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage cytochrome P450 (P450scc), were detected by Western blot analysis. The results showed that glucocorticoid pretreatment did not affect cortisol secretion under basal condition without ACTH challenge, but significantly enhanced ACTH-stimulated cortisol secretion. Furthermore, the protein content of GR, MC2R, StAR, and P450scc was all increased in groups pretreated with glucocorticoids. These results indicate that adrenocortical cells pretreated with glucocorticoids display higher steroidogenic capacity under ACTH challenge, through the upregulation of GR and other steroidogenic regulatory factors. PMID- 21557030 TI - Assessment of coronary artery calcium using dual-energy subtraction digital radiography. AB - Cardiovascular disease is the leading cause of global mortality, yet its early detection remains a vexing problem of modern medicine. Although the computed tomography (CT) calcium score predicts cardiovascular risk, relatively high cost ($250-400) and radiation dose (1-3 mSv) limit its universal utility as a screening tool. Dual-energy digital subtraction radiography (DE; <$60, 0.07 mSv) enables detection of calcified structures with high sensitivity. In this pilot study, we examined DE radiography's ability to quantify coronary artery calcification (CAC). We identified 25 patients who underwent non-contrast CT and DE chest imaging performed within 12 months using documented CAC as the major inclusion criteria. A DE calcium score was developed based on pixel intensity multiplied by the area of the calcified plaque. DE scores were plotted against CT scores. Subsequently, a validation cohort of 14 additional patients was independently evaluated to confirm the accuracy and precision of CAC quantification, yielding a total of 39 subjects. Among all subjects (n = 39), the DE score demonstrated a correlation coefficient of 0.87 (p < 0.0001) when compared with the CT score. For the 13 patients with CT scores of <400, the correlation coefficient was -0.26. For the 26 patients with CT scores of >=400, the correlation coefficient yielded 0.86. This pilot study demonstrates the feasibility of DE radiography to identify patients at the highest cardiovascular risk. DE radiography's accuracy at lower scores remains unclear. Further evaluation of DE radiography as an inexpensive and low-radiation imaging tool to diagnose cardiovascular disease appears warranted. PMID- 21557031 TI - Association between quality of care and the sociodemographic composition of physicians' patient panels: a repeat cross-sectional analysis. AB - BACKGROUND: Pay-for-performance programs could worsen health disparities if providers who care for disadvantaged patients face systematic barriers to providing high-quality care. Risk adjustment that includes sociodemographic factors could mitigate the financial incentive to avoid disadvantaged patients. OBJECTIVE: To test for associations between quality of care and the composition of a physician's patient panel. DESIGN: Repeat cross-sectional analysis PARTICIPANTS: Nationally representative sample of US primary care physicians responding to a panel telephone survey in 2000-2001 and 2004-2005 MAIN MEASURES: Quality of primary care as measured by provision of eight recommended preventive services (diabetic monitoring [hemoglobin A1c testing, eye examinations, cholesterol testing and urine protein analysis], cancer screening [screening colonoscopy/sigmoidoscopy and mammography], and vaccinations against influenza and pneumococcus) documented in Medicare claims data and the association between quality and the sociodemographic composition of physicians' patient panels. KEY RESULTS: Across eight quality measures, physicians' quality of care was not consistently associated with the composition of their patient panel either in a single year or between time periods. For example, a substantial number (seven) of the eighteen significant associations seen between sociodemographic characteristics and the delivery of preventive services in the first time period were no longer seen in the second time period. Among sociodemographic characteristics, panel Medicaid eligibility was most consistently associated with differences in the delivery of preventive services between time points; among preventive services, the delivery of influenza vaccine was most likely to demonstrate disparities in both time points. CONCLUSIONS: In a Medicare pay-for performance program, a better understanding of the effect of effect of patient panel composition on physicians' quality of care may be necessary before implementing routine statistical adjustment, since the association of quality and sociodemographic composition is small and inconsistent. In addition, we observed improvements between time periods among physicians with varying panel composition. PMID- 21557032 TI - Rethinking "abnormal" blood pressure: what is the value? PMID- 21557033 TI - From the editors' desk: The July effect. PMID- 21557034 TI - Leadership in creating accountable care organizations. AB - General internists need to take an active leadership position in the creation of accountable care organizations (ACOs). The basic idea behind ACOs is relatively simple. Physicians, hospitals, and other health care providers will continue to be paid fee-for-service by the Medicare program, but if they can work together to better manage people with chronic conditions, reduce avoidable complications, reduce unnecessary specialty referrals, and improve transfer of beneficiaries as they transition from one care provider to another; then there is the possibility of shared savings with the Medicare program. ACOs are likely to alter existing referral patterns among general internists and specialty physicians and engender debates over how to allocate any financial savings. They are scheduled to begin operation on January 2012. As ACOs are established, general internists should review the operation of the care management and disease management programs. They should understand the financial arrangements and quality indicators that the ACOs establish. They should be involved in identifying the patients that would benefit from better care management. They should identify changes in care processes and payment reforms that would improve the care for these patients. ACOs represent an opportunity for general internists to change the way medical care is delivered. PMID- 21557035 TI - Evolutionary convergence to ideal free dispersal strategies and coexistence. AB - We study a two species competition model in which the species have the same population dynamics but different dispersal strategies and show how these dispersal strategies evolve. We introduce a general dispersal strategy which can result in the ideal free distributions of both competing species at equilibrium and generalize the result of Averill et al. (2011). We further investigate the convergent stability of this ideal free dispersal strategy by varying random dispersal rates, advection rates, or both of these two parameters simultaneously. For monotone resource functions, our analysis reveals that among two similar dispersal strategies, selection generally prefers the strategy which is closer to the ideal free dispersal strategy. For nonmonotone resource functions, our findings suggest that there may exist some dispersal strategies which are not ideal free, but could be locally evolutionarily stable and/or convergent stable, and allow for the coexistence of more than one species. PMID- 21557036 TI - An exploration of the cultural context of kinship and genetics amongst Arabic Australians: implications for practice. AB - This paper examines the culturally determined attitudes and beliefs about kinship, causation of hereditary cancer and other illnesses and the importance of family history amongst Arabic-Australians. Ethnographic interviews were conducted initially with individuals who had attended a family cancer clinic and subsequently with community members. Our aim was to either verify or challenge the reported findings from the clinic sample. Interviews with 38 participants provided cultural descriptions of hereditary illnesses, including cancer, and their causes. While respondents recognized family history as an important factor that reflects on one's likelihood of successful child-bearing, models of kinship described were not in line with Western concepts. Important issues emerged which need to be recognized as potential barriers to access to genetics services and challenges in this community. These include a lack of awareness of inherited cancer and the impact of consanguinity on the understanding of kinship in this community. PMID- 21557037 TI - Achieving antral grinding forces in biorelevant in vitro models: comparing the USP dissolution apparatus II and the dynamic gastric model with human in vivo data. PMID- 21557038 TI - Photographic assessment of temperate forest understory phenology in relation to springtime meteorological drivers. AB - Phenology shows sensitive responses to seasonal changes in atmospheric conditions. Forest understory phenology, in particular, is a crucial component of the forest ecosystem that interacts with meteorological factors, and ecosystem functions such as carbon exchange and nutrient cycling. Quantifying understory phenology is challenging due to the multiplicity of species and heterogeneous spatial distribution. The use of digital photography for assessing forest understory phenology was systematically tested in this study within a temperate forest during spring 2007. Five phenology metrics (phenometrics) were extracted from digital photos using three band algebra and two greenness percentage (image binarization) methods. Phenometrics were compared with a comprehensive suite of concurrent meteorological variables. Results show that greenness percentage cover approaches were relatively robust in capturing forest understory green-up. Derived spring phenology of understory plants responded to accumulated air temperature as anticipated, and with day-to-day changes strongly affected by estimated moisture availability. This study suggests that visible-light photographic assessment is useful for efficient forest understory phenology monitoring and allows more comprehensive data collection in support of ecosystem/land surface models. PMID- 21557039 TI - CCN3-mediated promotion of sulfated proteoglycan synthesis in rat chondrocytes from developing joint heads. AB - Chondrocytes forming articular cartilage are embedded in a vast amount of extracellular matrix having physical stiffness and elasticity, properties that support the mechanical load from bones and enable the flexible movement of synovial joints. Unlike chondrocytes that conduct the growth of long bones by forming the growth plate, articular chondrocytes show suppressed cell proliferation, unless these cells are exposed to pathological conditions such as mechanical overload. In the present study, we found that one of the members of the CCN family, CCN3, was significantly expressed in chondrocytes isolated from the epiphyseal head in developing rat synovial joints. Evaluation of the effect of recombinant CCN3 on those chondrocytes revealed that CCN3 promoted proteoglycan synthesis, whereas this factor repressed the proliferation of the same cells. These results suggest a critical role for CCN3 in the regulation of the biological properties of articular chondrocytes. PMID- 21557040 TI - Treatment of epilepsy to optimize bone health. AB - OPINION STATEMENT: When treating a person with epilepsy, one must consider many factors in addition to the obvious need to treat the seizures. Both epilepsy itself and treatment with antiepileptic drugs (AEDs) subject one to numerous potential secondary long-term health concerns. Poor bone health is one of these concerns. Studies suggest that persons with epilepsy treated with AEDs have an increased risk of fracture, low bone mineral density (BMD), and abnormalities in bone metabolism. Multiple factors likely contribute to the increased risk. Falls during generalized tonic-clonic seizures, secondary effects of AEDs on balance, inactivity, low BMD, reduced calcium intake, reduced active vitamin D metabolites, and a genetic predisposition to low BMD may all contribute. Studies suggest a differential influence of AEDs. Phenytoin, phenobarbital, and primidone are most consistently associated with a negative impact on bone. Carbamazepine and valproate may also result in bone abnormalities, but data are mixed. Current studies suggest that lamotrigine has limited (if any) effect, but again, data are inconsistent. Other AEDs have received limited study. Screening for poor bone health includes serologic testing of vitamin D metabolites (notably 25 hydroxyvitamin D) as well as BMD testing using dual energy x-ray absorptiometry. Optimizing intake of calcium and vitamin D is important for all persons with epilepsy treated with AEDs. Although many treatments for low BMD are available, these agents have not been studied in persons with epilepsy treated with AEDs. Overall, physicians treating persons with epilepsy must consider the potential effect of having epilepsy and its main treatment, AED therapy, on bone health. For patients in whom bone health is a particular concern (eg, those with diagnosed bone disease or with significant risk factors for bone disease, including glucocorticosteroid use), it is best to avoid AEDs known to negatively affect bone. In addition, practitioners should work with other treating physicians to optimize bone health in these patients. PMID- 21557041 TI - Medical management of patients with brain tumors. AB - OPINION STATEMENT: Patients with brain tumors require meticulous attention to medical issues resulting from their disease or its therapy. The following specific issues are the ones most frequently arising in the purview of neurologists: (1) Vasogenic edema: Corticosteroids should be used in divided doses in the minimum amount required to control symptoms and should be tapered as quickly as possible. Some patients may require long-term steroid supplementation, and symptoms of adrenal insufficiency should be investigated with 8 AM: cortisol measurement and treated with appropriate repletion. (2) Seizures: Patients with brain tumors should receive antiepileptic drugs only if they have had seizures, and the drugs should be chosen to minimize cognitive effects and interactions with concurrently administered chemotherapy. Levetiracetam is an excellent choice for patients with partial seizures and is available both orally and parenterally. Lamotrigine is another reasonable choice but requires slow titration. (3) Venous thromboembolism: All brain tumor patients should receive perioperative venous thrombosis prophylaxis with compression boots and enoxaparin or dalteparin. Lifelong treatment with low molecular weight heparinoids or warfarin is required for those developing venous thromboembolism. (4) Other problems: Long-term survivors of brain tumors should be monitored indefinitely for cognitive problems, endocrine dysfunction, and development of secondary neoplasms. Modafinil can improve mood and attention impairments. PMID- 21557042 TI - Guest editorial: Role of monoclonal antibodies for the prevention and treatment of graft-versus-host disease. PMID- 21557043 TI - Regression of HIV-associated grade IV T cell lymphoma with combined antiretroviral therapy only. AB - The present report describes repeated long-term remissions of a high-grade T cell lymphoma in an HIV-positive patient upon cART only, without additional chemotherapy. A review of cases from the literature further illustrates the anti tumor effects of cART through the induction of a strong immune reconstitution in HIV-infected patients. PMID- 21557044 TI - Oxidative stress and diabetic kidney disease. AB - The number of people with diabetic kidney disease continues to increase worldwide despite current treatments. Of the pathophysiologic mechanisms that have been identified in the development and progression of diabetic nephropathy, oxidative stress (more accurately described as increased levels of reactive oxygen species; ROS) is of major importance. The increase in ROS is due to both increased production and to decreased and/or inadequate antioxidant function. To date, human clinical trials with antioxidants have not been shown to be effective. This is likely due, at least in part, to the lack of specificity of current agents. Recent research has determined both major sources of high glucose-induced cellular ROS production as well as high glucose-induced changes in antioxidant function. Treatments targeted at one or more of the specific diabetes-induced alterations in the regulation of ROS levels will likely lead to effective treatments that prevent the development and progression of diabetic kidney disease. PMID- 21557045 TI - Peer-nominated deviant talk within residential treatment: individual and group influences on treatment response. AB - This research examined deviant talk during summer residential treatment using peer nominations and extensive field observations. Participants were 239 youth (M (age) = 12.62, SD = 2.60; 67% male), nested in 26 treatment groups. Deviant talk was present in this setting, showed individual differences, and increased over time, especially for younger boys. As expected, its relationship to treatment response was moderated by peer behavior. Initial levels of individual deviant talk were related to clinical improvement, but primarily when peer deviant talk was low. Initial levels of peer deviant talk were related to higher than expected end of treatment aggression, especially for youth who were high in deviant talk. Deviant talk effects were observed for staff impressions of change and observations of aggression and adjustment. Initial antisocial behavior affected whether individual or peer levels of deviant talk more heavily influenced treatment response. Implications for clinical assessment and treatment monitoring are discussed. PMID- 21557046 TI - [Current trends in the management of primary hypospadias: indication for surgery and surgical goal]. AB - The therapeutic goal of surgical correction of hypospadias is the reconstruction of the primary malformation into a normal penis. Nowadays the operation is timed around the first birthday of the infant. The procedure is performed in different operative steps depending on the individual components to hypospadias. The current trend is to preserve and tubularize the urethral plate and to stage the procedure in proximal hypospadias with severe chordee. The perioperative management includes modern paediatric anaesthesia methods in combination with regional anaesthesia, urinary drainage into a double diaper and to waive the fixation of the baby at the bed. PMID- 21557047 TI - [Surgical trends in secondary hypospadias]. AB - The severity of secondary hypospadias can range from a mild cosmetic problem to severe functional impairment. Accordingly, surgical management of the defect can be either simple or extremely demanding. During the operation the penis should always be regarded as a functional unit so that the treatment goal of a good cosmetic and functional result can be achieved. In addition, the surgeon should have an extensive repertoire of operative techniques at his disposal and should be well versed in skin grafting methods so that he is able to adapt the procedure optimally to the intraoperative findings as necessary. If certain do's and don'ts of hypospadias correction are additionally observed good results can usually be obtained even in complicated hypospadias patients with multiple previous operations. Unreflected treatment, on the other hand, usually leads to further worsening of the problem resulting in the so-called hypospadias cripple. PMID- 21557048 TI - [Peyronie's disease: diagnostics and therapy]. AB - Peyronie's disease is a benign disorder of the penis but the etiology is still unknown. A wound healing disorder after repetitive microtraumatic lesions with inelastic scar formation of the tunica albuginea potentially leads to the typical symptoms of penile plaque formation, penile pain, deviation and erectile dysfunction. A non-surgical therapy based on a clear pathophysiology does not exist although the benefit of several conservative treatment options is under discussion. In the stable stage of the disease patients with Peyronie's disease frequently undergo penile surgery. Depending on the deviation angle, the penile length and the erectile dysfunction different straightening surgery can be performed. This article provides an overview of the natural history of the disease and describes present conservative management strategies and common surgical techniques for penile straightening. PMID- 21557053 TI - Oestradiol and psychosis: clinical findings and biological mechanisms. AB - Female sex steroids easily access the central nervous system and modulate a number of intracerebral processes via their specific receptors. Oestradiol is the biologically dominant female sex steroid and has been implicated in the aetiology and course of psychotic illnesses. There is evidence for interaction between oestradiol and several neurobiological systems that have been implicated in the pathogenesis of psychotic illnesses. Clinical studies have indicated that psychosis, and in particular schizophrenia, is associated with reduced ovarian function and that this may be inherent to the illness itself. In schizophrenia several studies have suggested a therapeutic effect of oestradiol and selective oestrogen modulators although research is still at an early stage. In bipolar disorder, the relationship between childbirth and first onsets or recurrences is one of the most reproducible findings in psychiatric research. Whether or not the rapid fall of oestrogens is the mediating mechanism is not yet clear but preliminary oestrogen treatment studies commenced immediately after childbirth are promising. Outside the perinatal context, tamoxifen, a selective oestrogen receptor modulator, has shown strong antimanic effects although further studies are necessary to test an effect in larger samples. Hormonal treatments should not yet be used in standard care but could be considered in women with treatment resistant psychoses. PMID- 21557054 TI - Adhesins of human pathogens from the genus Yersinia. AB - Bacteria of the Gram-negative genus Yersinia are environmentally ubiquitous. Three species are of medical importance: the intestinal pathogens Y. enterocolitica and Y. pseudotuberculosis, and the plague bacillus Y. pestis. The two former species, spread by contaminated food or water, cause a range of gastrointestinal symptoms and, rarely, sepsis. On occasion, the primary infection is followed by autoimmune sequelae such as reactive arthritis. Plague is a systemic disease with high mortality. It is a zoonosis spread by fleas, or more rarely by droplets from individuals suffering from pneumonic plague. Y. pestis is one of the most virulent of bacteria, and recent findings of antibiotic-resistant strains together with its potential use as a bioweapon have increased interest in the species. In addition to being significant pathogens in their own right, the yersiniae have been used as model systems for a number of aspects of pathogenicity. This chapter reviews the molecular mechanisms of adhesion in yersiniae. The enteropathogenic species share three adhesins: invasin, YadA and Ail. Invasin is the first adhesin required for enteric infection; it binds to beta(1) integrins on microfold cells in the distal ileum, leading to the ingestion of the bacteria and allows them to cross the intestinal epithelium. YadA is the major adhesin in host tissues. It is a multifunctional protein, conferring adherence to cells and extracellular matrix components, serum and phagocytosis resistance, and the ability to autoagglutinate. Ail has a minor role in adhesion and serum resistance. Y. pestis lacks both invasin and YadA, but expresses several other adhesins. These include the pH 6 antigen and autotransporter adhesins. Also the plasminogen activator of Y. pestis can mediate adherence to host cells. Although the adhesins of the pathogenic yersiniae have been studied extensively, their exact roles in the biology of infection remain elusive. PMID- 21557055 TI - Adhesive mechanisms of Salmonella enterica. AB - Salmonella enterica is an invasive, facultative intracellular pathogen of animal and man with the ability to colonize various niches in diverse host organisms. The pathogenesis of infections by S. enterica requires adhesion to various host cell surfaces, and a large number of adhesive structures can be found. Depending on the serotype of S. enterica, gene clusters for more than 10 different fimbrial adhesins were identified, with type I fimbriae such as Fim, Lpf (long polar fimbriae), Tafi (thin aggregative fimbriae) or the type IV pili of serotype Typhi. In addition, autotransporter adhesins such as ShdA, MisL and SadA and the type I secreted large repetitive adhesins SiiE and BapA have been identified. Although the functions of many of the various adhesins are not well understood, recent studies show the specific structural and functional properties of Salmonella adhesins and how they act in concert with other virulence determinants. In this chapter, we describe the molecular characteristics of Salmonella adhesins and link these features to their multiple functions in infection biology. PMID- 21557057 TI - Adhesins of Bartonella spp. AB - Adhesion to host cells represents the first step in the infection process and one of the decisive features in the pathogenicity of Bartonella spp. B. henselae and B. quintana are considered to be the most important human pathogenic species, responsible for cat scratch disease, bacillary angiomatosis, trench fever and other diseases. The ability to cause vasculoproliferative disorders and intraerythrocytic bacteraemia are unique features of the genus Bartonella. Consequently, the interaction with endothelial cells and erythrocytes is a focus in Bartonella research. The genus harbours a variety of trimeric autotransporter adhesins (TAAs) such as the Bartonella adhesin A (BadA) of B. henselae and the variably expressed outer-membrane proteins (Vomps) of B. quintana, which display remarkable variations in length and modular construction. These adhesins mediate many of the biologically-important properties of Bartonella spp. such as adherence to endothelial cells and extracellular matrix proteins and induction of angiogenic gene programming. There is also significant evidence that the laterally acquired Trw-conjugation systems of Bartonella spp. mediate host specific adherence to erythrocytes. Other potential adhesins are the filamentous haemagglutinins and several outer membrane proteins. The exact molecular functions of these adhesins and their interplay with other pathogenicity factors (e.g., the VirB/D4 type 4 secretion system) need to be analysed in detail to understand how these pathogens adapt to their mammalian hosts. PMID- 21557056 TI - Adhesion mechanisms of Borrelia burgdorferi. AB - The Borrelia are widely distributed agents of Lyme disease and Relapsing Fever. All are vector-borne zoonotic pathogens, have segmented genomes, and enigmatic mechanisms of pathogenesis. Adhesion to mammalian and tick substrates is one pathogenic mechanism that has been widely studied. At this point, the primary focus of research in this area has been on Borrelia burgdorferi, one agent of Lyme disease, but many of the adhesins of B. burgdorferi are conserved in other Lyme disease agents, and some are conserved in the Relapsing Fever Borrelia. B. burgdorferi adhesins that mediate attachment to cell-surface molecules may influence the host response to the bacteria, while adhesins that mediate attachment to soluble proteins or extracellular matrix components may cloak the bacterial surface from recognition by the host immune system as well as facilitate colonization of tissues. While targeted mutations in the genes encoding some adhesins have been shown to affect the infectivity and pathogenicity of B. burgdorferi, much work remains to be done to understand the roles of the adhesins in promoting the persistent infection required to maintain the bacteria in reservoir hosts. PMID- 21557058 TI - Adhesion mechanisms of plant-pathogenic Xanthomonadaceae. AB - The family Xanthomonadaceae is a wide-spread family of bacteria belonging to the gamma subdivision of the Gram-negative proteobacteria, including the two plant pathogenic genera Xanthomonas and Xylella, and the related genus Stenotrophomonas. Adhesion is a widely conserved virulence mechanism among Gram negative bacteria, no matter whether they are human, animal or plant pathogens, since attachment to the host tissue is one of the key early steps of the bacterial infection process. Bacterial attachment to surfaces is mediated by surface structures that are anchored in the bacterial outer membrane and cover a broad group of fimbrial and non-fimbrial structures, commonly known as adhesins. In this chapter, we discuss recent findings on candidate adhesins of plant pathogenic Xanthomonadaceae, including polysaccharidic (lipopolysaccharides, exopolysaccharides) and proteineous structures (chaperone/usher pili, type IV pili, autotransporters, two-partner-secreted and other outer membrane adhesins), their involvement in the formation of biofilms and their mode of regulation via quorum sensing. We then compare the arsenals of adhesins among different Xanthomonas strains and evaluate their mode of selection. Finally, we summarize the sparse knowledge on specific adhesin receptors in plants and the possible role of RGD motifs in binding to integrin-like plant molecules. PMID- 21557059 TI - Adhesion by pathogenic corynebacteria. AB - Pathogenic members of the genus Corynebacterium cause a wide range of serious infections in humans including diphtheria. Adhesion to host cells is a crucial step during infection. In Corynebacterium diphtheriae, adhesion is mediated primarily by filamentous structures called pili or fimbriae that are covalently attached to the bacterial cell wall. C. diphtheriae produces three distinct pilus structures, SpaA-, SpaD- and SpaH-type pili. Similar to other types, the prototype SpaA pilus consists of SpaA forming the pilus shaft and two minor pilins SpaB and SpaC located at the base and at the tip, respectively. The minor pilins SpaB/SpaC are critical for bacterial binding to human pharyngeal cells, and thus represent the major adhesins of corynebacteria. Like pili of many other gram-positive microbes, the assembly of corynebacterial pili occurs by a two-step mechanism, whereby pilins are covalently polymerized by a transpeptidase enzyme named pilin-specific sortase and the generated pilus polymer is subsequently anchored to the cell wall peptidoglycan via the base pilin by the housekeeping sortase or a non-polymerizing sortase. This chapter reviews the current knowledge of corynebacterial adhesion, with a specific focus on pilus structures, their assembly, and the mechanism of adhesion mediated by pili. PMID- 21557060 TI - Adhesion mechanisms of staphylococci. AB - Staphylococcal adherence to an either biotic or abiotic surface is the critical first event in the establishment of an infection with these serious pathogens. Especially Staphylococcus aureus harbours a variety of proteinaceous and non proteinaceous adhesins that mediate attachment to a multitude of host factors, such as extracellular matrix and plasma proteins and human host cells, or intercellular adhesion, which is essential for biofilm accumulation. Proteinaceous adhesins may be classified in covalently surface-anchored proteins of the MSCRAMM (microbial surface components recognizing adhesive matrix molecules) family or in proteins that are surface-associated by different means, such as ionic or hydrophobic interactions. Non-covalently surface-associated proteins include the autolysin/adhesins, proteins of the SERAM (secretable expanded repertoire adhesive molecules) family, or membrane-spanning proteins. Non-proteinaceous adhesins comprise the polysaccharide PIA (polysaccharide intercellular adhesin) and wall teichoic and lipoteichoic acids. The features and functions of surface and surface-associated protein adhesins as well as of non proteinaceous adhesins are discussed. PMID- 21557061 TI - Protein folding in bacterial adhesion: secretion and folding of classical monomeric autotransporters. AB - Bacterial adhesins mediate the attachment of bacteria to their niches, such as the tissue of an infected host. Adhesins have to be transported across the cell envelope to become active and during this secretion process they fold into their final conformation. This chapter focuses on the biogenesis of the classical monomeric autotransporter proteins, which are the most ubiquitous class of secreted proteins in Gram-negative bacteria. They may function as adhesins, but other functions are also known. Autotransporter proteins have a modular structure and consist of an N-terminal signal peptide and a C-terminal translocator domain with in between the secreted passenger domain that harbours the functions. The signal peptide directs the transport across the inner membrane to the periplasm via the Sec machinery. The translocator domain inserts into the outer membrane and facilitates the transport of the passenger to the cell surface. In this chapter, I will review our current knowledge of the secretion of classical monomeric autotransporters and the methods that have been used to assess their folding during the translocation, both in vitro and in vivo. PMID- 21557062 TI - Structure and biology of trimeric autotransporter adhesins. AB - Trimeric autotransporter adhesins (TAAs) are a family of secreted Gram-negative bacterial outer membrane (OM) proteins. These obligate homotrimeric proteins share a common molecular organisation, consisting of a N-terminal "passenger" domain followed by a C-terminal translocation unit/membrane anchor. All described TAAs act as adhesins. The passenger domain is responsible for specific adhesive and other activities of the protein and has a modular architecture. Its globular head domain(s), where ligands often bind, are projected away from the bacterial surface by an extended triple alpha-helical coiled coil stalk attached to the beta-barrel anchor. The head domains appear to be constructed from a limited set of subdomains. The beta-barrel anchor is the only part of the protein strictly conserved between family members. It appears that the extracellular export of the passenger does not require an external energy source or auxiliary proteins, though recent data indicate that an OM complex (the Bam complex) is involved in passenger domain secretion. The ability to bind to a variety of host molecules such as collagen, fibronectin, laminin or cell surface receptors via a structurally diverse elements suggests that TAAs have evolved a unique mechanism which closely links structure to folding and function. PMID- 21557063 TI - Crystallography and electron microscopy of chaperone/usher pilus systems. AB - Among bacteria, the chaperone-usher (CU) pathway is a widespread conserved assembly and translocation system for adhesive protein fibres, called pili or fimbriae. Pili are large linear polymers that protrude from the outer bacterial surface and consist of several subunits. Pili contain adhesin proteins at the tip that are used by pathogenic bacteria to mediate attachment to host cells and initiate infections. Well studied examples of CU pili are P and type 1 pili of uropathogenic Escherichia coli (UPEC), which are responsible for kidney and bladder infections, respectively. Upon secretion into the periplasm, pilus subunits are stabilized by periplasmic chaperones and the resulting chaperone:subunit complexes are guided to the usher located in the outer membrane. The usher catalyzes the ordered assembly of pilus subunits while releasing the chaperones and translocating the growing pilus stepwise to the outer surface. Here we review the structural biology of the chaperone-usher pathway that has helped to understand the mechanisms by which biogenesis of an important class of bacterial organelles occurs. PMID- 21557064 TI - Crystallography of gram-positive bacterial adhesins. AB - Both Gram-negative and Gram-positive pathogens display a multitude of proteins and protein assemblies (pili or fimbriae) on their cell surfaces, which are often used for adherence and initiate colonization and pathogenesis. Adhesive proteins known as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), anchored by a specific enzyme called sortase in Gram-positive bacteria, target the host's extracellular matrix proteins (ECM) like collagen, fibrinogen and fibronectin. In the past decade, structural analysis by X-ray crystallography has enhanced our understanding of the interactions between MSCRAMMs and the host ECM by revealing several novel structural features that dictate surface protein assembly and the mode of their adhesion to host tissue. The latest focus is on the recently discovered Gram-positive bacterial pili, assembly of which is assisted by yet another specific sortase. Novel features like inter- and intra-molecular isopeptide bonds that facilitate the stability of the pilins, and intra-molecular donor strand complementation to stabilize the adhesin-target interactions are specific to Gram-positive bacteria. This chapter describes and discusses the common structural details between surface proteins and pilins of Gram-positive bacteria and biological implications emanating from these structures. PMID- 21557065 TI - The nonideal coiled coil of M protein and its multifarious functions in pathogenesis. AB - The M protein is a major virulence factor of Streptococcus pyogenes (group A Streptococcus, GAS). This gram-positive bacterial pathogen is responsible for mild infections, such as pharyngitis, and severe invasive disease, like streptococcal toxic shock syndrome. M protein contributes to GAS virulence in multifarious ways, including blocking deposition of antibodies and complement, helping formation of microcolonies, neutralizing antimicrobial peptides, and triggering a proinflammatory and procoagulatory state. These functions are specified by interactions between M protein and many host components, especially C4BP and fibrinogen. The former interaction is conserved among many antigenically variant M protein types but occurs in a strikingly sequence-independent manner, and the latter is associated in the M1 protein type with severe invasive disease. Remarkably for a protein of such diverse interactions, the M protein has a relatively simple but nonideal alpha-helical coiled coil sequence. This sequence nonideality is a crucial feature of M protein. Nonideal residues give rise to specific irregularities in its coiled-coil structure, which are essential for interactions with fibrinogen and establishment of a proinflammatory state. In addition, these structural irregularities are reminiscent of those in myosin and tropomyosin, which are targets for crossreactive antibodies in patients suffering from autoimmune sequelae of GAS infection. PMID- 21557066 TI - Bacterial extracellular polysaccharides. AB - Extracellular polysaccharides are as structurally and functionally diverse as the bacteria that synthesise them. They can be present in many forms, including cell bound capsular polysaccharides, unbound "slime", and as O-antigen component of lipopolysaccharide, with an equally wide range of biological functions. These include resistance to desiccation, protection against nonspecific and specific host immunity, and adherence. Unsurprisingly then, much effort has been made to catalogue the enormous structural complexity of the extracellular polysaccharides made possible by the wide assortment of available monosaccharide combinations, non-carbohydrate residues, and linkage types, and to elucidate their biosynthesis and export. In addition, the work is driven by the commercial potential of these microbial substances in food, pharmaceutics and biomedical industries. Most recently, bacteria-mediated environmental restoration and bioleaching have been attracting much attention owing to their potential to remediate environmental effluents produced by the mining and metallurgy industries. In spite of technological advances in chemistry, molecular biology and imaging techniques that allowed for considerable expansion of knowledge pertaining to the bacterial surface polysaccharides, current understanding of the mechanisms of synthesis and regulation of extracellular polysaccharides is yet to fully explain their structural intricacy and functional variability. PMID- 21557067 TI - Carbohydrate mediated bacterial adhesion. AB - In the process of adhesion, bacteria often carry proteins on their surface, adhesins, that bind to specific components of tissue cells or the extracellular matrix. In many cases these components are carbohydrate structures. The carbohydrate binding specificities of many bacteria have been uncovered over the years. The design and synthesis of inhibitors of bacterial adhesion has the potential to create new therapeutics for the prevention and possibly treatment of bacterial infections. Unfortunately, the carbohydrate structures often bind only weakly to the adhesion proteins, although drug design approaches can improve the situation. Furthermore, in some cases linking carbohydrates covalently together, to create so-called multivalent systems, can also significantly enhance the inhibitory potency. Besides adhesion inhibition as a potential therapeutic strategy, the adhesion proteins can also be used for detection. Novel methods to do this are being developed. These include the use of microarrays and glyconanoparticles. New developments in these areas are discussed. PMID- 21557068 TI - The application of NMR techniques to bacterial adhesins. AB - Extracellular adhesins frequently compose large, highly-ordered structural assemblies that project away from the bacterial surface. These assemblies, known as pili or fimbriae, are rod-like polymeric structures that in some cases can extend up to several micrometers from the cell surface. Because these adhesin structures are critical to bacterial colonization of host cell surfaces, there is an incentive to understand their structure, assembly and mechanism of host cell attachment. Various methods in Nuclear Magnetic Resonance (NMR) spectroscopy have been used to address these topics, yielding structural information at the atomic level. Also, new methods in solid-state NMR spectroscopy have thus far been under utilized in the study of large adhesin structures and offer a powerful approach to overcoming problems with crystallization to better understand the structures of these complexes. The following is a brief overview of the contributions of NMR to the study of bacterial adhesins with an emphasis on the future potential of solid-state NMR. PMID- 21557069 TI - Electron microscopy techniques to study bacterial adhesion. AB - Since its introduction 70 years ago electron microscopy has become an invaluable tool for microbiology and the study of bacterial interaction. Technological development over the past decades has enabled researchers to resolve smaller and smaller details in bacterial samples, while new preparation techniques like cryo preparation now allow to investigate bacteria even closer to their natural state. In this chapter we give a brief overview of electron microscopy techniques suitable for the investigation of bacterial adhesion at molecular as well as cellular level and a short outlook on future technologies relevant to the field. PMID- 21557070 TI - EM reconstruction of adhesins: future prospects. AB - Both Gram-negative and Gram-positive pathogenic bacteria present a remarkable number of surface-exposed organelles and secreted toxins that allow them to control the primary stages of infection, bacterial attachment to host cell receptors and colonization. The mediators of these processes, called adhesins, form a heterogeneous group that varies in architecture, domain content and mechanism of binding. A full understanding of how adhesins mediate cellular adhesion and colonization requires quantitative functional assays to evaluate the strength of the binding interactions, as well as determination of the high resolution three-dimensional structures of the molecules to provide the atomic details of the interactions. The combination of classical imaging techniques like X-ray crystallography and Nuclear Magnetic Resonance (NMR) with the emerging technique of single-particle electron cryomicroscopy has become a tremendously helpful tool to understand the three-dimensional structure at near atomic-level resolution of newly discovered adhesins and their complexes. A detailed study of the structure of these molecules, both isolated and expressed on bacterial surface is a fundamental requirement for understanding the adhesion mechanism to host cells. This chapter will focus on the structure determination of such surface-exposed protein structures in both Gram-negative and Gram-positive bacterial adhesins. PMID- 21557071 TI - Atomic force microscopy to study intermolecular forces and bonds associated with bacteria. AB - Atomic force microscopy (AFM) operates on a very different principle than other forms of microscopy, such as optical microscopy or electron microscopy. The key component of an AFM is a cantilever that bends in response to forces that it experiences as it touches another surface. Forces as small as a few picoNewtons can be detected and probed with AFM. AFM has become very useful in biological sciences because it can be used on living cells that are immersed in water. AFM is particularly useful when the cantilever is modified with chemical groups (e.g. amine or carboxylic groups), small beads (e.g. glass or latex), or even a bacterium. This chapter describes how AFM can be used to measure forces and bonds between a bacterium and another surface. This paper also provides an example of the use of AFM on Staphylococcus aureus, a Gram-positive bacterium that is often associated with biofilms in humans. PMID- 21557072 TI - Assessing bacterial adhesion on an individual adhesin and single pili level using optical tweezers. AB - Optical tweezers (OT) are a technique that, by focused laser light, can both manipulate micrometer sized objects and measure minute forces (in the pN range) in biological systems. The technique is therefore suitable for assessment of bacterial adhesion on an individual adhesin-receptor and single attachment organelle (pili) level. This chapter summarizes the use of OT for assessment of adhesion mechanisms of both non-piliated and piliated bacteria. The latter include the important helix-like pili expressed by uropathogenic Escherichia coli (UPEC), which have shown to have unique and intricate biomechanical properties. It is conjectured that the large flexibility of this type of pili allows for a redistribution of an external shear force among several pili, thereby extending the adhesion lifetime of bacteria. Systems with helix-like adhesion organelles may therefore act as dynamic biomechanical machineries, enhancing the ability of bacteria to withstand high shear forces originating from rinsing flows such as in the urinary tract. This implies that pili constitute an important virulence factor and a possible target for future anti-microbial drugs. PMID- 21557073 TI - Short time-scale bacterial adhesion dynamics. AB - In natural conditions many bacterial populations are found as surface-attached communities exhibiting features distinct from those of planktonic cells. We focus here on the question of initial adhesion, the mechanisms of which are still far from being fully understood. Recently, the frontier between microbiologists and physicists has become increasingly permeable, boosting implementation of new methodological approaches for better elucidating the intricate aspects of initial bacterial adhesion. After discussing briefly the main sources of complexity that confuse the understanding of the early steps of cell-surface attachment, we present a selection of physical methods enabling real-time measurement of early adhesion kinetics in live cells. We also discuss the limitations and pitfalls that might appear when applying such methodologies - initially designed for studying physically ideal systems - to analysis of these, more complex, living systems. We address mainly on the use of dispersed-surfaces flow cytometry (DS FCM), quartz microbalance (QCM) and surface plasmon resonance (SPR) approaches, and give a brief survey of new perspectives in optical microscopy. We conclude that the use of combined and multiparametric technical approaches will lead to significant advances in providing a comprehensive understanding of the early events in bacterial adhesion. PMID- 21557074 TI - Deciphering biofilm structure and reactivity by multiscale time-resolved fluorescence analysis. AB - In natural, industrial and medical environments, microorganisms mainly live as structured and organised matrix-encased communities known as biofilms. In these communities, microorganisms demonstrate coordinated behaviour and are able to perform specific functions such as dramatic resistance to antimicrobials, which potentially lead to major public health and industrial problems. It is now recognised that the appearance of such specific biofilm functions is intimately related to the three-dimensional organisation of the biological edifice, and results from multifactorial processes. During the last decade, the emergence of innovative optical microscopy techniques such as confocal laser scanning microscopy in combination with fluorescent labelling has radically transformed imaging in biofilm research, giving the possibility to investigate non-invasively the dynamic mechanisms of formation and reactivity of these biostructures. In this chapter, we discuss the contribution of fluorescence analysis and imaging to the study at different timescales of various processes: biofilm development (hours to days), antimicrobial reactivity within the three-dimensional structure (minutes to hours) or molecular diffusion/reaction phenomena (pico- to milliseconds). PMID- 21557075 TI - Inhibition of bacterial adhesion on medical devices. AB - Microbial infections resulting from bacterial adhesion to biomaterial surfaces have been observed on almost all medical devices. Biofilm infections pose a number of clinical challenges due to their resistance to immune defence mechanisms and antimicrobials, and, regardless of the sophistication of the implant, all medical devices are susceptible to microbial colonisation and infection. Research efforts are currently directed towards eliminating or reducing infection of medical devices. Strategies to prevent biofilm formation include physiochemical modification of the biomaterial surface to create anti adhesive surfaces, incorporation of antimicrobial agents into medical device polymers, mechanical design alternatives, and release of antibiotics. Nevertheless, the success of these alternatives has been modest, mainly due to the various environments into which devices are placed and the diversity of ways in which organisms can colonise surfaces. Biosurfactants have been reported as a promising strategy as they effectively inhibit bacterial adhesion and retard biofilm formation, and are thus potentially useful as a new generation of anti adhesive and antimicrobial coatings for medical devices. PMID- 21557076 TI - Introduction to "a handbook of transcription factors". AB - This chapter briefly summarizes the topics in this volume. PMID- 21557077 TI - An overview of prokaryotic transcription factors : a summary of function and occurrence in bacterial genomes. AB - Transcriptional initiation is arguably the most important control point for gene expression. It is regulated by a combination of factors, including DNA sequence and its three-dimensional topology, proteins and small molecules. In this chapter, we focus on the trans-acting factors of bacterial regulation. Initiation begins with the recruitment of the RNA polymerase holoenzyme to a specific locus upstream of the gene known as its promoter. The sigma factor, which is a component of the holoenzyme, provides the most fundamental mechanisms for orchestrating broad changes in gene expression state. It is responsible for promoter recognition as well as recruiting the holoenzyme to the promoter. Distinct sigma factors compete with for binding to a common pool of RNA polymerases, thus achieving condition-dependent differential expression. Another important class of bacterial regulators is transcription factors, which activate or repress transcription of target genes typically in response to an environmental or cellular trigger. These factors may be global or local depending on the number of genes and range of cellular functions that they target. The activities of both global and local transcription factors may be regulated either at a post-transcriptional level via signal-sensing protein domains or at the level of their own expression. In addition to modulating polymerase recruitment to promoters, several global factors are considered as "nucleoid-associated proteins" that impose structural constraints on the chromosome by altering the conformation of the bound DNA, thus influencing other processes involving DNA such as replication and recombination. This chapter concludes with a discussion of how regulatory interactions between transcription factors and their target genes can be represented as a network. PMID- 21557078 TI - A catalogue of eukaryotic transcription factor types, their evolutionary origin, and species distribution. AB - Transcription factors (TFs) play key roles in the regulation of gene expression by binding in a sequence-specific manner to genomic DNA. In eukaryotes, DNA binding is achieved by a wide range of structural forms and motifs. TFs are typically classified by their DNA-binding domain (DBD) type. In this chapter, we catalogue and survey 91 different TF DBD types in metazoa, plants, fungi, and protists. We briefly discuss well-characterized TF families representing the major DBD superclasses. We also examine the species distributions and inferred evolutionary histories of the various families, and the potential roles played by TF family expansion and dimerization. PMID- 21557079 TI - Function and Evolution of C2H2 Zinc Finger Arrays. AB - Kruppel-type or C2H2 zinc fingers represent a dominant DNA-binding motif in eukaryotic transcription factor (TF) proteins. In Kruppel-type (KZNF) TFs, KZNF motifs are arranged in arrays of three to as many as 40 tandem units, which cooperate to define the unique DNA recognition properties of the protein. Each finger contains four amino acids located at specific positions, which are brought into direct contact with adjacent nucleotides in the DNA sequence as the KZNF array winds around the major groove of the alpha helix. This arrangement creates an intimate and potentially predictable relationship between the amino acid sequence of KZNF arrays and the nucleotide sequence of target binding sites. The large number of possible combinations and arrangements of modular KZNF motifs, and the increasing lengths of KZNF arrays in vertebrate species, has created huge repertoires of functionally unique TF proteins. The properties of this versatile DNA-binding motif have been exploited independently many times over the course of evolution, through attachment to effector motifs that confer activating, repressing or other activities to the proteins. Once created, some of these novel inventions have expanded in specific evolutionary clades, creating large families of TFs that are lineage- or species-unique. This chapter reviews the properties and their remarkable evolutionary history of eukaryotic KZNF TF proteins, with special focus on large families that dominate the TF landscapes in different metazoan species. PMID- 21557080 TI - Homeodomain subtypes and functional diversity. AB - The homeodomain is a protein domain of about 60 amino acids that is encoded by homeobox genes. The homeodomain is a DNA binding domain, and hence homeodomain proteins are essentially transcription factors (TFs). They have been shown to play major roles in many developmental processes of animals, as well as fungi and plants. A primary function of homeodomain proteins is to regulate the expression of other genes in development and differentiation. Thousands of homeobox genes have been identified, and they can be grouped into many different classes. Often other conserved protein domains are found linked to a homeodomain. Several particular types of homeobox genes are organized into chromosomal clusters. The best-known cluster, the HOX cluster, is found in all bilaterian animals. Tetrapods contain four HOX clusters that arose through duplication in early vertebrate evolution. The genes in these clusters are called Hox genes. Lower chordates, insects and nematodes tend to have only one HOX cluster. Of particular interest is that many of the HOX cluster genes function in the process of pattern formation along the anterior-posterior body axis. Many other types of homeodomain proteins play roles in the determination of cell fates and cell differentiation. Homeobox genes thus perform key roles for all aspects of the development of an organism. PMID- 21557081 TI - Nuclear Receptors: Small Molecule Sensors that Coordinate Growth, Metabolism and Reproduction. AB - One of the largest groups of metazoan transcription factors (TFs), the Nuclear Receptor superfamily, regulates genes required for virtually all aspects of development, reproduction and metabolism. Together, these master regulators can be thought of as a fundamental operating system for metazoan life. Their most distinguishing feature is a structurally conserved domain that acts as a switch, powered by the presence of small diffusible ligands. This ligand-responsive regulation has allowed the Nuclear Receptors to help their hosts adapt to a wide variety of physiological niches and roles, making them one of the most evolutionarily successful TF families. Originally discovered as receptors for steroid hormones, the Nuclear Receptor field has grown to encompass much more than traditional endocrinology. For example, recent work has highlighted the role of Nuclear Receptors as major regulators of metabolism and biological clocks. By monitoring endogenous metabolites and absorbed xenobiotics, these receptors also coordinate rapid, system-wide responses to changing metabolic and environmental states. While many new Nuclear Receptor ligands have been discovered in the past couple of decades, approximately half of the 48 human receptors are still orphans, with a significantly higher percentage of orphans in other organisms. The discovery of new ligands has led to the elucidation of new regulatory mechanisms, target genes, pathways and functions. This review will highlight both the common as well as newly emerging traits and functions that characterize this particularly unique and important TF family. PMID- 21557082 TI - Methods for Analysis of Transcription Factor DNA-Binding Specificity In Vitro. AB - Transcription of genes during development and in response to environmental stimuli is determined by genomic DNA sequence. The DNA sequences regulating transcription are read by sequence-specific transcription factors (TFs) that recognize relatively short sequences, generally between four and twenty base pairs in length. Transcriptional regulation generally requires binding of multiple TFs in close proximity to each other. Mechanistic understanding of transcription in an organism thus requires detailed knowledge of binding affinities of all its TFs to all possible DNA sequences, and the co-operative interactions between the TFs. However, very little is known about such co operative binding interactions, and even the simple TF-DNA binding information exists only for a very small proportion of all TFs - for example, mammals have approximately 1,300-2,000 TFs [1, 2], yet the largest public databases for TF binding specificity, Jaspar and Uniprobe [3, 4] currently list only approximately 500 moderate to high resolution profiles for human or mouse. This lack of knowledge is in part due to the fact that analysis of TF DNA binding has been laborious and expensive. In this chapter, we review methods that can be used to determine binding specificity of TFs to DNA, mainly focusing on recently developed assays that allow high-resolution analysis of TF binding specificity in relatively high throughput. PMID- 21557084 TI - How transcription factors identify regulatory sites in genomic sequence. AB - Binding of transcription factors to functional sites is a fundamental step in transcriptional regulation. In this chapter, we discuss how transcription factors are thought to achieve specificity to their functional targets, despite their typically low concentrations and degenerate binding specificities, and the fact that in large genomes their functional binding sites must compete with their widespread alternative binding sites. We highlight the importance of the chromatin structure context of the binding sites in this process, and its dependency on the genomic DNA sequence. PMID- 21557083 TI - Identification of Transcription Factor-DNA Interactions In Vivo. AB - Recent technological developments have revolutionized our understanding of transcriptional regulation by providing an unprecedented ability to interrogate in vivo transcription factor binding. The combination of high-throughput sequencing with chromatin precipitation of transcription factors and specifically labeled histones has allowed direct protein-DNA contacts to be visualized across genomes as large and complex as mammals at base-pair resolution. This chapter reviews the developments that led to these insights, with particular focus on examples of early protein-DNA localization experiments using genomic microarrays in mammals and yeast. Four state-of-the-art research directions are highlighted as examples of previously unimaginable frontiers now under active investigation. PMID- 21557085 TI - Transcription factor binding sites and other features in human and Drosophila proximal promoters. AB - Eukaryotic promoters determine transcription start sites (TSSs), and are often enriched for transcription factor binding sites (TFBSs), which presumably play a major role in determining the location and activity of the TSS. In mammalian systems, proximal promoters are enriched for the CpG dinucleotide. The TFBSs that are enriched in proximal promoters (-200 bps to the TSS) are CCAAT, ETS, NRF1, SP1, E-Box, CRE, BoxA, and TATA. Only TATA occurs in a DNA strand dependent manner. In Drosophila, proximal promoters are AT rich and many putative TFBSs are enriched in proximal promoters. These sequences are different from those that occur in human promoters, except for TATA and E-Box, and many occur on a single strand of DNA giving directionality to the promoter. Thus, fundamental differences have arisen as promoters evolved in metazoans. PMID- 21557086 TI - Interactions of transcription factors with chromatin. AB - Sequence-specific transcription factors (TFs) play a central role in regulating transcription initiation by directing the recruitment and activity of the general transcription machinery and accessory factors. It is now well established that many of the effects exerted by TFs in eukaryotes are mediated through interactions with a host of coregulators that modify the chromatin state, resulting in a more open (in case of activation) or closed conformation (in case of repression). The relationship between TFs and chromatin is a two-way street, however, as chromatin can in turn influence the recognition and binding of target sequences by TFs. The aim of this chapter is to highlight how this dynamic interplay between TF-directed remodelling of chromatin and chromatin-adjusted targeting of TF binding determines where and how transcription is initiated, and to what degree it is productive. PMID- 21557088 TI - Large-scale nuclear architecture and transcriptional control. AB - Transcriptional regulation is one the most basic mechanisms for controlling gene expression. Over the past few years, much research has been devoted to understanding the interplay between transcription factors, histone modifications and associated enzymes required to achieve this control. However, it is becoming increasingly apparent that the three-dimensional conformation of chromatin in the interphase nucleus also plays a critical role in regulating transcription. Chromatin localisation in the nucleus is highly organised, and early studies described strong interactions between chromatin and sub-nuclear components. Single-gene studies have shed light on how chromosomal architecture affects gene expression. Lately, this has been complemented by whole-genome studies that have determined the global chromatin conformation of living cells in interphase. These studies have greatly expanded our understanding of nuclear architecture and its interplay with different physiological processes. Despite these advances, however, most of the mechanisms used to impose the three-dimensional chromatin structure remain unknown. Here, we summarise the different levels of chromatin organisation in the nucleus and discuss current efforts into characterising the mechanisms that govern it. PMID- 21557087 TI - Transcription factor effector domains. AB - The last decade has seen an incredible breakthrough in technologies that allow histones, transcription factors (TFs), and RNA polymerases to be precisely mapped throughout the genome. From this research, it is clear that there is a complex interaction between the chromatin landscape and the general transcriptional machinery and that the dynamic control of this interface is central to gene regulation. However, the chromatin remodeling enzymes and general TFs cannot, on their own, recognize and stably bind to promoter or enhancer regions. Rather, they are recruited to cis regulatory regions through interaction with site specific DNA binding TFs and/or proteins that recognize epigenetic marks such as methylated cytosines or specifically modified amino acids in histones. These "recruitment" factors are modular in structure, reflecting their ability to interact with the genome via one region of the protein and to simultaneously bind to other regulatory proteins via "effector" domains. In this chapter, we provide examples of common effector domains that can function in transcriptional regulation via their ability to (a) interact with the basal transcriptional machinery and general co-activators, (b) interact with other TFs to allow cooperative binding, and (c) directly or indirectly recruit histone and chromatin modifying enzymes. PMID- 21557089 TI - Degradation and detoxification of acid orange 52 by Pseudomonas putida mt-2: a laboratory study. AB - INTRODUCTION: Acid orange 52 (AO52), extensively used in textile industries, was decolorized by Pseudomonas putida mt-2. AO52 azoreduction products such as N,N' dimethyl-p-phenylenediamine (DMPD) and 4-aminobenzenesulfonic acid (4-ABS), were identified in the static degradation mixture. These amines were identified only in media of static incubation, which is consistent with their biotransformation under shaken incubation (aerobic conditions). MATERIALS AND METHODS: Tests with azo products were carried out, and whole cells were found able to easily degrade DMPD contrary to 4-ABS. However, this last could be attacked by cell extract, and an oxygen uptake was observed during the reaction. RESULTS: Degradation of DMPD by entire cells led to the formation of catechol. These results show that P. putida was able to decolorize AO52 and metabolize its derivative amines. In addition, the ability of tested compounds was evaluated in vitro to reduce human plasma butyrylcholinesterase (BuChE) activity. CONCLUSION: Azoreduction products seem to be responsible for BuChE inhibition activity observed in static biodegradation extract. However, toxicity of AO52 completely disappears after shaken incubation with P. putida, suggesting that bacterium has a catabolism which enables it to completely degrade AO52 and especially, to detoxify the dye mixture. PMID- 21557090 TI - Family social support, community "social capital" and adolescents' mental health and educational outcomes: a longitudinal study in England. AB - PURPOSE: To examine the associations between family social support, community "social capital" and mental health and educational outcomes. METHODS: The data come from the Longitudinal Study of Young People in England, a multi-stage stratified nationally representative random sample. Family social support (parental relationships, evening meal with family, parental surveillance) and community social capital (parental involvement at school, sociability, involvement in activities outside the home) were measured at baseline (age 13 14), using a variety of instruments. Mental health was measured at age 14-15 (GHQ 12). Educational achievement was measured at age 15-16 by achievement at the General Certificate of Secondary Education. RESULTS: After adjustments, good paternal (OR = 0.70, 95% CI 0.56-0.86) and maternal (OR = 0.65, 95% CI 0.53-0.81) relationships, high parental surveillance (OR = 0.81, 95% CI 0.69-0.94) and frequency of evening meal with family (6 or 7 times a week: OR = 0.77, 95% CI 0.61-0.96) were associated with lower odds of poor mental health. A good paternal relationship (OR = 1.27, 95% CI 1.06-1.51), high parental surveillance (OR = 1.37, 95% CI 1.20-1.58), high frequency of evening meal with family (OR = 1.64, 95% CI 1.33-2.03) high involvement in extra-curricular activities (OR = 2.57, 95% CI 2.11-3.13) and parental involvement at school (OR = 1.60, 95% CI 1.37-1.87) were associated with higher odds of reaching the educational benchmark. Participating in non-directed activities was associated with lower odds of reaching the benchmark (OR = 0.79, 95% CI 0.70-0.89). CONCLUSIONS: Building social capital in deprived communities may be one way in which both mental health and educational outcomes could be improved. In particular, there is a need to focus on the family as a provider of support. PMID- 21557091 TI - [Tendon transfer in pediatric foot deformities]. AB - Tendon transfer surgery plays a central role in the treatment of pediatric foot deformities. Tendon transfers are essential for balancing in neurogenic deformities but also important for the treatment of congenital or idiopathic deformities. Furthermore tendon transfer represents an important management tool for revision surgery of failed treatment in foot deformities. Complications and pit-falls which can potentially lead to failure may occur during the indications and planning of the transfer as well as during the surgery. The identification and analysis of possible pitfalls and complications as well as their management is the central issue of this article. Knowledge about possible problems and their management are essential for successful treatment of pediatric foot deformities. PMID- 21557092 TI - [Rheumatology for orthopedic / trauma surgeons]. PMID- 21557093 TI - Comparing the housing trajectories of different classes within a diverse homeless population. AB - The paper presents findings from a longitudinal study identifying different classes of homeless individuals in a mid-size Canadian city based on health related characteristics and comparing the housing trajectories of these classes 2 years later. Using data collected through in-person interviews with a sample of 329 single persons who have experienced homelessness, the paper presents results of a latent class analysis. Results found four distinct latent classes characterized by different levels of severity of health problems--i.e., a class of individuals who are "Higher Functioning" (28.7%), a second class with "Substance Abuse Problems" (27.1%), a third class with "Mental Health Substance Abuse Problems" (22.6%), and a fourth class with "Complex Physical and Mental Health Problems" (21.6%) that included having diminished physical functioning, multiple chronic physical health conditions, mental health difficulties, and in some cases substance abuse problems. Follow-up interviews with 197 of these individuals (59.9%) 2 years later showed the class of individuals with substance abuse problems experiencing the greatest difficulty in exiting homelessness and achieving housing stability. Implications of these findings for social policy development and program planning are discussed. PMID- 21557095 TI - Therapy with omalizumab for patients with severe allergic asthma improves asthma control and reduces overall healthcare costs. AB - BACKGROUND: Patients with asthma who have persistent symptoms despite treatment with inhaled steroids and long-acting beta agonists are considered to have severe asthma. Omalizumab is a monoclonal antibody directed against IgE, which is used as an add-on treatment for patients who have severe persistent allergic asthma. AIMS: The aim of this study was to assess the clinical benefit and healthcare utilisation of patients who responded to omalizumab therapy and to establish an overall cost implication. METHODS: This was an observational retrospective cohort study designed to investigate the effect of omalizumab on exacerbations of asthma before and after 6 months of treatment in Irish patients. RESULTS: Centres who had treated patients with severe allergic asthma for the 6 months prior and post omalizumab treatment were audited with a standardised assessment tool. Sixty three (32 male) patients were studied. In the 6 months prior to omalizumab 41 of 63 (66%) had been hospitalised, and this fell to 15 of 63 (24%), p < 0.0001 in the 6 months after treatment was started. Hospital admissions reduced from 2.4 +/ 0.41 to 0.8 +/- 0.37 and the mean number of bed days occupied was reduced from 16.6 +/- 2.94 to 5.3 +/- 2.57 days, p < 0.001. The number of oral corticosteroid doses used fell from 3.1 +/- 0.27 to 1.2 +/- 0.17, p < 0.001. The overall cost saving per omalizumab responder patients for 6 months was 834. CONCLUSIONS: Six months therapy with omalizumab reduced the number of bed days, the number of hospitalisations and the use of oral corticosteroids compared to the 6 months prior to commencement. Despite the cost of the additional therapy there were overall savings in health costs. PMID- 21557096 TI - Estimation of the lifetime risk of hip fracture for women and men in Canada. AB - In Canada in 2008, based on current rates of fracture and mortality, a woman or man at age 50 years will have a projected lifetime risk of fracture of 12.1% and 4.6%, respectively, and 8.9% and 6.7% after incorporating declining rates of hip fracture and increases in longevity. INTRODUCTION: In 1989, the lifetime risk of hip fractures in Canada was 14.0% (women) and 5.2% (men). Since then, there have been changes in rates of hip fracture and increased longevity. We update these estimates to 2008 adjusted for these trends, and in addition, we estimated the lifetime risk of first hip fracture. METHODS: We used national administrative data from fiscal year April 1, 2007 to March 31, 2008 to identify all hip fractures in Canada. We estimated the crude lifetime risk of hip fracture for age 50 years to end of life using life tables. We projected lifetime risk incorporating national trends in hip fracture and increased longevity from Poisson regressions. Finally, we removed the percentage of second hip fractures to estimate the lifetime risk of first hip fracture. RESULTS: From April 1, 2007 to March 31, 2008, there were 21,687 hip fractures, 15,742 (72.6%) in women and 5,945 (27.4%) in men. For women and men, the crude lifetime risk was 12.1% (95%CI, 12.1, 12.2%) and 4.6% (95%CI, 4.5, 4.7%), respectively. When trends in mortality and hip fractures were both incorporated, the lifetime risk of hip fracture were 8.9% (95%CI, 2.3, 15.4%) and 6.7% (95%CI, 1.2, 12.2%). The lifetime risks for first hip fracture were 7.3% (95%CI, 0.8, 13.9%) and 6.2% (95%CI, 0.7, 11.7%). CONCLUSIONS: The lifetime risk of hip fracture has fallen from 1989 to 2008 for women and men. Adjustments for trends in mortality and rates of hip fracture with removing second fractures produced non-significant differences in estimates. PMID- 21557097 TI - Treatment outcome of 42 replanted permanent incisors with a median follow-up of 2.8 years. AB - AIM: To evaluate the treatment outcome of avulsed and replanted permanent incisors. MATERIAL AND METHODS: 42 avulsed and replanted permanent incisors in 37 individuals were followed over a median observation period of 2.8 years (range: one year to five years). The mean age was 16.3 years at the time of replantation, with 81% of patients being younger than 20 years. RESULTS: The tooth survival rate after replantation was 83.3% (35/42 teeth). Periodontal healing was observed in 20 teeth. External root resorption was the most frequent complication and was found in 22 of the 42 avulsed teeth: 21 teeth had replacement resorption. Of these 21 teeth, 14 teeth were still in situ at time of recall examination, seven teeth had to be extracted during the follow-up period due to progressive replacement resorption. One tooth had surface resorption. In contrast, infection related resorption could not be observed in this sample. With regard to periodontal healing, no differences were found between teeth with short (less than 14 days) versus prolonged duration of splinting. Higher incidence of replacement resorption correlated with the extended duration of non-physiologic extraoral storage. CONCLUSION: Use of a strict endodontic treatment protocol after replantation minimized the risk of infection-related root resorption. The occurrence of replacement resorption was mainly influenced by the duration of the non-physiologic extraoral storage time and storage medium. PMID- 21557098 TI - Scholarship and residency programs. PMID- 21557099 TI - Scholarly activity in family medicine residency programs: a national survey. AB - BACKGROUND AND OBJECTIVES: In 2006, the Family Medicine Review Committee (RC) began requiring resident scholarly activity. This study sought to (1) determine how resident scholarly activity requirements and productivity changed after this alteration, (2) delineate characteristics of scholarship within family medicine residencies, and (3) determine the factors within programs that are associated with resident scholarly productivity. METHODS: We sent a 38-item electronic survey to all 450 US family medicine program directors. Multivariate analysis was performed to determine significant predictors of scholarship. RESULTS: Fifty-five percent of surveys were returned; 42.8% of programs modified scholarship requirements after 2006, and 48.6% required resident scholarship in 1997 versus 89.6% in 2009. A total of 76.6% have research curricula versus 51.5% in 1997; 87.5% report that <25% of residents authored publications within 2 years, yet 46.1% of programs report >50% of residents conducted research during that same time. Three factors were associated with >=25% of residents publishing within 2 years: "Residency director publishing" (OR=4.1, 95% CI=1.5-11.5), ">=6 faculty publications within 2 years" (OR=7.8, 95% CI=3.0-20.3), and "Residency opened before 1980" (OR=3.7, 95% CI=1.4-9.6). Five factors were associated with participation by >=50% of program's residents in a research project: "Resident recognition for scholarship" (OR=2.2, 95% CI=1.1-4.1), "Dedicated resident time for research" (OR=2.3, 95% CI=1.2-4.4), "Local Research Day" (OR=2.5, 95% CI=1.3 5.1), "Academic advancement linked to scholarship" (OR=1.9, 95% CI=0.9-3.9), and "Residency director performs research" (OR=2.7, 95% CI=1.4-5.1). CONCLUSIONS: Many family medicine residency programs have increased resident scholarly activity requirements since 2006. To date, these changes have not increased scholarly output, and most programs have low resident scholarship. This study confirms that dedicating resources and time to research combined with active faculty scholarship will likely increase resident scholarly production. PMID- 21557100 TI - 2011 ACGME duty hour week proposal--a national survey of family medicine residents. AB - BACKGROUND AND OBJECTIVES: In July 2010, the Accreditation Council for Graduate Medical Education (ACGME) published its proposed duty-hour regulations. We conducted a national online survey to assess current family medicine residents' perceptions of the proposed changes. METHODS: A 27-question survey was used to assess four ACGME proposal domains: resident supervision, 80-duty-hour week, maximum duty-period length, and maximum frequency of in-hospital duty. Additionally, we surveyed opinions on reasonable weekly work hours, under reporting practice, and residents' activities during hours off, residents' perceptions of their program's ability to comply with future duty-hour regulations, and their overall satisfactions. Members of the Association of Family Medicine Residency Directors (AFMRD) were invited to send the survey Web link to their residents. RESULTS: Out of 720 respondents, 30% supported revision of current duty-hour work rules; 58% disagreed with limiting interns' working hours to 16 hours per day; 48% perceived revision of resident supervision favorably; 26% expressed concern about continuing the current 80-duty-hour week rule; 75% supported limiting night duty to six consecutive nights; 83% agreed that reasonable resident weekly work hours should be 60-80 hours; and 18% admitted under-reporting of duty hours. Residents' hours off activities varied. Only 57% believed that their program will be able to implement the new changes effectively. Overall satisfaction with the future duty-hour rules were mixed: very satisfied (7%), satisfied (24%), somewhat satisfied (27%), unsatisfied (23%), and very unsatisfied (18%). CONCLUSIONS: Support for the proposed ACGME duty-hour regulations was mixed among current family medicine residents. Respondents and residency program directors shared similar concerns about some of the recommended changes. PMID- 21557101 TI - Rethinking professionalism in medical education through formation. AB - BACKGROUND: Contemporary educational approaches to professionalism do not take into account the dominant influence that the culture of academic medicine has on the nascent professional attitudes, beliefs, and behaviors of medical learners. This article examines formation as an organizing principle for professionalism in medical education. Virtue, the foundation to understanding professionalism, is the habits and dispositions that are fostered in individuals but that are embedded in learning environments. Formation, the ongoing integration of an individual, growing in self-awareness and in recognition of a life of service, with others who share in the common mission of a larger group, depicts this process. One model of formation considers a continuum from novice to more advance stages that is predicated on rules that must be applied in greater contextually shaped situations. Within medical education, formation is the process by which lives of service are created and sustained by learning communities that promote human capacities for intuition, empathy, and compassion. An imagined curriculum in formation would link the lived experiences of mentors and learners with an interdisciplinary set of didactic materials in an intentionally progressive fashion. PMID- 21557102 TI - Conscientious refusal in family medicine residency training. AB - BACKGROUND AND OBJECTIVES: Conscientious refusal among physicians to provide medical care is known to exist. The prevalence of conscientious refusal in residents and behaviors surrounding moral objections is largely unknown. The purpose of this study was to identify the prevalence of moral objections among family medicine residents and faculty members and to identify beliefs and actions surrounding conscientious refusal. METHODS: A Web-based survey was e-mailed to residents and faculty in six family medicine residency programs. Those respondents identifying a moral objection were asked about their beliefs and practices regarding disclosure and referral. RESULTS: A total of 154 physicians responded (44.9% response rate).The majority reported a moral objection to at least one procedure with abortion for gender selection eliciting the largest number of moral objections (79.2%). Of the 14 procedures identified, at least four respondents (2.6%) reported an objection. The majority believed that a physician with a moral objection has a duty to disclose his or her objection to colleagues, but the majority had not done so. Resident and faculty physicians were generally felt to have the same right to refuse. Fifty-five percent of all respondents reported having participated in morally objectionable care based on medical futility. CONCLUSIONS: This study is the first to demonstrate the prevalence of moral objection to legally available medical procedures among family medicine residents and faculty. The survey responses demonstrate that conscientious objection exists and that there is support for physicians exercising moral objection in clinical practice, provided they engage in appropriate patient education and referral. PMID- 21557103 TI - Adult learning models for large-group continuing medical education activities. AB - BACKGROUND: Despite evidence suggesting that other learning modalities are more effective, large-group continuing medical education (CME) activities continue to be predominantly lecture based. METHODS: Using convenience sampling, a cross sectional survey was administered to health care professionals attending the 2009 American Academy of Family Physicians (AAFP) Scientific Assembly. Participants were asked to describe their preferred learning format for CME activities. Participants were asked which formats they felt were most effective in helping them retain information or change their medical practice. RESULTS: Nearly half (46%) of sampled respondents indicated that they prefer lecture-based format for CME activities. Interestingly, interactive (39%) and procedural (27%) formats were more effective than lecture (24%) in helping health care professionals retain information. A similar response pattern was noted for which CME activities were more likely to change individual practice patterns. More physicians correctly answered board-type questions when attending interactive sessions compared with traditional lectures. DISCUSSION: Health care professions prefer traditional lecture-based format CME activities but recognize that interactive sessions are more effective, helping them to retain information and change practice behaviors. Interactive sessions are equal or superior to lecture in short-term knowledge acquisition. CME planners should take these findings into consideration when organizing large-group CME activities. PMID- 21557104 TI - Why do physicians order unnecessary preoperative tests? A qualitative study. AB - BACKGROUND: Routine preoperative testing is ineffective and costly. We explored reasons for the continued use of unnecessary preoperative tests and approaches to limit such testing. METHODS: We interviewed 23 physicians and nurse administrators involved in preoperative decision-making in our local health care environment. We conducted interviews using a semi-structured format and analyzed the data using a template organizing style. RESULTS: Some interviewees feel routine preoperative tests are beneficial, others are ambivalent about preoperative tests in their practice, and many believe there is considerable unnecessary testing. As interviewees discussed factors that lead to the ordering of unnecessary preoperative tests, five major themes emerged: practice tradition, belief that other physicians want the tests done, medicolegal worries, concerns about surgical delays or cancellation, and lack of awareness of evidence and guidelines. Interviewees suggested that a consensus guideline, improved education, and increased collaboration between specialities could decrease unnecessary testing. CONCLUSIONS: Our qualitative findings demonstrate barriers to limiting unnecessary preoperative testing but also suggest interventions that could improve the preoperative testing process. Minimizing unnecessary preoperative tests could decrease cost, maximize quality, and improve the patient experience. PMID- 21557105 TI - Reasons for preferring a primary care physician for care if depressed. AB - BACKGROUND: Most studies showed that patients would first go to their primary care physicians (PCPs) when depressed. This choice is probably due to PCP being the entry point into the health care system. We studied the general population's initial choice of mental care in Hong Kong, where patients were unclear about family medicine and free to choose doctors of any specialty. METHODS: A combined qualitative and quantitative approach was adopted. We held focus groups with participants recruited from community centers and a telephone survey with adults ages 18 or above randomly selected from the domestic telephone directory. RESULTS: Of 1,647 adults successfully interviewed, 49.0% would seek help from their regular PCP, 19.3% from psychiatrists, 4.8% from any doctors, 16.5% from non-medical resources; 6.9% would not seek any help, and 3.5% were uncertain of what to do. Those who did not seek any help were more likely to be male or without regular doctors. The focus group participants highlighted the stigmatizing effect of consulting psychiatrists and expressed strong expectation of empathic relationship, time, and communication skills from their care providers. Some participants were not aware that PCP could manage mental illness. CONCLUSIONS: Given free choice of health care service, most people would first consult their regular doctors for treatment of depression specifically because of better relationship and no stigmatization. To draw depressed patients to seek help, especially from primary care, public education of the PCPs role in mental health should be promoted, and the PCPs could demonstrate their empathy and listening skills to patients. PMID- 21557106 TI - The value of personal health records for chronic disease management: what do we know? AB - BACKGROUND AND OBJECTIVES: Electronic personal health records (PHRs) allow patients access to their medical records, self-management tools, and new avenues of communication with their health care providers. They will likely become a valuable component of the primary care Patient-centered Medical Home model. Primary care physicians, who manage the majority of chronic disease, will use PHRs to help patients manage their diabetes and other chronic diseases requiring continuity of care and enhanced information flow between patient and physician. In this brief report, we explore the evidence for the value of PHRs in chronic disease management. METHODS: We used a comprehensive review of MEDLINE articles published in English between January 2000 and September 2010 on personal health records and related search terms. RESULTS: Few published articles have described PHR programs designed for use in chronic disease management or PHR adoption and attitudes in the context of chronic disease management. Only three prospective randomized trials have evaluated the benefit of PHR use in chronic disease management, all in diabetes care. These trials showed small improvements in some but not all diabetes care measures. All three trials involved additional interventions, making it difficult to determine the influence of patient PHR use in improved outcomes. CONCLUSIONS: The evidence remains sparse to support the value of PHR use for chronic disease management. With the current policy focus on meaningful use of electronic and personal health records, it is crucial to investigate and learn from new PHR products so as to maximize the clinical value of this tool. PMID- 21557107 TI - Wednesdays with Maureen. PMID- 21557108 TI - Gifts traumatic brain injury brought me. PMID- 21557109 TI - Eight months and 35 seconds. PMID- 21557110 TI - Gayle Stephens and Festschrift. PMID- 21557111 TI - Biologics in rheumatoid arthritis--recommendations for Swiss practice. AB - The new paradigm of therapy in rheumatoid arthritis is to aim toward early and complete remission, using a larger use of conventional DMARDs and biologic agents. The present recommendations were established through a consensus to help practitioners in their daily use of those agents, to reflect the current "best practice" in Switzerland. PMID- 21557112 TI - Chronic liver inflammation and hepatocellular carcinoma: persistence matters. AB - Inflammatory responses in the liver--a central constituent of hepatic wound healing--can be self-limited or persistent depending on the aetiology, liver health state, concentration of toxins or pathogens, and the time frame of exposure to toxins or infection. In case the immune system eradicates a pathogen or in case toxin-exposure is transient, acute hepatitis resolves and the affected liver tissue regenerates ad integrum. However, in many cases liver damage remains chronic. Irrespective of the aetiology, chronic liver damage drives chronic hepatitis and hepatocyte death as well as compensatory proliferation, reflecting liver regeneration. Over time this potentially promotes further hepatic damage, fibrosis, cirrhosis and liver cancer. Here, we review the current knowledge on how chronic liver injury and inflammation is triggered and maintained, and how inflammation is linked to liver cancer. We also discuss the most frequently used animal models for damage or inflammation induced liver cancer and their suitability for conducting clinically relevant research. PMID- 21557113 TI - High-sensitive cardiac troponin: friend or foe? AB - Cardiac troponin I and T (cTn) are structural proteins unique to the heart. Detection of cTn in peripheral blood indicates cardiomyocyte necrosis. As acute myocardial infarction (AMI) is the most important cause of cardiomyocyte necrosis, cTns have become an integral part in the diagnosis of AMI. In this indication, cTns are superior to all other biomarkers indicating cardiomyocyte necrosis such as CK-MB and myoglobin, and are therefore considered the preferred marker in the diagnosis of AMI. It is important to highlight that cTn indicates and quantifies cardiomyocyte necrosis irrespective of its cause? The major limitation of contemporary cTn assays is a sensitivity deficit in the first few hours of AMI due to a delayed increase of circulating levels. Recent advances in assay technology have lead to a refinement in cardiac troponin (cTn) assays that have had a profound impact on clinical practice. High-sensitive cTn assays have two differentiating features from contemporary cTn assays: 1) detection of cTn in healthy persons and 2) a precise definition of what is "normal" (= the 99th percentile). Recent multicentre studies have shown that high-sensitive cTn assays improve the early diagnosis of AMI. To achieve the best clinical use, cTn has to be interpreted as a quantitative variable. Rising and/or falling levels differentiate acute from chronic cardiomyocyte necrosis. The term "troponin positive" should therefore be avoided. "Detectable" levels will become the norm and have to be clearly differentiated from "elevated" levels. The differential diagnosis of a small amount of cardiomyocyte necrosis and therefore mild elevation of cTn is broad and includes acute and chronic cardiac disorders. The differential diagnosis of a large amount of cardiomyocyte necrosis and therefore substantial elevation of cTn is much smaller and largely restricted to AMI, myocarditis and tako-tsubo cardiomyopathy. PMID- 21557114 TI - The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy. AB - OBJECTIVE: Various research programmes have shown that intraoperative infusion of remifentanil has been associated with postoperative hyperalgesia. Previous studies have demonstrated that low-dose ketamine can inhibit central sensitisation and prevent opioid-induced hyperalgesia (OIH). However, the optimal ketamine dose to prevent OIH has not been determined. In the present study we aimed to determine the ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy. METHODS: Fifty-four patients undergoing laparoscopic cholecystectomy were randomised into two groups: group C and group K. Group K was given ketamine before skin incision. An equal volume of normal saline was given to the patients in group C. Pain was assessed using visual analog scale (VAS) at 10 min after tracheal extubation. The ED50 and ED95 were determined by modified up-and-down method and the incidences of adverse effects were recorded. RESULTS: The incidences of adverse effects were similar in the two groups and the VAS score was significantly lower in group K than in group C. The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia were 0.24 mg/kg (95%CI, 0.20~0.30 mg/kg) and 0.33 mg/kg (95%CI, 0.28~0.62 mg/kg) respectively. CONCLUSIONS: The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy were 0.24 mg/kg and 0.33 mg/kg respectively. PMID- 21557115 TI - Chronic haemodialysis: the access determines the outcome? PMID- 21557117 TI - Activity experiences shape perceived fitness trajectories: results from a 6-month randomized controlled trial in older women. AB - In this study we addressed the subjective benefits of activity interventions that were designed to improve cognitive fitness in old age. Two hundred and fifty-nine women (aged 70-93 years) were randomized to participate in an exercise or a computer course or a control condition for 6 months. Subjective ratings of the perceived change of cognitive and physical fitness components were captured before, during, after the intervention interval, and at a 10-month follow-up. Positive and negative affect levels and objective cognitive fitness parameters served as possible covariates. Multilevel modeling revealed that the computer group rated memory and concentration as having improved at 4 months and again at 6 months. The exercise group, in contrast, perceived physical capacities as maintained or improved. The characteristics of the activity experience seem to determine the perceived fitness changes. We conclude that actual learning experiences improve one's self-concept of abilities. PMID- 21557118 TI - Dissociated deficits of visuo-spatial memory in near space and navigational space: evidence from brain-damaged patients and healthy older participants. AB - Defects confined to spatial memory can severely affect a variety of daily life activities, such as remembering the location of objects or navigating the environment, until now the skills involved have been mostly assessed with regard to the visual domain using traditional pencil and paper tests. Our aim was to test the efficacy of a recently developed psychometric instrument (Walking Corsi Test: WalCT) to assess the specific contribution of spatial memory to the complex task of retrieving route knowledge. The WalCT is a 3 * 2.5-m version of the well known Corsi Block-tapping Test (CBT), in which patients are required to memorize (and replicate) a sequence of body displacements. We assessed the ability of left and right brain-damaged patients, as well as healthy young and senior controls, to perform both the CBT and the WalCT. Results showed differences related to age in the healthy individuals and specific functional dissociations in the brain damaged patients. The double dissociations found in this study demonstrate the importance of having a task able to detect navigational disorders, because virtual reality tasks are often much too difficult for aged brain-damaged patients to perform. PMID- 21557119 TI - Spatial memory and executive functions in children. AB - A computerized hidden pathway maze-learning task was used to examine the development of spatial memory and executive functions in 6- to 9-year-olds. Pathway length was manipulated to investigate the impact of increases in maze matrix size on these abilities. Analysis showed that maze matrix size (and ipso facto pathway length) and age interacted to affect executive functions but not spatial memory. Executive errors differed as a function of age on the most difficult maze. Results are discussed in terms of factors affecting the development of executive functions and spatial memory. PMID- 21557120 TI - Revisiting the relation between contingency awareness and attention: evaluative conditioning relies on a contingency focus. AB - Although evaluative conditioning has occasionally been demonstrated in the absence of contingency awareness, many recent studies imply that its acquisition depends on the availability of attentional resources during conditioning. In previous experiments attention has typically been manipulated in a general way rather than looking at the particular focus of attention. The present study investigated the role of a focus on the CS-US contingency. Two separate distraction tasks were designed that either diverted attention from the stimuli or directed it to the stimuli while drawing attention away from the contingency between the stimuli. Both types of distraction were shown to eliminate evaluative conditioning. Significant evaluative conditioning was observed in a third group of participants who were required to attend the contingencies. A mediation analysis showed that the observed discrepancy in evaluative conditioning effects between groups was mediated by contingency awareness. The results imply that attention in terms of a stimulus focus is not sufficient for evaluative conditioning to occur. Rather, attention to the contingencies between stimuli appears to be crucial in evaluative conditioning, because it is supposed to foster the acquisition of contingency awareness. PMID- 21557121 TI - Face to face with emotion: holistic face processing is modulated by emotional state. AB - Negative emotions are linked with a local, rather than global, visual processing style, which may preferentially facilitate feature-based, relative to holistic, processing mechanisms. Because faces are typically processed holistically, and because social contexts are prime elicitors of emotions, we examined whether negative emotions decrease holistic processing of faces. We induced positive, negative, or neutral emotions via film clips and measured holistic processing before and after the induction: participants made judgements about cued parts of chimeric faces, and holistic processing was indexed by the interference caused by task-irrelevant face parts. Emotional state significantly modulated face processing style, with the negative emotion induction leading to decreased holistic processing. Furthermore, self-reported change in emotional state correlated with changes in holistic processing. These results contrast with general assumptions that holistic processing of faces is automatic and immune to outside influences, and they illustrate emotion's power to modulate socially relevant aspects of visual perception. PMID- 21557123 TI - Levels of PCDD/Fs, PCBs and PBDEs in butter from Turkey and estimated dietary intake from dairy products. AB - Polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs), dioxin-like and non dioxin-like (indicator) polychlorinated biphenyls (PCBs) and polybrominated diphenylethers (PBDEs) were monitored in butterfat obtained from 18 different areas in Turkey, both rural and industrial. The results obtained both at RIKILT in the Netherlands and in a food control laboratory in Turkey for PCDD/Fs and PCBs were in good agreement. The sum of PCDD/Fs+dl-PCBs, total indicator PCBs and PBDEs were in the range 0.26-3.82 pg TEQ g(-1) fat, 0.20-3.04 ng g(-1) fat and 0.18-5.00 ng g(-1) fat, respectively. Despite the very low levels measured, slightly elevated PCDD/F and PCB levels were found in Izmir-Aliaga, Kocaeli, Denizli, and Zonguldak. The only result exceeding the EU action level was the dl PCB concentration in Izmir-Aliaga. Ratios of PCDD/Fs and PCBs indicate that contamination in the elevated areas originated from different sources. High BDE 209 levels were detected in Mersin and Bursa. For the 18 regions analysed, the average total daily intake of total TEQ (dioxins and dl-PCBs) from butterfat was 0.09 pg TEQ(1998) (0.08 pg TEQ(2005)) kg(-1) body weight, while those for indicator PCBs and PBDEs were 58.8 and 35.1 pg kg(-1) body weight, respectively. The average total daily intake from dairy products were 0.26 pg TEQ(1998) (0.20 pg TEQ(2005)), 183 and 103 pg kg(-1) body weight, respectively. PMID- 21557124 TI - The influence of climate variables on dengue in Singapore. AB - In this work we correlated dengue cases with climatic variables for the city of Singapore. This was done through a Poisson Regression Model (PRM) that considers dengue cases as the dependent variable and the climatic variables (rainfall, maximum and minimum temperature and relative humidity) as independent variables. We also used Principal Components Analysis (PCA) to choose the variables that influence in the increase of the number of dengue cases in Singapore, where PC1 (Principal component 1) is represented by temperature and rainfall and PC2 (Principal component 2) is represented by relative humidity. We calculated the probability of occurrence of new cases of dengue and the relative risk of occurrence of dengue cases influenced by climatic variable. The months from July to September showed the highest probabilities of the occurrence of new cases of the disease throughout the year. This was based on an analysis of time series of maximum and minimum temperature. An interesting result was that for every 2-10 degrees C of variation of the maximum temperature, there was an average increase of 22.2-184.6% in the number of dengue cases. For the minimum temperature, we observed that for the same variation, there was an average increase of 26.1 230.3% in the number of the dengue cases from April to August. The precipitation and the relative humidity, after analysis of correlation, were discarded in the use of Poisson Regression Model because they did not present good correlation with the dengue cases. Additionally, the relative risk of the occurrence of the cases of the disease under the influence of the variation of temperature was from 1.2-2.8 for maximum temperature and increased from 1.3-3.3 for minimum temperature. Therefore, the variable temperature (maximum and minimum) was the best predictor for the increased number of dengue cases in Singapore. PMID- 21557125 TI - Injury prevention priority setting based on the National Injury Surveillance data in Korea. AB - For the reduction of injury burden, injury prevention efforts are essential. However, financial, material and human resources are far from sufficient, and this situation necessitates setting priorities for effective injury prevention. Hence, the aim of this study is to prioritise 13 injury mechanisms for prevention of injury using four injury burden criteria. National death certificate, hospital discharge data and emergency data during 2004 were used. According to the 13 most frequent injury mechanisms (ICD-10), mortality priority score, years of potential life lost (YPLL) priority score, morbidity priority score and hospital charge priority score were calculated. Injury mechanisms which were ranked fourth or higher on at least three of the four criteria scores were arranged in rank orders. Traffic crashes ranked highest on all four of the priority criteria for injury prevention followed by fall and poisoning in second and third positions, respectively. Categorised by age groups, in 0-19 year olds, traffic crashes, suffocation and drowning; in 20-59 years, traffic crashes, suffocation and poisoning; and in 60 and over, traffic crashes and fall were shown to be significant injury prevention priority in rank orders. Injury prevention priorities identified from this study could be useful in strategically allocating limited resources and implementing more focused prevention policies in Korea. PMID- 21557126 TI - A case-control study on risk factors of domestic accidents in an elderly population. AB - The aim of this study was to evaluate the combined influence of several lifestyle, health and housing factors in the occurrence of home injuries (HIs) among the elderly. The subjects were recruited from 10 hospitals in Rome, Italy. This study is a paired case-control study. Cases included subjects, aged 65-85 years, who visited the Emergency Department for an HI and were subsequently hospitalised (15 September 2004-30 June 2005). Controls were the subjects of the same gender, age (+/-3 years) and area of residence of cases. A conditional logistic regression model was used for analysing the variables obtained. In this study, we enrolled 107 hospitalised cases. It was found that the living room was the place where 33% of the accidents occurred. Eighty-seven per cent of the accidents were falls, and 33% of the accidents were the immediate consequence of sudden malaise. One-half of the cases reported one or more leg fractures. The variables that were independently associated with HI were poor household illumination, poor emotional status, regular physical activities and housekeeping activities. We conclude that this study shows the areas of intervention to target HI prevention activities. PMID- 21557127 TI - Parsimony for non-communicable disease prevention: a checklist. PMID- 21557128 TI - Short-term monitoring of formaldehyde: comparison of two direct-reading instruments to a laboratory-based method. AB - Airborne formaldehyde concentrations can be measured using several different techniques, including laboratory-based methods and direct-reading instruments. Two commercially available direct-reading instruments, an RKI Instruments Model FP-30 and a PPM Technology Formaldemeter htV, were compared with National Institute for Occupational Safety and Health Method 2016 in different test environments to determine if these direct-reading instruments can provide comparable results. The methods yielded the following mean concentrations for 47 samples: NIOSH Method 2016, 0.37 ppm; FP-30, 0.29 ppm; and htV, 0.34 ppm. Results from both of the direct-reading instruments were correlated with the laboratory based method (R2 = 0.78 for FP-30, and 0.902 for htV). Comparison of the means of the three methods showed that on average the FP-30 instrument (p < 0.001) differed statistically from NIOSH Method 2016, whereas the htV (p = 0.15) was not statistically different from the NIOSH method. Sensitivity and specificity tests demonstrated that the FP-30 had sensitivity above 60% to detect formaldehyde concentrations at all the cutoff levels tested, whereas the htV appeared to have greater sensitivity above 88% for the levels evaluated. PMID- 21557129 TI - Asymmetric sleep in rats. AB - Five Wistar rats were surgically implanted with cortical and parietal electrodes for conventional polysomnography to test for sleep-related EEG asymmetries during 48 hours of continuous recording. When the animals were grouped not according to right-left dominance (which would represent a population bias) but instead according to preferred vs non-preferred hemisphere, significant light/dark circadian changes in side dominance were found in delta power during NREM; in theta and beta power during REM; and in alpha 1, alpha 2, and theta power during wakefulness. The changes have been interpreted as a response to temporal variations in the capability to respond to environmental challenges. PMID- 21557130 TI - The original instructions for the Edinburgh Handedness Inventory are misunderstood by a majority of participants. AB - The Edinburgh Handedness Inventory (EHI) is the most widely used handedness inventory. This study examined the rate at which the EHI instructions were followed using a large sample (n = 423) of males who were administered the instrument. Using liberal criteria for response coding, it was determined that only 47.3% were able to follow the instructions completely. This is in contrast to 88.2% successfully following instructions on a different, Likert-style instrument administered concurrently. Participants' level of education and handedness significantly predicted their adherence to instructions. Implications for the use of the EHI are discussed. PMID- 21557131 TI - Modulating wheelchair navigation in patients with spatial neglect. AB - Patients who have had a stroke resulting in the deficit of visuo-spatial neglect are normally not provided with a powered wheelchair, as they are either considered or found to be unsafe navigating about their environment. As these patients are relatively unlikely to regain functional mobility by walking, the denial of alternative forms of mobility is of particular concern. Modest progress has been made over the past two decades with regards to the rehabilitation of neglect but there have been calls for further research which addresses "real world" measures of independence such as wheelchair navigation. In this study, we investigated the ability of patients with neglect to improve their performance when navigating a powered wheelchair by using theoretically-driven strategies that have shown promise in previous studies (spatial cueing and limb activation). Strategies were applied and tested in the most realistic and practical manner for each individual, based on their abilities and concurrent deficits. Performance was improved by the experimental strategies. The data suggest it is possible to apply theoretically-driven strategies to improve wheelchair navigation in patients with neglect and are supportive of further studies that could lead to improved access to powered mobility by this population in the future. PMID- 21557132 TI - Analysis of Cognitive Environmental Support (ACES): preliminary testing. AB - Although the environment can impact, or otherwise support, cognition, no measure currently exists to help the clinician identify items within the environment that may support cognition. To address this gap in the literature, the Analysis of Cognitive Environmental Support (ACES) was developed. Here, content validity, concurrent validity and inter-rater reliability were assessed, in parallel, for the ACES. Based on the findings, modifications were made to the tool, which is included in an effort to initiate further research regarding its clinical utility. PMID- 21557134 TI - Increasing calcium intake in young women through gain-framed, targeted messages: a randomised controlled trial. AB - BACKGROUND: Adequate calcium consumption during early adulthood can help prevent osteoporosis in women. PURPOSE: The effects of gain-framed, targeted messaging on calcium intake were examined over 12 months. METHODS: Young women (18-19 years) not consuming sufficient calcium were randomly assigned to receive standard care materials (control) or gain-framed, targeted materials (experimental). Health belief model (HBM) constructs, calcium intake and markers of bone formation, resorption and bone mineral density were assessed at various time points throughout the year. RESULTS: Calcium intake increased significantly more in the experimental versus the control condition (p < 0.01). Self-efficacy was the only HBM construct to improve significantly more in the experimental condition versus control (p = 0.05). The HBM did not mediate changes in calcium intake. Measures of bone health did not differ between conditions by the end of this nonpharmacological intervention (p's > 0.05). CONCLUSIONS: It is possible to increase young women's calcium consumption through gain-framed, targeted messages. PMID- 21557135 TI - What went wrong? Therapists' reflections on their role in premature termination. AB - The present study used Consensual Qualitative Research methodology to explore how experienced therapists understand and learn from impactful cases of premature termination. Eleven board certified psychologists were interviewed regarding a former client who left treatment prematurely. Participants were asked to reflect on client and therapist factors that may have contributed to premature termination, and on how the termination affected their work and professional development. Results indicated that therapist reactions and mistakes may contribute to the risk of premature termination, and that therapists may experience complex and lasting personal reactions to such outcomes. While they may face considerable uncertainty, therapists can learn valuable lessons by reflecting on departed clients. Implications for research and practice are discussed. PMID- 21557142 TI - [Airway complications following lung transplantation - clinic, diagnosis, and interventional management]. AB - Tracheobronchial complications following lung transplantation are defined as local structural or infectious alterations of the airways, which occur early or several months after lung transplantation (LTx). They preferentially develop in the region of the bronchial anastomosis. The most frequently reported complications are bronchial stenosis, bronchial dehiscence, exophytic excessive granulation tissue formation, tracheo-bronchomalacia, bronchial fistulas, and endobronchial infections. Airway complications are mainly attributed to ischaemia of the donor bronchus during the immediate post-transplant period. The most relevant risk factors for the development of airway complications include local infections, surgical techniques, and the immunosuppressive regimen. Thus, management of post-transplant bronchial complications requires early interventional bronchoscopic procedures including balloon bronchoplasty, cryotherapy, laser photoresection, endobronchial brachytherapy, and bronchial stents. In addition, antibiotic treatment, or non-invasive positive-pressure ventilation may be necessary. The procedures required depend on the time of occurrence, the type, and clinical relevance of the airway complication. This review summarises clinical presentation, risk factors, the diagnostic methods as well as management options for the most common LTx-associated airway complications. PMID- 21557143 TI - Assessment of the prognostic value of horner syndrome in perinatal brachial plexus palsy. AB - The aim of this study was to evaluate the prognostic value of Horner syndrome as an indicator of preganglionic injuries of the lower part of the brachial plexus. The study investigated 18 cases of children with perinatal brachial plexus injury and coexistent Horner syndrome. The following data sets were analyzed: the degree of severity of the brachial plexus injury, the results of imaging examinations, the intraoperative view, the kind of operative treatment and the resultant hand function. On the basis of a clinical material analysis, it was established that Horner syndrome accompanying upper and upper-middle brachial plexus injuries has no prognostic importance. In total injuries the presence of this syndrome is not a definite proof of preganglionic injury to the C8-Th1 roots of the spinal nerves. PMID- 21557144 TI - Long-term follow-up of pediatric patients treated with mitoxantrone for multiple sclerosis. AB - The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple sclerosis (MS) in adults. Its use, however, is limited by the risk of severe adverse events including cardiotoxicity, myelosuppression, liver toxicity and secondary leukemia. The aim of this retrospective study is to present data on the safety, tolerability and efficacy of mitoxantrone in a small cohort of children with MS. 4 pediatric MS patients with a high relapse rate or severe, disabling relapses were treated with mitoxantrone and followed for 3.8-18 years. The cumulative dose of mitoxantrone was 36, 68, 84 and 120 mg/m (2), respectively. The frequency and severity of relapses as well as disability scores, decreased in the year after treatment onset. Short-term adverse events were transient in all cases. Cardiac monitoring by transthoracic echocardiography (TTE) showed asymptomatic left ventricular dysfunction during treatment in 1 patient, which was again normal at the next assessment. Long-term adverse events, including late-onset mitoxantrone-induced cardiotoxicity or secondary leukemia did not occur during the follow-up period. In our cohort of pediatric MS patients, mitoxantrone showed short-term reduction of disease activity and no long-term adverse events on follow-up. However, the risk of mitoxantrone-induced cardiotoxicity or toxic leukemia remains a life-long threat. PMID- 21557145 TI - Cutaneous, mediastinal and hepatic hemangiomas in a girl followed during 12 years. AB - We present in this paper the case of a 12-year-old girl who had the clinical features of 2 different disorders: neurofibromatosis 1 (NF1) and 3 hemangiomas located in the skin, liver and mediastinum. The patient did not receive any specific treatment and showed a normal progressive evolution that lasted 1 / to 2 years and a very slow regression that lasted for a more prolonged time than expected (the 3 hemangiomas have not completely disappeared yet), although all 3 have been asymptomatic. MRI of the brain did not disclose a hemangioblastoma of the cerebellum or any other vascular lesion of the brain. Mental development of this girl was in the borderline range, as is commonly seen in Pascual-Castroviejo II syndrome (P-CIIS)/PHACE syndrome and in NF1, 2 syndromes which have not been reported to be associated in the same patient previously. PMID- 21557146 TI - Epilepsy with myoclonic absences - favourable response to add-on rufinamide treatment in 3 cases. AB - BACKGROUND: Epilepsy with myoclonic absences (EMA) is a rare epileptic syndrome with frequently poor response to antiepileptic treatment. Rufinamide (RUF) is a relatively new EMEA- and FDA-approved anticonvulsant licensed as an orphan drug for the adjunctive treatment of patients with Lennox-Gastaut syndrome. METHODS: A retrospective data analysis in 3 patients was performed. RESULTS: Add-on RUF treatment was initiated in 3 boys with EMA refractory to conventional antiepileptic therapy (primidone + valproic acid, n=1; levetiracetame + ethosuximide, n=2). It resulted in complete cessation of all seizures in 2, and a 50% reduction of the seizure frequency in one child, respectively. CONCLUSIONS: RUF add-on therapy should be considered in children with EMA not responding to conventional antiepileptic therapy. PMID- 21557147 TI - Contrast enhancement of brainstem tracts in Zellweger spectrum disorder: evidence of inflammatory demyelination? AB - Zellweger spectrum disorder, resulting from mutations in the peroxisome assembly mechanism, is genetically heterogeneous and phenotypically varied in disease characteristics and severity. In addition to manifesting gyration anomalies, affected individuals typically have white matter abnormalities ranging from hypomyelination in infancy to a more diffuse demyelinating leukoencephalopathy pattern in those surviving into childhood. Here we report a unique presentation in a 2/-year-boy with acute neurological deterioration and MRI demonstrating avid contrast enhancement suggesting inflammatory demyelination in the brainstem. PMID- 21557148 TI - [Coping strategies and health-related quality of life in multiple sclerosis patients]. AB - In the last years there has been a growing interest in self assessment of Health related quality of life (HRQOL). Studies show a reduced HRQOL in patients with Multiple Sclerosis (MS). A sample of n=3 157 members of the German Multiple Sclerosis Association (71.7% women, aged 48.2 years on average) was analyzed regarding the correlation between coping styles and HRQOL in MS patients. The findings show reduced HRQOL in MS patients in comparison to the general population in West Germany. MSQOL-54- and MSIS-29-sumscales and FKV-LIS-scales "depressive coping" and "minimizing importance" correlate significant: a depressive or trivializing coping style accompanies with reduced mental and physical HRQOL. PMID- 21557149 TI - Involvement of nitric oxide in corticosterone release and glucose metabolism in food deprived rats. AB - This study was performed to investigate the involvement of nitric oxide (NO) in corticosterone, endpoint product of hypothalamo-pituitary-adrenal (HPA) axis activation, and metabolic responses to 3 days of food deprivation. To investigate this aim, we used a nonspecific inhibitor of nitric oxide synthases, N-nitro- L arginine methyl ester (L-NAME). In food deprived group we have noted a significant increase in plasma corticosterone concentration accompanied by a significant depletion in hepatic glycogen content with concomitant increase in glycogen phosphorylase (GP) activity by 63.72%, key enzyme of glycogenolysis and decrease in hexokinase (HK) activity by 25.16%, leading to significant decrease in glucose concentration. However, L-NAME administration in food deprived rats decreased slightly corticosterone level and GP activity (16.39%) and increased HK activity (11.26%) as compared to food deprived group. Considering these results, we can deduce that in food deprivation nitric oxide is involved in the regulation of corticosterone release and in glucose metabolic responses via glycogenolysis activation by the stimulation of GP activity and the inhibition of HK activity. However, more studies are necessary to further clarify the mechanisms by which NO induces these responses. PMID- 21557150 TI - Supraphysiological triiodothyronine doses diminish leptin and adiponectin gene expression, but do not alter resistin expression in calorie restricted obese rats. AB - Thyroid hormones regulate energy balance and act on adipokines. However, while it is unclear what the effects are of calorie restriction and high doses of triiodothyronine (T(3)) on adipokines in obesity, thyroid hormones are illicitly administered in isolation or in association with a hypocaloric diet as an obesity treatment. The present study determined the effect of T(3) on serum concentrations and gene expression of the adipokines leptin, resistin, and adiponectin in calorie-restricted obese rats. Male Wistar rats received a hypercaloric diet for 20 weeks followed by calorie restriction for 8 weeks. The animals were then randomly divided into 3 groups: calorie restriction (OR), OR with 5 MUg of T(3)/100 g BW (RS1), and OR with 25 MUg of T(3)/100 g BW (RS2) for 2 weeks. Blood and adipose tissue samples were collected for biochemical, hormonal, and gene expression analyses. Serum concentrations of leptin (OR: 3.7+/ 0.6, RS1: 3.8+/-1, RS2 0.2+/-0.07 ng/dl) and resistin (OR: 2.5+/-0.6, RS1: 2.5+/ 0.5, RS2 1.6+/-0.3 ng/dl) were diminished at the higher dose, while serum adiponectin (OR: 31+/-7, RS1: 24+/-5, RS2 26+/-7 ng/dl) levels were lower in the low dose group. Administration of T(3) reduced leptin gene expression (OR: 0.91+/ 0.1, RS1: 0.95+/-0.1, RS2 0.22+/-0.1) only at the higher dose, resistin expression (OR: 1.06+/-0.2, RS1: 1.04+/-0.1, RS2 0.88+/-0.2) was not influenced by T(3) treatment, and adiponectin expression (OR: 1.55+/-0.5, RS1: 0.95+/-0.15, RS2 0.97+/-0.13) was diminished independent of the T(3) dose. These results indicate that T(3), directly or indirectly, inhibits the expression of leptin and adiponectin in calorie restricted obese animals. PMID- 21557151 TI - Inhibition of insulin degrading enzyme by racecadotril in the brain of Wistar rats. AB - Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i. c. v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K (ATP) channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i. c. v. pretreatment with insulin antibody or glibenclamide. Also, i. c. v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K (ATP) channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain. PMID- 21557152 TI - Bone and cellular immune system of multiparous sows are insensitive to ovariectomy and nutritive calcium shortage. AB - Research in osteoporosis, which is a complex systemic disease, demands suitable large animal models. In pigs, most research has been done in growing minipigs, which probably are not ideal models for postmenopausal osteoporosis. Therefore, our aim was to analyze the effects of ovariectomy (OVX) and nutritive calcium shortage on multiparous Large White sows. 32 animals were randomly assigned to 4 groups in a cross design with OVX vs. sham and physiological calcium supplementation (0.75% calcium) vs. dietary calcium shortage (0.3% calcium). The observation period was 10 months with blood sampling every 2 months for hematological, immunological, and biochemical bone marker measurements. At the termination of the experiment, animals were sacrificed. Samples of trabecular bone of distal radius, proximal tibia, and sixth lumbar vertebra were subjected to micro-computed tomography imaging and ashed afterwards. Dual X-ray absorptiometry scans of the proximal femora were performed with prepared bones being placed in a water bath for mimicking soft tissue. Analyses of bone marker and cytokine profile kinetics, distribution of leukocyte subpopulations, and morphometrical and densitometrical analyses showed no evidence of any impact of OVX or calcium shortage. In conclusion, the skeleton of adult sows of a conventional breed is seemingly protected from effects of OVX and calcium shortage. PMID- 21557153 TI - Serious complication following use of StomaphyX. PMID- 21557154 TI - Visible peritoneal catheter during colonscopy. PMID- 21557155 TI - A novel hybrid technique using transanal endoscopic microsurgery and balloon dilation in the treatment of a benign complete colorectal anastomotic stricture. PMID- 21557156 TI - Bronchobiliary fistula as a complication after long-term stenting of hepatic ducts, applied by ERCP after hepatobiliary surgery due to hydatid cyst. PMID- 21557157 TI - Detection of mucin-hypersecreting bile duct tumor by direct peroral cholangioscopy. PMID- 21557158 TI - Endoscopic ultrasound-guided transgastric pancreatic duct drainage after Whipple surgery in a patient with chronic pancreatitis. PMID- 21557159 TI - Pseudostratified ciliated metaplasia of the distal esophagus diagnosed at adolescence. PMID- 21557160 TI - Clinical use of lymphangiography for intractable spontaneous chylothorax. AB - OBJECTIVES: Aim of this study was to discuss the clinical value of lymphangiography for intractable spontaneous chylothorax. METHODS: From 2002 to 2009, 15 cases of intractable spontaneous chylothorax underwent lymphangiography in two institutions. Patient history, imaging data, therapeutic options and follow-up were recorded and retrospectively analyzed. RESULTS: Twelve cases had successful lymphangiography while lymphangiography failed in the other 3 cases. No procedure-related complications occurred. Lymphangiography was useful for the diagnosis of lymphatic vessel disease and underlying disease in 6 (50 %) cases, but the etiology in the remaining 6 cases (50 %) remained uncertain. Signs of leakage or contrast extravasation were directly detected in 5 (42 %) patients. Based on the lymphangiography findings, 5 cases underwent surgical intervention with satisfactory results, with one recurrence 5 years later. Two patients had steatorrhea and chyluria after successful thoracic duct ligation. Seven cases were treated conservatively, 5 of whom were cured while the other 2 cases had temporary remission of symptoms. CONCLUSIONS: Lymphangiography can help to diagnose lymphatic vessel disease and underlying diseases, localize the leakage site for surgical therapy and prevent unnecessary surgical interventions. It may also play a role in occluding the leakage site and predicting the occurrence of adverse events due to thoracic duct ligation. We recommend lymphangiography in patients with intractable spontaneous chylothorax. PMID- 21557161 TI - Approach to patients with chylothorax complicating pulmonary resection. AB - Mediastinal lymph node dissection, an important part of surgery for non-small cell lung cancer, is associated with a risk of chylothorax. Although mortality has significantly decreased in recent years, it still worries thoracic surgeons. In this report we reviewed our experience on chylothorax with 26 cases and assessed the outcomes after conservative and surgical approaches. Between January 2000 and June 2010, twenty-six patients developed chylothorax after pulmonary resection performed for non-small cell lung cancer. Initially, all cases were treated conservatively with cessation of oral intake and the application of talc poudrage. If the conservative method failed, a surgical approach was used, which consisted either of suturing the leak or of mass ligation. The mean age of patients was 56 +/- 9.05 years, and 3 were female. Chylothorax was more common on the right side, in lobectomy cases, in cases with adenocarcinoma, and in patients with advanced stage lung cancer, but the difference did not reach statistical significance. Conservative treatment was successful in 19 of 26 (73 %) patients, four of whom had undergone pneumonectomy. Seven out of 26 cases (27%) required thoracotomy to control the chylous leak. Though thoracotomy was required mostly for the right side (6 right vs. 1 left, p = 0.15), and in patients who had had pneumonectomy as their first operation (4 patients vs. 3, p = 0.18), this did not reach statistical significance. No patient died as a result of surgical intervention. In conclusion, chylothorax is not rare after pulmonary resection performed for lung cancer. But it is not as dangerous as it used to be. Talc pleurodesis has increased the success of conservative management and minimized the need for surgical intervention. In cases of high output leak the surgeon should not hesitate to perform surgery. VATS can be performed instead of open surgery in suitable cases. PMID- 21557162 TI - Congenital heart surgery: expected versus observed surgical performance according to the Aristotle complexity score. AB - BACKGROUND: The Aristotle score quantifies the complexity involved in congenital heart surgery. It defines surgical performance as complexity score times hospital survival. We studied how expected and observed surgical performance evolved over time. METHODS: 2312 main procedures carried out between 2006 and 2010 were analyzed. The Aristotle basic score, corresponding hospital survival and related observed surgical performance were estimated. Expected survival was based on the mortality risks published by O'Brien and coauthors. Observed performance divided by expected performance was called the standardized ratio of performance. This should trend towards a figure above 100%. Survival rates and performance are given with 95% confidence intervals. RESULTS: The mean Aristotle basic score was 7.88 +/- 2.68. 51 patients died: observed hospital survival was 97.8 % (97.1 % 98.3%). 115 deaths were anticipated: expected survival was 95.2% (93.5%-96.3%). Observed and expected surgical performance reached 7.71 (7.65-7.75) and 7.49 (7.37-7.59), respectively. Therefore the overall standardized ratio of performance was 102.94%. The ratio increased from 2006 (ratio = 101.60%) to 2009 (103.92%) and was 103.42% in 2010. Performance was high for the repair of congenital corrected transposition of the great arteries and ventricular septal defect (VSD) by atrial switch and Rastelli procedure, the Norwood procedure, repair of truncus arteriosus, aortic arch repair and VSD closure, and the Ross Konno procedure, with corresponding standardized ratios of 123.30%, 116.83%, 112.99%, 110.86% and 110.38%, respectively. With a ratio of 82.87%, performance was low for repair of Ebstein's anomaly. CONCLUSION: The standardized ratio of surgical performance integrates three factors into a single value: procedure complexity, postoperative observed survival, and comparison with expected survival. It constitutes an excellent instrument for quality monitoring of congenital heart surgery programs over time. It allows an accurate comparison of surgical performance across institutions with different case mixes. PMID- 21557163 TI - Persistent left fifth aortic arch with pentalogy of Fallot. AB - Congenital double-lumen aortic arch resulting from persistence of the fifth aortic arterial arch (PFAA) is a rare congenital anomaly. It appears as a vascular structure running inferior and parallel to the "real" aortic arch from the innominate artery to the left subclavian artery. We report a case of persistent fifth aortic arch (systemic-to-systemic arterial connection) with pentalogy of Fallot in a patient who underwent successful intracardiac repair with a transannular patch with very proximal aortic cannulation for cardiopulmonary bypass (CPB). PMID- 21557164 TI - Bartonella quintana endocarditis of the tricuspid and mitral valves. AB - Bartonella quintana is a gram-negative microorganism that can lead to culture negative infective endocarditis (IE) in immunocompromised patients. Here, we present an exceptionally rare case of a 70-year-old male with Bartonella quintana associated IE primarily limited to the tricuspid valve that spread to the mitral valve after tricuspid valve replacement. This was then complicated by infective spondylodiscitis of the thoracic vertebrae, ultimately resulting in death due to cardiac arrest. PMID- 21557165 TI - [Osteopathy--part of scientific medicine or paramedical method?]. PMID- 21557166 TI - [Irritable bowel syndrom--a misnomer?]. PMID- 21557167 TI - Removal of over the scope clips (OTSC) with an Nd:YAG Laser. AB - Until recently there has been no technique available which reproducibly and safely allows endoscopic closures of penetrating defects within the digestive tract. With the new "over the scope clipping system" (OTSC system), which regarding design and function is similar to a bear-trap, a method is available for the endoscopic closure of fistulas and perforations. The OTSC-systems are designed for permanent placement. However, in the case of misplacement or the need to remove the clip after healing of the defect, a technique for destroying and removing the clip should be available. We demonstrate for the first time the successful removal of the deeply penetrating OTSC system by using the Nd:YAG Laser in 3 cases: (i) after closure of an oesophageal fistula, (ii) after closure of a perforation of the distal common bile duct in the roof of the papilla and (iii) after clip misplacement in a case of a wide oesophagomediastinal fistula resulting in a severe oesophageal stenosis. Clinically relevant thermal lesions were not observed after the procedure. If clinically necessary, the OTSC-system can be safely removed by the Nd:YAG Laser in centres for interventional endoscopy. Because of the small number of cases the method must still be considered as experimental and requires further validation. This will be possible with the help of a newly established OTSC registry ( www.endodo.de ). PMID- 21557168 TI - [How physicians inform about colorectal cancer and screening]. AB - Screening colonoscopy is an efficient and safe instrument for the early detection of colonic neoplasia. The cumulative participation rate in Germany remains low with 15.5% of eligible men and 17.2% of eligible women. Reasons for this are not well understood. Especially physicians have an important role. The aim of this study was to analyse information and recommendations of primary care physicians, urologists and gynaecologists on colorectal cancer screening. A survey of 239 primary care physicians, urologists and gynaecologists by a structured questionnaire on information concerning colorectal cancer and colorectal cancer prevention was carried out. Statistical analysis was performed by pair-wise comparison of the three groups. There were only small differences between primary care physicians, urologists and gynaecologists. Primary care physicians offer patients more consulting time for this information than the other two groups. In the majority of cases colonoscopy is recommended. Gynaecologists less often recommend the classical guaiac-based faecal occult blood test, but more frequently immunochemical tests. The complication rate of colonoscopy is overestimated at 1.25% (0 - 40%). The majority of physicians have previously participated in colorectal cancer screening. Information about the risk of colorectal cancer and screening has a high priority. The level of knowledge of physicians may be improved. PMID- 21557169 TI - Peripapillary duodenal varices as a rare cause of severe bleeding in a patient with no other signs of portal hypertension--successful endoscopic treatment with cyanoacrylate injection. AB - Duodenal varices (DVs) are a rare cause of upper gastrointestinal bleeding and rather suspected in patients with portal hypertension. Bleeding DVs are difficult to manage and often fatal due to delayed diagnosis. We report on a 71-year-old patient with massive upper gastrointestinal haemorrhage, who did not show any clinical signs of portal hypertension; however, he had a history of duodenal segmental resection 8 years before. The source of bleeding could not be detected with different imaging methods such as angiography and computed tomography. Upper gastrointestinal endoscopy finally revealed DVs, which were located just adjacent to the papilla. After endoscopic injection therapy with n-butyl 2-cyanoacrylate the bleeding stopped immediately and the patient soon stabilised. Despite the peripapillar localisation no signs of pancreatitis or cholestasis occurred; during 10-month follow-up a marked regression of the varices without further signs of variceal bleeding was observed. PMID- 21557170 TI - Severe agranulocytosis as a rare side effect of pegylated interferon therapy for chronic hepatitis B. AB - We report on a 19-year-old male patient with chronic HBeAg-positive hepatitis B infection and agranulocytosis as a severe side effect of pegylated interferon alpha therapy. Within the first six months of therapy the hepatitis B virus DNA became undetectable in parallel with a significant decrease of the HBsAg serum concentration. After a six-month course of therapy the patient was admitted to our emergency unit. He appeared significantly ill and reported that he had fever for two days, painful oral mucosa, throat pain and general fatigue and discomfort. A complete blood cell count was performed and revealed a complete agranulocytosis with no detectable neutrophilic granulocytes in the blood smear. Antiviral therapy was immediately stopped and he was admitted to our clinic where a supportive therapy and an empirical course of broadband antibiotics were initiated. A few days later an additional treatment with intravenous prednisolone was started. Within the next week the agranulocytosis resolved and the neutrophil count was completely restored. In parallel, the clinical status improved quickly. This case demonstrates the need for our awareness of agranulocytosis as a rare but severe and potentially life-threatening side effect of interferon alpha therapy. PMID- 21557171 TI - [Patient-controlled analgo-sedation for elective colonoscopy]. PMID- 21557172 TI - [Radiofrequency ablation for treatment of metastatic colorectal carcinoma: state of the art despite of missing randomized trials?]. PMID- 21557174 TI - [Medicine in Tunisia: from protectorate till today]. PMID- 21557176 TI - [Cardiac conduction disorders in athletes: diagnosis and management]. AB - BACKGROUND: The sino-atrial or atrio-ventricular conduction disturbances are commonly seen in athletes. They are due to predominant effect of the parasympathetic tone. AIM: To describe the physiological cardiac adaptation to physical exercises and to specify the limits of this activity in front of persons with conduction abnormalities. METHODS: Review of literature and lecture of recommendations. RESULTS: conduction disturbances in athletes disappear during physical activities. Their frequency is variously reported in literature. These disorders should be well considered particularly when they are priors to sport practice and need definitive implantable devices. Such decision must be taken after a detailed evaluation of the nature of the physical activity wished and the conduction disturbance type. CONCLUSION: The decision to allow competition should be take after a careful evaluation of the conduction disorder and the type of sport. PMID- 21557177 TI - [Faecal calprotectin in inflammatory bowel diseases: review]. AB - BACKGROUND: The clinical course of inflammatory bowel disease (IBD) is characterised by a succession of relapses and remissions. A regular and a long term monitoring of such patients is required. Faecal markers, especially calprotectin's use, seem to be useful in these patients. Faecal calprotectin is a reliable maker of intestinal inflammation in IBD. Its level is assessed by a simple and a non invasive test. AIM: We proposed to review main indications and study results of faecal calprotectin test use in IBD patients. METHODS: Review of literature. RESULTS: Faecal calprotectin assessment isn't an IBD specific test. Selective use is required to have a good benefit-cost ratio. Prediction of relapses in asymptomatic patients as well as post operative reccurence seems to be the main indications for its use. CONCLUSION: Mucosal healing assessment after anti-TNF treatment can also be an interesting indication although it isn't well evaluated. PMID- 21557178 TI - [Abrikosoff's tumor: a clinicopathologic study of nine cases]. AB - BACKGROUND: Abrikossoff's tumour or granular cell tumor or is a benign neurogenic tumour. It is ubiquitous with the most frequently affected site is the head and neck region. AIMS: To report a series of granular cell tumors and to discuss its clinicopathologic features and histogenesis. METHODS: We report a series of nine cases diagnosed between January 2004 and December 2006 in the Pathology Department of the University Hospital of Sfax. We have collected the clinical aspects and we have proceeded on a pathological, cytochemical (PAS and PAS diastasis) and immunohistochemical study. RESULTS: Nine cases of TCG are presented: 5 females and 4 males. The median age was 33.9 years (extremes: 7 and 53 years). All tumours were unique. The most common localization was in the head and neck region (5 cases). The diagnosis was suspected using standard histologic criteria and confirmed by immunohistochemistry: tumour cells expressed vimentine (90%), S100 protein (100%) and neuron specifique enolase (80%). In all cases patients were treated by excisional resection and had a benign course with no evidence of recurrence (median follow up: 2 years). CONCLUSION: Granular cell tumours are rare neoplasm which must be recognised because they demonstrate a benign behaviour after their surgical excision. Histological features of granular cell tumours are commonly characteristic but some times they can be misdiagnosed as malignant tumours especially when the biopsy is superficial. The staining for neurogen markers and PAS are useful tools. PMID- 21557179 TI - [Effect of inhaled corticosteroids on bone mineral density in asthmatic adults: a 20 cases study]. AB - BACKGROUND: Inhaled corticosteroids are widely used in the treatment of asthma but their safety on bone density is controversial. AIM: To study in a population of adults with asthma receiving inhaled corticosteroids for long term, the effect of this therapy on bone mineral density. METHODS: Prospective study including 20 asthmatics, aged from 20 to 45 years, treated with inhaled corticosteroids for 12 months or more, with no risk factors for osteoporosis. We compared osteodensitometric parameters in our patients, bone mass and T-score at vertebral and femoral witness to a population matched by age and sex. RESULTS: The average age of our patients was 35.45 +/- 5.43 years and the average BMI was 30.03 +/- 5.77 kg/m2. The average daily dose of corticosteroid was 925 +/- 133.27g of equivalent of beclometasone with an average take of 33.5 +/- 21.3 months. The vertebral site bone mass average was 1216 +/- 0106 g/cm2 in the studied group and 1201 +/- 0099 g/cm2 in the control group without significant difference (p = 0380). At femur, the bone mass average was 1037 +/- 0143 g/cm2 in the patient group and 1056 +/- 0107 g/cm2 in the control group (p = 0380). We did not find a significant link between bone mineral density and cumulative dose or the duration of taking inhaled corticosteroids, BMI and tobacco. CONCLUSION: Our work confirms like other previous studies the safety of inhaled corticosteroids on bone mineral density. PMID- 21557180 TI - [Sclerotherapy of idiopatic hydrocele with polidocanol: a study about 190 cases]. AB - AIM: To evaluate the efficacy and side-effects of Polidocanol used as sclerosing agent for testicular hydrocele. METHODS: One hundred and ninety men, with a median age of 55,9 years (40-89), treated for idiopatic hydrocele were assessed. After puncture and aspiration, the empty sac was instilled with 3% Polidocanol. We recorded recurrence, complications and associated pain on a visual analogue scale. RESULTS: With a median follow-up of 19 months, The cure rate of hydroceles after one sclerotherapy session was 62,1%, and the overall cure rate using the procedure was 82,6%. Re-instillation was done for recurrences in 41% of patients. Polidocanol therapy was almost pain-free. A low rate of complications was observed. CONCLUSION: Polidocanol is a useful sclerosing agent for treating testicular hydrocele. Due to its ease of administration, low frequency of complications, high rate of effectiveness, and excellent tolerability; we recommend sclerotherapy with polidocanol as the primary treatment for hydroceles. PMID- 21557181 TI - [Evaluation of small bowel involvement in Crohn's disease by small- bowel videocapsule endoscopy: a prospective comparative study with computed-tomography enteroclysis and small bowel radiography]. AB - BACKGROUND: Small-bowel videocapsule endoscopy (VCE) is a new technique in evaluation of intestinal involvement in several pathologies. Crohn's disease affects principally terminal ileum. Small bowel involvement in Crohn's disease is not well estimated by endoscopic and radiologic conventional techniques. AIMS: To evaluate the performances of VCE in detection of asymptomatic proximal small bowel lesions in consecutive patients with Crohn's disease with terminal ileal involvement, to compare the results of VCE to small bowel radiography and CT enteroclysis and to determine the therapeutic impact of VCE in these patients. METHODS: A prospective study which included Crohn's disease patients with distal ileal involvement, based on radiological or endoscopic findings. We performed in all patients small bowel radiography, CT enteroclysis and VCE. Proximal involvement was characterized by presence of aphtoid, superficial or deep ulcerations in the jejunum or the proximal ileum. RESULTS: We studied 20 patients (12 men, mean age 31.6 years). VCE confirmed the distal ileal involvement in all patients. Significative proximal lesions was observed in nine patients (jejunum only: one case, jejunum and ileum: six cases and proximal ileum: two cases), in most cases aphtoid or superficial lesions. Deep ulcerations were observed in two patients. Small bowel radiography showed proximal ileal lesions in only two patients, and CT-enteroclysis in only one patient. Treatment by azathioprine was prescribed in two patients with severe and extended small bowel lesions in VCE examination. CONCLUSION: VCE is more accurate than radiologic techniques in detection of small bowel lesions in Crohn's disease. In cases of severe and extended small bowel involvement, VCE can conduct to changes of therapeutic approach. PMID- 21557182 TI - [Anatomic variations of the hepatic artery : a study of 33 cases and review]. AB - BACKGROUND: The hepatic artery is prone to numerous anatomic variations dictated by certain variables of the organogenesis. Aim : To research study the anatomic variations of the hepatic artery as well as their implications within surgical practice. METHODS: Study of a post-mortem series of 33 cases of dissection of the hepatic pedicle with fresh corpses (deaths amounting no longer than 24 hours), carried out in conditions that are quite close to those met with the living ones. RESULTS: The common hepatic artery was divided at the foot of the hepatic pedicle into a gastro duodenal artery and into a proper hepatic artery in 94% of the cases. In 6% of the cases, we noticed a three level change, a branching of the average hepatic artery into a gastro duodenal artery, a right hepatic artery and a left hepatic artery. The proper hepatic artery represented the pedicle segment of the hepatic artery in 94% of the cases. In 36% of the cases, the liver was irrigated by two hepatic arteries. In 12% of the cases, there was the matter of the right hepatic artery, branch of the mesenteric artery. In 24% of the cases, there was the matter of the left hepatic artery branch of the left gastric artery. CONCLUSION: The perfect knowledge in preoperative and preoperative stages of the anatomic variations of the hepatic pedicle is quite essential. Actually, the lack of knowledge of these variations exposes to the risk of certain complications which are sometimes deadly during hepatic transplants, pancreatic surgery, cholecystectomies, through laroscopic way as well as in the treatment of gastro-esophagus surging. PMID- 21557183 TI - Vascular complications after pediatric kidney transplantation. AB - BACKGROUND: Vascular complications, especially those including the renal vein, remain a major cause of lost graft. AIMS: To evaluate retrospectively the incidence and management of vascular complications after pediatric renal transplantation and to assess possible risk factors and their effects on patient and graft. METHODS: A total of 82 consecutive renal transplants were performed in 79 patients at a single institution. The diagnosis of vascular complications was suspected in the presence of suggestive symptoms and confirmed by Doppler ultrasound and if necessary by a computed tomographic angiography. Urgent exploration was performed in all suspected cases. RESULTS: There were seven vascular complications (8,5%), including renal vein thrombosis in four patients, renal artery stenosis in one, and sural thrombophlebitis in two. The thrombosis of the graft vein which is the main complication occurred at mean 24 hours after renal transplantation. All these patients needed transplant nephrectomy after thrombosis event. In the remaining cases, the outcome was favorable even for the patient with transplant renal artery stenosis. CONCLUSIONS: Vascular complications are common and serious events affecting patient and graft survivals. A perfect surgical technique and rigorous radiological monitoring may result in decreased incidence and severity of these complications. PMID- 21557184 TI - [Obesity has a protective effect on radiographic joint damage in rheumatoid arthritis]. AB - BACKGROUND: Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines and, in general, the presence of high levels of inflammatory markers is associated with a severe disease course and joint damage. AIM: To assess the impact of obesity on disease activity, quality of life and articular damage in patients with established RA. METHODS: Between July 2009 to December 2009, 119 RA patients were included and divided in two groups according to the body mass index (obeses and controls). RA activity was assessed by the Disease Activity Score (DAS) 28, quality of life by the Health Assessment Questionnaire (HAQ) and radiographic joint damage by the modified Sharp score. RESULTS: Obesity was not correlated with worsen RA activity (p=0.71) nor quality of life impairment (p=0.51). The obese group had a lower modified Sharp score than the control group (64.97versus113.64; p < 0.032) and this association remained significant after adjustment for age, sex, disease activity, extraarticular manifestations, comorbidities, presence of rheumatoid factor, and disease duration. CONCLUSION: Obesity does not have an impact on disease activity nor changes in quality of life, but it has a protective effect on the amount of joint destruction in established rheumatoid arthritis. PMID- 21557185 TI - [Linkage analysis of six Algerian families with autosomal recessive non specific mental retardation]. AB - BACKGROUND: Mental retardation is one of the most frequent major handicap, with a 1-3 % frequency in the general population. The recent progress of molecular biology and cytogenetic allowed to identify new genes for non syndromic autosomal recessive mental retardation. AIM: To seek a genetic linkage to the loci implied in the nonspecific mental retardation transmitted into autosomal recessive (ARNSMR) in Algerian families with several affected members and to make the Genetic analysis of ARNSMR for 4 known loci: 3p25-pter; 4q24- q25, 19p13.12 and 1p21.1-p13. METHODS: The study concerned 34 individuals including 15 patients, belonging to six consanguineous Algerian families. Genotyping was made using polymorphic microsatellite markers and the analysis carried out thanks to the program Gene Mapper software. Statistical analyses were validated using the Fast Link programme of the Easy linkage software (V4:00 betas). RESULTS: The study carried out made it possible to exclude linkage of all loci for 3 families, nevertheless the linkage of one family to the locus 1p21.1-p13.3 remains possible. CONCLUSION: The absence of linkage of 4 Algerian families with autosomal recessive mental retardation to 3 well known loci, confirms the genetic heterogeneity of mental retardation. We have to pursue research of candidate genes by whole genome scan. PMID- 21557186 TI - [Traumatic perilymphatic fistulae : about 13 cases]. AB - BACKGROUND: Post-traumatic peri-lymphatic fistulas have been described following ear and temporal bone injury, particularly in the setting of temporal bone fractures. The symptoms and signs of perilymphatic fistulae (PLF) are very varied and frequently misleading. The diagnosis can be suspected on the bases of the clinical and the audiometrial findings. Indications for exploratory surgery in cases of trauma are vague and not well described. AIM: To assess the principal clinical and radiologic signs of PLF. METHOD: Study of 13 patients with different symptoms of posttraumatic peri-lymphatic fistulae. RESULTS: Ten patients had vertigo, and 2 presented otoliquorreha. Two patients had tympanic perforation. Nine patients presented neurosensorinal hearing loss and 5 were completely deaf. A CT Scann was realized in 12 cases and showed the fracture in 10 cases (91%) with a pneumolabyrinth in 4 cases. Medical and postural treatment was indicated for all the patients then a surgery was indicated in all of them in an average wait of 4 months realizing an ear exclusion in one case and a filling-up for 12 patients. Vertigo improved in 10 cases and the hearing loss in 2 cases. CONCLUSION: The diagnostic of perilymphatic fistulae is not easy. The trauma and the clinical signs can help but the confirmation is surgical. The indication of surgery and its timing are still discussed. PMID- 21557187 TI - [Colo-urachal-cutaneous fistula in an adult]. AB - BACKGROUND: An infected urachal cyst is an uncommon finding in adults. AIM: To report a case of a sigmoid- urachal- cutaneous fistula. CASE REPORT: A 51 years old adult male presented with fecaloid leaking from rupture of an infected urachal cyst. Definitive management consisted of resection of the urachus with a bladder cuff, along with removal of the affected bowel segments. CONCLUSION: Colo urachal-cutaneous fistula is a rare condition; its management is rather complex. PMID- 21557188 TI - Non-syndromic autosomal recessive mental retardation in Tunisian families : exclusion of GRIK2 and TUSC3 genes. AB - BACKGROUND: Mental retardation is one of the most frequent major handicap, with a 1-3 % frequency in the general population, it appear a major problem of public health. The recent progress of molecular biology and cytogenetic allowed to identify new genes for non syndromic autosomal recessive mental retardation (NSAR MR). AIM: Genetic analysis of NSAR-MR: the GRIK2 gene (6q16.3-q21) and the TUSC3 gene (8p22). METHODS: Four Tunisian families with NSAR-MR were included in this study. Genotyping was made using polymorphic microsatellite markers and statistical analysis was validated using the Fast Link programme of the Easy linkage software (V4:00beta). RESULTS: Genotyping and linkage analysis excluded linkage of the GRIK2 gene and TUSC3 gene. CONCLUSION: Our results confirm the extreme genetic heterogeneity of NSAR-MR. PMID- 21557189 TI - [Hyalinosis cutis et mucosae : 5 cases from Tabarka (Tunisia)]. AB - BACKGROUND: Hyalinosis cutis et mucosae (HCM), is a rare autosomal recessive genodermatosis. Cutaneous features are characteristic and allow to suspect diagnosis. AIM: To report a series of HCM. METHODS: A retrospective study of all cases of HCM, diagnosed in a dermatology department over a period of 25 years (1983-2007). RESULTS: Over the considered period, 5 new cases of HCM were diagnosed. Patients were aged between 14 and 41 years. They were 3 females and 2 males. All patients were native of Tabarka (northwestern Tunisia). The age of the onset of the disease varied from neonatal period to 5 years. Hoarseness was the first clinical manifestation in all cases. Skin lesions developed between the ages of 3 and 8 years. Vesiculobullous lesions were observed in 2 patients. Moniliform blepharosis was seen in all patients. Warty and hyperkeratotic papules were observed in 3 patients. Diffuse thickening of the skin was seen in 3 patients. Lesions were primarily distributed on the face. All patients presented diffuse scars. Linear palmoplantar keratoderma was seen in one patient. Asymptomatic endocranial calcifications were noted in 4 patients. A pituitary adenoma was noted in one patient. Histopathological examination of a skin lesion revealed a typical pattern of HCM. Two patients were treated with systemic retinoids without improvement. CONCLUSION: We reported five new cases of HCM. All patients were native from Tabarka. We report also one case of linear palmar keratoderma associated with HCM. This association was not reported in the literature. Finally, the association HCM-pituitary adenoma, seen in one patient, may be fortuitous. PMID- 21557190 TI - [Allergic bronchopulmonary aspergillosis. A review of 3 cases]. AB - BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a rare affection, initially described in 1952. Its pathophysiology incriminate several mechanisms in relation with the organism of the patient and the bronchial colonisation by the fongic agent. AIM: To report three cases of ABPA. CASES REPORT: Three patients had been treated for ABPA in Ibn Nafiss department in Abderrahmen Mami hospital in Ariana. ABPA had been discovered in the three cases by a cortico dependant asthma, refractory for different therapeutics. Positive diagnosis reposed in the 3 patients at 6 major and one minor criterion. Treatment was essentially based in corticotherapy. CONCLUSION: Positive diagnosis of ABPA is actually well established, however, its treatment, although based on corticotherapy, remind not clearly codified. Association of antifongic treatment may improve the prognosis. PMID- 21557191 TI - [Rosai -Dorfman disease: a two cases report]. AB - BACKGROUND: Rosai-Dorfman disease (RDD) is a benign lymphoproliferatif disorder characterized by cervical lymphadenopathies with a consistent risk of airways' compression and esthetical prejudice. Extra nodal localizations are also described. AIM: To report two pediatric cases of RDD. CASES: the first case concerned a patient with a prolonged nodal involvement of RDD. Remission seems to be natural although it coincided with a sulfamethoxazole- trimethoprime therapy. The second case illustrated an extranodal form of RDD localized in soft tissue and paranasal sinus with extension to nasal cavity which were corticodependant. CONCLUSION: RDD is usually a benign disorder. Particular localizations, lack of effective therapy and the high risk of recurrence are important issues in this rare affection. PMID- 21557192 TI - [Nephroblastoma of the adult with intracaval extension]. PMID- 21557193 TI - Eagle's syndrome: a rare cause of neck pain. PMID- 21557194 TI - Comparison of cigarette and waterpipe smoking among pupils in the urban area of Sousse, Tunisia. Tunis Med. 2010 Jul; 88(7):470-3.(Letter to editor). Pro. PMID- 21557195 TI - Comparison of cigarette and waterpipe smoking among pupils in the urban area of Sousse, Tunisia. Tunis Med. 2010 Jul; 88(7):470-3. (Reply). Con. PMID- 21557196 TI - [Upper urinary tract infections in adults: about 261 episodes. Tunis Med 2010; 88:629-33. (Letter to editor). Pro]. PMID- 21557197 TI - [Upper urinary tract infections in adults: about 261 episodes. Tunis Med 2010; 88:629-33. (Reply). Con]. PMID- 21557199 TI - Reverse engineering of protein secretion by uncoupling of cell cycle phases from growth. AB - The demand for recombinant proteins both for biopharmaceutical and technical applications is rapidly growing, and therefore the need to establish highly productive expression systems is steadily increasing. Yeasts, such as Pichia pastoris, are among the widely used production platforms with a strong emphasis on secreted proteins. Protein secretion is a limiting factor of productivity. There is strong evidence that secretion is coupled to specific growth rate (u) in yeast, being higher at higher u. For maximum productivity and product titer, high specific secretion rates at low u would be desired. At high secretion rates cultures contain a large fraction of cells in the G2 and M phases of cell cycle. Consequently, the cell design target of a high fraction of cells in G2 + M phase was achieved by constitutive overexpression of the cyclin gene CLB2. Together with predictive process modeling this reverse engineered production strain improved the space time yield (STY) of an antibody Fab fragment by 18% and the product titer by 53%. This concept was verified with another secreted protein, human trypsinogen. PMID- 21557200 TI - Evaluation of electro-coagulation-flocculation for harvesting marine and freshwater microalgae. AB - Although microalgae are considered as a promising feedstock for biofuels, the energy efficiency of the production process needs to be significantly improved. Due to their small size and low concentration in the culture medium, cost efficient harvesting of microalgae is a major challenge. In this study, the use of electro-coagulation-flocculation (ECF) as a method for harvesting a freshwater (Chlorella vulgaris) and a marine (Phaeodactylum tricornutum) microalgal species is evaluated. ECF was shown to be more efficient using an aluminum anode than using an iron anode. Furthermore, it could be concluded that the efficiency of the ECF process can be substantially improved by reducing the initial pH and by increasing the turbulence in the microalgal suspension. Although higher current densities resulted in a more rapid flocculation of the microalgal suspension, power consumption, expressed per kg of microalgae harvested, and release of aluminum were lower when a lower current density was used. The aluminum content of the harvested microalgal biomass was less than 1% while the aluminum concentration in the process water was below 2 mg L(-1). Under optimal conditions, power consumption of the ECF process was around 2 kWh kg(-1) of microalgal biomass harvested for Chlorella vulgaris and ca. 0.3 kWh kg(-1) for Phaeodactylum tricornutum. Compared to centrifugation, ECF is thus more energy efficient. Because of the lower power consumption of ECF in seawater, ECF is a particularly attractive method for harvesting marine microalgae. PMID- 21557201 TI - Effects of cell culture conditions on antibody N-linked glycosylation--what affects high mannose 5 glycoform. AB - The glycosylation profile of therapeutic antibodies is routinely analyzed throughout development to monitor the impact of process parameters and to ensure consistency, efficacy, and safety for clinical and commercial batches of therapeutic products. In this study, unusually high levels of the mannose-5 (Man5) glycoform were observed during the early development of a therapeutic antibody produced from a Chinese hamster ovary (CHO) cell line, model cell line A. Follow up studies indicated that the antibody Man5 level was increased throughout the course of cell culture production as a result of increasing cell culture medium osmolality levels and extending culture duration. With model cell line A, Man5 glycosylation increased more than twofold from 12% to 28% in the fed batch process through a combination of high basal and feed media osmolality and increased run duration. The osmolality and culture duration effects were also observed for four other CHO antibody producing cell lines by adding NaCl in both basal and feed media and extending the culture duration of the cell culture process. Moreover, reduction of Man5 level from model cell line A was achieved by supplementing MnCl2 at appropriate concentrations. To further understand the role of glycosyltransferases in Man5 level, N-acetylglucosaminyltransferase I GnT-I mRNA levels at different osmolality conditions were measured. It has been hypothesized that specific enzyme activity in the glycosylation pathway could have been altered in this fed-batch process. PMID- 21557202 TI - A pseudo steady-state model for galacto-oligosaccharides synthesis with beta galactosidase from Aspergillus oryzae. AB - A pseudo steady-state model for the kinetically controlled synthesis of galacto oligosaccharides (GOS) with Aspergillus oryzae beta-galactosidase is presented. The model accounts for the dynamics of lactose consumption and production of galactose, glucose, di, tri, tetra, and penta-oligosaccharides during the synthesis, being able to describe the total GOS content in the reaction medium at the experimental conditions evaluated. Experimental results show that the formation of GOS containing only galactose residues is significant at high conversions of substrate, which was taken into account in the model. The formation of enzyme transition complexes was considered and reasonable assumptions were made to reduce the number of parameters to be determined. The model developed has 8 parameters; 2 of them were experimentally determined and the other 6 were estimated by fitting to the experimental data using multiresponse regression. Temperature effect on kinetic and affinity constants was determined in the range from 40 to 55 degrees C, and the data were fitted to Arrhenius type equation. Parameters of the proposed model are independent from the enzyme load in the reaction medium and, differently from previously reported models, they have a clear biochemical meaning. The magnitude of the kinetic and affinity constants of the enzyme suggests that the liberation of galactose from the galactosyl-enzyme complex is a very slow reaction and such complex is driven into GOS formation. It also suggests that the affinity for sugars of the galactosyl-enzyme complex is higher than that of the free enzyme. PMID- 21557203 TI - Flow dynamics within a bioreactor for tissue engineering by residence time distribution analysis combined with fluorescence and magnetic resonance imaging to investigate forced permeability and apparent diffusion coefficient in a perfusion cell culture chamber. AB - This study reveals that residence time distribution (RTD) analysis with pH monitoring after acid bolus injection can be used to globally study the flow dynamics of a perfusion bioreactor, while fluorescence microscopy and magnetic resonance imaging (MRI) were used to locally investigate mass transport within a hydrogel scaffold seeded or not with cells. The bioreactor used in this study is a close-loop tubular reactor. A dispersion model in one dimension has been used to describe the non-ideal behavior of the reactor. From open-loop experiments (single-cycle analysis), the presence of stagnant zones and back mixing were observed. The impact of the flow rate, the compliance chamber volume and mixing were investigated. Intermediate flows (30, 45, 60, and 90 mL min(-1)) had no effect over RTD function expressed in reduced time (theta). Lower flow rates (5 and 15 mL min(-1)) were associated to smaller extent of dispersion. The compliance chamber volume greatly affected the dynamics of the RTD function, while the effects of mixing and flow were small to non-significant. An empirical equation has been proposed to localize minima of the RTD function and to predict Per . Finally, cells seeded in a gelatin gel at a density of 800,000 cells mL(-1) had no effect over the permeability and the apparent diffusion coefficient, as revealed by fluorescent microscopy and MRI experiments. PMID- 21557204 TI - Reduction of acetone to isopropanol using producer gas fermenting microbes. AB - Gasification-fermentation is an emerging technology for the conversion of lignocellulosic materials into biofuels and specialty chemicals. For effective utilization of producer gas by fermenting bacteria, tar compounds produced in the gasification process are often removed by wet scrubbing techniques using acetone. In a preliminary study using biomass generated producer gas scrubbed with acetone, an accumulation of acetone and subsequent isopropanol production was observed. The effect of 2 g/L acetone concentrations in the fermentation media on growth and product distributions was studied with "Clostridium ragsdalei," also known as Clostridium strain P11 or P11, and Clostridium carboxidivorans P7 or P7. The reduction of acetone to isopropanol was possible with "C. ragsdalei," but not with P7. In P11 this reaction occurred rapidly when acetone was added in the acidogenic phase, but was 2.5 times slower when added in the solventogenic phase. Acetone at concentrations of 2 g/L did not affect the growth of P7, but ethanol increased by 41% and acetic acid concentrations decreased by 79%. In the fermentations using P11, growth was unaffected and ethanol concentrations increased by 55% when acetone was added in the acidogenic phase. Acetic acid concentrations increased by 19% in both the treatments where acetone was added. Our observations indicate that P11 has a secondary alcohol dehydrogenase that enables it to reduce acetone to isopropanol, while P7 lacks this enzyme. P11 offers an opportunity for biological production of isopropanol from acetone reduction in the presence of gaseous substrates (CO, CO2, and H2). PMID- 21557205 TI - Submersible microbial fuel cell sensor for monitoring microbial activity and BOD in groundwater: focusing on impact of anodic biofilm on sensor applicability. AB - A sensor, based on a submersible microbial fuel cell (SUMFC), was developed for in situ monitoring of microbial activity and biochemical oxygen demand (BOD) in groundwater. Presence or absence of a biofilm on the anode was a decisive factor for the applicability of the sensor. Fresh anode was required for application of the sensor for microbial activity measurement, while biofilm-colonized anode was needed for utilizing the sensor for BOD content measurement. The current density of SUMFC sensor equipped with a biofilm-colonized anode showed linear relationship with BOD content, to up to 250 mg/L (~233 +/- 1 mA/m(2)), with a response time of <0.67 h. This sensor could, however, not measure microbial activity, as indicated by the indifferent current produced at varying active microorganisms concentration, which was expressed as microbial adenosine triphosphate (ATP) concentration. On the contrary, the current density (0.6 +/- 0.1 to 12.4 +/- 0.1 mA/m(2)) of the SUMFC sensor equipped with a fresh anode showed linear relationship, with active microorganism concentrations from 0 to 6.52 nmol-ATP/L, while no correlation between the current and BOD was observed. It was found that temperature, pH, conductivity, and inorganic solid content were significantly affecting the sensitivity of the sensor. Lastly, the sensor was tested with real contaminated groundwater, where the microbial activity and BOD content could be detected in <3.1 h. The microbial activity and BOD concentration measured by SUMFC sensor fitted well with the one measured by the standard methods, with deviations ranging from 15% to 22% and 6% to 16%, respectively. The SUMFC sensor provides a new way for in situ and quantitative monitoring contaminants content and biological activity during bioremediation process in variety of anoxic aquifers. PMID- 21557207 TI - Perioperative use of a neutrophil elastase inhibitor in video-assisted thoracoscopic oesophagectomy for cancer. AB - BACKGROUND: This study was undertaken to assess the value of administering perioperative sivelestat sodium hydrate (SSH), a selective neutrophil elastase inhibitor, after video-assisted thoracoscopic oesophagectomy for cancer. METHOD: Thirty-one consecutive patients with thoracic oesophageal cancer selected to undergo video-assisted thoracoscopic oesophagectomy with lymph node dissection between March 2007 and March 2009 were assigned randomly to a treatment group that received SSH intravenously for 7 days from the beginning of surgery (16 patients) and a control group that received saline (15). The primary endpoint was pulmonary function based on the arterial partial pressure of oxygen/fraction of inspired oxygen ratio (P/F ratio) during the first 9 days after surgery. Secondary endpoints included platelet count, serum C-reactive protein (CRP) concentration, plasma neutrophil elastase-alpha(1)-antitrypsin complex level, duration of mechanical ventilation and systemic inflammatory response syndrome (SIRS), and length of intensive care unit (ICU) and hospital stay. RESULTS: The mean P/F ratio of patients who received SSH was significantly higher than that of the control group on postoperative days 1-5 and 7. Duration of mechanical ventilation and SIRS, and length of ICU stay were significantly shorter in the treatment group. Serum CRP concentration on postoperative day 9 was significantly lower (P = 0.048), platelet counts on days 2, 3 and 5 were higher (P = 0.012, P = 0.049 and P = 0.006 respectively), and the incidence of postoperative acute lung injury was significantly lower following SSH treatment (P = 0.023). CONCLUSION: Perioperative sivelestat may maintain postoperative pulmonary function following video-assisted oesophagectomy. PMID- 21557208 TI - Development of a composite endpoint for randomized controlled trials in liver surgery. AB - BACKGROUND: The feasibility of randomized controlled trials (RCTs) in liver surgery using a single-component clinical endpoint is low as such endpoints require large sample sizes owing to their low incidence. A liver surgery-specific composite endpoint (CEP) could solve this problem. The aim of this study was to develop a liver surgery-specific CEP with well-defined components. METHODS: Components of a liver surgery-specific CEP were selected based on a systematic literature search and consensus among 28 international hepatopancreatobiliary (HPB) surgeons. As an example, two prospective cohorts of patients who had undergone liver surgery in high-volume HPB centres were used to assess the event rate and effect of implementing a liver surgery-specific CEP. RESULTS: Components selected for the liver surgery-specific CEP were ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality, all with a Clavien-Dindo grade of at least 3 and occurring within 90 days after initial surgery. The incidence of this liver surgery specific CEP was 19.2 per cent in one cohort and 10.7 per cent in the other. These rates led to an approximately twofold reduction in the theoretical sample size required for an adequately powered RCT in liver surgery using the CEP as primary endpoint. CONCLUSION: The proposed liver surgery-specific CEP consists of ascites, postresectional liver failure, bile leakage, intra-abdominal haemorrhage, intra-abdominal abscess and operative mortality. It has a considerably higher event rate than any of its components. Its use as the primary endpoint will increase the feasibility and comparability of RCTs in liver surgery. PMID- 21557209 TI - Cancer survivorship and sexual orientation. AB - BACKGROUND: Lesbian, gay, and bisexual populations are not part of cancer surveillance, resulting in scarce information about the cancer survivorship of these populations. To address this information gap, the authors examined the prevalence of cancer survivorship by sexual orientation and cancer survivors' self-reported health by sexual orientation. METHODS: The authors explored these issues by analyzing pooled data from the California Health Interview survey from 2001, 2003, and 2005. By using descriptive statistics and logistic regressions, they examined the cancer prevalence in men and women by sexual orientation and subsequently compared the self-reported health of male and female cancer survivors by sexual orientation. RESULTS: Among women, the authors found no significant differences in cancer prevalence by sexual orientation, but lesbian and bisexual female cancer survivors had 2.0 and 2.3* the odds of reporting fair or poor health compared with heterosexual female cancer survivors. Among men, we found significant differences in cancer prevalence, with gay men having 1.9* the odds of reporting a cancer diagnosis compared with heterosexual men. There were no differences by sexual orientation in male cancer survivors' self-reported health. CONCLUSIONS: Our novel findings suggest sex differences in the impact of cancer on lesbian, gay, and bisexual cancer survivors. Lesbian and bisexual cancer survivors need to be targeted by programs and services to assist these cancer survivors in improving their health perceptions, whereas healthcare providers and public health agencies need to be made aware of the higher prevalence of cancer in gay men to prevent future cancers through increased screening and primary prevention. PMID- 21557210 TI - CD4(+) CD25(low) GITR(+) cells: a novel human CD4(+) T-cell population with regulatory activity. AB - Treg subsets play a role in sustaining peripheral tolerance, are characterized by markers such as forkhead winged-helix transcription factor (FOXP3) and CD25, and produce suppressive cytokines, such as IL-10 and TGF-beta. Glucocorticoid-induced TNF receptor family-related (GITR) protein has been suggested to regulate Treg activity in mice. The aim of our study was to investigate GITR expression in human CD4(+) T lymphocytes and its possible role in Treg function. Results indicate that a subset of CD4(+) T cells in the peripheral blood expresses GITR and low levels of CD25 (CD4(+) CD25(low) GITR(+) ). These cells show Treg features as they express FOXP3, IL-10, TGF-beta and are anergic but, as opposed to natural Tregs, express low levels of CTLA-4 and are CD127(high) . CD4(+) CD25(low) GITR(+) cells represent a low percentage of the CD4(+) T-cell population (0.32-1.74%) and are mostly memory cells. Functional experiments demonstrated that CD4(+) CD25(low) GITR(+) cells have relevant suppressive activity that depends on TGF-beta. Moreover, an anti-GITR Ab inhibited their suppressive activity, as observed in CD4(+) CD25(+) murine Tregs. Taken together, these data indicate that human CD4(+) CD25(low) GITR(+) cells represent a distinct Treg subpopulation. PMID- 21557211 TI - Actin-independent exclusion of CD95 by PI3K/AKT signalling: implications for apoptosis. AB - The immune system eliminates infected or transformed cells through the activation of the death receptor CD95. CD95 engagement drives the recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates and activates initiator caspases-8 and -10. The CD95-mediated apoptotic signal relies on the capacity to form the CD95/FADD/caspases complex termed the death-inducing signalling complex (DISC). Cells are classified according to the magnitude of DISC formation as either type I (efficient DISC formation) or type II (inefficient). CD95 localised to lipid rafts in type I cells, whereas the death receptor was excluded from these domains in type II cells. Here, we show that inhibition of both PI3K class IA and serine-threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal. Strikingly, these molecular events took place independently of CD95L and the actin cytoskeleton. Overall, these findings highlight that the oncogenic PI3K/Akt signalling pathway participates in maintaining cells in a type II phenotype by excluding CD95 from lipid rafts. PMID- 21557212 TI - Synovial fibroblasts promote immunoglobulin class switching by a mechanism involving BAFF. AB - Fibroblast-like synoviocytes (FLSs) are important actors in rheumatoid arthritis (RA) pathogenesis. The autoimmune nature of RA is attributed to autoantibody production, which confers to B cells a predominant role in RA. Several arguments support an induction of class switch recombination (CSR) in RA synovium, causing- in conjunction with somatic hypermutation--the production of potentially pathogenic IgG. To determine whether RA FLSs can directly promote CSR and to analyze the role of external factors like TLR signals and BAFF (B cell activating factor) family cytokines in this FLS-B cell crosstalk, we performed cocultures of blood B cells (from normal individuals or RA patients) with RA FLSs and analyzed CSR induction by quantification of AICDA (encoding activation-induced cytidine deaminase, AID) and switch circular transcripts expression, and IgG secretion. RA FLSs--and to a lesser extent osteoarthritis or control FLSs--promoted CSR, and TLR3 stimulation potentialized it. In addition, induction of CSR by RA FLSs was totally dependent on cell-cell contact in basal conditions, and partially dependent in the case of TLR3 stimulation. Finally, we showed that the mechanism by which RA FLSs induce CSR is mostly BAFF-dependent. Our results support the hypothesis that CSR can be induced outside the ectopic lymphoid structures in RA. PMID- 21557213 TI - NKT cells are required to induce high IL-33 expression in hepatocytes during ConA induced acute hepatitis. AB - Interleukin-33 (IL-33) is thought to be released during cellular death as an alarming cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl(4) ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl(4) treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes. PMID- 21557214 TI - Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. AB - The small, water soluble molecule Dichloroacetate (DCA) is recently arousing lively interests in the field of cancer therapy for it has been shown to be able to inhibit the growth of human tumors acting specifically on the mitochondria of cancer cells without perturbing the physiology of nonmalignant cells. Neuroblastoma was one of the tumor types on which DCA was considered ineffective as it is composed of cells with few recognized mitochondrial anomalies. Neuroblastoma, however, is composed of different cell types in terms of metabolism, phenotype and malignant potential. Despite the above prediction, in this work, we show that (i) DCA exhibits an unexpected anticancer effect on NB tumor cells and (ii) this effect is selectively directed to very malignant NB cells, whereas the more differentiated/less malignant NB cells are refractory to DCA treatment. This result supports the need of a detailed investigation of DCA anticancer properties against this tumor type with the final aim of its possible use as therapeutic agent. PMID- 21557215 TI - YC-1 rescues cancer cachexia by affecting lipolysis and adipogenesis. AB - Loss of adipose tissue, primarily due to increased lipolysis but also to an impairment of adipogenesis, is a key feature of weight loss in cancer cachexia. Because of the myriad pathogenic signaling pathways essential for atrophy of adipose tissue, effective therapeutic agents for cachectic adipose loss are lacking and urgently needed. The authors evaluated the effects of YC-1 on adipogenesis of 3T3-L1 preadipocytes, TNF-alpha- and tumor-cell-induced lipolysis in 3T3-L1 adipocytes, and cachectic weight loss in colon-26 adenocarcinoma bearing mice because YC-1 has been shown to possess versatile pharmacological actions, including anticancer activity. It was found that YC-1 promotes the differentiation of 3T3-L1 preadipocytes into adipocytes through activation of Akt and extracellular signal-regulated kinase (ERK) signaling pathways as well as activation of several adipogenic mediators, such as peroxisome proliferator activated receptor gamma (PPARgamma), insulin receptor alpha (IRalpha), insulin receptor substrate-3 (IRS-3) and glucose transporter-4 (GLUT-4). In the in vitro lipolysis models, YC-1 attenuates TNF-alpha-induced lipolysis of adipocytes by antagonizing TNF-alpha-mediated activation of ERK and downregulation of perilipin (PLIN). It was also found that YC-1 inhibits colon-26 adenocarcinoma cell-induced lipolysis of 3T3-L1 adipocytes. Moreover, YC-1 effectively rescues cachectic weight loss in colon-26 adenocarcinoma-bearing mice by blocking lipolysis, involving insulin. Taken together the results show that YC-1 with its anticancer and anticachexia talents is highly worth developing as a novel agent for cancer therapy. PMID- 21557216 TI - p53 mutation is common in microsatellite stable, BRAF mutant colorectal cancers. AB - The majority of "serrated pathway" colorectal cancers have mutation of the BRAF oncogene and display the CpG island methylator phenotype (CIMP). Half these cancers have microsatellite instability (MSI) and an excellent prognosis. In the absence of MSI (microsatellite stable, MSS), BRAF mutation has been associated with a particularly poor prognosis. "Traditional pathway" cancers are BRAF wild type. Mutation of p53 is common and this correlates with advanced stage. We therefore hypothesized that p53 mutation would be common in MSS/BRAF mutant colorectal cancer. One thousand and eighty-one colorectal cancers were screened for BRAF mutation to identify two BRAF mutant study groups (MSI: n = 77; MSS: n = 69) and a BRAF wild type control group (n = 101). These were screened for p53 mutation by high resolution melt analysis and classified for CIMP and MGMT methylation by quantitative methylation specific PCR. Molecular data were compared to patient age, gender, tumor location and stage. p53 was mutated significantly more frequently in MSS/BRAF mutant (28/69, 40.6%) compared to MSI/BRAF mutant cancers (13/77, 16.9%), but this mutation rate did not differ from MSS/BRAF wild type cancers (47/101, 46.5%)(p < 0.0001). CIMP was less common in MSS/BRAF mutant (26/47, 55.3%) compared to MSI/BRAF mutant cancers (41/54, 75.9%), but was more common than in MSS/BRAF wild type cancers (3/85, 3.5%) (p < 0.0001). MSS/BRAF mutant cancers were more commonly proximal (38/54, 70.3%), but were similar to MSS/BRAF wild type cancers in terms of patient age, gender distribution and stage at presentation. MSS/BRAF mutant cancers share molecular and clinical features of both the serrated and traditional pathways of colorectal tumorigenesis. PMID- 21557217 TI - Human dendritic cells efficiently phagocytose adenoviral oncolysate but require additional stimulation to mature. AB - Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor restricted virus infection and cell lysis. Clinical trials have shown that oncolytic adenoviruses are well tolerated in patients but also that their antitumor activity needs improvement. A promising strategy toward this end is to trigger systemic and prolonged antitumor immunity by adenoviral oncolysis. Antitumor immune activation depends in large part on antigen presentation and T cell activation by dendritic cells (DCs). Thus, it is likely that the interaction of lysed tumor cells with DCs is a key determinant of such "oncolytic vaccination." Our study reveals that human DCs effectively phagocytose melanoma cells at late stages of oncolytic adenovirus infection, when the cells die showing preferentially features of necrotic cell death. Maturation, migration toward CCL19 and T cell stimulatory capacity of DCs, crucial steps for immune induction, were, however, not induced by phagocytosis of oncolysate, but could be triggered by a cytokine maturation cocktail. Therefore, oncolytic adenoviruses and adenoviral oncolysate did not block DC maturation, which is in contrast to reports for other oncolytic viruses. These results represent a rationale for inserting immunostimulatory genes into oncolytic adenovirus genomes to assure critical DC maturation. Indeed, we report here that adenoviral transduction of melanoma cells with CD40L during oncolysis triggers the maturation of human DCs with T cell stimulatory capacity similar to DCs matured by cytokines. We conclude that triggering and shaping DC-induced antitumor immunity by oncolytic adenoviruses "armed" with immunostimulatory genes holds promise for improving the therapeutic outcome of viral oncolysis in patients. PMID- 21557218 TI - Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. AB - The detection of nonsmall cell lung cancer (NSCLC) at an early stage presents a daunting challenge due to the lack of a specific noninvasive marker. The discovery of microRNAs (miRNAs), particularly those found in serum, has opened a new avenue for tumor diagnosis. To determine whether the expression profile of serum miRNAs can serve as a NSCLC fingerprint, we performed Taqman probe-based quantitative RT-PCR assay to selected differentially expressed serum miRNAs from a sample set including 400 NSCLC cases and 220 controls, and risk score analysis to evaluate the diagnostic value of the serum miRNA profiling system. After a two phase selection and validation process, 10 miRNAs were found to have significantly different expression levels in NSCLC serum samples compared with the control serum samples. Risk score analysis showed that this panel of miRNAs was able to distinguish NSCLC cases from controls with high sensitivity and specificity. Under ROC curves, the AUC for tumor identification in training set and validation set were 0.966 and 0.972, respectively. Furthermore, the expression profile of the 10-serum miRNAs was correlated with the stage of NSCLC patients, especially in younger patients and patients with current smoking habits. More importantly, the serum miRNA-based biomarker for early NSCLC detection was supported by a retrospective analysis in which the 10-serum miRNA profile could accurately classify serum samples collected up to 33 months ahead of the clinical NSCLC diagnosis. Taken together, we demonstrate that the profiling of 10-serum miRNAs provides a novel noninvasive biomarker for NSCLC diagnosis. PMID- 21557219 TI - Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is 'too big to fail'. AB - With each failure of anti-amyloid-beta therapy in clinical trials, new trials are initiated with no hint of slowing down. This may be due, in part, to the fact that the amyloid cascade hypothesis has been so modified over time that it is now impossible to confirm or deny. The hypothesis now states, in effect, that invisible molecules target invisible structures. Still relevant, however, are multiple factors that surely cast some doubt but have either been rationalized or overlooked. Among these are the poor correlation between amyloid-beta deposits and disease, the substantial differences between familial and sporadic disease, pathological assessment that indicates the secondary nature of lesions/proteins/cascades, the fact that soluble species are poorly reproducible laboratory phenomena, and the irrelevance of synaptic assessment to pathological interpretation. Although not yet dogma, the premature addition of mild cognitive impairment as the implied in vivo homologue to the soluble toxin-synapse interaction is also problematic. In either case, the amyloid cascade hypothesis continues to dominate the Alzheimer's disease literature and grant applications. The more the neuroscience community perseverates along these lines in the face of accumulating outcome data to the contrary, the more one is left to wonder whether the hypothesis is too big to fail. PMID- 21557220 TI - Myd88 deficiency influences murine tracheal epithelial metaplasia and submucosal gland abundance. AB - Tracheal epithelial remodelling, excess mucus production, and submucosal gland hyperplasia are features of numerous lung diseases, yet their origins remain poorly understood. Previous studies have suggested that NF-kappaB signalling may regulate airway epithelial homeostasis. The purpose of this study was to determine whether deletion of the NF-kappaB signalling pathway protein myeloid differentiation factor 88 (Myd88) influenced tracheal epithelial cell phenotype. We compared wild-type and Myd88-deficient or pharmacologically inhibited adult mouse tracheas and determined that in vivo Myd88 deletion resulted in increased submucosal gland number, secretory cell metaplasia, and excess mucus cell abundance. We also found that Myd88 was required for normal resolution after acute tracheal epithelial injury. Microarray analysis revealed that uninjured Myd88-deficient tracheas contained 103 transcripts that were differentially expressed relative to wild-type and all injured whole tracheal samples. These clustered into several ontologies and networks that are known to functionally influence epithelial cell phenotype. Comparing these transcripts to those expressed in airway progenitor cells revealed only five common genes, suggesting that Myd88 influences tracheal epithelial homeostasis through an extrinsic mechanism. Overall, this study represents the first identification of Myd88 as a regulator of adult tracheal epithelial cell phenotype. PMID- 21557221 TI - Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium. AB - Goblet cell hyperplasia is a common feature of chronic obstructive pulmonary disease (COPD) airways, but the mechanisms that underlie this epithelial remodelling in COPD are not understood. Based on our previous finding of hypoxia inducible factor-1alpha (HIF-1alpha) nuclear localization in large airways from patients with COPD, we investigated whether hypoxia-inducible signalling could influence the development of goblet cell hyperplasia. We evaluated large airway samples obtained from 18 lifelong non-smokers and 13 former smokers without COPD, and 45 former smokers with COPD. In these specimens, HIF-1alpha nuclear staining occurred almost exclusively in COPD patients in areas of airway remodelling. In COPD patients, 93.2 +/- 3.9% (range 65-100%) of goblet cells were HIF-1alpha positive in areas of goblet cell hyperplasia, whereas nuclear HIF-1alpha was not detected in individuals without COPD or in normal-appearing pseudostratified epithelium from COPD patients. To determine the direct effects of hypoxia inducible signalling on epithelial cell differentiation in vitro, human bronchial epithelial cells (HBECs) were grown in air-liquid interface cultures under hypoxia (1% O(2)) or following treatment with a selective HIF-1alpha stabilizer, (2R)-[(4-biphenylylsulphonyl)amino]-N-hydroxy-3-phenyl-propionamide (BiPS). HBECs grown in hypoxia or with BiPS treatment were characterized by HIF-1alpha activation, carbonic anhydrase IX expression, mucus-producing cell hyperplasia and increased expression of MUC5AC. Analysis of signal transduction pathways in cells with HIF-1alpha activation showed increased ERK1/2 phosphorylation without activation of epidermal growth factor receptor, Ras, PI3K-Akt or STAT6. These data indicate an important effect of hypoxia-inducible signalling on airway epithelial cell differentiation and identify a new potential target to limit mucus production in COPD. PMID- 21557222 TI - Using mouse models to investigate the biological and physiological consequences of defects in the Fanconi anaemia/breast cancer DNA repair signalling pathway. AB - Fanconi anaemia (FA) is a rare, predominantly autosomal recessive syndrome (with one X-linked form) that results in congenital defects, abnormal haematopoiesis and a greatly increased risk of solid tumours in humans. Mutations in at least 14 different genes have been shown to cause FA, and several of these genes, including FANCJ/BRIP1, FANCD1/BRCA2 and FANCN/PALB2, also predispose to breast cancer in heterozygote carriers. The FA genes code for proteins that act in complexes to coordinate the repair of damaged DNA, and thus the FA repair network is intimately linked with hereditary breast cancer. Much remains to be learnt about the functions and interactions of the FA proteins and one experimental approach involves the generation of mice that are deficient in various FA genes. Mouse models for FANCN/PALB2 have recently been generated, including one reported in a recent issue of The Journal of Pathology. Given the pivotal role of the PALB2 protein, which interacts with both BRCA1 and BRCA2, these mice provide valuable insights into the FA phenotype and mechanisms of tumourigenesis caused by disruption of the FA protein network. PMID- 21557223 TI - Effect of benzyl alcohol on recombinant human interleukin-1 receptor antagonist structure and hydrogen-deuterium exchange. AB - Benzyl alcohol, a preservative commonly added to multidose therapeutic protein formulations, can accelerate aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra). To investigate the interactions between benzyl alcohol and rhIL-1ra, we used nuclear magnetic resonance to observe the effect of benzyl alcohol on the chemical shifts of amide resonances of rhIL-1ra and to measure hydrogen-deuterium exchange rates of individual rhIL-1ra residues. Addition of 0.9% benzyl alcohol caused significant chemical shifts of amide resonances for residues 90-97, suggesting that these solvent-exposed residues participate in the binding of benzyl alcohol. In contrast, little perturbation of exchange rates was observed in the presence of either sucrose or benzyl alcohol. PMID- 21557224 TI - Quality by design approach of a pharmaceutical gel manufacturing process, part 2: near infrared monitoring of composition and physical parameters. AB - We applied the principles of quality by design to the production process of a pharmaceutical gel by using the near infrared spectroscopy (NIRS) technique in combination with multivariate chemometric tools. For this purpose, we constructed a D-optimal experimental design having normal operational condition (NOC) batches as central point. The primary aim here was to develop an expeditious NIRS method for determining the composition of a pharmaceutical gel and assess the temporal changes in major physical factors affecting the quality of the product (specifically, viscosity and pH). Gel components were quantified by using partial least squares (PLS) calibration models of the PLS1 type. The study was completed by using the batch statistical process control method to compare product batches included in the experimental design with NOC batches. Similarities and differences between the two types of batches were identified by using control charts for residuals (Q-statistic) and Hotteling's T2 (D-statistic). The ensuing models, which were subject to errors less than 5%, allowed the gel production process to be effectively monitored. As shown in this work, the NIRS technique is a highly suitable tool for process analytical technology. PMID- 21557225 TI - Prognostic molecular biomarkers for cutaneous malignant melanoma. AB - Molecular signatures of melanoma have propelled new approaches to early diagnosis, monitoring of treatment response, and targeted therapy. This review discusses messenger RNA (mRNA), genomic, and epigenomic melanoma biomarkers in blood and tissue specimens. The major focus is on tissue-based molecular assays to upstage sentinel lymph nodes (SLNs), and blood-based assays to detect melanoma progression by monitoring levels of circulating tumor cells (CTC) and circulating DNA. PMID- 21557226 TI - The significance of HER-2/neu receptor positivity and immunophenotype in ductal carcinoma in situ with early invasive disease. AB - INTRODUCTION: Biologic markers that predict development of invasive breast cancer (IBC) in patients diagnosed with ductal carcinoma in situ (DCIS) are needed to improve personalized therapy. In this study, we examined the incidence of early IBC in DCIS subgroups defined by immunophenotype. METHODS: Clinical and histologic materials of 143 patients with radiographically suggesting DCIS without obvious evidence of IBC were reviewed. All patients underwent initial biopsy followed by short-term subsequent resection. The presence of IBC, histopathologic features of DCIS and IBC, when present, and their estrogen receptor (ER), progesterone receptor (PR), and HER2 phenotypes were evaluated. RESULTS: Early IBC was identified on initial biopsy in 6 (4%) and subsequent resection in 24 (17%) patients. HER2 positivity in DCIS was the dominant factor associated with IBC. There was also a significant association between ER/PR/HER2+ DCIS and the presence of IBC. The ER/PR/HER2+ DCIS appeared to be the most unstable precursor, because of the highest invasion rate and frequent association with a discordant phenotype. CONCLUSIONS: HER2 positivity and ER/PR/HER2 phenotype may be used to identify DCIS patients at higher risk of harboring or potentially developing IBC. Strategies targeting HER2 in DCIS may be of potential benefit in preventing IBC in patients with DCIS. PMID- 21557227 TI - Adipose tissue-derived stromal cells protect hair cells from aminoglycoside. AB - BACKGROUND: Previous studies have demonstrated the therapeutic paracrine activity of adipose tissue-derived stromal cells (ADSCs). This study aimed to examine the ADSC potential for protecting auditory hair cells from aminoglycoside toxicity via paracrine of multiple growth factors and cytokines. STUDY DESIGN: Experimental study. METHODS: We assessed hair cell protection from neomycin toxicity by ADSC-derived factors using an explant culture system, in which cochlear explants and ADSCs were separated by a culture mesh insert to avoid direct contact. We measured the levels of growth factors and cytokines in ADSC culture media using an enzyme-linked immunosorbent assay (ELISA). RESULTS: Neomycin induced severe degeneration of auditory hair cells in cochlear explants, but co-culture with ADSCs significantly increased the number of surviving hair cells in explants. ELISA analysis revealed that ADSCs secreted insulin-like growth factor-1, nerve growth factor, vascular epithelial growth factor, transforming growth factor beta1, monocyte chemotactic protein-1, and most prominently hepatocyte growth factor. CONCLUSIONS: These findings demonstrate that ADSCs have the capacity to protect auditory hair cells, and can be a useful strategy to develop therapy for deafness in the clinic. The multiple paracrine growth factors and cytokines secreted by ADSCs might be involved in this effect. Laryngoscope, 2011. PMID- 21557228 TI - Empty nose syndrome: radiologic findings and treatment outcomes of endonasal microplasty using cartilage implants. AB - OBJECTIVES/HYPOTHESIS: To describe the radiologic characteristics of empty nose syndrome (ENS) and to assess outcomes of endonasal microplasty using cartilage implants in patients with ENS. STUDY DESIGN: A retrospective clinical chart review. METHODS: We assessed 17 patients diagnosed with ENS who had undergone prior nasal turbinate surgery. The presence of sinus opacity and the nasal mucosal thickening on the lesion side was evaluated with computed tomography in 11 patients and compared with control. To assess the effect of sinusitis on the nasal mucosal thickening, the thickness of lesion-side mucosae in unilateral sinusitis patients were compared with their contralateral mucosae. Twelve patients were managed by submucosal implantation of cartilage at the inferolateral nasal wall, just below the turbinate remnant, to create a neoturbinate. Symptom scores expressed as visual analogue scale (VAS) were compared before and after surgery. RESULTS: Opacity of the ipsilateral maxillary sinus was observed in seven of 11 patients. All lesion sides of ENS showed mucosal thickening of the nasal cavity, with an average thickness significantly greater than that in controls, whereas mucosal thickening was not found in the lesion-side mucosae of unilateral sinusitis patients. Patients reported significantly improved VAS score in excessive airflow, nasal obstruction, and nasal or facial pain. Complications of surgery included undercorrection in three patients. CONCLUSIONS: Radiologic abnormalities associated with ENS include ipsilateral sinus opacity and nasal mucosal thickening. Endonasal microplasty by submucosal implantation of cartilage may be a useful treatment option in the management of ENS. PMID- 21557229 TI - A new method that uses cyanoacrylate tissue adhesive to fill scoring incisions in septal cartilage correction. AB - OBJECTIVES/HYPOTHESIS: Numerous methods are used in the correction of deviated septal cartilage. One of these methods is to perform partial-thickness incisions (scoring) on the concave side of the deviated cartilage. In this retrospective report, we present a series of patients who were treated by filling the scoring incision gaps with cyanoacrylate-based tissue adhesives to increase the effectiveness of scoring incisions and to maintain stability of the corrected concave cartilage segments. STUDY DESIGN: A retrospective clinical study presenting a patient group who was treated using a new surgical method for septal deviation. METHODS: Twenty-three patients with septum deviation and nasal deformity underwent surgery with the open rhinoplasty approach. Intra- or extracorporeal scoring incisions were performed on the concave side of the deviated septal cartilage, and cyanoacrylate tissue adhesives were applied to the incisions of the corrected cartilage. After polymerization and hardening of the cyanoacrylate tissue adhesive, the operation continued in the normal manner. Preoperative and postoperative clinical results and computed tomography images of the patients were assessed. RESULTS: With a mean 24-month follow-up, all patients with respiratory complaints related to deviated septum reported improvement in nose breathing. Clinical and radiologic observations showed that the corrected septum was stable in its new position. There were no complications arising from the use of cyanoacrylate. CONCLUSIONS: Cyanoacrylate is an effective, instant, safe method of treatment in correcting deviated septal cartilage with scoring incisions and filling the gaps of the incisions. PMID- 21557230 TI - Functional outcomes and suitability of the temporalis myofascial flap for palatal and maxillary reconstruction after oncologic resection. AB - OBJECTIVES/HYPOTHESIS: The temporalis myofascial flap (TMF) is a method of palatal reconstruction that offers a single-stage, reliable, and functional technique to repair oncologic defects involving the oral cavity following tumor removal. It is hypothesized that both speech and swallowing function are preserved following TMF. STUDY DESIGN: In a retrospective and prospective case series, this study evaluated the surgical outcomes of 72 patients undergoing surgical resection and reconstruction of the hard and soft palate using a TMF. Of this series, 25 patients underwent nasalence and swallowing quality-of-life testing to determine speech and swallowing function following this procedure. METHODS: Reliability, safety, and effectiveness data endpoints on TMF reconstruction were collected and analyzed. Instrumental measures of nasalence (KayPentax Nasometer, Lincoln Park, NJ) and swallowing quality of life measures (MD Anderson Dysphagia Inventory [MDADI] were acquired. RESULTS: All TMF's were successfully transferred with complete healing of the oncologic defect. The group mean nasalence for connected speech tasks were within normal limits for connected speech--high- and low-pressure tasks (M = 21% and M = 17%). The group mean nasalence scores for sustained vowels were mildly affected (M = 26%). The group mean MDADI score was 79 (SD = 16), indicating good to mildly affected swallowing quality of life. Neither nasalence nor MDADI scores appeared to vary as a function of defect region. CONCLUSIONS: The TMF is an oncologically safe and effective method of palate reconstruction that affords excellent quality of life to appropriately selected patients without reliance on other reconstructive techniques. PMID- 21557231 TI - Nonresponders to pharyngeal surgery for obstructive sleep apnea: insights from drug-induced sleep endoscopy. AB - OBJECTIVES/HYPOTHESIS: To examine drug-induced sleep endoscopy (DISE) findings in nonresponders to previous pharyngeal obstructive sleep apnea (OSA) surgery. STUDY DESIGN: Cross-sectional. METHODS: DISE using propofol for unconscious sedation was performed in nonresponders to previous OSA surgery (including palate surgery with or without tonsillectomy and possible other procedures). Nonresponders were defined as subjects with a postoperative apnea-hypopnea index more than 10 events/hr. Recorded findings from DISE included the presence and degree of obstruction in the palatal and hypopharyngeal regions, the contributions of specific structures (velum, oropharyngeal lateral walls, tongue, and/or epiglottis) to upper airway obstruction, and the degree of mouth opening. RESULTS: Thirty-three nonresponders underwent DISE examinations. Age was 46.2 +/- 11.8 years, and 9% (3 of 33) were female. On diagnostic sleep studies prior to DISE, the apnea-hypopnea index was 43.4 +/- 26.6 events/hr. During DISE, a majority of subjects demonstrated residual palatal obstruction, and almost all demonstrated hypopharyngeal obstruction. A diversity of individual structures contributed to upper airway obstruction, often in combination. Moderate to severe mouth opening occurred in one-third of subjects and was associated with narrowing of upper airway dimensions. CONCLUSIONS: Residual upper airway obstruction in surgery nonresponders likely occurs due to multiple mechanisms, and DISE may enhance the understanding of them. PMID- 21557232 TI - Genetic characteristics in children with cochlear implants and the corresponding auditory performance. AB - OBJECTIVES/HYPOTHESIS: To explore the genetic characteristics of children with cochlear implants (CIs) and to correlate the auditory performance after implantation to the genetic diagnosis of children with CIs. STUDY DESIGN: Prospective cohort study. METHODS: Mutations of four common deafness-associated genes, GJB2, SLC26A4, the mitochondrial 12S rRNA gene, and OTOF, were screened in 743 unrelated children with idiopathic sensorineural hearing impairment, including 180 and 563 children with and without CIs, respectively. The allele frequencies and audiologic features were compared between both groups. The Categories of Auditory Performance (CAP) scores at 3 years after implantation were then analyzed according to the genotypes. RESULTS: A definitive genetic diagnosis was made in 37 (20.6%) of the 180 CI children. A significant difference in allele frequencies between CI and non-CI children was found in GJB2 mutations (chi-square test, P < .01), but not in SLC26A4 mutations, mitochondrial 12S rRNA mutations, or OTOF mutations (all P > .05). Further analysis revealed that the difference might have resulted from distinct audiological features in each group. Among the 110 CI children who had received more than 3 years of rehabilitation after implantation, the 35 children with mutations had better CAP scores than the 75 children without mutations. CONCLUSIONS: A significant prevalence of genetic mutations was identified in children with CIs, suggesting the need for routine genetic assessments. The frequencies of common deafness-associated mutations were different between children with and without CIs. The presence of genetic mutations was associated with an excellent long-term auditory performance outcome after implantation. PMID- 21557233 TI - Selection and placement of oral ventilation tubes based on tracheal morphometry. AB - OBJECTIVE/HYPOTHESIS: Evidence-based guidelines for the selection of appropriately sized ventilation tubes as well as their placement do not exist, although iatrogenic injuries to the trachea and larynx following endotracheal intubation are not infrequent. Our objective was to provide selection recommendations for ventilation tubes based on anatomic criteria. STUDY DESIGN: Prospective cross-sectional study at a tertiary care hospital. METHODS: From January 2010 to June 2010 all patients more than 16 years who underwent computer tomography of the neck were included. Contraindications were intubation, tracheotomy, fractures of the lower jaw, tumors, and head or neck deformities. Radiologic data was used to determine the distance between the lower incisors and cricoid cartilage and the smallest laryngotracheal diameter. The results were correlated with patient characteristics and compared with properties of ventilation tubes. RESULTS: One hundred fifty-nine patients were included in the study. The laryngotracheal constriction was subcricoidal with a mean diameter of 15.5 +/- 3.2 mm coronal and 17.1 +/- 2.6 mm sagittal. The mean distance between lower incisors and cricoid cartilage was 176.5 +/- 14.8 mm. Patient height correlated significantly with the coronal subcricoid tracheal diameter (r = .51; P < .001) as well as with the distance between lower incisors and cricoid cartilage (r = .64; P < .001). No statistically significant gender or age-related correlations were found. Despite having the same specifications, tubes from different manufacturers differed considerably in their dimensions. CONCLUSIONS: Selection of size and placement of ventilation tubes can be based on patient height. Considerable differences in the dimensions of ventilation tubes necessitate a height-based nomogram for evidence-based tube selection and placement. A uniform system of tube labeling based on biometric data is required. PMID- 21557234 TI - Validation of edible taste strips for identifying PROP taste recognition thresholds. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to validate the use of edible taste strips for measuring taste recognition thresholds for the bitter tasting compound 6-n-propylthiouracil (PROP). STUDY DESIGN: Taste recognition thresholds for PROP were obtained by two separate methods. Thresholds were also identified in subjects whose airflow through the nose was blocked. Threshold values were then compared to genotype analysis of the TAS2R38 taste receptor, which is the major determinant for the detection of PROP. METHODS: Edible taste strips were used to examine taste recognition thresholds for PROP. Thresholds were determined by the method of ascending limits and by the method of reversals. Single nucleotide polymorphism analysis of the TAS2R38 gene was used to identify PROP taster status. RESULTS: Taste recognition thresholds for PROP formed two distributions. Thresholds for one group varied from 4 to 219 nmol and represented PROP tasters. The second group could not detect the bitter taste of PROP at <=800 nmol and represented PROP nontasters. The method of ascending limits and the method of reversals yielded similar threshold results. The expression of a PAV allele permitted detection of PROP, but AVI homozygotes could not detect the bitter taste of PROP. CONCLUSIONS: Edible taste strips were successfully used to detect PROP thresholds at values equal to or lower than those obtained in previous studies using PROP solutions or PROP-impregnated filter papers. This study provides validity evidence for the use of edible taste strips for identifying PROP in the human population. PMID- 21557235 TI - In reference to proposed definitive grading system tool for the assessment of adenoid hyperplasia. PMID- 21557236 TI - A new and less invasive procedure for arytenoid adduction surgery: endoscopic assisted arytenoid adduction surgery. AB - OBJECTIVES/HYPOTHESIS: Arytenoid adduction (AA) is the most effective procedure for improving voice function in patients affected by unilateral vocal fold paralysis (UVFP), but it is often associated with severe complications following airway obstruction. The aim of this study is to describe a new and less invasive AA surgical procedure termed endoscopic-assisted AA surgery (EAAS) and to evaluate its voice outcomes. STUDY DESIGN: We demonstrated this method using extirpated larynges from three laryngeal cancer patients. Ten patients with severe UVFP underwent EAAS alone or combined with type I thyroplasty or lipoinjection laryngoplasty. METHODS: EAAS involves the placement of permanent adducting sutures around the muscular process (MP) of the arytenoid cartilage using two needles, a penetration needle and a loop needle, under endoscopic guidance. To define the anatomic position of the MP for safer needle insertion, the location of the MP was measured relative to three landmarks on computed tomography/X-ray images of the larynges and in resected larynges. For all patients with UVFP, the maximum phonation time, mean airflow rate, and three acoustic analysis parameters were measured before and after EAAS. RESULTS: The values of the three variables were similar in all cases. Most patients achieved a maximum phonation time of more than 10 seconds and a mean airflow rate of less than 200 mL/second. All three acoustic analysis parameters were significantly improved after surgery. CONCLUSIONS: EAAS is a simple and effective arytenoid rotation procedure. PMID- 21557237 TI - What faces reveal: impaired affect display in facial paralysis. AB - OBJECTIVES/HYPOTHESIS: To evaluate affect display in patients with facial paralysis as compared with normal subjects. We hypothesized that patients with facial paralysis would have impaired affect display and be perceived as displaying a negative affect as compared with normal subjects. STUDY DESIGN: Randomized controlled experiment. METHODS: Forty naive observers viewed pictures of patients with facial paralysis and normal faces. Observers classified the affect display of the patients and normal subjects by using a survey containing choices regarding primary emotions and personal attributes. RESULTS: An exploratory latent class analysis was performed on the survey results, and the faces were categorized into three types: positive, negative, and neutral. The probability of interpreting normal smiling faces as positive was 98%; the probability of interpreting those in repose as neutral or positive was 60%. The faces with facial paralysis were much more likely to be regarded as negative or neutral. The probability for classification into the negative class was 73% for the paralyzed faces in repose and 69% for the paralyzed smiling faces. In the latent class regression, smiling normal faces were six times more likely to be classified as positive, and smiling paralyzed faces were three times less likely to be in that class. CONCLUSIONS: Patients with facial paralysis were classified as having a negative affect display the vast majority of the time. Antithetically, normal faces in repose were classified as neutral the majority of the time; they were classified as positive the majority of the time when smiling. These novel results demonstrate the impact of the facial paralysis defect on perception by observers. Laryngoscope, 2011. PMID- 21557238 TI - Pictorial ultrasound reports combined with fine needle washout thyroglobulin assay to aid thyroid surgery. PMID- 21557239 TI - The grainyhead-like 2 gene (GRHL2) single nucleotide polymorphism is not associated with age-related hearing impairment in Han Chinese. AB - OBJECTIVES/HYPOTHESIS: The grainyhead-like 2 gene (GRHL2) was found to be associated with age-related hearing impairment (ARHI) in Europeans. We tested whether the same association exists in the Han Chinese population. STUDY DESIGN: Individual cohort study. METHODS: Among a total of 1,175 Han Chinese volunteers, 310 were classified into the case group (the 26% with poorest hearing), and 308 were placed into the control group (the 26% with best hearing) according to the Zhigh scores converted from the original frequency-specific hearing thresholds. The GRHL2 single nucleotide polymorphism locus (rs10955255: A/G) in intron 1 (coordinate: 102605581) shown in the HapMap was genotyped with correlation to the audiologic phenotypes. RESULTS: The genotype distributions of GRHL2 (AA/AG/GG) were not significantly different between the control and the case groups (P = .349). Compared to genotype AA, the odds ratios of the GRHL2 genotypes AG and GG for ARHI were not significantly different after adjustment for other environmental risk factors by logistic regression analyses; 0.78 +/- 0.139, 95% confidence interval (CI) = 0.55-1.10, P = .160 for AG; 0.85 +/- 0.283, 95% CI = 0.44-1.63, P = .625 for GG. In each audiogram pattern, AA was most common, but the adjusted odds ratios of the genotypes AG and GG for ARHI still were not significantly different. CONCLUSIONS: Our results showed no positive association between GRHL2 polymorphisms and ARHI in Han Chinese individuals. Population differences might be a key factor leading to nonreplication of the association. PMID- 21557240 TI - Evidence of extraesophageal reflux in idiopathic subglottic stenosis. AB - OBJECTIVES/HYPOTHESIS: Idiopathic subglottic stenosis (iSGS) is a disease predominantly of females that, by definition, has no known etiology. Collagen vascular disease, localized trauma, extraesophageal reflux (EER), and hormonal alterations have all been postulated as potential etiologies of iSGS. It is hypothesized that iSGS is a reflux mediated disease and that evidence of EER exists in affected patients. STUDY DESIGN: Case-control study. METHODS: Patients with iSGS were identified prospectively over a 2.5-year period (2007-2010). During their endoscopic management, biopsies of the subglottic scar and postcricoid area were evaluated for the presence of pepsin, an indicator of exposure to gastric refluxate. Control patients had similar biopsies while undergoing operative management for disease unrelated to reflux. Charts of both patients and controls were reviewed for clinical history of reflux, pH-metry, and laboratory testing for collagen-vascular disease. RESULTS: Twenty-two patients with iSGS were treated. All patients were female. No patient had serology positive for collagen-vascular disease. Thirteen (59%) patients with iSGS had pepsin present in their larynx or trachea. Control patients did not have detectable pepsin in their tissue (P = .041). Dual probe 24-hour pH studies were performed in 10 (45%) patients. These studies were positive for EER in seven patients but this did not statistically correlate to the presence of pepsin in their tissue (P = 1.0). CONCLUSIONS: iSGS is a disease almost exclusively of women. EER is implicated in the development of iSGS. Pepsin is detectable in the subglottic scar and larynges of patients with iSGS. Standard pH-metry may be inadequate in predicting degree of EER in patients with iSGS. PMID- 21557241 TI - Prospective multi-arm evaluation of surgical treatments for vocal fold scar and pathologic sulcus vocalis. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to compare the clinical effectiveness of type I thyroplasty, injection laryngoplasty, and graft implantation for the treatment of vocal fold scar and pathologic sulcus vocalis. STUDY DESIGN: Prospective, multi-arm, quasi-experimental research design. METHODS: Twenty-eight patients with newly diagnosed vocal fold scar and/or pathologic sulcus vocalis were assigned to one of three treatment modalities: type I thyroplasty (n = 9), injection laryngoplasty (n = 9), and graft implantation (n = 10). Psychosocial, auditory-perceptual, acoustic, aerodynamic, and videostroboscopic data were collected pretreatment and at 1, 6, 12, and 18 months posttreatment. RESULTS: Type I thyroplasty and graft implantation both resulted in reduced voice handicap with no concomitant improvement in auditory perceptual, acoustic, aerodynamic, or vocal fold physiologic performance. Injection laryngoplasty resulted in no improvement on any vocal function index. Patients who underwent graft implantation exhibited the slowest improvement trajectory across the 18-month follow-up period. CONCLUSIONS: A persistent challenge in this area is that no single treatment modality is successful for the majority of patients, and there is no evidence-based decision algorithm for matching a given treatment to a given patient. Progress therefore requires the identification and categorization of predictive clinical features that can drive evidence-based treatment assignment. PMID- 21557242 TI - Radiofrequency tissue volume reduction for treatment of auricle keloids. AB - OBJECTIVES/HYPOTHESIS: Keloids are often refractive to treatment, and recurrences occur quite frequently. Radiofrequency tissue volume reduction (RFTVR) is a surgical technology that induces extensive fibrosis at the target tissues. METHODS: We applied RFTVR in 14 patients (19 auricles, 5 patients treated bilaterally; 9 female, 5 male; range, 10-66 years) with keloids of the auricle. Keloids were located at the earlobe in 4 patients (5 auricles), helix in 9 patients (12 auricles), and at both earlobe and helix in 1 patient (2 auricles). In 6 patients (8 auricles) RFTVR was the sole treatment modality applied, and in 7 patients (10 auricles) intralesional steroid injection was also performed. Patients underwent one to seven sessions of RFTVR. Patients were followed up between 2 and 92 months postoperatively (median, 24.5 months). RESULTS: Good cosmetic results were achieved in 10 of 14 patients (13 auricles). Three patients (5 auricles) were refractive to treatment, and 1 patient (1 auricle) showed progressive disease despite treatment. CONCLUSIONS: Radiofrequency tissue volume reduction may be considered as a new, minimally invasive treatment option for keloids of the auricle. PMID- 21557243 TI - Parathyroid localization with modified 4D-computed tomography and ultrasonography for patients with primary hyperparathyroidism. AB - OBJECTIVES: In this article, we report our decade-long experience in using modified 4D-computed tomography in combination with ultrasonography (Mod 4D CT/US) to localize abnormal parathyroid glands in patients with primary hyperparathyroidism. STUDY DESIGN: Retrospective medical record review at a university-based academic medical center. METHODS: Patients with primary hyperparathyroidism who underwent a Mod 4D-CT/US and parathyroidectomy between January 1998 and May 2009 were included in the study. Results from preoperative localization studies were compared with operative findings, pathologic data, and biochemical measurements to assess the sensitivity and specificity as well as the positive and negative predictive values of Mod 4D-CT/US. RESULTS: Mod 4D-CT/US demonstrated 94% sensitivity and 96% specificity when these imaging studies were used to lateralize the hyperfunctioning parathyroid glands to one side of the neck. In regard to localizing abnormal parathyroid glands to a specific quadrant of the neck (i.e., right-left; superior-inferior), the sensitivity and specificity of Mod 4D-CT/US was 82% and 93%, respectively. Mod 4D-CT/US had a 92% positive predictive value for single-gland disease and 75% for multigland disease. The negative predictive value for single and multigland disease (MGD) were 73% and 92%, respectively. CONCLUSIONS: Mod 4D-CT/US provides excellent sensitivity and specificity in terms of localizing abnormal parathyroid glands to the correct side and quadrant in patients with primary hyperparathyroidism, and it correctly identifies many patients with MGD. PMID- 21557244 TI - Terminology and classification of neuroendocrine neoplasms of the larynx. AB - OBJECTIVES: To review the history and literature on neuroendocrine neoplasms of the larynx and discuss the terminology and classification of these tumors. STUDY DESIGN: Contemporary review. METHODS: Published journal articles identified through PubMed and conference proceedings were reviewed. RESULTS: Neuroendocrine neoplasms of the larynx include both epithelial (carcinomas) and neural-type lesions (paragangliomas).The nomenclature of these tumors has changed quite a bit over time, but recently, clearer categories have emerged that are biologically meaningful. They can overlap clinically and histologically so that segregation into the clinically relevant subtypes can be difficult, but it is extremely important to do so as they have a wide range of behaviors going from benign to rapidly fatal. CONCLUSIONS: Neuroendocrine neoplasms of the larynx can be clearly categorized into the five tumor types: typical carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, and paraganglioma. These have concrete biologic and clinical significance and clearly dictate patient treatment. PMID- 21557246 TI - Contemporary management of acoustic neuromas. AB - OBJECTIVES/HYPOTHESIS: This review of the literature on vestibular schwannomas focuses on the developments in the fields of surgery, radiosurgery, and observation during the past decade that have redefined the treatment algorithm. The authors hope to derive some recommendations that are evidence based and applicable to everyday clinical practice while advancing the dialogue regarding the optimal management of these lesions. STUDY DESIGN: Contemporary review. METHODS: English literature search for acoustic neuroma or vestibular schwannoma. RESULTS: Radiosurgical treatment appears to maintain strong tumor control during an ever-increasing number of years of follow-up. Fractionated radiation therapy, with attention to limiting the cochlear radiation dose, seems to afford the best hearing-nerve functional outcomes. Microsurgical treatment remains the best cytoreductive therapy, and although it cannot achieve the facial and hearing nerve outcomes of radiosurgery, it is still the preferred treatment for large lesions causing mass effect and obstructive hydrocephalus. Bevacizumab holds substantial promise for the treatment of neurofibromatosis type 2-associated progressive lesions. CONCLUSIONS: Our review of the literature suggests that near total or extensive subtotal resection of vestibular schwannomas may confer much improved functional outcomes without significant detriment to acceptable rates of tumor control. However, further follow-up is needed in patients treated with this relatively novel surgical paradigm. PMID- 21557245 TI - Prostaglandin (PG)E2 exhibits antifibrotic activity in vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: Prostaglandin (PG)E2 has been implicated in a variety of disease processes. It has been described as antifibrotic in the lower airway, yet scar-inducing in the skin. We seek to describe the effects of PGE2 on vocal fold fibroblasts and its interactions with transforming growth factor (TGF)-beta1. In addition, we describe a novel organotypic model, a critical step in the development of therapeutic trials. STUDY DESIGN: In vitro, ex vivo. METHODS: Collagen secretion by human vocal fold fibroblasts (HVFF) was assayed in response to TGF-beta1, PGE2 , and specific EP receptor agonists. Basal HVFF migratory rate was also quantified in response to PGE2 . TGF-beta1 induced COX-2 mRNA expression/PGE2 secretion was assayed. Excised vocal folds were subjected to exogenous IL-1beta; PGE2 secretion into the supernatant was then assayed. RESULTS: TGF-beta1-induced collagen secretion was blunted in a dose-dependent manner in response to PGE2 . This effect appears to be mediated primarily through the EP1 and EP2 receptors. TGF-beta1 induced COX-2 mRNA expression and PGE2 secretion. In our organ culture model, IL-1beta stimulated PGE2 secretion in a dose-dependent manner. CONCLUSIONS: PGE2 is antifibrotic; this finding suggests that the upper airway response to this inflammatory mediator differs significantly from the lower airway. These data have important clinical implications for a variety of pathological processes. Furthermore, exogenous TGF beta1 elicits induction of COX-2, suggesting inherent complexity regarding these processes and PGE2 signaling, specifically. In addition, our organ culture model may prove useful as a means to quantify biological phenomena in the vocal folds. PMID- 21557247 TI - Sleep magnetic resonance imaging: dynamic characteristics of the airway during sleep in obstructive sleep apnea syndrome. AB - OBJECTIVES/HYPOTHESIS: To determine the dynamic characteristics of airway obstruction in subjects with obstructive sleep apnea (OSA) syndrome. STUDY DESIGN: A prospective cohort study of 20 OSA patients and 19 control subjects who underwent real-time magnetic resonance imaging (MRI) evaluation between 2006 and 2008. METHODS: The dynamics of the upper airway were visualized using real-time MRI (RTHawk system, Stanford, CA) during natural sleep. Respiratory and desaturation events were correlated to polysomnogram results, and anatomic site of obstruction was determined from the real-time MRI sequences. The relation between visually observed airway obstructions and autonomic system changes was quantified and reliability calculated (Cronbach alpha, Aabel 2009; Gigawiz, Ltd., Tulsa, OK). An automated analysis tool was developed to determine which respiratory event is associated with the longest duration and location of obstruction in the posterior airway space (Matlab 2009; Mathworks, Inc., Natick, MA). RESULTS: Airway obstructions visualized on Sleep MRI during natural sleep included retropalatal, retroglossal, and combined obstruction. Respiratory events (mean rate of 31.9 per hour per subject) and desaturations (mean rate of 19.4 per hour per subject) temporally coincided with airway obstructive events. Intrarater reliability coefficients ranged from a low of 0.95 to a high of 1.0 for each rater. Inter-rater reliability coefficients ranged from a low of 0.85 to a high of 1.0. CONCLUSIONS: Sleep MRI is a novel and reliable approach to simultaneously evaluate airway obstructions and respiratory events in real time during natural sleep. Sleep MRI can define the dynamic characteristics of airway obstruction in both surgically naive and postsurgical OSA patients. PMID- 21557248 TI - Three-dimensional computed tomography in obstructive sleep apneics treated by maxillomandibular advancement. AB - OBJECTIVES/HYPOTHESIS: The goal of this study was to understand the changes to the head and neck musculoskeleton and the pharyngeal airway after surgery. We tested the correlation between the changes in the skeleton and pharyngeal airway and the apnea-hypopnea index (AHI). STUDY DESIGN: Prospective, noncontrolled study. METHODS: In a pilot study, 12 consecutive subjects (3 women, body mass index: 22.4 Kg/m(2) +/- 2.7, AHI: 35.9/sec +/- 18.0) with Class II dentoskeletal malocclusion and high mandibular plane underwent segmental maxillomandibular rotational advancement (SMMRA). Subjects underwent overnight polysomnography and three-dimensional computed tomography scanning of the head and neck before and 3 months after surgery. Linear, angular, and area measurements were obtained from skeletal images placed in the Frankfort horizontal position and from horizontal cross-sectional tomograms derived from the upright pharyngeal airway. Skeletal movements, dimensional changes of the airway, and correlations between measurements and AHI were calculated. A linear regression model was generated using significant bivariate correlations. RESULTS: The AHI was significantly reduced to 4.6/sec +/- 4.1 with improvement in the nadir oxygen saturation from 83.0% +/- 7.2 to 90.6% +/- 3.6 after SMMRA. Following skeletal advancement, the hyoid bone was advanced and elevated by 7.5 mm +/- 2.9 and 6.7 mm +/- 5.5, respectively; the cervical spine was rotated forward by 4.6 degrees +/- 2.8; and the airway length was shortened by 6.8 mm +/- 4.0 (all P < .01). Variable improvement of airway dimensions was noted at each horizontal level. A quadratic regression model was derived using the measurements of the Sella-Nasion-B point angle and AHI (Rsq = 0.557, sig = 0.000). CONCLUSIONS: Dimensions of pharyngeal airway were correlated with dimensions of craniofacial skeleton. Sella-Nasion-B point angle could be used as a guidance in achieving normalized AHI after surgery. PMID- 21557249 TI - Otologic diagnoses in the elderly: current utilization and predicted workload increase. AB - OBJECTIVES/HYPOTHESIS: To establish the current outpatient workload for otologic conditions in the elderly and to estimate its potential increase based on an anticipated aging population. STUDY DESIGN: Cross-sectional analysis of a national database. METHODS: All outpatient clinic visits for patients aged >= 65 years receiving one of six common otologic diagnoses from 2005 to 2007 in the United States were determined from the National Ambulatory Medical Care Survey. The distribution of the visits for these diagnoses across 15 specialties was assessed. The number of visits was projected to the 2020 population based on changes in population demographics predicted by the US Census Bureau. RESULTS: An estimated 4.48 +/- 0.49 million clinic visits with an otologic issue as a coded diagnosis were conducted in 2005 to 2007 in patients aged >= 65 years. These consisted of 230,000 visits for benign positional paroxysmal vertigo, 263,000 visits for vestibular neuritis, 292,000 visits for Meniere's disease, 1.09 million visits for tinnitus, and 2.85 million visits for sensorineural hearing loss. Otolaryngology, internal medicine, family practice, and neurology managed the most visits, seeing 57.0%, 21.0%, 14.3%, and 2.2% of the cases, respectively. With expected changes in population demographics by 2020, annual clinic visits for an otologic diagnosis will increase from 1.49 +/- 0.78 million to 2.14 million visits in the elderly, annualized, including 1.218 million visits to otolaryngology. CONCLUSIONS: These data quantify the current outpatient otology workload and predict a substantial increase for many specialties, including otolaryngology. Efforts to prepare for this increase including manpower planning and education appear imperative. PMID- 21557250 TI - Complete resolution of diffuse placenta increta in a primigravida with twin pregnancy: sonographic monitoring. AB - We report a case of timely diagnosis of placenta increta by sonography during the third stage of labor, which avoided any attempt at manual removal of a retained placenta and thus prevented additional postpartum bleeding. The use of intra cervical injection of vasopressin and methotrexate and application of transcatheter arterial embolization of bilateral uterine arteries and right internal iliac arteries resulted in a good outcome. PMID- 21557251 TI - Influence of proteinuria on renal Doppler sonographic measurements in chronic kidney disease and in diabetes mellitus. AB - PURPOSE: To evaluate the influence of proteinuria on renal Doppler sonographic (US) measurements in patients with chronic kidney disease (CKD) with or without diabetes mellitus (DM). METHODS: Renal resistance index (RI), pulsatility index (PI), and maximum kidney length were measured by US in 113 patients suffering from CKD without DM (non-DM CKD patients) and in 120 patients with diabetic nephropathy (DM patients). Other data collected were sex, age, body mass index, blood pressure, estimated glomerular filtration rate, urinary protein level, and medical history. The effect of proteinuria on RI and PI was evaluated using single regression analyses, multiple regression analyses, and comparison of regression lines. RESULTS: Single and multiple regression analyses revealed that RI and PI in the two subgroups and in the entire group of patients were correlated with urinary protein level (p < 0.05). Comparison of regression lines of each subgroup showed statistically significant differences in two regression intercepts concerning these indices in relation to urinary protein level (p < 0.001, RI: 0.71 in non-DM CKD patients versus 0.76 in DM patients, PI: 1.39 in non-DM CKD patients versus 1.60 in DM patients) (p < 0.001). CONCLUSIONS: Renal RI and PI can reflect damages related to proteinuria and DM. PMID- 21557252 TI - First-trimester diagnosis of conjoined twins aided by spatiotemporal image correlation. AB - A case of conjoined twins after frozen embryo transfer at early blastocyst stage is described. The diagnosis was made early at 7 weeks by vaginal sonography and later confirmed by spatiotemporal image correlation with power Doppler. The value of spatiotemporal image correlation with Doppler in facilitating an early diagnosis of conjoined twinning is discussed. PMID- 21557253 TI - Ultrafiltration for acute decompensated heart failure: cost, reimbursement, and financial impact. AB - In addition to the proposed pathophysiologic mechanisms whereby ultrafiltration (UF) can be advantageous over diuretics in the treatment of heart failure, there can also be financial and resource-utilization reasons for pursuing this extracorporeal strategy. In those cases in which the clinical outcomes would be equivalent, however, the decision whether to pursue UF will depend greatly on the anticipated hospitalization length of stay (LOS), the patient population's pay or mix, the needs and costs for high-acuity (eg, intensive care unit) care, and widely varying expenses for the equipment and disposable supplies. From a fiscal perspective, the financial viability of UF programs revolves around how improvements in LOS, resource utilization, and readmissions relate to the typical diagnosis-driven (eg, diagnosis-related group) reimbursement. We analyzed the impact of these various factors so as to better understand how the intensity (and expense) of pharmaceutical and extracorporeal therapies impacts a single admission, as well as to serve as the basis for developing strategies for optimizing long-term care. PMID- 21557254 TI - Strain imaging in morbid obesity: insights into subclinical ventricular dysfunction. AB - BACKGROUND: Obesity has become an important health problem throughout the world. Early detection of cardiovascular abnormalities may be useful in the future for patient management. This study aimed to identify subclinical ventricular dysfunction in obese patients. HYPOTHESIS: Morbid obesity is associated with ventricular dysfunction. METHODS: Doppler echocardiogram was performed in 92 morbidly obese and in 31 healthy controls. Conventional echocardiography and tissue Doppler-based strain imaging were used to analyze ventricular function. Intra- and interobserver strain imaging variabilities were tested on 15 randomly selected cases. RESULTS: Left ventricular (LV) global strain (22.5% +/- 3.5 vs 24.4% +/- 2.5, P<0.005) and right ventricular (RV) strain (25.8% +/- 5.2 vs 28.2% +/- 5.2, P<0.029) were lower in obese patients when compared with healthy controls. Echocardiographic parameters of diastolic function were also different from controls. LV strain correlated with LV mass, E/e' ratio, left atrial volume, and RV strain. At multivariate analysis, morbid obesity remained a significant determinant of global LV strain, independently of associated comorbidities. CONCLUSIONS: These findings suggest that incipient biventricular dysfunction is present in morbidly obese patients when new echocardiographic indices are used to investigate ventricular function. In addition, strain imaging may provide a more accurate assessment of the ventricular function in obese patients. PMID- 21557255 TI - Gender-related differences in patients with ST-elevation myocardial infarction: results from the registry study of the ST elevation myocardial infarction network Essen. AB - BACKGROUND: The Myocardial Infarction Network Essen was initiated in order to establish a standardized procedure with immediate reopening of the infarcted vessel for patients with ST-elevation myocardial infarction (STEMI) in the city of Essen, Germany. The present study aims to evaluate gender-related differences in presentation of disease and clinical outcome. HYPOTHESIS: Gender is associated with differences in presentation and outcome of STEMI. METHODS: All patients with STEMI were included without exception. Parameters such as risk profile, mortality, and relevant time intervals were documented. The follow-up period was 1 year. RESULTS: For this study, 1365 patients (72.1% male) were recruited. Women were significantly older, with higher prevalence of diabetes (28.1% vs 20.3%, P = 0.004) and hypertension (76.5% vs 64.8%, P<0.0005). Analysis of time intervals between symptoms to actions showed no significant differences. However, women tended to wait longer before calling for medical assistance (358 vs 331 min, P = 0.091). In-hospital mortality was comparable with respect to gender, whereas women had higher 1-year mortality (18.6% vs 13.2%). Age and diabetes were associated with a higher mortality. Adjusted for age, gender is no longer an independent risk factor. In the follow-up period, significantly more women were readmitted to the hospital without a difference in the frequency of reangiography, surgery, or target-vessel revascularization. CONCLUSIONS: The present data display a successful implementation of a standardized procedure in patients with STEMI. Although differences between genders are not as obvious as expected, efforts should be taken to perform a gender-specific risk analysis as well as to promote education about proper behavior in case of new onset of angina. PMID- 21557256 TI - Correlation between HLA-DRB1, HLA-DQB1 polymorphism and autoantibodies against angiotensin AT(1) receptors in Chinese patients with essential hypertension. AB - BACKGROUND: The autoantibodies (AAs) against angiotensin AT(1) receptors (AT(1) AAs) have been discovered in patients with preeclampsia, malignant hypertension, and essential hypertension (EH); however, the mechanism of AA production remains to be investigated. HYPOTHESIS: Polymorphisms of HLA-DRB1 or HLA-DQB1 are related to production of AAs in autoimmune diseases. We hypothesis that the polymorphisms of the HLA molecules are also associated with production of AT(1) -AAs in patients with EH. METHODS: We enrolled 394 patients with EH and 224 normotensive subjects in this study. Autoantibodies in sera of donors were detected by enzyme linked immunosorbent assay. The subjects' clinical data were collected, including gender, age, body mass index, blood pressure, smoking status, and diabetes. The patients and the normotensive subjects were classified respectively into AA positive and AA-negative groups. Typing of DNA for HLA-DRB1 and HLA-DQB1 alleles was done by polymerase chain reaction amplification with sequence-specific primers. RESULTS: Thirteen HLA-DRB1 and 7 HLA-DQB1 alleles were found in this population. The frequencies of AT(1) -AAs were related to blood pressure level. The frequency of AT(1) -AAs in the EH group was higher than that in the normotensive group (P = 0.0001). The levels of AAs in different groups of EH show a significant difference (P = 0.027). In addition, HLA-DRB1(*) 04 and HLA-DRB1(*) 14 (odds ratio [OR]: 3.06, 95% confidence interval [CI]: 1.56-5.97, P = 0.001; and OR: 2.53, 95% CI: 1.080-5.91, P = 0.033, respectively) were related to AT(1) AA production in normotensive subjects after adjusting for covariants. The HLA DRB1(*) 04 allele might be related to AT(1) -AA production in hypertensive subjects, and the P value was of baseline statistical significance after adjusting for blood pressure and other covariants (OR: 1.63, 95% CI: 0.95-2.78, P = 0.070). CONCLUSIONS: These results suggest a difference in the immunogenetic background between the positive and negative AAs with hypertension or normotension. The HLA-DRB1(*) 04 allele increases the risk for AT(1) -AA production. PMID- 21557257 TI - Sequence-specific predictive chromatography to assist mass spectrometric analysis of asparagine deamidation and aspartate isomerization in peptides. AB - Deamidation of asparagine and spontaneous isomerization of aspartic acid in proteins and peptides occur frequently. These modifications result in a mixture of peptide variants containing all three residues in the sequences. Identification and isomer quantification for these systems are challenging tasks for tandem mass spectrometry commonly utilized in protein analysis. Chromatographic data provide a set of sequence-specific information complementary to mass spectrometry. In order to compare measured retention times (RTs) with those calculated from the sequences derived from protein databases, it is necessary to develop chromatographic models and tools allowing the prediction of RT and elution order for peptides with modified residues. In this work we extended recently introduced critical liquid chromatography of biomacromolecule model for prediction of RTs for peptides containing asparagines, aspartic acid, and isoaspartic acid residues. PMID- 21557258 TI - Electrophoretic fingerprint metallothionein analysis as a potential prostate cancer biomarker. AB - Prostate-specific antigen (PSA) is a routinely used marker of prostate cancer; however, the cut-off values for unambiguous positive/negative prostate cancer diagnoses are not defined. Therefore, despite the best effort, certain percentage of misdiagnosed cases is being recorded every year. For this reason, search for more specific diagnostic markers is of great interest. In this study, systematic comparison of PSA and metallothionein (MT) levels in blood serum of 46 prostate cancer-diagnosed patients is presented. It is clearly demonstrated that PSA levels vary significantly and despite normal total PSA values in the range of 0 - 4 ng/mL were obtained in over 36.9% of cases, positive prostate cancer was diagnosed by biopsy. In contrary, MT levels were considerably elevated in all tested samples and no significant variations were observed. These results are indicating the potential of MT as an additional prostate cancer marker reducing, in combination with PSA, the probability of false positive/negative diagnosis. To increase the throughput of the screening, chip-based capillary electrophoresis was suggested as a rapid and effective method for the fingerprinting analysis of prostate cancer from diseased blood sera. PMID- 21557259 TI - Quantitative gel electrophoresis: new records in precision by elaborated staining and detection protocols. AB - Gel electrophoresis (GE) is a very common analytical technique for proteome research and protein analysis. Despite being developed decades ago, there is still a considerable need to improve its precision. Using the fluorescence of Colloidal Coomassie Blue -stained proteins in near-infrared (NIR), the major error source caused by the unpredictable background staining is strongly reduced. This result was generalized for various types of detectors. Since GE is a multi step procedure, standardization of every single step is required. After detailed analysis of all steps, the staining and destaining were identified as the major source of the remaining variation. By employing standardized protocols, pooled percent relative standard deviations of 1.2-3.1% for band intensities were achieved for one-dimensional separations in repetitive experiments. The analysis of variance suggests that the same batch of staining solution should be used for gels of one experimental series to minimize day-to-day variation and to obtain high precision. PMID- 21557260 TI - Haplotyping of putative microRNA-binding sites in the SNAP-25 gene. AB - Synaptosomal-associated protein 25 (SNAP-25) plays a crucial role in exocitosis. Single nucleotide polymorphisms (rs3746544 and rs1051312) in the 3' un-translated region of the SNAP-25 gene have been described to be in association with attention-deficit hyperactivity disorder. As the disease affects millions of children world-wide, understanding the genetic background of attention-deficit hyperactivity disorder is of crucial importance. Efficient and reliable PCR-RFLP protocols were elaborated for the genotyping of the rs3746544 and rs1051312 SNPs employing a high-throughput capillary electrophoresis method for fragment analysis. A novel real-time PCR-based technique was used applying sequence specific TaqMan probes to haplotype the two SNPs, and the G-C haplotype could not be detected in a large Caucasian population (N=1376). These findings have been confirmed by molecular biology tools as well as by the PHASE Bayesian computational approach. In silico analyses have suggested that the two SNPs might alter microRNA binding and thus have an effect on SNAP-25 production. We have demonstrated that this biological information can be revealed only by direct haplotype analysis emphasizing the importance of our novel molecular haplotye analysis protocol. Results of the study of the two SNPs might shed light on the association of SNAP-25 variants and pathological phenotypes at the molecular level. PMID- 21557261 TI - Proteomic biomarker discovery: it's more than just mass spectrometry. AB - The previous decade witnessed an enormous number of studies with the singular goal of identifying protein biomarkers for diseases such as cancer. A large majority of these studies have focused on comparative studies of serum or plasma obtained from disease-affected and control patients. In these studies, proteins identified in the samples using MS were compared with the hope that differences between samples would reveal useful biomarkers. Unfortunately, finding clinically relevant biomarkers has often been elusive and frustrating. As with most research efforts, both successes and failures, much has been learned about what strategies work and which do not. Part of the problem can be attributed to underestimating the effort required to discover novel biomarkers and depending too heavily on MS analysis of peripheral blood samples. Fortunately, the future for biomarker discovery still appears bright. MS technology continues to increase in sensitivity, throughput, and accuracy while novel types of samples and clever experimental designs coupled with innovative bioinformatics will make this vision of routine biomarker discovery a reality. To achieve ultimate success is going to require concomitant application of a number of different technologies, all providing the information necessary for discovering and validating clinically useful biomarkers. PMID- 21557262 TI - Proteomic identification of exosomal LRG1: a potential urinary biomarker for detecting NSCLC. AB - In the present research, we aimed to screen for non-small cell lung cancer (NSCLC)-related proteins in urinary exosomes by comparing urinary exosomes proteome of normal controls and NSCLC patients. Urinary exosomes were isolated by ultracentrifugation and identified by electron microscopy. Exosomal proteins were separated by 1-D SDS-PAGE and the differentially expressed bands between healthy controls and NSCLC patients ranging in size from 35 to 45 kD were cut from the gel. After tryptic digestion, 18 proteins were identified by nano-HPLC-chip MS/MS. The differential expression of leucine-rich alpha-2-glycoprotein (LRG1) was further validated in urinary exosomes by Western blot and in lung tissue by immunohistochemistry. The LRG1 was found to be expressed at higher levels in urinary exosomes and lung tissue of NSCLC patients. These results suggested that LRG1 may be a candidate biomarker for non-invasive diagnosis of NSCLC in urine. PMID- 21557264 TI - A review of studies on androgen and estrogen exposure in fish early life stages: effects on gene and hormonal control of sexual differentiation. AB - Teleost fish are unique among vertebrates in that phenotypic sex or onset of sex inversion can be easily manipulated by hormonal treatments. In recent years, researchers have begun reporting concentrations of synthetic and natural hormones in the environment. Although concentrations are very low (in the parts per trillion to low parts per billion), they are still of concern because of the high potency of synthetic hormones and the enhanced susceptibility of teleost fishes, especially early life stages, to hormonal exposures. In this review, we will focus on sex differentiation in teleost fishes and how these processes in fish early life stages may be impacted by environmental hormones which are known to contaminate aquatic environments. We will start by reviewing information on sources and concentrations of hormones in the environment and continue by summarizing the state of knowledge of sex differentiation in teleost gonochoristic fishes, including information on genes involved (e.g. cyp19, dmrt1, sox9 and foxl2). We will end our review with a summary of studies that have examined the effects of androgens and estrogens on fish sex differentiation after exposure of fish embryos and larvae and with ideas for future research. PMID- 21557263 TI - A versatile method for systematic conformational searches: application to CheY. AB - A novel molecular structure prediction method, the Z Method, is described. It provides a versatile platform for the development and use of systematic, grid based conformational search protocols, in which statistical information (i.e., rotamers) can also be included. The Z Method generates trial structures by applying many changes of the same type to a single starting structure, thereby sampling the conformation space in an unbiased way. The method, implemented in the CHARMM program as the Z Module, is applied here to an illustrative model problem in which rigid, systematic searches are performed in a 36-dimensional conformational space that describes the relative positions of the 10 secondary structural elements of the protein CheY. A polar hydrogen representation with an implicit solvation term (EEF1) is used to evaluate successively larger fragments of the protein generated in a hierarchical build-up procedure. After a final refinement stage, and a total computational time of about two-and-a-half CPU days on AMD Opteron processors, the prediction is within 1.56 A of the native structure. The errors in the predicted backbone dihedral angles are found to approximately cancel. Monte Carlo and simulated annealing trials on the same or smaller versions of the problem, using the same atomic model and energy terms, are shown to result in less accurate predictions. Although the problem solved here is a limited one, the findings illustrate the utility of systematic searches with atom-based models for macromolecular structure prediction and the importance of unbiased sampling in structure prediction methods. PMID- 21557265 TI - Quantification of asenapine and three metabolites in human plasma using liquid chromatography-tandem mass spectrometry with automated solid-phase extraction: application to a phase I clinical trial with asenapine in healthy male subjects. AB - The development and validation of methods for determining concentrations of the antipsychotic drug asenapine (ASE) and three of its metabolites [N desmethylasenapine (DMA), asenapine-N(+) -glucuronide (ASG) and 11-O-sulfate asenapine (OSA)] in human plasma using LC-MS/MS with automated solid-phase extraction is described. The three assessment methods in human plasma were found to be acceptable for quantification in the ranges 0.0250-20.0 ng/mL (ASE), 0.0500 20.0 ng/mL (DMA and OSA) and 0.250-50.0 ng/mL (ASG). PMID- 21557266 TI - Chromatographic determination of fungicides in biological and environmental matrices. New achievements. AB - The newest results in the chromatographic analysis of synthetic and natural fungicides present in biological and environmental matrices are collected and critically evaluated. Examples of the employment of gas chromatography, liquid chromatographic technologies, such as thin-layer chromatography and high performance liquid chromatographic methods as well as electrically driven systems are presented. The advantages and disasdvantages of the various chromatographic technologies are briefly discussed and the efficacies of the methodologies are compared. PMID- 21557267 TI - A replication study examining three common single-nucleotide polymorphisms and the risk of prostate cancer in a Japanese population. AB - BACKGROUND: Recently, genome-wide association studies have independently identified multiple prostate cancer risk variants on 8q24 and 17q in European and American populations. In this study, we examined the association between three key single-nucleotide polymorphisms (SNPs) in these two regions and the risk of prostate cancer in a Japanese population. METHODS: The associations between the rs6983561, rs4430796, and rs1859962 SNPs and prostate cancer susceptibility and tumor aggressiveness were examined in a total of 950 Japanese subjects (518 with sporadic prostate cancer (SPCa), 109 with latent prostate cancer (LPCa), and 323 controls). RESULTS: After adjustments for age, the C allele of rs6983561 and the A allele of rs4430796 were significantly more frequent among the SPCa patients than among the controls. Men who carry these risk alleles have an estimated odds ratio (OR) of 1.55 and 1.35, respectively. Furthermore, the SNPs rs6983561 and rs4430796 were associated with a susceptibility to aggressive prostate cancer, whereas rs1859962 was associated with non-aggressive prostate cancer. However, no significant difference was observed between these three polymorphisms and the risk of LPCa. We also examined the cumulative association of these three SNPs and prostate cancer susceptibility. Compared with men who do not have any risk alleles, the ORs increased according to the number of risk alleles that were present (P-value for trend: 8.1 * 10(-4) ). CONCLUSION: Our results further confirmed that variants at 8q24 and 17q are associated with the risk of prostate cancer and play an important role in tumor aggressiveness. PMID- 21557268 TI - 5alpha-reductase type 3 expression in human benign and malignant tissues: a comparative analysis during prostate cancer progression. AB - BACKGROUND: A third isozyme of human 5alpha-steroid reductase, 5alpha-reductase 3, was identified in prostate tissue at the mRNA level. However, the levels of 5alpha-reductase-3 protein expression and its cellular localization in human tissues remain unknown. METHODS: A specific monoclonal antibody was developed, validated, and used to characterize for the first time the expression of 5alpha reductase-3 protein in 18 benign and 26 malignant human tissue types using immunostaining analyses. RESULTS AND CONCLUSIONS: In benign tissues, 5alpha reductase-3 immunostaining was high in conventional androgen-regulated human tissues, such as skeletal muscle and prostate. However, high levels of expression also were observed in non-conventional androgen-regulated tissues, which suggest either multiples target tissues for androgens or different functions of 5alpha reductase-3 among human tissues. In malignant tissues, 5alpha-reductase-3 immunostaining was ubiquitous but particularly over-expressed in some cancers compared to their benign counterparts, which suggests a potential role for 5alpha reductase-3 as a biomarker of malignancy. In benign prostate, 5alpha-reductase-3 immunostaining was localized to basal epithelial cells, with no immunostaining observed in secretory/luminal epithelial cells. In high-grade prostatic intraepithelial neoplasia (HGPIN), 5alpha-reductase-3 immunostaining was localized in both basal epithelial cells and neoplastic epithelial cells characteristic of HGPIN. In androgen-stimulated and castration-recurrent prostate cancer (CaP), 5alpha-reductase-3 immunostaining was present in most epithelial cells and at similar levels, and at levels higher than observed in benign prostate. Analyses of expression and functionality of 5alpha-reductase-3 in human tissues may prove useful for development of treatment for benign prostatic enlargement and prevention and treatment of CaP. PMID- 21557269 TI - Endothelial progenitor cells and circulating endothelial cells in early prostate cancer: a comparison with plasma vascular markers. AB - BACKGROUND: Separate studies indicate that endothelial perturbation, as demonstrated by abnormal endothelial progenitor cells (EPCs), circulating endothelial cells (CECs), and plasma markers such as von Willebrand factor (vWf) and soluble E selectin (sEsel) are present in cancer. However, there are no reports where these indices are compared. Accordingly, we hypothesized altered EPCs and CECs in prostate cancer that would correlate with vWf, sEsel, and prostate specific antigen (PSA). METHODS: We recruited 29 men with biopsy proven prostate cancer, with 25 with benign prostate disease and 27 free of prostate disease. CECs were defined on flow cytometry as being CD34+, CD146+, CD45-, and CD309-, EPCs were similarly defined as being CD34+, CD309+,CD45-, and CD146-. vWf, sEsel, and PSA were measured by immunoassay. RESULTS: Despite higher PSA, sE sel, and vWf in prostate cancer (all P < 0.02), neither EPCs, CECs, nor their ratio, were significantly different. EPCs and CECs correlated significantly with each other in each group (r > 0.48, P < 0.01) but failed to correlate with any plasma marker. CONCLUSION: Unlike plasma endothelial markers, CECs and EPCs may play little part in the pathophysiology of early prostate cancer. PMID- 21557270 TI - Chromosome 8q24 variants are associated with prostate cancer risk in a high risk population of African ancestry. AB - BACKGROUND: Earlier studies on the role of germline variations in the disproportionate higher burden of prostate cancer in men of African ancestry have been largely unrewarding. However, the successful replication of recent genome wide association findings implicating some regions of chromosome 8q24 in the disparate prostate cancer susceptibility in men of European and African ancestry have been encouraging. This case-control study was designed to evaluate the association between germline variations in chromosome 8q24 and prostate cancer risk in Afro-Caribbean Tobago men, a population of predominantly West African ancestry. METHODS: High molecular weight genomic DNA was isolated from blood clots using Qiagen kits. Genotyping was performed on genomic DNA using a pre designed TaqMan SNP assay according to the manufacture's protocol on a 7900HT Fast Real-Time PCR system (Applied Biosystems, Foster City, CA). RESULTS: SNP rs16901979 in region 2 was associated with significantly increased risk of prostate cancer (OR = 1.41, 95% confidence interval [CI] 1.02-1.95, P = 0.04) with the risk stronger in men with early-onset prostate cancer (OR = 2.37, 95% CI 1.40-3.99, P = 0.001). There was a tendency towards significantly increased risk for SNPs rs1447295 and rs6983267 in men with early-onset prostate cancer. CONCLUSIONS: The replication of the association of chromosome 8q24 variants with increased prostate cancer risk in Tobago men and the higher frequency of the risk alleles in controls in populations of African ancestry further strengthens the possible role of this genomic region in the disproportionate higher burden of prostate cancer in men of African ancestry. PMID- 21557271 TI - Inhibition of acid ceramidase by a 2-substituted aminoethanol amide synergistically sensitizes prostate cancer cells to N-(4-hydroxyphenyl) retinamide. AB - BACKGROUND: The purpose of this study was to determine whether the therapeutic efficacy of fenretinide (4-HPR), a ceramide-generating anticancer agent, could be enhanced in prostate cancer cells by inclusion of a novel synthetic acid ceramidase (AC) inhibitor, DM102, a pivaloylamide of a 2-substituted aminoethanol. In prostate cancer, AC plays a role in progression and resistance to chemotherapy. METHODS: PC-3 and DU 145 hormone-refractory human prostate cancer cell lines were used. Cells were exposed to 4-HPR, DM102, and combinations; viability, apoptosis, cell migration, ceramide metabolism, and levels of reactive oxygen species (ROS) were assessed. RESULTS: Single agent 4 HPR and DM102 (2.5-10 uM) were weakly cytotoxic; however, combinations synergistically decreased cell viably to as low as 1.5% of control. N oleoylethanolamine (NOE), a frequently employed AC inhibitor, was not effective in producing synergy. The 4-HPR/DM102 regimen enhanced caspase activity and increased [(3) H](dihydro)ceramide and ROS levels 6- and 30-fold over control, respectively. The antioxidant vitamin E, but not the de novo ceramide synthesis inhibitor myriocin, partially rescued cells from 4-HPR/DM102 cytotoxicity. The 4 HPR/DM102 combination also elicited synergistic cytotoxicity in DU 145 cells, another human hormone-refractory prostate cancer cell line. CONCLUSION: This study shows that 4-HPR cytotoxicity is enhanced in a synergistic fashion by inclusion of the AC inhibitor DM102, by a mechanism that enlists generation of ROS, and thus provides a system to raise 4-HPR therapeutic potential. The role of ceramide however in the cytotoxic response is not clear, as blocking ceramide generation failed to rescue PC-3 cells from 4-HPR/DM102 cytotoxicity. PMID- 21557272 TI - Sec62 protein level is crucial for the ER stress tolerance of prostate cancer. AB - BACKGROUND: We previously reported that over-expression of the SEC62 gene is a widespread phenomenon in prostate cancer. Since the use of endoplasmic reticulum (ER) stress-inducing substances such as thapsigargin in prostate cancer therapy is widely discussed in the literature, we investigated the influence of Sec62 protein content on the cellular response to these drugs. METHODS: Growth effects were analyzed by real-time cell analysis and viability tests in DU145-cells representing an increased SEC62 expression or PC3- and LNCaP-cells representing a similar SEC62 expression compared to non-tumor cells. Ca(2+) -imaging in an established HeLa-system with fluorescent dye was used to study molecular effects of Sec62 depletion. RESULTS: We found a lower propensity toward apoptotic cell death after thapsigargin treatment for DU145 cells compared to PC3 or LNCaP and siRNA-mediated silencing of SEC62 resulted in a reduced viability of thapsigargin treated PC3 cells, indicating that Sec62 functions in cellular stress response. Measurement of cytosolic [Ca(2+) ] demonstrated the influence of Sec62 on the cellular response to thapsigargin on a molecular level. Using real-time cell analysis, we observed the loss of androgen stimulation of LNCaP cells in the presence of thapsigargin, and an additional negative effect on cell growth of Sec62 depletion. Also, for PC3- and DU145-cells Sec62 depletion inhibited growth after thapsigargin treatment. CONCLUSIONS: Our data indicate a crucial function of Sec62 in the response to thapsigargin-induced ER stress. This will be of great significance on the background of elevated Sec62 protein levels in prostate cancer cells when treatment with thapsigargin analogs is considered. PMID- 21557273 TI - Expression of nodal and nodal receptors in prostate stem cells and prostate cancer cells: autocrine effects on cell proliferation and migration. AB - BACKGROUND: Nodal, a TGFbeta like growth factor, functions as an embryonic morphogen that maintains the pluripotency of embryonic stem cells. Nodal has been implicated in cancer progression; however, there is no information on expression and functions of Nodal in prostate cancer. In this study, we have investigated the expression of Nodal, its receptors, and its effects on proliferation and migration of human prostate cells. METHODS: RT-PCR, qPCR, and Western blot analyses were performed to analyze expression of Nodal and Nodal receptors and its effects on phosphorylation of Smad2/3 in prostate cells. The effects on proliferation and migration were determined by (3) H-Thymidine incorporation and cell migration assays in the presence or absence of Nodal receptor inhibitor (SB431542). RESULTS: Nodal was highly expressed in WPE, DU145, LNCaP, and LNCaP C81 cells with low expression in RWPE1 and RWPE2 cells, but not in PREC, PC3 and PC3M cells. Nodal receptors are expressed at varying levels in all prostate cells. Treatment with exogenous Nodal induced phosphorylation of Smad2/3 in WPE, DU145, and PC3 cells, which was blocked by SB431542. Nodal dose-dependently inhibited proliferation of WPE, RWPE1 and DU145 cells, but not LNCaP and PC3 cells. Nodal induced cell migration in PC3 cells, which was inhibited by SB431542; Nodal had no effect on cell migration in WPE and DU145 cells. The effects of Nodal on cell proliferation and migration are mediated via ALK4 and ActRII/ActRIIB receptors and Smad 2/3 phosphorylation. CONCLUSIONS: Nodal may function as an autocrine regulator of proliferation and migration of prostate cancer cells. PMID- 21557274 TI - Dedifferentiation of prostate smooth muscle cells in response to bacterial LPS. AB - BACKGROUND: Prostate smooth muscle cells (SMCs) are strongly involved in the development and progression of benign prostatic hyperplasia and prostate cancer. However, their participation in prostatitis has not been completely elucidated. Thus, we aimed to characterize the response of normal SMC to bacterial lipopolysaccharide (LPS). METHODS: Primary prostate SMCs from normal rats were stimulated with LPS (0.1, 1, or 10 ug/ml) for 24 or 48 hr. The phenotype was evaluated by electron microscopy, immunofluorescence, and Western blot of SMCalpha-actin (ACTA2), calponin, vimentin, and tenascin-C, while the innate immune response was assessed by immunodetection of TLR4, CD14, and nuclear NF kappaB. The secretion of TNFalpha and IL6 was determined using ELISA. RESULTS: Bacterial LPS induces SMCs to develop a secretory phenotype including dilated rough endoplasmic reticulum cisternae with well-developed Golgi complexes. Furthermore, SMCs displayed a decrease in ACTA2 and calponin, and an increase in vimentin levels after LPS challenge. The co-expression of ACTA2 and vimentin, together with the induction of tenascin-C expression indicate that a myofibroblastic-like phenotype was induced by the endotoxin. Moreover, LPS elicited a TLR4 increase, with a peak in NF-kappaB activation occurring after 10 min of treatment. Finally, LPS stimulated the secretion of IL6 and TNFalpha. CONCLUSIONS: Prostate SMCs are capable of responding to LPS in vitro by dedifferentiating from a contractile to a miofibroblastic-like phenotype and secreting cytokines, with the TLR4 signaling pathway being involved in this response. In this way, prostate SMCs may contribute to the pathophysiology of inflammatory diseases by modifying the epithelial-stromal interactions. PMID- 21557275 TI - Expression of semenogelins I and II and its prognostic significance in human prostate cancer. AB - BACKGROUND: Little is known about the role of semenogelins, seminal plasma proteins that play critical roles in semen clotting and subsequent liquefaction in the presence of zinc and prostate-specific antigen, in human malignancies. METHODS: We investigated the expression of semenogelins in four human prostate cancer lines by RT-PCR and Western blotting as well as in 70 radical prostatectomy specimens by immunohistochemistry. Effects of semenogelin overexpression on prostate cancer cell proliferation were also assessed. RESULTS: mRNA/protein signals for semenogelins I (SgI) and II (SgII) were detected only in androgen-sensitive LNCaP cells cultured with zinc. Transfection of SgI/SgII increased/decreased cell growth of androgen receptor (AR)-positive/semenogelin negative CWR22Rv1 in the presence of zinc, whereas it showed marginal effects in AR-negative/semenogelin-negative PC-3 and DU145. Immunohistochemical studies showed that SgI and SgII stain positively in 55 (79%) and 31 (44%) cancer tissues, respectively, which was significantly higher than in corresponding benign tissues [SgI-positive in 13 (19%) cases (P < 0.0001) and SgII-positive in 15 (21%) cases (P = 0.0066)]. Among the histopathological parameters available for our patient cohort, there was an inverse association only between Gleason score (GS) and SgII expression (GS <= 7 vs. GS >= 8: P = 0.0150; GS7 vs. GS >= 8: P = 0.0111). Kaplan-Meier and log-rank tests further revealed that patients with SgI-positive/SgII-negative tumor have the highest risk for biochemical recurrence (P = 0.0242). CONCLUSIONS: These results suggest the involvement of semenogelins in prostate cancer and their prognostic values in predicting cancer progression after radical prostatectomy. Additional functional analyses of semenogelins are necessary to determine their biological significance in prostate cancer. PMID- 21557276 TI - Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: implications for chemoprevention of prostate cancer. AB - BACKGROUND: Although finasteride is recognized for its role as a chemopreventive agent for prostate cancer, higher grades of malignancy have been reported. It is questioned whether blocking of testosterone conversion to dihydrotestosterone (DHT) by finasteride in prostate tissue will change expression of androgen receptor (AR). Therefore, this study evaluated the effects of finasteride on AR expression in prostate tissue and in the LNCaP cell line. METHODS: Between January and December 2006, we retrospectively selected and evaluated 47 cases of benign prostatic hyperplasia treated with variable duration of finasteride (5 mg QD) before transurethral resection of the prostate. AR expression in prostate tissue was semiquantified by immunostaining and compared with duration of finasteride treatment. An androgen-dependent prostate cancer cell line (LNCaP) was cultured in charcoal/dextran-treated FBS with DHT or testosterone, and treated with finasteride for 1-3 weeks. Samples of total RNA were collected to analyze expression of AR by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Immunohistochemical study revealed significant upregulation of ARs by finasteride treatment for 30-180 days. In cell line study, quantitative real-time reverse transcription polymerase chain reaction revealed significant upregulation of ARs treated by finasteride. CONCLUSIONS: In our study, finasteride influenced AR expression in benign prostate tissue and prostate cancer cell. Before we can use finasteride in chemoprevention with confidence, we still need to clarify the influence of finasteride in ARs and its regulation pathway. PMID- 21557277 TI - Functional polymorphisms in cell death pathway genes FAS and FAS ligand and risk of prostate cancer in a Chinese population. AB - BACKGROUND: Apoptosis is the physiological mechanism of programmed cell death and abnormal regulation of this pathway can lead to carcinogenesis. We hypothesized that the FAS -1377G>A, -670A>G, and FASL -844T>C polymorphisms are associated with risk of prostate cancer (PCa). MATERIALS AND METHODS: We genotyped polymorphisms in a hospital-based case-control study of 602 patients diagnosed with PCa and 703 cancer-free controls in a Chinese population using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: We found a significantly decreased risk associated with FAS -1377GA [adjusted odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.56-0.90] genotype compared with the -1377GG genotype and decreased risk associated with FAS -670AG and -670GG genotypes (OR 0.75, 95% CI: 0.59-0.95; OR 0.70, 95% CI: 0.50-0.96) compared with the -670AA genotype. Consistently, we found that individuals carrying haplotype genotype with 0 or 1 risk allele (-1377G and -670A) had a lower risk of PCa than those with two risk alleles (OR 0.48, 95% CI: 0.28-0.80; OR 0.60, 95% CI: 0.41 0.87; OR 0.82, 95% CI: 0.69-0.97 for the AA, GG, and AG haplotype, respectively). In addition, when we evaluated these two FAS polymorphisms together, we found that the combined genotype with 4 risk alleles was associated with a significantly increased risk of PCa compared with those with 0-3 variants (OR 1.51, 95% CI: 1.19-1.91), and this increased risk was more pronounced among subgroups of Gleason score <7 and >7, and PSA > 20 ng/ml (OR 1.49, 95% CI: 1.08 2.04; OR 1.72, 95% CI: 1.25-2.44; OR 1.61, 95% CI: 1.23-2.13, respectively). CONCLUSIONS: These results suggested that the FAS polymorphisms may contribute to PCa risk in a Chinese population. PMID- 21557278 TI - Diagnosing steatohepatitis and predicting liver-related mortality in patients with NAFLD: two distinct concepts. PMID- 21557279 TI - A new set of classifications for ductal plate malformations. PMID- 21557280 TI - Genetic susceptibility testing for beryllium: worker knowledge, beliefs, and attitudes. AB - BACKGROUND: We sought to gain insight into workers' knowledge, beliefs, and attitudes on the subject of testing for genetic susceptibility to beryllium. METHODS: Five focus groups were held with 30 current and former beryllium workers and nine family members. Audio recordings were transcribed and assessed by hierarchical coding using an inductive approach. RESULTS: Some workers were unclear about the distinction between genotoxicity and heritability. A key finding is that they perceived the benefits of a positive test result to be related to enhanced autonomous decision-making. The major concern cited by participants was potential abuse of genetic information by employers. Complete financial separation of a prospective testing entity from the employer was seen as crucial. CONCLUSIONS: A window of opportunity exists to create regional partnerships for translational research on genetic susceptibility testing. Such partnerships would involve labor, management, public health scientists, primary care professionals, and other stakeholders. They would be critical to identifying testing strategies that maximize worker autonomy along with the public health advantages of genetic testing. PMID- 21557281 TI - An innovative approach to interdisciplinary occupational safety and health education. AB - BACKGROUND: The New York and New Jersey Education and Research Center (ERC) provides a range of graduate continuing education for occupational safety and health (OSH) professionals in training. A key element of the education is to provide interdisciplinary training to industrial hygienists, ergonomists, occupational medicine physicians and other health and safety trainees to prepare them for the collaboration required to solve the complex occupational health and safety problems they will face in their careers. METHODS: This center has developed an innovative interdisciplinary training approach that provides an historical aspect, while allowing the graduate students to identify solutions to occupational issues from a multi-disciplinary approach. The ERC developed a tour that brings students to sites of historical and/or contemporary significance in the occupational safety and health and environmental fields. RESULTS: The ERC has conducted five tours, and has included 85 students and residents as participants. 80% of participants rated the tour as providing a high amount of OSH knowledge gained. 98% of the participants felt the goal of providing interdisciplinary education was achieved. CONCLUSIONS: This tour has been successful in bridging the OSH fields to better understand how occupational and environmental exposures have occurred, in order to prevent future exposures so that workplace conditions and health can be improved. PMID- 21557282 TI - The impact of the World Trade Center attack on FDNY firefighter retirement, disabilities, and pension benefits. AB - BACKGROUND: Our goal was to examine the effect of the World Trade Center (WTC) attack and subsequent New York City Fire Department (FDNY) rescue/recovery activities on firefighter retirements. We also analyzed the financial impact associated with the increased number and proportion of service-connected "accidental" disability retirements on the FDNY pension system. METHODS: A total of 7,763 firefighters retired between 9/11/1994 and 9/10/2008. We compared the total number of retirements and the number and proportion of accidental disability retirements 7 years before and 7 years after the WTC attack. We categorized WTC-related accidental disability retirements by medical cause and worked with the New York City Office of the Actuary to approximate the financial impact by cause. RESULTS: In the 7 years before 9/11 there were 3,261 retirements, 48% (1,571) of which were accidental disability retirements. In the 7 years after 9/11, there were 4,502 retirements, 66% (2,970) were accidental disability retirements, of which 47% (1,402) were associated with WTC-related injuries or illnesses. After 9/11, the increase in accidental disability retirements was, for the most part, due to respiratory-related illnesses. Additional increases were attributed to psychological-related illnesses and musculoskeletal injuries incurred at the WTC site. Pension benefits associated with WTC-related accidental disability retirements have produced an increased financial burden of over $826 million on the FDNY pension system. CONCLUSIONS: The WTC attacks affected the health of the FDNY workforce resulting in more post 9/11 retirements than expected, and a larger proportion of these retirees with accidental disability pensions. PMID- 21557283 TI - Reproducibility of asbestos body counts in digestions of autopsy and surgical lung tissue. AB - BACKGROUND: Asbestos body (AB) counting by a single observer is the most commonly used objective technique to demonstrate asbestos deposition in the lung. In this study, the accuracy and reliability of this procedure is analyzed by evaluating the degree of agreement between two experienced readers. METHODS: Lung tissue specimens from 66 individuals, most of whom had not been exposed to asbestos, were studied: 35 were obtained in postmortem studies (upper, middle, and lower lung) and 31 were from patients who underwent surgery for lung cancer. Overall, 167 samples were analyzed. Lung tissue sections weighing 0.5 g were obtained prospectively and processed, and the inorganic residue was analyzed by light microscopy at 400* magnification by two experienced readers. Results were expressed as AB/g of dry lung tissue. Interobserver variability was analyzed using the Spearman correlation coefficient and agreement was evaluated by the Bland-Altman method and the kappa index. RESULTS: The interobserver correlation was 0.8975: 0.8029 for autopsy samples and 0.9592 for biopsy samples. Bland Altman plots showed that most values were grouped around the 95% limits of agreement. The kappa index was 0.87 for all samples, and 0.79, 0.65, and 0.54 for upper, middle, and lower lung specimens, respectively. CONCLUSIONS: Asbestos body counting by a single reader is a reliable method, especially at low concentrations of asbestos bodies in lung tissue. Double reading may be indicated in borderline cases with asbestos body levels close to levels of 1 000 AB/g. PMID- 21557284 TI - Analysis of the hydrogenotrophic microbiota of wild and captive black howler monkeys (Alouatta pigra) in palenque national park, Mexico. AB - Intestinal methanogenesis is one of the major pathways for consumption of hydrogen produced by bacterial fermentation and is considered to affect the efficiency of host energy harvest; however, little information is available regarding the hydrogenotrophic pathways of nonhuman primates in the wild, in general, and of howler monkeys, in particular. Microbial fermentation of plant structural carbohydrates is an important feature in wild howlers owing to the high fiber and low available energy content of leaves, which make up the primary component of their diet. In contrast, captive howlers may consume greater quantities of fruits and vegetables that are higher in water, lower in fiber, and, along with commercial monkey chow commonly added to captive monkey diets, more readily digestible than the natural diet. In this study, we analyzed the composition of methanogens and sulfate-reducing bacteria (SRB) from fecal samples of black howler monkeys (Alouatta pigra) in the wild and in captivity. The hydrogenotrophic microbiota of three groups of monkeys was evaluated by PCR denaturing gradient gel electrophoresis (DGGE) fingerprinting, small clone library construction, and quantitative real-time PCR. Abundance of methanogens was lower than SRB in all howler monkey groups studied. DGGE banding patterns were highly similar within each wild and captive group but distinct among groups. Desulfovibrionales-enriched DGGE showed reduced microbial diversity in the captive animals compared with their wild counterparts. Taken together, the data demonstrate that environmental or dietary changes of the host imposed by captivity likely influence the composition of intestinal hydrogenotrophs in black howler monkeys. PMID- 21557285 TI - Observer choices during experimental foraging tasks in brown capuchin monkeys (Cebus apella). AB - We investigated whether capuchin monkeys (Cebus apella) would choose to observe a high- or low-status adult female from their group during experimental foraging tests. The subject was located in the center of a test chamber, with a low- and high-ranking demonstrator on either side of two partitions. A peephole allowed the subject to observe the models by looking through either respective partition. Each model was trained on one of the two different methods, lift or pull, for retrieving food from a foraging apparatus. There were 22 subjects and four models. During the 40-trial test sessions, subjects could choose which model they would watch in each trial. It was predicted that subjects would prefer observing the model with whom it was closer in rank, and therefore share greater affiliation with. Results showed that only half the subjects showed a preference and that preference was not linked to status. Relatedness played a larger role in determining if a subject showed a preference for a model, and a correlation was found for relatedness and observer preference. After the observer preference tests, subjects were presented with the foraging apparatus to determine if they displayed a preference for one of the two tasks. The majority of subjects (17/22) showed a preference for the pull method, suggesting that this method may have been more salient to the monkeys in this study. PMID- 21557286 TI - Experimental evidence for olfactory predator recognition in wild mouse lemurs. AB - Although primates have remarkable olfactory capabilities, their ability for olfactory predator recognition is still understudied. We investigated this cognitive ability in wild gray and golden-brown mouse lemurs (Microcebus murinus and M. ravelobensis) that were confronted with four different olfactory stimuli, derived from two Malagasy predators (fossa and barn owl) and two local nonpredator species (brown lemur and sifaka). The predator response was tested (1) in a systematic cage setup and (2) in a two-way choice experiment with two Sherman traps on platforms in the forest (stimulus trap vs. nonstimulus trap). For part 1, the study animals were housed in cages during habituation and 5 days of experiments. One stimulus was tested per night and was presented underneath a drinking bottle. The changes in the time spent close to the stimulus and the drinking time at the bottle were used as indicators of predator recognition. A timidity score was established by classifying the strength of the antipredator response during the experiment. The study animals spent significantly less time drinking and less time in the stimulus area when confronted with fossa odor compared with the other stimuli. The timidity score was significantly higher during the fossa stimulus compared with the nonpredator and the control stimuli. The two-way choice experiments revealed a complete avoidance of the fossa odor, which was not found with the other stimuli. Thus, wild mouse lemurs showed clear signs of olfactory predator recognition in the case of the fossa in both experiments, but no signs of avoidance to the other presented stimuli. The lack of owl avoidance may be explained by less or no aversive metabolites in the owl stimulus or by lower significance for olfactory recognition of aerial predators. Furthermore, the results showed slight differences between the two mouse lemur species that may be linked to differences in their ecology. PMID- 21557287 TI - Primate population dynamics over 32.9 years at Ngogo, Kibale National Park, Uganda. AB - We present census data for eight primate species spanning 32.9 years along the same transect at Ngogo, Kibale National Park, Uganda, demonstrating major changes in the composition of the primate community. Correlated with an estimated decline of ~89% in the red colobus population was an increase in encounter rates with chimpanzee parties. Our data, along with the unusually high rates of predation by chimpanzees on red colobus at Ngogo and the fact that the chimpanzee community at Ngogo is the largest ever recorded, support the conclusion that the red colobus decline was caused primarily by chimpanzee predation. This seems to be the first documented case of predation by one nonhuman primate causing the population decline in another. We evaluated disease and interspecific competition as other possible causes of the red colobus decline, but judged them to be relatively insignificant compared with predation by chimpanzees. Notable changes in encounter rates with other primate species may have resulted from forest expansion. Those for mangabeys, redtails, and black and white colobus increased significantly. Encounter rates increased for l'Hoest's monkeys too, but the increased sightings may have been an artifact of increased habituation. Sightings of blue monkey and baboon groups declined. There was no significant change in encounter rates for all species combined. The Ngogo primate community seemed to be in a nonequilibrium state, changing from one dominated by two species, a folivore (red colobus) and a frugivorous omnivore (redtails), to one dominated by three species of frugivorous omnivores (redtails, mangabeys, and chimpanzees). This study demonstrates the importance of long-term monitoring in understanding population dynamics and the role of intrinsic variables in shaping the species composition of a community. PMID- 21557288 TI - A proportional hazards regression model for the subdistribution with right censored and left-truncated competing risks data. AB - With competing risks failure time data, one often needs to assess the covariate effects on the cumulative incidence probabilities. Fine and Gray proposed a proportional hazards regression model to directly model the subdistribution of a competing risk. They developed the estimating procedure for right-censored competing risks data, based on the inverse probability of censoring weighting. Right-censored and left-truncated competing risks data sometimes occur in biomedical researches. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with right-censored and left-truncated data. We adopt a new weighting technique to estimate the parameters in this model. We have derived the large sample properties of the proposed estimators. To illustrate the application of the new method, we analyze the failure time data for children with acute leukemia. In this example, the failure times for children who had bone marrow transplants were left truncated. PMID- 21557289 TI - Enhancement of the capabilities of liquid chromatography-mass spectrometry with derivatization: general principles and applications. AB - The integration of liquid chromatography-mass spectrometry (LC-MS) with derivatization is a relatively new and unique strategy that could add value and could enhance the capabilities of LC-MS-based technologies. The derivatization process could be carried out in various analytical steps, for example, sampling, storage, sample preparation, HPLC separation, and MS detection. This review presents an overview of derivatization-based LC-MS strategy over the past 10 years and covers both the general principles and applications in the fields of pharmaceutical and biomedical analysis, biomarker and metabolomic research, environmental analysis, and food-safety evaluation. The underlying mechanisms and theories for derivative reagent selection are summarized and highlighted to guide future studies. PMID- 21557290 TI - Advances in mass spectrometry for the identification of pathogens. AB - Mass spectrometry (MS) has become an important technique to identify microbial biomarkers. The rapid and accurate MS identification of microorganisms without any extensive pretreatment of samples is now possible. This review summarizes MS methods that are currently utilized in microbial analyses. Affinity methods are effective to clean, enrich, and investigate microorganisms from complex matrices. Functionalized magnetic nanoparticles might concentrate traces of target microorganisms from sample solutions. Therefore, nanoparticle-based techniques have a favorable detection limit. MS coupled with various chromatographic techniques, such as liquid chromatography and capillary electrophoresis, reduces the complexity of microbial biomarkers and yields reliable results. The direct analysis of whole pathogenic microbial cells with matrix-assisted laser desorption/ionization MS without sample separation reveals specific biomarkers for taxonomy, and has the advantages of simplicity, rapidity, and high-throughput measurements. The MS detection of polymerase chain reaction (PCR)-amplified microbial nucleic acids provides an alternative to biomarker analysis. This review will conclude with some current applications of MS in the identification of pathogens. PMID- 21557291 TI - Requirement for the endocannabinoid system in social interaction impairment induced by coactivation of dopamine D1 and D2 receptors in the piriform cortex. AB - The dopamine receptor family consists of D1-D5 receptors (D1R-D5R), and we explored the contributions of each dopamine receptor subtype in the piriform cortex (PirC) to social interaction impairment (SII). Rats received behavioral tests or electrophysiological recording of PirC neuronal activity after injection of the D1R/D5R agonist SKF38393, the D2R/D3R/D4R agonist quinpirole, or both, with or without pretreatment with dopamine receptor antagonists, D1R or D5R antisense oligonucleotides, the cannabinoid CB1 receptor antagonist AM281, or the endocannabinoid transporter inhibitor VDM11. Systemic injection of SKF38393 and quinpirole together, but not each one alone, induced SII and increased PirC firing rate, which were blocked by D1R or D2R antagonist. Intra-PirC microinfusion of SKF38393 and quinpirole together, but not each one alone, also induced SII, which was blocked by D1R antisense oligonucleotides or D2R antagonist but not by D3R or D4R antagonist or D5R antisense oligonucleotides. SII induced by intra-PirC SKF38393/quinpirole was blocked by AM281 and enhanced by VDM11, whereas neither AM281 nor VDM11 alone affected social interaction behavior. Coadministration of SKF38393 and quinpirole produced anxiolytic effects without significant effects on locomotor activity, olfaction, and acquisition of olfactory short-term memory. These findings suggest that SII induced by coactivation of PirC D1R and D2R requires the endocannabinoid system. PMID- 21557292 TI - Cell-extracellular matrix versus cell-cell interactions during the development of the cochlear-vestibular ganglion. AB - Cells destined to become the neurones of the cochlear-vestibular ganglion (CVG) originate within the otic epithelium. Early in development they detach from their neighbors and migrate out of the epithelium, where they coalesce to form the CVG. To accomplish this process, the neuroblasts must modify their interactions with other cells within the epithelium and with proteins in the extracellular matrix to allow for repositioning. The aim of this study was to investigate the roles of the major families of adhesion molecules that mediate cellular interactions with the extracellular matrix, the integrins, and with other cells, the cadherins, in neuroblast segregation from the otic epithelium. The expression of classical cadherins increased in migrating neuroblasts compared with the otic epithelium. Quantitative RT-PCR revealed that this was concomitant with down-regulation of E cadherin and up-regulation of N-cadherin in the migrating cells. In contrast, the level of beta1 integrin expression by the epithelium was maintained in migrating neuroblasts. However, although multiple integrin ligands were expressed within the otic basement membrane at this stage of development, only fibronectin (FN) supported neuroblast migration along the substrate in vitro. Inhibition of beta1 integrins resulted in significantly reduced linear migration on FN. Importantly, neuroblasts retained the ability to segregate from the epithelium but remained compacted immediately adjacent to the originating tissue, suggesting dominance of cell-cell over cell-matrix interactions. These data suggest that the balance between cell-cell and cell-substratum interactions directs otic neuroblast migration and gangliogenesis. PMID- 21557293 TI - Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells. AB - Neuronal death has been reported to involve mitochondrial dysfunction and cell cycle reentry. In this report, we used Nerve Growth Factor (NGF)-differentiated PC12 cells to investigate mechanisms linking mitochondrial dysfunction and cell cycle activation during neuronal death induced by NGF withdrawal and/or oxidative stress. We found that loss of survival following H(2) O(2) -induced oxidative stress or NGF deprivation was preceded by a decrease in mitochondrial membrane potential (DeltaPsim), increase in reactive oxygen species (ROS), and up regulation of cyclin D1 and phosphorylation (Ser-780) of protein retinoblastoma (P-pRb), without an increase of proliferation rates. Treatment with H(2) O(2) , but not NGF deprivation, also induced the phosporylation (Ser-10) of p27(kip1) and the appearance of a cleaved P-p27(kip1) fragment of about 15 kDa. The extent of cell cycle activation appeared to be inversely correlated to the duration of toxic stimuli (pulse/continuous). H(2) O(2) -induced mitogenic responses appeared to be mediated by induction of P-MAPK and P-Akt and were blocked by p38MAPK and JNK inhibitors as well as by the CDK inhibitor flavopiridol (Flav) and by sodium selenite (Sel), a component of selenoproteins, including glutathione peroxidases. Inhibition of p38MAPK and JNK, instead, did not affect cyclin D1 changes following NGF deprivation. Finally, both Flav hydrochloride and Sel partially prevented mitochondrial dysfunction and cell death following NGF withdrawal or H(2) O(2) toxicity, but not during oxidative stress in the absence of NGF. Taken together, these data suggest that H(2) O(2) -induced oxidative stress can determine distinct patterns of mitogenic responses as a function of mitochondrial dysfunction depending on 1) intensity/duration of stress stimuli and/or 2) presence of NGF. PMID- 21557294 TI - Biochemical modulation of the sleep-wake cycle: endogenous sleep-inducing factors. AB - Regulation of the sleep-wake cycle involves diverse brain circuits and molecules. Further complexity has been introduced by the recognition of sleep-promoting factors that accumulate in the brain naturally or during prolonged waking. The variety of sleep-inducing molecules includes peptides, cytokines, and lipids. With regard to the lipids, current evidence indicates the existence of endogenous lipids, called endocannabinoids, that mimic the pharmacological actions of the psychoactive ingredient of marijuana and that are likely to be essential factors in sleep promotion. This Mini-Review presents current knowledge concerning the role of endogenous compounds with sleep-promoting properties. PMID- 21557295 TI - Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells. AB - Safe and efficient transplantation of embryonic stem (ES) cells to the brain requires that local inflammatory and immune responses to allogeneic grafts are inhibited. To investigate cytokines that affect graft cell survival and differentiation, we used stromal cell-derived inducing activity to induce the differentiation of neural progenitor cells (NPCs) from mouse ES cells and transplanted the NPCs into mouse brain. Examination of surrounding brain tissue revealed elevated expression levels of interleukin (IL)-1beta, IL-4, and IL-6 in response to NPC transplantation. Among these, only IL-6 reduced neuronal differentiation and promoted glial differentiation in vitro. When we added anti IL-6 receptor antibodies to NPCs during transplantation, this single and local blockade of IL-6 signaling reduced the accumulation of host-derived leukocytes, including microglia. Furthermore, it also promoted neuronal differentiation and reduced glial differentiation from the grafted NPCs to an extent similar to that with systemic and continuous administration of cyclosporine A. These results suggest that local administration of anti-IL-6 receptor antibodies with NPCs may promote neuronal differentiation during the treatment of neurological diseases with cell replacement therapy. PMID- 21557296 TI - Local establishment of repetitive long-term potentiation-induced synaptic enhancement in cultured hippocampal slices with divided input pathways. AB - Long-term potentiation (LTP) in the rodent hippocampus is a popular model for synaptic plasticity, which is considered the cellular basis for brain memory. Because most LTP analysis involves acutely prepared brain slices, however, the longevity of single LTP has not been well documented. Using stable hippocampal slice cultures for long-term examination, we previously found that single LTP disappeared within 1 day. In contrast, repeated induction of LTP led to the development of a distinct type of plasticity that lasted for more than 3 weeks and was accompanied by the formation of new synapses. Naming this novel plastic phenomenon repetitive LTP-induced synaptic enhancement (RISE), we proposed it as a model for the cellular processes involved in long-term memory formation. However, because in those experiments LTP was induced pharmacologically in the whole slice, it is not known whether RISE has input-pathway specificity, an essential property for memory. In this study, we divided the input pathway of CA1 pyramidal neurons by a knife cut and induced LTP three times, the third by tetanic stimulation in one of the divided pathways to express RISE specifically. Voltage-sensitive dye imaging and Golgi-staining performed 2 weeks after the three LTP inductions revealed both enhanced synaptic strength and increased dendritic spine density confined to the tetanized region. These results demonstrate that RISE is a feasible cellular model for long-term memory. PMID- 21557297 TI - Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E cadherin. AB - EGFR is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas (HNSCC). However, the mechanism by which EGFR may stimulate tumor cell invasion and metastasis still need to be elucidated. In this study, we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion, and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition (EMT)-like phenotype change. Interestingly, activation of EGFR by EGF induced production of matrix metalloproteinase-9 (MMP 9) and soluble E-cadherin (sE-cad), and knockdown of MMP-9 by siRNA inhibited sE cad production induced by EGF in SCC10A. Moreover, both MMP-9 knockdown and E cadherin overexpression inhibited cell migration and invasion induced by EGF in SCC10A. The results indicate that EGFR activation promoted cell migration and invasion through inducing MMP-9-mediated degradation of E-cadherin into sE-cad. Pharmacologic inhibition of EGFR, MEK, and PI3K kinase activity in SCC10A reduced phosphorylated levels of ERK-1/2 and AKT, production of MMP-9 and sE-cad, cell migration and invasion, and expressional changes of EMT markers (E-cadherin and N cadherin) induced by EGF, indicating that EGFR activation promotes cell migration and invasion via ERK-1/2 and PI3K-regulated MMP-9/E-cadherin signaling pathways. Taken together, the data suggest that EGFR activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin into sE-cad related to activation of ERK-1/2 and PI3K signaling pathways. PMID- 21557298 TI - Alteration of integrin-dependent adhesion and signaling in EMT-like MDCK cells established through overexpression of calreticulin. AB - Calreticulin (CRT) is a multi-functional Ca(2+) -binding molecular chaperone in the endoplasmic reticulum. We previously reported that kidney epithelial cell derived Madin-Darby Canine Kidney cells were transformed into mesenchymal-like cells by gene transfection of CRT. In this study, we investigated the altered characteristics of cell adhesion in these epithelial-mesenchymal transition (EMT) like cells. Several extracellular matrix substrata were tested, and cell adhesion to fibronectin was found to be specifically increased in the CRT-overexpressing cells compared to controls. The expression of integrins was significantly up regulated in subunits alpha5 and alphaV, resulting in an increase in the formation of complexes such as alpha5beta1 and alphaVbeta3. These integrins also contributed to the enhanced binding of fibronectin. In the CRT-overexpressing cells, the phosphorylation of Akt, a downstream target of integrin-linked kinase (ILK), was up-regulated on attachment to fibronectin or collagen IV. Integrin associated signaling through ILK was also promoted on attachment to fibronectin, suggesting some of the correlation between ILK and Akt in the CRT-overexpressing cells. Furthermore, on treatment with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N' tetraacetic acid tetra (acetoxymethyl) ester, a membrane-permeable Ca(2+) chelator, the enhanced Akt signaling was suppressed with a concomitant decrease in the formation of complexes between integrins and ILK in the CRT-overexpressing cells. In conclusion, these findings demonstrate that CRT regulates cell substratum adhesion by modulating integrin-associated signaling through altered Ca(2+) homeostasis in the CRT-overexpressing EMT-like cells, suggesting a novel regulatory role for CRT in EMT. PMID- 21557299 TI - Efficacy of sacral neuromodulation in treatment of bladder pain syndrome: long term follow-up. AB - AIMS: This study was sought to evaluate the efficacy and durability of sacral neuromodulation in the treatment of bladder pain syndrome (BPS) patients. METHODS: A retrospective chart review was performed of patients who had unilateral sacral nerve stimulator (InterStim(r)) for refractory BPS between June 2002 and December 2004. Patients were qualified for permanent implantation by showing >= 50% improvement in their bladder pain and voiding symptoms 1-week post percutaneous nerve evaluation (PNE). Voiding diary was completed at pre implantation, 1 year, and on the last visit. Urinary distress inventory short form was completed pre-implantation and on the last visit. Bladder pain was evaluated by visual analogue scale. Primary outcome was improvement in bladder pain. Differences among groups were compared by one-way ANOVA and t-test. Statistical significance was set at P <= 0.05. RESULTS: Twenty-one female patients diagnosed with BPS had PNE; 11 patients (52%) showed >= 50% improvement in their bladder pain and voiding symptoms and they consider candidates for permanent implantation (Table I), while 10 patients (48%) failed to show 50% improvement in their voiding symptoms or bladder pain (Table II). In those 11 patients who underwent permanent implantation, the average patient's age was 44.3 +/- 8.9 years; average time since diagnosis was 3 +/- 0.8 years; the average follow- up was 71.5 +/- 9.3 months (Table III). There was significant improvement in the bladder pain and voiding parameters at 1-year follow-up, which was maintained at 5-year follow-up. There was continuous improvement in urgency (1.2 +/- 0.68) at 1-year follow-up, and (0.98 +/- 0.72) at the last visit. Average voided volume was also continuously improved from 242 +/- 62.7 ml at 1-year follow-up to 276 +/- 64.7 ml on the last visit. CONCLUSION: Sacral neuromodulation as part of multimodal treatment provides an effective long-term treatment option for sub-group of refractory BPS. PMID- 21557300 TI - Evaluation of potential variables contributing to the development and duration of plantar lesions in a population of aquarium-maintained African penguins (Spheniscus demersus). AB - Bumblefoot (pododermatitis), often described as the most significant environmental disease of captive penguins, is commonly due to excessive pressure or trauma on the plantar surface of the avian foot, resulting in inflammation or necrosis and causing severe swelling, abrasions, or cracks in the skin. Although not formally evaluated in penguins, contributing factors for bumblefoot are thought to be similar to those initiating the condition in raptors and poultry. These factors include substrate, body weight, and lack of exercise. The primary purpose of this retrospective study was to evaluate variables potentially contributing to the development and duration of plantar lesions in aquarium maintained African penguins (Spheniscus demersus), including sex, weight, age, season, exhibit activity, and territory substrate. Results indicate that males develop significantly more plantar lesions than females. Penguins weighing between 3.51 and 4.0 kg develop plantar lesions significantly more often than penguins weighing between 2.5 and 3.5 kg, and because male African penguins ordinarily weigh significantly more than females, weight is likely a contributing factor in the development of lesions in males compared with females. Significantly more plantar lesions were observed in penguins standing for greater than 50% of their time on exhibit than swimming. Penguins occupying smooth concrete territories developed more plantar lesions compared with penguins occupying grate territories. Recommendations for minimizing bumblefoot in African penguins include training penguins for monthly foot examinations for early detection of plantar lesions predisposing for the disease, encouraging swimming activity, and replacing smooth surfaces on exhibit with surfaces providing variable degrees of pressure and texture on the feet. PMID- 21557301 TI - ACL reconstruction using bone-tendon-bone graft engineered from the semitendinosus tendon by injection of recombinant BMP-2 in a rabbit model. AB - We attempted to generate a bone-tendon-bone structure by injecting human-type recombinant human bone morphogenetic protein-2 (rhBMP-2) into the semitendinosus tendon, and an anterior cruciate ligament (ACL) defect was reconstructed by grafting the engineered bone-tendon-bone graft. Two ossicles with a separation distance of 1 cm were generated within the left semitendinosus tendon of a rabbit 6 weeks after the injection of rhBMP-2 (15 ug at each site). The engineered bone tendon-bone graft was transplanted in order to reconstruct the ACL by passing the graft through the bone tunnels. In the control group, the ACL was reconstructed with the semitendinosus tendon without BMP-2 using the same methods as those used in the experimental group. The animals were harvested at 4 or 8 weeks after surgery and examined by radiographic, histological, and biomechanical methods. In the experimental group, ossicles in the bone-tendon-bone graft were successfully integrated into the host bone of the femur and tibia. Histological analysis revealed that characteristic features identical to the normal direct insertion morphology had been restored. Biomechanical pull-out testing showed that the ultimate failure load and stiffness of the reconstructed ACL in the experimental group were significantly higher than those in the control group at both 4 and 8 weeks (p < 0.05). These results indicate the potential of regenerative reconstruction of the ACL, and the reconstruction resulted in the restoration of morphology and function equivalent to those of the normal ACL. PMID- 21557302 TI - Calcineurin/nuclear factor of activated T cells (NFAT) signaling in cobalt chromium-molybdenum (CoCrMo) particles-induced tumor necrosis factor-alpha (TNFalpha) secretion in MLO-Y4 osteocytes. AB - Aseptic loosening is the devastating long term complication of total hip arthroplasty and orthopedic implant debris has been shown to trigger an intense inflammatory reaction leading to resorption of the bone matrix. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFalpha), have been implicated in this process and osteocytes may play a role in its production. We previously demonstrated that cobalt-chromium-molybdenum (CoCrMo) particles upregulate TNFalpha production by MLO-Y4 osteocytes in vitro, but the underlying mechanism has not been elucidated. Based on previous studies by others, we hypothesized that the calcineurin-nuclear factor of activated T cells (NFAT) pathway mediates CoCrMo particle-induced TNFalpha production in MLO-Y4 osteocytes. MLO-Y4 osteocytes exposed to CoCrMo particle treatment resulted in a rapid and significant increase in calcineurin activity. We also demonstrate that CoCrMo particle-induced upregulation of TNFalpha is reduced to control levels with calcineurin-NFAT inhibitors and this was also confirmed at mRNA level. Moreover, we demonstrate the localization of NFATs in MLO-Y4 osteocytes and that NFAT1 and 2 translocate to the nucleus upon CoCrMo particle treatment. Our results suggest that calcineurin-NFAT signaling is involved in TNFalpha production by MLO-Y4 osteocytes after CoCrMo particle treatment. PMID- 21557303 TI - Repair of complete nerve lacerations at the forearm: an outcome study using Rosen Lundborg protocol. AB - A comparison of outcomes based on a scoring system for assessments, described by Rosen and Lundborg, after sharp complete laceration of median and/or ulnar nerves at various levels in the forearm was carried out. There were 66 males (90.4%) and 7 females (9.6%), with a mean age of 31 years (range: 14-62 years). The patients were categorized into three groups according to the type of nerve injury. The median nerve was injured in 25 cases (group M, 34.3%), the ulnar in 27 (group U, 36.9%), and both the nerves in 21 (group MU, 28.8%). The demographic data of the patients and the mechanism of injury were recorded. We also examined the employment status at the time of the injury and we estimated the percentage of patients who returned to their work after trauma. In all cases, a primary epineural repair was performed. Concomitant injuries were repaired in the same setting. The mean period of time between injury and surgery was 5.3 hours (range: 2-120 hours). A rehabilitation protocol and a reeducation program were followed in all cases. The mean follow-up was 3 years (range: 2-6 years), with more distal injuries having a shorter follow-up period. The total score was 2.71 in group M (range: 0.79-2.99) and 2.63 in group U (range: 0.63-3), with no significant differences observed. There was a significant difference between these two groups and group MU (total score 2.03, range: 0.49-2.76, P = 0.02). Up to the last follow-up, 61 patients (83.5%) had returned to their previous work. The Rosen Lundborg model can be a useful and simple tool for the evaluation of the functional outcome after nerve injury and repair temporally reflecting the processes of regeneration and reinnervation. PMID- 21557304 TI - Upper and lower trapezius muscle transfer to restore shoulder abduction and external rotation in longstanding upper type palsies of the brachial plexus in adults. AB - Lesions affecting the upper roots of the brachial plexus result in paralysis of shoulder abduction and external rotation. In longstanding lesions, neurological surgery is not recommended in which case muscle transfers become an option to improve shoulder function. We describe the surgical treatment of seven adult patients with longstanding lesions of the upper roots of the brachial plexus, in whom the upper trapezius muscle was transferred to the humeral head, whereas the lower trapezius muscle was sutured to the infraspinatous muscle tendon. Within an average of 11.7 months after surgery, patients had recovered 38 degrees of abduction and 104 degrees of external rotation, as measured from full internal rotation. The results of this preliminary series involving the combined transfer of both the upper and lower trapezius muscle seems promising for the treatment of chronic paralysis of abduction and external rotation following brachial plexus injury. PMID- 21557305 TI - Clinical application of inside-out vein grafts for the treatment of sensory nerve segmental defect. AB - PURPOSE: The gold standard for the treatment of segmental nerve defect is an autogenous nerve graft. However, donor site morbidity is an inevitable complication. We substituted an autogenous nerve graft with an inside-out vein graft for the treatment of segmental sensory nerve defect and the clinical results were evaluated retrospectively. PATIENTS AND METHODS: Eleven patients of sensory nerve defects have undertaken inside-out vein grafts for the recovery of sensation. The involved nerves were digital nerves in three cases, peroneal nerves in two cases, saphenous nerve in two cases, and superficial radial nerves in four cases. The average length of defects was 2.71 cm (1-6 cm). Donor veins were harvested 4 mm longer than nerve defects and everted to promote nerve regeneration. Patients' objective satisfactions and two-point discriminations were determined, the Semmes-Weinstein monofilament test was performed, and British Medical Council sensory functional scores were evaluated. RESULTS: Sensory functional scores recovered to over S3 in all cases. No donor site morbidity was caused by vein harvesting, and all patients achieved satisfactory results with protective sensation at involved sites. CONCLUSION: The inside-out vein graft offers a good surgical alternative to an autogenous nerve graft for the reconstruction of sensory nerve defects without donor site morbidity. PMID- 21557306 TI - Secondary ectopic transfer for replantation salvage after severe wound infection. AB - BACKGROUND: Ectopic transfer has been described as a salvage procedure in failing replants. The experience in three cases of infected failing replantations treated with secondary temporary ectopic transfer of the replanted part is presented. METHODS: Three patients with replanted traumatic amputations (one transhumeral, one transmetacarpal, and one transtibial) that developed severe wound infections and thrombosis of the anastomoses were treated with urgent ectopic transfer of the replanted part. The ectopic recipient vessels were the femoral, posterior tibial, and the descending branch of the lateral femoral circumflex arteries. The stumps were surgically cleansed and the ectopically replanted parts were retransferred some days later. RESULTS: The infection reccurred in one case and the replant (transmetacarpal) was lost. The two other cases were successfully retransferred orthotopically, 9 and 20 days later, respectively. In one case (transtibial) multiple additional surgical procedures were necessary. Functional results in these two cases were acceptable. CONCLUSIONS: Delayed ectopic transfer is a useful, yet demanding technique for the salvage of complicated replants in the context of severe wound infection and vascular thrombosis or impending failure. Given the complexity of the procedure it should only be considered in selected cases. PMID- 21557307 TI - Reinnervation of thenar muscle after repair of total brachial plexus avulsion injury with contralateral C7 root transfer: report of five cases. AB - OBJECTIVE: In this report, we present the findings of reinnervation of the thenar muscle in five patients who underwent the contralateral C7 nerve root transfers for repair of total brachial plexus root avulsions. PATIENTS AND METHODS: Five (2 children and 3 adults) of 32 patients who received two-staged procedures of the contralateral C7 nerve root transfers to the median nerves showed reinnervation of thenar muscle were evaluated. The patients also received other procedures including the intercostal nerve transfer to the musculocutaneous nerve, the spinal accessory nerve to the suprascapular nerve, and the ipsilateral phrenic nerve to the musculocutaneous nerve before the contralateral C7 nerve root transfers. The patients were followed up from 24 to 118 months after surgery. RESULTS: Varied degrees of functional restorations were achieved after different procedures. The strength of abductor pollicis brevis (APB) muscle with Grade M2 was found in four patients. The incomplete interference pattern in the APB muscle was detected by electromyogram (EMG) in two patients, and the minority motor unit potential (MUP) was detected in other two patients. The strength of APB muscle was found with Grade M1 in one patient with EMG showing MUP. CONCLUSION: The findings from our series show reinnervation of thenar muscles after repair of the median nerve with the contralateral C7 nerve root transfer, which provides evidence for further investigation of reconstruction of the brachial plexus root avulsion injury with this procedure. PMID- 21557308 TI - Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. AB - The skeleton has been shown recently to regulate glucose metabolism through an osteoblast-specific hormone, osteocalcin, which favors beta-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. An implication of this finding is that a decrease in osteoblast numbers would compromise glucose metabolism in an osteocalcin-dependent manner. To test this hypothesis, osteoblasts were inducibly ablated by cross-breeding transgenic mice expressing a tamoxifen-regulated Cre under the control of the osteocalcin promoter with mice in which an inactive form of the diphtheria toxin A chain was introduced into a ubiquitously expressed locus. Ablation of osteoblasts in adult mice profoundly affected glucose metabolism. In a manner similar to what is seen in the case of osteocalcin deficiency, a partial ablation of this cell population resulted in hypoinsulinemia, hyperglycemia, glucose intolerance, and decreased insulin sensitivity. However, and unlike what is seen in osteocalcin-deficient mice, osteoblast ablation also decreased gonadal fat and increased energy expenditure and the expression of resistin, an adipokine proposed to mediate insulin resistance. While administration of osteocalcin reversed (fully) the glucose intolerance and reinstated normal blood glucose and insulin levels, it only partially restored insulin sensitivity and did not affect the improved gonadal fat weight and energy expenditure in osteoblast-depleted mice. These observations not only strengthen the notion that osteoblasts are necessary for glucose homeostasis and energy expenditure but also suggest that in addition to osteocalcin, other osteoblast-derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism. PMID- 21557309 TI - The risk of fracture in patients with multiple sclerosis: the UK general practice research database. AB - Patients with multiple sclerosis (MS) may be at an increased risk of fracture owing to a greater risk of falling and decreased bone mineral density when compared with the general population. This study was designed to estimate the relative and absolute risk of fracture in patients with MS. We conducted a population-based cohort study using data from the UK General Practice Research Database linked to the National Hospital Registry (1997-2008). Incident MS patients (n = 5565) were matched 1:6 by year of birth, sex, and practice with patients without MS (controls). Cox proportional-hazards models were used to derive adjusted hazard ratios (HRs) for fracture associated with MS. Time dependent adjustments were made for age, comorbidity, and drug use. Absolute 5- and 10-year risks of fracture were estimated for MS patients as a function of age. Compared with controls, MS patients had an almost threefold increased risk of hip fracture [HR = 2.79, 95% confidence interval (CI) 1.83-4.26] and a risk of osteoporotic fracture that was increased 1.4-fold (HR = 1.35, 95% CI 1.13-1.62). Risk was greater in patients who had been prescribed oral/intravenous glucocorticoids (GCs; HR = 1.85, 95% CI 1.14-2.98) or antidepressants (HR = 1.79, 95% CI 1.37-2.35) in the previous 6 months. Absolute fracture risks were low in younger MS patients but became substantial when patients were older than 60 years of age. It is concluded that MS is associated with an increased risk of fracture. Fracture risk assessment may be indicated in patients with MS, especially those prescribed GCs or antidepressants. PMID- 21557310 TI - Microtubule assembly affects bone mass by regulating both osteoblast and osteoclast functions: stathmin deficiency produces an osteopenic phenotype in mice. AB - Cytoskeleton microtubules regulate various cell signaling pathways that are involved in bone cell function. We recently reported that inhibition of microtubule assembly by microtubule-targeting drugs stimulates osteoblast differentiation and bone formation. To further elucidate the role of microtubules in bone homeostasis, we characterized the skeletal phenotype of mice null for stathmin, an endogenous protein that inhibits microtubule assembly. In vivo micro computed tomography (uCT) and histology revealed that stathmin deficiency results in a significant reduction of bone mass in adult mice concurrent with decreased osteoblast and increased osteoclast numbers in bone tissues. Phenotypic analyses of primary calvarial cells and bone marrow cells showed that stathmin deficiency inhibited osteoblast differentiation and induced osteoclast formation. In vitro overexpression studies showed that increased stathmin levels enhanced osteogenic differentiation of preosteoblast MC3T3-E1 cells and mouse bone marrow-derived cells and attenuated osteoclast formation from osteoclast precursor Raw264.7 cells and bone marrow cells. Results of immunofluorescent studies indicated that overexpression of stathmin disrupted radial microtubule filaments, whereas deficiency of stathmin stabilized the microtubule network structure in these bone cells. In addition, microtubule-targeting drugs that inhibit microtubule assembly and induce osteoblast differentiation lost these effects in the absence of stathmin. Collectively, these results suggest that stathmin, which alters microtubule dynamics, plays an essential role in maintenance of postnatal bone mass by regulating both osteoblast and osteoclast functions in bone. ? PMID- 21557311 TI - Individual trabecula segmentation (ITS)-based morphological analysis of microscale images of human tibial trabecular bone at limited spatial resolution. AB - Individual trabecula segmentation (ITS), a rigorous model-independent 3D morphological analysis, has been developed to assess trabecular plate and rod microstructure separately based on micro-computed tomographic (uCT) images. We examined the influence of the limited spatial resolution, noise, and artifact of high-resolution peripheral quantitative CT (HR-pQCT) on ITS measurements of human tibial trabecular bone. In comparison with measurements from "gold standard" uCT images (25 um), decreased spatial resolution (40, 60, and 80 um) of uCT had minimal influence on the correlations of the scale of trabecular plates (ie, plate bone volume fraction, thickness, and surface area) and the orientation (ie, axial bone volume fraction) and structural type (ie, plate tissue fraction) of the trabecular network. ITS measurements of HR-pQCT images correlated significantly with those of uCT images at a similar voxel size (80 um, r = 0.71 0.94); correlations were stronger for plate-related parameters, suggesting that measurements of trabecular rods are more subject to noise and artifact associated with HR-pQCT imaging technology. In comparison with measurements of "gold standard" uCT images, the percent absolute errors of HR-pQCT measurements such as axial and plate bone volume fraction, plate number and tissue fraction, and plate and rod thickness (3.5% to 10.3%) were comparable with those of bone volume fraction (9.3%). For both HR-pQCT and uCT images, measurements of the scale and junction densities of trabecular plates and orientation and structural type were strong and positive indicators of the elastic modulus of trabecular bone (r = 0.59-0.95). We conclude that ITS measurements of HR-pQCT images are highly reflective of trabecular bone microarchitecture from a biomechanical perspective. PMID- 21557312 TI - The structural involvement of the cingulate cortex in premanifest and early Huntington's disease. AB - The impact of Huntington's disease neuropathology on the structure of the cingulate is uncertain, with evidence of both cortical enlargement and atrophy in this structure in early clinical disease. We sought to determine differences in cingulate volume between premanifest Huntington's disease and early Huntington's disease groups compared with controls using detailed manual measurements. Thirty controls, 30 subjects with premanifest Huntington's disease, and 30 subjects with early Huntington's disease were selected from the Vancouver site of the TRACK-HD study. Subjects underwent 3 Tesla magnetic resonance imaging and motor, cognitive, and neuropsychiatric assessment. The cingulate was manually delineated and subdivided into rostral, caudal, and posterior segments. Group differences in volume and associations with performance on 4 tasks thought to utilize cingulate function were examined, with adjustment for appropriate covariates. Cingulate volumes were, on average, 1.7 mL smaller in early Huntington's disease (P=.001) and 0.9 mL smaller in premanifest Huntington's disease (P=.1) compared with controls. Smaller volumes in subsections of the cingulate were associated with impaired recognition of negative emotions (P=.04), heightened depression (P=.009), and worse visual working memory performance (P=.01). There was no evidence of associations between volume and ability on a performance-monitoring task. This study disputes previous findings of enlargement of the cingulate cortex in Huntington's disease and instead suggests that the cingulate undergoes structural degeneration during early Huntington's disease with directionally consistent, nonsignificant differences seen in premanifest Huntington's disease. Cingulate atrophy may contribute to deficits in mood, emotional processing, and visual working memory in Huntington's disease. PMID- 21557313 TI - Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. AB - BACKGROUND: The safety and efficacy of the oral iron-chelating agent deferiprone on magnetic resonance pallida iron concentration and on clinical status were investigated in 10 patients affected by pantothenate kinase-associated neurodegeneration. METHODS: Nine patients (age range, 7-39 years) completed the study. RESULTS: A significant median reduction in globus pallidus iron content as assessed by T2* relaxometry (and calculated R2* maps; P=.008) was observed at the end of the study. None of the patients demonstrated a change in clinical status as assessed by the Burke-Fahn and Marsden Dystonia Rating scales and by a health related quality-of-life scale. Deferiprone was well tolerated, and no serious adverse events occurred. CONCLUSIONS: Future trials assessing the clinical efficacy of chelating therapy should consider early symptomatic patients and a longer treatment period. PMID- 21557314 TI - Structural modeling and molecular dynamics simulation of the actin filament. AB - Actin is a major structural protein of the eukaryotic cytoskeleton and enables cell motility. Here, we present a model of the actin filament (F-actin) that not only incorporates the global structure of the recently published model by Oda et al. but also conserves internal stereochemistry. A comparison is made using molecular dynamics simulation of the model with other recent F-actin models. A number of structural determents such as the protomer propeller angle, the number of hydrogen bonds, and the structural variation among the protomers are analyzed. The MD comparison is found to reflect the evolution in quality of actin models over the last 6 years. In addition, simulations of the model are carried out in states with both ADP or ATP bound and local hydrogen-bonding differences characterized. PMID- 21557315 TI - A parameterized, continuum electrostatic model for predicting protein pKa values. AB - Recognizing the limits of trying to achieve chemical accuracy for pK(a) calculations with a purely electrostatic model, we include empirical corrections into the Poisson-Boltzmann solver macroscopic electrostatics with atomic detail (Bashford, Biochemistry 1990;29:10219-10225), to improve the reliability and accuracy of the model. The total number of parameters is kept to a minimum to maximize the robustness of the model for compounds outside of the fitting dataset. The parameters are based on: (a) the electrostatic interaction between functional groups close to the titratable site, (b) the electrostatic work required to desolvate the residue, and (c) the site-to-site interactions. These interactions are straightforward to calculate once the electrostatic field has been solved for each residue using the linearized Poisson-Boltzmann equation and are assumed to be linearly related to the intrinsic pK(a). Two hundred and eighty six residues from 30 proteins are used to determine the empirical parameters, which result in a root mean square error (RMSE) of 0.70 for the entire set. Eight proteins with 46 experimentally known values were excluded from the parameterization to test the model. This test set had a RMSE of 1.08. We show that the parameterized model improves the results over other models, although like other models the error is strongly correlated with the degree to which a residue is buried. The parameters themselves indicate that local effects are most important for determining the pK(a), whereas site-to-site interactions are found to be less significant. PMID- 21557316 TI - Analysis of water patterns in protein kinase binding sites. AB - Deregulation of protein kinases is associated with numerous diseases, making them important targets for drug discovery. The majority of drugs target the catalytic site of these proteins, but due to the high level of similarity within the ATP binding sites of protein kinases, it is often difficult to achieve the required pharmacological selectivity. In this study, we describe the identification and subsequent analysis of water patterns in the ATP binding sites of 171 protein kinase structures, comprising 19 different kinases from various branches of the kinome, and demonstrate that structurally similar binding sites often have significantly different water patterns. We show that the observed variations in water patterns of different, but structurally similar kinases can be exploited in the structure-based design of potent and selective kinase inhibitors. PMID- 21557317 TI - Computer simulation study of amyloid fibril formation by palindromic sequences in prion peptides. AB - We simulate the aggregation of large systems containing palindromic peptides from the Syrian hamster prion protein SHaPrP 113-120 (AGAAAAGA) and the mouse prion protein MoPrP 111-120 (VAGAAAAGAV) and eight sequence variations: GAAAAAAG, (AG)(4) , A8, GAAAGAAA, A10, V10, GAVAAAAVAG, and VAVAAAAVAV The first two peptides are thought to act as the Velcro that holds the parent prion proteins together in amyloid structures and can form fibrils themselves. Kinetic events along the fibrillization pathway influence the types of structures that occur and variations in the sequence affect aggregation kinetics and fibrillar structure. Discontinuous molecular dynamics simulations using the PRIME20 force field are performed on systems containing 48 peptides starting from a random coil configuration. Depending on the sequence, fibrillar structures form spontaneously over a range of temperatures, below which amorphous aggregates form and above which no aggregation occurs. AGAAAAGA forms well organized fibrillar structures whereas VAGAAAAGAV forms less well organized structures that are partially fibrillar and partially amorphous. The degree of order in the fibrillar structure stems in part from the types of kinetic events leading up to its formation, with AGAAAAGA forming less amorphous structures early in the simulation than VAGAAAAGAV. The ability to form fibrils increases as the chain length and the length of the stretch of hydrophobic residues increase. However as the hydrophobicity of the sequence increases, the ability to form well-ordered structures decreases. Thus, longer hydrophobic sequences form slightly disordered aggregates that are partially fibrillar and partially amorphous. Subtle changes in sequence result in slightly different fibril structures. PMID- 21557318 TI - Free-energy function for discriminating the native fold of a protein from misfolded decoys. AB - In this study, free-energy function (FEF) for discriminating the native fold of a protein from misfolded decoys was investigated. It is a physics-based function using an all-atom model, which comprises the hydration entropy (HE) and the total dehydration penalty (TDP). The HE is calculated using a hybrid of a statistical mechanical theory applied to a molecular model for water and the morphometric approach. The energetic component is suitably taken into account in a simple manner as the TDP. On the basis of the results from a careful test of the FEF, which have been performed for 118 proteins in representative decoy sets, we show that its performance is distinctly superior to that of any other function. The FEF varies largely from model to model for the candidate models for the native structure (NS) obtained from nuclear magnetic resonance experiments, but we can find models or a model for which the FEF becomes lower than for any of the decoy structures. A decoy set is not suited to the test of a free-energy or potential function in cases where a protein isolated from a protein complex is considered and the structure in the complex is used as the model NS of the isolated protein without any change or where portions of the terminus sides of a protein are removed and the percentage of the secondary structures lost due to the removal is significantly high. As these findings are made possible, we can assume that our FEF precisely captures the features of the true NS. PMID- 21557319 TI - Quaternion-based definition of protein secondary structure straightness and its relationship to Ramachandran angles. AB - We describe here definitions of "local helical axis" and "straightness" that are developed using a simple quaternion-based analysis of protein structure without resort to least-squares fitting. As part of this analysis, it is shown how quaternion differences can be visualized to depict accurately the local helical axis relating any two adjacent amino acid residues in standard, nonidealized proteins. Three different options for the definition of amino acid residue orientation in terms of quaternion frames are described. Two of these, the "C(alpha) frame" and the "P frame," are shown to be correlated strongly with a simple approximate measure derived solely from Ramachandran angles. The relationship between quaternion-based straightness and recognized DSSP-derived secondary structure motifs is discussed. PMID- 21557320 TI - Crystal structure of the catalytic domain of cholesterol-alpha glucosyltransferase from Helicobacter pylori. PMID- 21557321 TI - Early days of protein hydrogen exchange: 1954-1972. AB - Hydrogen exchange (HX) is recognized today as one of the most powerful and versatile tools available to protein scientists, especially for studying protein conformational change. This short history traces the beginnings of the HX method and the basic problems that faced the founders. Protein HX began as a simple idea with a straightforward goal, but the first experiments revealed both the unexpected complexity of the subject and the potential power of the method for probing deep into how proteins work. By 1972, the chemistry of the exchange reaction in peptides began to be well understood, but the challenge of getting and interpreting data on HX for individual peptide NH protons in proteins remained for decades longer. PMID- 21557322 TI - Toward the quantum chemical calculation of nuclear magnetic resonance chemical shifts of proteins. AB - Despite the many protein structures solved successfully by nuclear magnetic resonance (NMR) spectroscopy, quality control of NMR structures is still by far not as well established and standardized as in crystallography. Therefore, there is still the need for new, independent, and unbiased evaluation tools to identify problematic parts and in the best case also to give guidelines that how to fix them. We present here, quantum chemical calculations of NMR chemical shifts for many proteins based on our fragment-based quantum chemical method: the adjustable density matrix assembler (ADMA). These results show that (13)C chemical shifts of reasonable accuracy can be obtained that can already provide a powerful measure for the structure validation. (1)H and even more (15)N chemical shifts deviate more strongly from experiment due to the insufficient treatment of solvent effects and conformational averaging. PMID- 21557323 TI - The ygeW encoded protein from Escherichia coli is a knotted ancestral catabolic transcarbamylase. PMID- 21557324 TI - Leukocyte integrin alphaLbeta2 transmembrane association dynamics revealed by coarse-grained molecular dynamics simulations. AB - Integrins are transmembrane (TM) proteins that mediate bidirectional mechanical signaling between the extracellular matrix and the cellular cytoskeletal network. Each integrin molecule consists of non-covalently associated alpha- and beta subunits, with each subunit consisting of a large ectodomain, a single-pass TM helix, and a short cytoplasmic tail. Previously we found evidence for a polar interaction (hydrogen bond) in the outer membrane clasp (OMC) of the leukocyte integrin alphaLbeta2 TMs that is absent in the platelet integrin alphaIIbeta3 OMC. Here, we compare the self-assembly dynamics of alphaLbeta2 and alphaIIbeta3 TM helices in a model membrane using coarse-grained molecular dynamics simulations. We found that although alphaIIbeta3 TM helices associate more easily, packing is suboptimal. In contrast, alphaLbeta2 TM helices achieve close to-optimal packing. This suggests that alphaLbeta2 TM packing is more specific, possibly due to the interhelix hydrogen bond. Theoretical association free energy profiles show a deeper minimum at a smaller helix-helix separation for alphaLbeta2 compared with alphaIIbeta3. The alphaIIbeta3 profile is also more rugged with energetic barriers whereas that of alphaLbeta2 is almost without barriers. Disruption of the interhelix hydrogen bond in alphaLbeta2 via the beta2T686G mutation results in poorer association and a similar profile as alphaIIbeta3. The OMC polar interaction in alphaLbeta2 thus plays a significant role in the packing of the TM helices. PMID- 21557325 TI - Observing the osmophobic effect in action at the single molecule level. AB - Protecting osmolytes are widespread small organic molecules able to stabilize the folded state of most proteins against various denaturing stresses in vivo. The osmophobic model explains thermodynamically their action through a preferential exclusion of the osmolyte molecules from the protein surface, thus favoring the formation of intrapeptide hydrogen bonds. Few works addressed the influence of protecting osmolytes on the protein unfolding transition state and kinetics. Among those, previous single molecule force spectroscopy experiments evidenced a complexation of the protecting osmolyte molecules at the unfolding transition state of the protein, in apparent contradiction with the osmophobic nature of the protein backbone. We present single-molecule evidence that glycerol, which is a ubiquitous protecting osmolyte, stabilizes a globular protein against mechanical unfolding without binding into its unfolding transition state structure. We show experimentally that glycerol does not change the position of the unfolding transition state as projected onto the mechanical reaction coordinate. Moreover, we compute theoretically the projection of the unfolding transition state onto two other common reaction coordinates, that is, the number of native peptide bonds and the weighted number of native contacts. To that end, we augment an analytic Ising-like protein model with support for group-transfer free energies. Using this model, we find again that the position of the unfolding transition state does not change in the presence of glycerol, giving further support to the conclusions based on the single-molecule experiments. PMID- 21557326 TI - Dissection of the oncogenic MYCN transcriptional network reveals a large set of clinically relevant cell cycle genes as drivers of neuroblastoma tumorigenesis. AB - Amplification of the oncogenic transcription factor MYCN plays a major role in the pathogenesis of several pediatric cancers, including neuroblastoma, medulloblastoma, and rhabodomyosarcoma. For neuroblastoma, MYCN amplification is the most powerful genetic predictor of poor patient survival, yet the mechanism by which MYCN drives tumorigenesis is only partially understood. To gain an insight into the distribution of MYCN binding and to identify clinically relevant MYCN target genes, we performed an integrated analysis of MYCN ChIP-chip and mRNA expression using the MYCN repressible SHEP-21N neuroblastoma cell line. We hypothesized that genes exclusively MYCN bound in SHEP-21N cells over-expressing MYCN would be enriched for direct targets which contribute to the process of disease progression. Integrated analysis revealed that MYCN drives tumorigenesis predominantly as a positive regulator of target gene transcription. A high proportion of genes (24%) that are MYCN bound and up-regulated in the SHEP-21N model are significantly associated with poor overall patient survival (OS) in a set of 88 tumors. In contrast, the proportion of genes down-regulated when bound by MYCN in the SHEP-21N model and which are significantly associated with poor overall patient survival when under-expressed in primary tumors was significantly lower (5%). Gene ontology analysis determined a highly statistically significant enrichment for cell cycle related genes within the over-expressed MYCN target group which were also associated with poor OS. We conclude that the over expression of MYCN leads to aberrant binding and over-expression of genes associated with cell cycle regulation which are significantly correlated with poor OS and MYCN amplification. PMID- 21557327 TI - Rictor regulates MMP-9 activity and invasion through Raf-1-MEK-ERK signaling pathway in glioma cells. AB - Glioblastoma multiforme (GBM) is the most common and highly aggressive type of primary brain tumor. Tumor-associated macrophages (TAMs) secrete TNF-alpha that activates important survival pathways including Akt (PKB)/mTOR network. The mammalian target of rapamycin (mTOR) network functions downstream of PI3K/Akt pathway to regulate cell growth, proliferation and survival. mTOR exists in two distinct complexes-mTORC1 and mTORC2 that differ in their components and sensitivity to rapamycin. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, Rictor, mSin1 and Protor and regulates the actin cytoskeleton in addition to activating Akt (protein kinase B). The present study aimed to investigate the role of Rictor-a core component of mTORC2 in regulating proliferation, survival, and invasion in gliomas. siRNA-mediated loss of Rictor function in human glioma cell lines, LN18 and LN229 and in primary GBM cells resulted in elevated expression and activity of MMP-9 and significant increase in the invasive potential of these cells. Mechanistic studies revealed that the activation of Raf-1-MEK-ERK pathway was essential for induction of MMP-9 activity and enhanced invasion. Interestingly, ablation of Rictor did not affect TNF-alpha induced MMP-9 activity and invasiveness suggesting that TNF-alpha in the microenvironment of tumor might overrule the function of Rictor as a negative regulator of MMP-9 and invasion. Silencing Rictor had no effect on the survival or proliferation in the cell lines in the presence or absence of TNF-alpha. Our findings identify a role for Rictor in bridging two major pathways-Akt (PKB)/mTOR and Raf-1-MEK-ERK in regulating MMP-9 activity and invasion of glioma tumor cells. PMID- 21557328 TI - Inhibition of ERK oscillations by ionizing radiation and reactive oxygen species. AB - The shuttling of activated protein kinases between the cytoplasm and nucleus is an essential feature of normal growth factor signaling cascades. Here we demonstrate that transforming growth factor alpha (TGFalpha) induces oscillations in extracellular signal regulated kinase (ERK) cytoplasmic-nuclear translocations in human keratinocytes. TGFalpha-dependent ERK oscillations mediated through the epidermal growth factor receptor (EGFR) are inhibited by low dose X-irradiation (10 cGy) and low concentrations of hydrogen peroxide (0.32-3.26 uM H(2)O(2)) used as a model reactive oxygen species (ROS). A fluorescent indicator dye (H2-DCFDA) was used to measure cellular ROS levels following X-irradiation, 12-O tetradecanoyl phorbol-13-acetate (TPA) and H(2)O(2). X-irradiation did not generate significant ROS production while 0.32 uM H(2)O(2) and TPA induced significant increases in ROS levels with H(2)O(2) > TPA. TPA alone induced transactivation of the EGFR but did not induce ERK oscillations. TPA as a cotreatment did not inhibit TGFalpha-stimulated ERK oscillations but qualitatively altered TGFalpha-dependent ERK oscillation characteristics (amplitude, time-period). Collectively, these observations demonstrate that TGFalpha-induced ERK oscillations are inhibited by ionizing radiation/ROS and perturbed by epigenetic carcinogen in human keratinocytes. PMID- 21557329 TI - Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. AB - Ultraviolet (UV) of sunlight is a complete carcinogen that can burn skin, enhance inflammation, and drive skin carcinogenesis. Previously, we have shown that sulforaphane (SFN) inhibited chemically induced skin carcinogenesis via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and others have shown that broccoli sprout extracts containing high SFN protected against UV-induced skin carcinogenesis in SKH-1 hairless mice. A recent study showed that there was no difference between Nrf2 knockout (Nrf2 KO) and Nrf2 wild-type (WT) BALB/C mice after exposing to high dose of UVB. Since Nrf2 plays critical roles in the anti oxidative stress/anti-inflammatory responses, it is relevant to assess the role of Nrf2 for photoprotection against UV. In this context, the role of Nrf2 in UVB induced skin inflammation in Nrf2 WT and Nrf2 KO C57BL/6 mice was studied. A single dose of UVB (300 mJ/cm(2)) resulted in skin inflammation in both WT and Nrf2 KO (-/-) mice (KO mice) at 8 h and 8 d following UVB irradiation. In the WT mice inflammation returned to the basal level to a greater extent when compared to the KO mice. SFN treatment of Nrf2 WT but not Nrf2 KO mice restored the number of sunburn cells back to their basal level by 8 d after UVB irradiation. Additionally, UVB-induced short-term inflammatory biomarkers (interleukin-1beta and interleukin-6) were increased in the KO mice and UVB-induced apoptotic cells in the KO mice were significantly higher as compared to that in the WT. Taken together, our results show that functional Nrf2 confers a protective effect against UVB-induced inflammation, sunburn reaction, and SFN-mediated photoprotective effects in the skin. PMID- 21557330 TI - The nuclear receptor constitutive active/androstane receptor arrests DNA-damaged human hepatocellular carcinoma Huh7 cells at the G2/M phase. AB - Here, we have demonstrated that xenobiotic activation of the nuclear receptor (CAR, NR1I3) can result in arresting DNA-damaged human hepatocellular carcinoma Huh7 cells at the G2/M phase. Huh7 cells over-expressing CAR were either treated with dimethyl sulfoxide, the CAR activator TCPOBOP (1,4-bis[2-(3,5 dichloropyridyloxy)]benzene; androstenol, 16,(5alpha)-androsten-3alpha-OL), or repressor androstenol; these treatments were then followed by adriamycin treatment to damage DNA. FACS analysis revealed that CAR-activation by TCPOBOP increased the rate of arrested Huh7 cells at the G2/M phase (4N DNA content) after DNA damage by adriamycin. This increase correlated with the increase of cell viability in TCPOBOP-treated Huh7 cells, as determined by MTT assays. Real time polymerase chain reaction analysis determined that, as regulated by CAR, the growth arrest and DNA damage-inducible gamma (GADD45gamma) and Cyclin G2 genes increased and decreased, respectively, as TCPOBOP increased the number of Huh7 cells arrested at the G2/M phase. Thus, the results suggest that CAR regulates cell cycle, increasing G2/M arrest, and delaying the death of DNA-damaged cells. PMID- 21557331 TI - Oroxylin A reverses multi-drug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-kappaB signaling pathway. AB - In this study, oroxylin A showed strong reversal potency in BEL7402/5-FU cells and the reversal fold (RF) reached 4.69. Simultaneously, rhodamine-123 accumulation assay and flow cytometry analysis demonstrated oroxylin A could increase drug accumulation. When combined with oroxylin A, 5-FU showed inducing apoptosis effect more seriously in DAPI staining experiment. Moreover, the mRNA and protein expression of multi-drug resistance gene (MDR1) were also decreased by oroxylin A. Further experiments exhibited that oroxylin A can downregulate P gp expression through inhibiting nuclear factor-kappaB (NF-kappaB) signaling pathway, which might be the mechanism of reversal resistance of oroxylin A. In summary, oroxylin A could be a good candidate for the development of new MDR reversal agent and its reversal mechanism probably due to the suppression of P-gp expression via inhibiting NF-kappaB signaling pathway. PMID- 21557332 TI - Pharmacological inhibition of Mdm2 triggers growth arrest and promotes DNA breakage in mouse colon tumors and human colon cancer cells. AB - The p53 tumor suppressor protein performs a number of cellular functions, ranging from the induction of cell cycle arrest and apoptosis to effects on DNA repair. Modulating p53 activity with Mdm2 inhibitors is a promising approach for treating cancer; however, it is presently unclear how the in vivo application of Mdm2 inhibitors impact the myriad processes orchestrated by p53. Since approximately half of all colon cancers (predominately cancers with microsatellite instability) are p53-normal, we assessed the anticancer activity of the Mdm2 inhibitor Nutlin 3 in the mouse azoxymethane (AOM) colon cancer model, in which p53 remains wild type. Using a cell line derived from an AOM-induced tumor, we found that four daily exposures to Nutlin-3 induced persistent p53 stabilization and cell cycle arrest without significant apoptosis. A 4-day dosing schedule in vivo generated a similar response in colon tumors; growth arrest without significantly increased apoptosis. In adjacent normal colon tissue, Nutlin-3 treatment reduced both cell proliferation and apoptosis. Surprisingly, Nutlin-3 induced a transient DNA damage response in tumors but not in adjacent normal tissue. Nutlin-3 likewise induced a transient DNA damage response in human colon cancer cells in a p53 dependent manner, and enhanced DNA strand breakage and cell death induced by doxorubicin. Our findings indicate that Mdm2 inhibitors not only trigger growth arrest, but may also stimulate p53's reported ability to slow homologous recombination repair. The potential impact of Nutlin-3 on DNA repair in tumors suggests that Mdm2 inhibitors may significantly accentuate the tumoricidal actions of certain therapeutic modalities. PMID- 21557333 TI - FHIT gene and flanking region on chromosome 3p are subjected to extensive allelic loss in Egyptian breast cancer patients. AB - The fragile histidine triad gene (FHIT) is a candidate tumor suppressor gene at chromosome 3p14.2. Deletions in FHIT gene were reported in different types of cancer including breast cancer. In this study, we investigated the loss of heterozygosity (LOH) incidence that target FHIT genomic structure and chromosome 3p in cancerous and pre-neoplastic lesions of Egyptian breast patients. Genomic DNA was isolated from tumor tissues and their normal counterparts of 55 Egyptian patients diagnosed with breast cancer and 11 patients diagnosed with preneoplastic breast lesions. LOH was detected in 51% of breast cancer cases in at least one microsatellite marker of the four investigated markers. While, none of the markers showed LOH among the pre-neoplastic breast lesions. We also observed a significant association between LOH and invasive ductal carcinoma (IDC) histopathological type while no association observed between LOH and patients' age, tumor grade, or lymph node involvement. We also investigated FHIT gene expression profiles in breast cancer using Oncomine database. We found that FHIT is significantly reduced in all investigated studies. We conclude that, FHIT is underexpressed in breast cancer tissues compared to their normal counterparts due to the extensive allelic loss that is observed in its gene structure. PMID- 21557337 TI - Novel biodegradable shape-memory elastomers with drug-releasing capabilities. PMID- 21557334 TI - Urinary polyphenols, glutathione S-transferases copy number variation, and breast cancer risk: results from the Shanghai women's health study. AB - In vitro studies have found that flavanol epigallocatechin (EGC) and flavonols, but not flavanol epicatechin (EC), activate glutathione S-transferases (GSTs), a family of phase II enzymes that detoxify reactive oxygen species, such as catechol estrogen metabolites. This study was designed to investigate prospectively whether urinary excretion of tea polyphenols interacts with GST polymorphisms to influence breast cancer risk. We conducted a study of 352 incident breast cancer cases and 701 individually matched controls nested within the Shanghai Women's Health Study cohort of women aged 40-70 yr at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR was used to quantify the copy number variation in the GSTM1 and GSTT1 genes. Urinary excretion of flavonols and flavanols, particularly EGC (P = 0.02), was significantly higher among women null for GSTM1 than those positive for GSTM1. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, with a P-value of 0.04 for the interaction between EGC and GSTM1 polymorphism. In contrast, among women possessing both GSTM1 and GSTT1, breast cancer risk increased with levels of flavonols, particularly kaempferol. The differential associations between polyphenols and breast cancer risk by GST polymorphisms, if confirmed, may provide a new avenue for the personalized prevention of breast cancer. PMID- 21557338 TI - Bioinspired effective prevention of restacking in multilayered graphene films: towards the next generation of high-performance supercapacitors. PMID- 21557339 TI - Synthesis and radioluminescence of PEGylated Eu(3+) -doped nanophosphors as bioimaging probes. PMID- 21557340 TI - Simultaneous optimization of charge-carrier balance and luminous efficacy in highly efficient white polymer light-emitting devices. PMID- 21557343 TI - Reaction mechanism of aerobic oxidation of alcohols conducted on activated-carbon supported cobalt oxide catalysts. AB - Catalytic performances and the reaction mechanism of Co(3)O(4)/AC (AC=activated carbon) for aerobic oxidation of alcohols carried out in the liquid phase were investigated. Co(3)O(4)/AC shows a high activity for aerobic oxidation of benzyl alcohol, comparable to noble metal catalysts (e.g., Au/AC) even in the absence of additives or promoters (e.g., NaOH). Changing preparation conditions, such as treatment temperature and/or time, can affect the catalytic performances of Co(3)O(4)/AC, due to decomposition of surface groups of the carbon support. Careful studies show that low alcohol conversions are obtained with either Co(3)O(4) or AC alone, which indicates that the high conversion observed over the Co(3)O(4)/AC is due to a synergistic effect between Co(3)O(4) and AC. Parallel experiments using a high-surface-area covalent triazine framework or oxygen-inert carbon nitride as support for the Co(3)O(4) catalyst also show lower conversions, which suggest that the ability of AC (in Co(3)O(4)/AC) to activate molecular oxygen is essential for the reaction. FTIR and XPS spectra taken from catalysts before and after the reaction confirm that oxygen activation proceeds mainly on the carbon support. As a result, it can be assumed that the alcohol dehydrogenation step proceeds on the metal oxide, whereas the oxygen activation step occurs mainly on the carbon support. PMID- 21557344 TI - Synthesis, characterization, and DNA-binding and -photocleavage properties of water-soluble lanthanide porphyrinate complexes. AB - A series of cationic lanthanide porphyrinate complexes of the general formula [(Por)Ln(H(2)O)(3)](+) (Ln(3+)=Yb(3+) and Er(3+)) were synthesized in moderate yields through the interaction of meso-pyridyl-substituted porphyrin free bases (H(2)Por) with [Ln{N(SiMe(3))(2)}(3)].x[LiCl(thf)(3)], and the corresponding neutral derivatives [(Por)Ln(L(OMe))] (L(OMe)(-)=[(eta(5) C(5)H(5))Co{P(=O)(OMe)(2)}(3)](-)) were also prepared from [(Por)Ln(H(2)O)(3)](+) by the addition of the tripodal anion, L(OMe)(-), an effective encapsulating agent for lanthanide ions. Furthermore, the water-soluble lanthanide(III) porphyrinate complexes--including [(cis-DMPyDPP)Yb(H(2)O)(3)]Cl(3) (cis DMPyDPP=5,10-bis(N-methylpyridinium-4'-y1)-15,20-di(phenyl)porphyrin), [(trans DMPyDPP)Yb(H(2)O)(3)]Cl(3) (trans-DMPyDPP=5,15-bis(N-methylpyridinium-4'-y1) 10,20-di(phenyl)porphyrin), [(TMPyP)Yb(L(OMe))]I(4), and [(TMPyP)Er(L(OMe))]I(4) (TMPyP=tetrakis(N-methylpyridinium-4-y1)porphyrin)--were obtained by methylation of the corresponding complexes with methyl iodide and unambiguously characterized. The binding interactions and photocleavage activities of the water soluble lanthanide(III) porphyrinate complexes towards DNA were investigated by UV-visible, fluorescence, and near-infrared luminescence spectroscopy, as well as circular dichroism and gel electrophoresis. PMID- 21557345 TI - Analysis of tertiary phosphanes, arsanes, and stibanes as bridging ligands in dinuclear Group 9 complexes. AB - The unusual bridging and semi-bridging binding mode of tertiary phosphanes, arsanes, and stibanes in dinuclear low-valent Group 9 complexes have been studied by density functional methods and bonding analyses. The influence of various parameters (bridging and terminal ligands, metal atoms) on the structural preferences and bonding of dinuclear complexes of the general composition [A(1)M(1)(MU-CH(2))(2)(MU-EX(3))M(2)A(2)] (M(1), M(2) = Co, Rh, Ir; A(1), A(2) = F, Cl, Br, I, kappa(2)-acac; E = P, As, Sb, X = H, F, CH(3)) has been analyzed. A number of factors have been identified that favor bridging or semi-bridging modes for the phosphane ligands and their homologues. A more symmetrical position of the bridging ligand EX(3) is promoted by more polar E-X bonding, but by less electronegative (softer) terminal anionic ligands. Among the Group 9 metal elements Co, Rh, and Ir, the computations clearly show that the 4d element rhodium exhibits the largest preference for a {M(1)(MU-EX(3))M(2)} bridge, in agreement with experimental observation. Iridium complexes should be valid targets, whereas cobalt does not seem to support well a symmetric bridging mode. Analyses of the Electron Localization Function (ELF) indicate a competition between a delocalized three-center bridge bond and direct metal-metal bonding. PMID- 21557346 TI - Electron delocalization in homoconjugated 7,7-diarylnorbornane systems: a computational and experimental study. AB - A joint computational-experimental study has been carried out to analyze the homoconjugative interactions in 7,7-diarylnorbornane (DPN) derivatives. The experimentally observed new bands in their UV/Vis have been accurately assigned by means of TD-DFT calculations. Both experimental data and computations show that aromatic homoconjugation in acyclic systems is an effective mechanism for electron delocalization that resembles the situation described for polyphenylenes and polyenes. The effective homoconjugation length in homoconjugated oligomers is in the range of 6-7 aryl rings. The effect of substituents directly attached to the para carbon atom of the DPN moiety have been also studied. We found that the HOMO->LUMO vertical transitions can indeed be modified by the nature of the aromatic substituents in order to provoke dramatic changes in the electronic properties (i.e., in the absorption spectra) of the studied species. PMID- 21557347 TI - A foldamer at the liquid/graphite interface: the effect of interfacial interactions, solvent, concentration, and temperature. AB - The unfolding process and self-assembly of a foldable oligomer (foldamer 1) at the liquid/graphite interface were investigated by scanning tunnelling microscopy. At the level of molecular conformation, we identified several molecular conformations (A(z), B, C, D, E) that represent intermediate states during unfolding, which may help to elucidate the unfolding process at the liquid/graphite interface. Adsorption at the interface traps the intermediate states of the unfolding process, and STM has proved to be a powerful technique for investigating folding and unfolding of a foldamer at the molecular level, which are not accessible by other methods. The STM observations also revealed that varying the solvent and/or concentration results in different self assemblies of foldamer 1 as a result of variations in molecular conformations. The solvent and concentration effects were attributed to the changes in existing states (extended or folded) of foldamers in solution, which in turn affect the distribution of adsorbed molecular conformations at the interface. This mechanism is quite different from other systems in which solvent and concentration effects were also observed. PMID- 21557348 TI - Oligo(p-phenylene-ethynylene)s with backbone conformation controlled by competitive intramolecular hydrogen bonds. AB - A series of conjugated oligo(p-phenylene-ethynylene) (OPE) molecules with backbone conformations (that is, the relative orientations of the contained phenylene units) controlled by competitive intramolecular hydrogen bonds to be either co-planar or random were synthesised and studied. In these oligomers, carboxylate and amido substituents were attached to alternate phenylene units in the OPE backbone. These functional groups were able to form intramolecular hydrogen bonds between neighbouring phenylene units. Thereby, all phenylene units in the backbone were confined in a co-planar conformation. This planarised structure featured a more extended effective conjugation length than that of regular OPEs with phenylene units adopting random orientation due to a low rotational-energy barrier. However, if a tri(ethylene glycol) (Tg) side chain was appended to the amido group, it enabled another type of intramolecular hydrogen bond, formed by the Tg chain folding back and the contained ether oxygen atom competing with the ester carbonyl group as the hydrogen-bond acceptor. The outcome of this competition was proven to depend on the length of the alkylene linker joining the ether oxygen atom to the amido group. Specifically, if the Tg chain folded back to form a five-membered cyclic structure, this hydrogen-bonding motif was sufficiently robust to overrule the hydrogen bonds between adjacent phenylene units. Consequently, the oligomers assumed non-planar conformations. However, if the side chain formed a six-membered ring by hydrogen bonding with the amido NH group, such a motif was much less stable and yielded in the competition with the ester carbonyl group from the adjacent phenylene unit. Thus, the hydrogen bonds between the phenylene units remained, and the co-planar conformation was manifested. In our system, the hydrogen bonds formed by the back folded Tg chain and amido NH group relied on a single oxygen atom as the hydrogen bond acceptor. The additional oxygen atoms in the Tg chain made a negligible contribution. A bifurcated hydrogen-bond motif was unimportant. From our results, in combination with the results from an independent study by Meijer et al., it is evident that intramolecular hydrogen bonds involving back-folded oligo(ethylene glycol) moieties may differ in their structural details. Absorption spectroscopy served as a convenient yet sensitive technique for analysing hydrogen-bonding motifs in our study. PMID- 21557349 TI - Uptake of liquid alcohols by the flexible Fe(III) metal-organic framework MIL-53 observed by time-resolved in situ X-ray diffraction. AB - A comprehensive, time-resolved, energy-dispersive X-ray diffraction study of the uptake of liquid alcohols (methanol, ethanol, propan-1-ol and propan-2-ol) by the flexible metal-organic framework solid MIL-53(Fe)[H(2)O] is reported. In the case of the primary alcohols, a fluorinated version of the MIL-53(Fe) host (C2/c symmetry V ca. 1000 A(3)), in which a fraction of framework hydroxides are replaced by fluoride, shows uptake of alcohols to give initially a partially expanded phase (C2/c symmetry, V ca. 1200 A(3)) followed by an expanded form of the material (either Imcm or Pnam symmetry, V ca. 1600 A(3)). In the case of methanol-water mixtures, the EDXRD data show that the partially open intermediate phase undergoes volume expansion during its existence, before switching to a fully open structure if concentrated methanol is used; analogous behaviour is seen if the initial guest is propan-2-ol, which then is replaced by pyridine, where a continuous shift of Bragg peaks within C2/c symmetry is observed. In contrast to the partially fluorinated materials, the purely hydroxylated host materials show little tendency to stabilise partially open forms of MIL-53(Fe) with primary alcohols and the kinetics of guest introduction are markedly slower without the framework fluorination: this is exemplified by the exchange of water by propan-2-ol, where a partially open C2/c phase is formed in a step-wise manner. Our study defines the various possible pathways of liquid-phase uptake of molecular guests by flexible solid MIL-53(Fe). PMID- 21557350 TI - One-dimensional magnetic nanowires obtained by protein fibril biotemplating. AB - Magnetic nanowires were obtained through the in situ synthesis of magnetic material by Fe-controlled nanoprecipitation in the presence of two different protein (human serum albumin (HSA) and lysozyme (Lys)) fibrils as biotemplating agents. The structural characteristics of the biotemplates were transferred to the hybrid magnetic wires. They exhibited excellent magnetic properties as a consequence of the 1D assembly and fusion of magnetite nanoparticles as ascertained by SQUID magnetometry. Prompted by these findings, we also checked their potential applicability as MRI contrast agents. The magnetic wires exhibited large r(2)* relaxivities and sufficient contrast resolution even in the presence of an extremely small amount of Fe in the magnetic hybrids, which would potentially enable their use as T(2) contrast imaging agents. PMID- 21557351 TI - Synthesis and characterization of red-luminescent graphene oxide functionalized with silica-coated Eu3+ complex nanoparticles. AB - Traditional dye-doped fluorescent graphene oxide (GO) reveals a low quantum yield and a short life expectancy. Herein, red-luminescent silica-coated Eu(3+) complex nanoparticles were synthesized and covalently coupled to GO nanosheets by means of a carbodiimide-mediated amidation process. SEM and TEM studies demonstrated successful attachment of the silica-coated Eu(3+) complex nanoparticles onto the GO surface. Spectroscopic studies showed that the GO-nanoparticle conjugates exhibit strong luminescence, long lifetimes, as well as good photostability, which suggests that this new type of luminescent nanomaterial has the potential for highly sensitive time-resolved fluorescence cyto- and histochemistry imaging. PMID- 21557352 TI - Multiplex detection of endonucleases by using a multicolor gold nanobeacon. AB - A highly sensitive and selective assay based on a novel enzyme-responsive multicolor gold nanobeacon has been developed for the multiplex detection of endonucleases, a group of very important nucleases. The nanobeacon takes advantage of the high specificity of DNA cleavage reactions combined with the unique fluorescence-quenching property of gold nanoparticles (AuNPs). To prepare the nanobeacon, three hairpin DNA reporters, each labeled at the 5' terminus with a fluorescent dye (i.e., fluorescein amidite (FAM), carboxy-X-rhodamine (ROX), cyanine dye (Cy5)), that respond to one of three different endonucleases are co assembled at the surface of AuNPs (15 nm). This assembly brings the dyes into very close proximity with the AuNP, which leads to significant quenching of the fluorescence due to the nanosurface energy-transfer (NSET) effect. When the nanobeacon is exposed to the targeted endonucleases, specific DNA cleavage occurs and pieces of DNA fragments are released from the AuNP surface along with the fluorescent dye, which results in the fluorescence recovery that provides the basis for a quantitative measurement of endonuclease activity. Three endonucleases, namely HaeIII, EcoRI, and EcoRV, were studied as the proof-of concept analytes. These endonucleases in homogeneous mixture solutions were simultaneously quantified by the proposed assay with high sensitivity and specificity. The limits of detection obtained were in the range of 5.0*10(-4) U mL(-1) to 1.0*10(-3) U mL(-1) of endonuclease; these limits are at least 100 times more sensitive than the previously reported endonuclease assays. Endonuclease inhibitors impair the DNA cleavage, so it is anticipated that the present method has great potential for screening inhibitors of endonucleases. To demonstrate this application, the inhibitory effects of certain anticancer drugs on HaeIII, EcoRI, and EcoRV activities were studied. The present protocol proved to be sensitive, reliable, and easy to carry out. PMID- 21557353 TI - Palladium-catalyzed direct arylations of azoles with aryl silicon and tin reagents. PMID- 21557354 TI - Gram-scale synthesis of iejimalide B. AB - Iejimalide B (2) is the most promising member of a small family of marine polyene macrolides endowed with remarkably selective activity against human cancer cell lines. As this product, however, is hardly available from the natural sources, a detailed evaluation requires the development of an efficient and practical synthetic approach. This challenge has now been met by adapting the first total synthesis of 2 previously reported by our group to the needs of high material throughput. Redesigning the access routes to the five required building blocks in combination with a careful optimization of the fragment coupling processes provided gram amounts of this valuable compound in a sequence of no more than 16 linear steps with an overall yield of about 7%. Key elements of the successful strategy include: i) three hydrostannylation processes of elaborate terminal alkynes with "lower order" stannyl cuprates, ii) a Brown allylation, a Noyori transfer hydrogenation, and a Marshall propargylation to set the chiral centers at C9, C17, C22 and C23, and iii) a modified Takai-Utimoto olefination for the preparation of the very labile skipped 1,4-diene flanking the ester group. The assembly process benefited from a particularly mild protocol for the Stille cross coupling previously developed in this laboratory, which clearly outperformed the alternative Suzuki reaction in terms of yield and scalability. The 24-membered macrocyclic frame was forged by a remarkably selective ring-closing metathesis reaction (RCM), in which two out of the ten double bonds present in the cyclization precursor were selectively activated with the aid of a second generation Grubbs catalyst. PMID- 21557355 TI - Molecular editing and assessment of the cytotoxic properties of iejimalide and progeny. AB - Systematic variation of all substructures embedded into the framework of iejimalide B (2) led to a panel of synthetic analogues of this polyunsaturated macrolide, featuring structural modifications that are not accessible by derivatization of the natural lead compound itself. The assessment of the cytotoxicity of these compounds with the aid of a monolayer proliferation assay (12 human tumor cell lines in vitro) as well as a colony formation assay (24 human tumor xenografts ex vivo) revealed the exceptional potency of 2 and several of its synthetic congeners, with IC(50) values in the picomolar range for the most sensitive cell lines. Whereas structural modifications of the macrocycle or of the side chain generally lead to a decrease in activity, changes of the peptidic terminus are not only well accommodated but engender increased tumor selectivity as well. 2 and two of the most promising analogues were selected for in vivo studies in mice, in which their activity against human tumor xenografts of breast cancer (MAXF 401) and prostate cancer (PRXF PC-3M) was tested. In contrast to a previous report in the literature however, which had claimed in vivo activity for the parent iejimalides, these tests did not show a significant therapeutic effect against the chosen solid tumors upon intraperitoneal administration. PMID- 21557356 TI - Synthesis, characterisation and application of iridium(III) photosensitisers for catalytic water reduction. AB - The synthesis of novel, monocationic iridium(III) photosensitisers (Ir-PSs) with the general formula [Ir(III)(C^N)(2)(N^N)](+) (C^N: cyclometallating phenylpyridine ligand, N^N: neutral bidentate ligand) is described. The structures obtained were examined by cyclic voltammetry, UV/Vis and photoluminescence spectroscopy and X-ray analysis. All iridium complexes were tested for their ability as photosensitisers to promote homogeneously catalysed hydrogen generation from water. In the presence of [HNEt(3)][HFe(3)(CO)(11)] as a water-reduction catalyst (WRC) and triethylamine as a sacrificial reductant (SR), seven of the new iridium complexes showed activity. [Ir(6-iPr-bpy)(ppy)(2)]PF(6) (bpy: 2,2'-bipyridine, ppy: 2-phenylpyridine) turned out to be the most efficient photosensitiser. This complex was also tested in combination with other WRCs based on rhodium, platinum, cobalt and manganese. In all cases, significant hydrogen evolution took place. Maximum turnover numbers of 4550 for this Ir-PS and 2770 for the Fe WRC generated in situ from [HNEt(3)][HFe(3)(CO)(11)] and tris[3,5-bis(trifluoromethyl)phenyl]phosphine was obtained. These are the highest overall efficiencies for any Ir/Fe water-reduction system reported to date. The incident photon to hydrogen yield reaches 16.4% with the best system. PMID- 21557357 TI - Chiral ionic liquid/ESI-MS methodology as an efficient tool for the study of transformations of supported organocatalysts: deactivation pathways of Jorgensen Hayashi-type catalysts in asymmetric Michael reactions. AB - The deactivation pathways of Jorgensen-Hayashi-type organocatalysts modified with an ionic liquid fragment in asymmetric Michael reactions of alpha,beta-enals with C- (nitromethane, dimethylmalonate) or N-nucleophiles (N carbobenzyloxyhydroxylamine) that involved an iminium-ion formation step were studied for the first time by the electrospray ionization mass spectrometry (ESI MS). "Parasitic" side reactions and undesirable cation intermediates that poisoned the catalysts were identified in accordance with their m/z values as well as their relation to the reported mechanisms of Michael reactions in the presence of O-TMS-alpha,alpha-diarylprolinol (TMS=trimethylsilyl) derivatives. The proposed approach may be useful for the study of transformations of other types of organocatalysts modified with ionic groups in various organocatalytic reactions and for the development of novel robust catalysts and processes that would be suitable for large-scale industrial applications. PMID- 21557358 TI - Recognition of oxalate by a copper(II) polyaza macrobicyclic complex. AB - A new polyamine macrobicyclic compound was synthesised through a [1+1] "tripod tripod coupling" strategy and using a Schiff base condensation reaction, followed by sodium borohydride reduction. The resulting compound is a heteroditopic cage (btpN(7)) in which one of the head units is appropriate for the coordination of copper(II), whereas the other head is available for additional hydrogen-bonding and electrostatic interactions with substrates. The acid-base behaviour of the new compound, the stability constants of its complex with the Cu(2+) ion and the association constants of the copper(II) cryptate with oxalate (oxa(2-)), malonate (mal(2-)), succinate (suc(2-)), maleate (male(2-)) and fumarate (fum(2-)) were determined by potentiometry at 298.2 K in aqueous solution and at an ionic strength of 0.10 mol dm(-3) in KNO(3). These studies revealed a clear preference of the receptor [CuH(h)btpN(7)H(2)O]((2+h)+) for oxa(2-) over the other dicarboxylate substrates. This arises from co-operativity between metal-anion coordination and electrostatic and hydrogen-bonding interactions, in accordance with the ideal size of this dicarboxylate, which allow it to take full advantage of the potential binding sites of the receptor. A qualitative indicator displacement study, in agreement with the potentiometric studies, demonstrated that the copper cryptate receptor can be used as a selective visual sensor for oxalate. PMID- 21557359 TI - Structural investigation and biological activity of the lipooligosaccharide from the psychrophilic bacterium Pseudoalteromonas haloplanktis TAB 23. AB - Pseudoalteromonas haloplanktis TAB 23 is a Gram-negative psychrophilic bacterium isolated from the Antarctic coastal sea. To survive in these conditions psychrophilic bacteria have evolved typical membrane lipids and "antifreeze" proteins to protect the inner side of the microorganism. As for Gram-negative bacteria, the outer membrane is mainly constituted by lipopoly- or lipooligosaccharides (LPS or LOS, respectively), which lean towards the external environment. Despite this, very little is known about the peculiarity of LPS from Gram-negative psychrophilic bacteria and what their role is in adaptation to cold temperature. Here we report the complete structure of the LOS from P. haloplanktis TAB 23. The lipid A was characterized by MALDI-TOF MS analysis and was tested in vitro showing a significant inhibitory effect on the LPS-induced pro-inflammatory cytokine production when added in culture with LPS from Escherichia coli. The product obtained after de-O-acylation of the LPS was analyzed by MALDI-TOF MS revealing the presence of several molecular species, differing in phosphorylation degree and oligosaccharide length. The oligosaccharide portion released after strong alkaline hydrolysis was purified by anion-exchange chromatography-pulsed amperometric detection (HPAEC-PAD) to give three main fractions, characterized by means of 2D NMR spectroscopy, which showed a very short highly phosphorylated saccharidic chain with the following general structure. alpha-Hepp3R,6R,4R'-(1->5)-alpha-Kdop4P-(2->6)-beta-GlcpN4R-(1->6) alpha-GlcpN1P (R=-H(2)PO(3) or -H; R'=alpha-Galp-(1->4)-beta-Galp-(1-> or H-). PMID- 21557360 TI - Chromogenic, specific detection of the nerve-agent mimic DCNP (a tabun mimic). PMID- 21557361 TI - Pd-catalyzed [2+2+1] coupling of alkynes and arenes: phenol diazonium salts as mechanistic trapdoors. AB - Alkynes and phenol diazonium salts undergo a Pd-catalyzed [2+2+1] cyclization reaction to spiro[4,5]decatetraene-7-ones. This structure was confirmed for one example by X-ray single-crystal structure analysis. The reaction is believed to proceed through oxidative addition of the phenol diazonium cation to Pd(0), subsequent insertion of two alkynes, followed by irreversible spirocyclization. PMID- 21557362 TI - Nanometer-sized reactor--a porphyrin-based model system for anion species. AB - Although many cagelike molecules can create a catalytic environment for promoting chemical reactions, the construction of receptors that can host anionic species and sensitize their reaction is novel. Here we report the photochemically induced dimerization of the anion radicals of TCNQ (7,7,8,8-tetracyano-para quinodimethane) in organic solvent under aerobic conditions when they are encapsulated inside a cationic photoactive receptor. There is clear evidence for a rate increase of over two orders of magnitude, photosensitization of the host, and demonstrated turnover of the catalyst. PMID- 21557363 TI - Hydrolysis of a basic bismuth nitrate--formation and stability of novel bismuth oxido clusters. AB - The synthesis of the nanoscaled bismuth oxido clusters [Bi(38)O(45)(NO(3))(20)(DMSO)(28)](NO(3))(4).4DMSO (1a) and [Bi(38)O(45)(OH)(2)(pTsO)(8)(NO(3))(12)(DMSO)(24)](NO(3))(2).4DMSO.2H(2)O (2) starting from the basic bismuth nitrate [Bi(6)O(4)(OH)(4)](NO(3))(6).H(2)O is reported herein. Single-crystal X-ray diffraction analysis, ESI mass spectrometry, thermogravimetric analysis, and molecular dynamics simulation were used to study the formation, structure, and stability of these large metal oxido clusters. Compounds 1a and 2 are based on a [Bi(38)O(45)](24+) core, which is structurally related to delta-Bi(2)O(3). Examination of the fragmentation pathways of 1a and 2 by infrared multi-photon dissociation (IRMPD) tandem MS experiments allows the identification of novel bismuth oxido cluster species in the gas phase. PMID- 21557364 TI - Luminescent, colloidal, F-substituted, hydroxyapatite nanocrystals. PMID- 21557365 TI - An unsupported uranium-rhenium complex prepared by alkane elimination. PMID- 21557366 TI - Catalyst-free regio- and stereospecific synthesis of beta-sulfonamido dithiocarbamates: efficient ring-opening reactions of N-tosyl aziridines by dialkyldithiocarbamates. PMID- 21557367 TI - Inhibition of preadipocyte differentiation and lipid accumulation by Orengedokuto treatment of 3T3-L1 cultures. AB - Obesity is a major cause of metabolic syndrome and is due to an increase in the number and hypertrophy of adipocytes. Accordingly, inhibition of the differentiation and proliferation of adipocytes may be used in the treatment and prevention of metabolic syndrome. This study investigated the effects of 50 commonly used Kampo medicines on the differentiation of 3T3-L1 preadipocytes to search for a drug with an antiobesity effect. Kampo medicines were screened, and the strongest differentiation-inhibitory effect was noted with Orengedokuto. To explore the active ingredients in Orengedokuto, the effects of four crude drug components of Orengedokuto were investigated. It was found that the differentiation-inhibitory effect of Orengedokuto was accounted for by Coptidis rhizome and Phellodendri cortex. Furthermore, berberine, a principal ingredient common to Coptidis rhizome and Phellodendri cortex, showed a differentiation inhibitory effect. The effect of berberine involves an inhibition of the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha). Moreover, berberine inhibited lipid accumulation in adipocytes. These findings suggest that an antiobesity effect could be a new indication for Orengedokuto and that its active ingredient is berberine, with a mechanism involving the inhibition of PPARgamma and C/EBPalpha expression. PMID- 21557368 TI - Effect of contrast agent on the results of in vivo 1H MRS of breast tumors - is it clinically significant? AB - Choline (Cho) signal identification and quantification in (1)H MRS are used in breast cancer diagnosis. However, an influence of the gadolinium-based contrast agent on the Cho amplitude has been reported experimentally. This study aims to identify the impact of gadolinium-based contrast agents on Cho detection and quantification in postcontrast breast MRS. Consecutive patients were recruited prospectively and randomly allocated to two groups. Group A received a neutral (gadolinium diethylenetriaminepentaacetic acid bis-methylamide) and group B an ionic (gadolinium diethylenetriaminepentaacetic acid) contrast agent, each at a dosage of 0.1 mmol/kg. First, the presence of Cho was identified visually. Then, the normalized Cho intensity in malignant lesions was quantified. Multivariate analysis was applied to identify independent influencing factors on Cho. Sixty three lesions were investigated [A, n = 34; B, n = 29; 43 malignant (one bilaterally malignant), 20 benign]. Cho was identified visually in 14 of 20 malignant tumors in group A and 12 of 22 malignant tumors in group B (p = 0.477). Normalized Cho differed significantly (p = 0.001) between groups A (mean, 26.8 +/ 6.0 AU) and B (mean, 18.2 +/- 12.5 AU). No linewidth differences were identified (p > 0.05). Multivariate analysis revealed only group membership (A versus B) as an independent predictor of Cho (p = 0.017). The results suggest stronger negative effects of an ionic relative to a neutral gadolinium-based contrast agent on breast tumor MRS in vivo. These results should be considered when conducting and comparing quantitative Cho measurements in the breast. PMID- 21557369 TI - Neurobehavioral outcomes in preterm, growth-restricted infants with and without prenatal advanced signs of brain-sparing. AB - OBJECTIVE: To evaluate the neurobehavioral outcomes of preterm infants with intrauterine growth restriction (IUGR), with and without prenatal advanced brain sparing. METHODS: A cohort of IUGR infants (birth weight < 10(th) percentile with abnormal umbilical artery Doppler) born before 34 weeks of gestation was compared with a control group of appropriate-for-gestational age infants matched for gestational age at delivery. MCA pulsatility index was determined in all cases within 72 hours before delivery. Neonatal neurobehavior was evaluated at 40 weeks' ( +/- 1) corrected age using the Neonatal Behavioral Assessment Scale. The effect of abnormal MCA pulsatility index (< 5(th) percentile) on each neurobehavioral area was adjusted for maternal smoking status and socioeconomic level, mode of delivery, gestational age at delivery, pre-eclampsia, newborn illness severity score and infant sex by multiple linear and logistic regression. RESULTS: A total of 126 preterm newborns (64 controls and 62 IUGR) were included. Among IUGR fetuses, the proportion of abnormal MCA Doppler parameters was 53%. Compared with appropriate-for-gestational age infants, newborns in the IUGR subgroup with abnormal MCA Doppler had significantly lower neurobehavioral scores in the areas of habituation, motor system, social-interactive and attention. Similarly, the proportion of infants with abnormal neurobehavioral scores was significantly higher in the IUGR subgroup with abnormal MCA Doppler parameters in the areas of habituation, social-interactive, motor system and attention. CONCLUSION: Abnormal MCA Doppler findings are predictive of neurobehavioral impairment among preterm newborns with IUGR, which suggests that this reflects an advanced stage of brain injury with a higher risk of abnormal neurological maturation. PMID- 21557370 TI - Evaluation of an objective method of image assessment for first-trimester nasal bone. AB - OBJECTIVE: To evaluate the degree of agreement in first-trimester nasal bone assessment in a group of sonographers before and after training, using a semi quantitative scoring system. METHODS: Four sonographers who routinely perform first-trimester screening were first shown 46 images from both normal and trisomy 21 pregnancies. For each image, they were asked to score from 0 (disagree) to 3 (agree) on five different criteria that were deemed important in nasal-bone assessment, including image size, plane and visibility of nasal bone. A training program was then conducted, and a repeat exercise was carried out using the same 46 images. Finally, in a third exercise, images from 42 patients were presented, some having more than one image. The sonographers were required to give one overall nasal-bone score for each patient. In each exercise interobserver agreement was evaluated by intraclass correlation coefficient (ICC). RESULTS: Before training, the sonographers agreed reasonably well on the five proposed criteria (ICC, 0.752), with some disagreement on their perceived image quality. The training program further improved the agreement (ICC, 0.790), particularly on whether the nasal bone was the biggest and brightest echogenic component. Agreement was excellent when they were asked to give one overall score on the nasal bone based on multiple images from one patient (ICC, 0.929). CONCLUSION: The proposed scoring system can be used to improve consistency and reliability in first-trimester nasal-bone assessment. PMID- 21557371 TI - Effect of gel-instillation sonography on Doppler ultrasound findings in endometrial polyps. AB - OBJECTIVE: Saline infusion sonohysterography has been reported to suppress the color signal within the endometrium at color or power Doppler evaluation. The aim of this study was to evaluate if gel-instillation sonography (GIS) affects the power Doppler signal in patients with endometrial polyps. METHODS: Ultrasound volumes of the uterus, obtained by three-dimensional ultrasound imaging of 25 women with histologically confirmed endometrial polyps, were assessed offline by six gynecologists with a special interest in gynecological ultrasound. Each woman contributed four volumes: one gray-scale volume and one power Doppler volume before GIS, and one gray-scale volume and one power Doppler volume at GIS. Power Doppler features before and after gel infusion were compared. RESULTS: At unenhanced ultrasound a pedicle artery was seen in 27-46% of cases, whereas, after gel infusion the examiners reported a pedicle artery in 30-46% of cases (Exact McNemar's test P-values ranged from 0.50 to 1.00). The level of agreement between unenhanced ultrasound and GIS ranged from 59 to 91% (Cohen's kappa values ranged from 0.17 to 0.79). There was no tendency for a pedicle artery to be identified less often at GIS than before gel instillation. CONCLUSION: Gel infusion does not affect the power Doppler signal in patients with endometrial polyps. PMID- 21557372 TI - Left-right difference in fetal liver oxygenation during hypoxia estimated by BOLD MRI in a fetal sheep model. AB - OBJECTIVE: The purpose of this study was to measure differences in oxygenation between the left and right sides of the fetal liver during varying oxygenation levels. METHODS: Eight ewes carrying singleton fetuses at gestational age 125 days (term, 145 days) were included in the study. Under anesthesia the ewes were ventilated with gas containing different levels of oxygen, thereby subjecting the fetuses to hyperoxia (mean +/- SD maternal arterial partial pressure of oxygen (pO2), 23.2 +/- 8.2 kPa) and hypoxia (mean maternal arterial pO2, 7.1 +/- 0.5 kPa). Changes in oxygenation within the fetal liver were assessed by blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). RESULTS: During hyperoxia there was no difference between the BOLD signal in the left and right sides of the fetal liver; mean change in BOLD (DeltaBOLD)(hyperox), -0.9 +/- 3.7%. During hypoxia, however, the decrease in the BOLD signal was more pronounced in the right side as compared with the left side, thereby creating a significant increase in the left-right difference in the BOLD signal; mean DeltaBOLD(hypox), 5.2 +/- 2.2% (P = 0.002, paired t-test). The left-right difference was directly proportional to the degree of hypoxia (R2 = 0.86, P = 0.007). CONCLUSIONS: To our knowledge, this is the first study demonstrating differences in oxygenation between the left and right sides of the fetal liver during hypoxia, a difference that can be explained by increased ductus venosus shunting. Thus, the BOLD MRI technique is a promising non-invasive tool that might be useful for the future monitoring of the human fetus. PMID- 21557373 TI - Four-vessel umbilical cord. PMID- 21557374 TI - Fetal hemodynamic development in macrosomic growth. AB - OBJECTIVE: To determine the venous and arterial hemodynamics underlying macrosomic fetal growth. METHODS: Fifty-eight healthy women who previously had given birth to a large neonate were included in a prospective longitudinal study. Of these, 29 gave birth to neonates with birth weight >= 90th percentile and were included in the statistical analysis. Umbilical vein blood flow and Doppler measurements of the ductus venosus, left portal vein and the hepatic, splenic, superior mesenteric, cerebral and umbilical arteries were repeated at 3-5 examinations during the second half of pregnancy and compared with the corresponding reference values. Ultrasound biometry was used to estimate fetal weight. RESULTS: Umbilical blood flow increased faster in macrosomic fetuses, showed less blunting near term and was also significantly higher when normalized for estimated fetal weight (P < 0.0001). The portocaval perfusion pressure of the liver (expressed by the ductus venosus systolic blood velocity) and the left portal vein blood velocity (expressing umbilical venous distribution to the right liver lobe) were significantly higher. Systolic velocity was higher in the splenic, superior mesenteric, cerebral and umbilical arteries, while the pulsatility index was unaltered in the cerebral, hepatic, splenic and mesenteric arteries, but lower in the umbilical artery. CONCLUSIONS: There is an augmented umbilical flow in macrosomic fetuses particularly near term, also when normalized for estimated fetal weight, providing increased liver perfusion, including the right liver lobe. Signs of increased vascular cross section and flow are also seen on the arterial side but not expressed in the pulsatility index of organs with prominent auto-regulation (i.e., brain, liver, spleen and gut). PMID- 21557375 TI - An anti-hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop. AB - Conventional anti-hapten antibodies typically bind low-molecular weight compounds (haptens) in the crevice between the variable heavy and light chains. Conversely, heavy chain-only camelid antibodies, which lack a light chain, must rely entirely on a single variable domain to recognize haptens. While several anti-hapten VHHs have been generated, little is known regarding the underlying structural and thermodynamic basis for hapten recognition. Here, an anti-methotrexate VHH (anti MTX VHH) was generated using grafting methods whereby the three complementarity determining regions (CDRs) were inserted onto an existing VHH framework. Thermodynamic analysis of the anti-MTX VHH CDR1-3 Graft revealed a micromolar binding affinity, while the crystal structure of the complex revealed a somewhat surprising noncanonical binding site which involved MTX tunneling under the CDR1 loop. Due to the close proximity of MTX to CDR4, a nonhypervariable loop, the CDR4 loop sequence was subsequently introduced into the CDR1-3 graft, which resulted in a dramatic 1000-fold increase in the binding affinity. Crystal structure analysis of both the free and complex anti-MTX CDR1-4 graft revealed CDR4 plays a significant role in both intermolecular contacts and binding site conformation that appear to contribute toward high affinity binding. Additionally, the anti-MTX VHH possessed relatively high specificity for MTX over closely related compounds aminopterin and folate, demonstrating that VHH domains are capable of binding low-molecular weight ligands with high affinity and specificity, despite their reduced interface. PMID- 21557376 TI - Structural and enzymatic characterization of NanS (YjhS), a 9-O-Acetyl N acetylneuraminic acid esterase from Escherichia coli O157:H7. AB - There is a high prevalence of sialic acid in a number of different organisms, resulting in there being a myriad of different enzymes that can exploit it as a fermentable carbon source. One such enzyme is NanS, a carbohydrate esterase that we show here deacetylates the 9 position of 9-O-sialic acid so that it can be readily transported into the cell for catabolism. Through structural studies, we show that NanS adopts a SGNH hydrolase fold. Although the backbone of the structure is similar to previously characterized family members, sequence comparisons indicate that this family can be further subdivided into two subfamilies with somewhat different fingerprints. NanS is the founding member of group II. Its catalytic center contains Ser19 and His301 but no Asp/Glu is present to form the classical catalytic triad. The contribution of Ser19 and His301 to catalysis was confirmed by mutagenesis. In addition to structural characterization, we have mapped the specificity of NanS using a battery of substrates. PMID- 21557377 TI - A profile of patients with hyperparathyroidism undergoing lithium therapy for affective psychiatric disorders. AB - BACKGROUND: Our objective was to evaluate whether lithium-induced hyperparathyroidism (LIHPT) is caused by single-gland versus multigland disease. METHODS: Medical records of 7 patients who underwent parathyroidectomy for LIHPT were reviewed. RESULTS: The mean preoperative calcium was 11.1 +/- 0.7 mg/dL. Six of 7 patients were rendered eucalcemic with surgery. Of the 6 patients successfully treated with surgery, 4 had single-gland disease, 1 had double adenomas, and 1 had 4-gland hyperplasia. Intraoperative intact serum parathyroid hormone (iPTH) accurately predicted resolution of hyperparathyroidism in 6 of 7 patients. One patient then subsequently developed persistent hyperparathyroidism refractory to further surgery. Localization studies defined the extent of disease in 5 of 7 patients. CONCLUSION: LIHPT presents with a spectrum of disease ranging from single-gland to multigland disease. The utility of preoperative localization studies and intraoperative iPTH in this population is uncertain. Bilateral exploration may be best to achieve a resolution of LIHPT. PMID- 21557378 TI - The predictive validity of subjective adherence measures in patients with schizophrenia. AB - Despite frequent use of subjective adherence measures in patients with schizophrenia as well as other chronic conditions, there are several reports that question the validity of these instruments. Three well known, representative subjective measures are the Medication Adherence Questionnaire (MAQ), the Drug Attitude Inventory (DAI), and the Compliance Rating Scale (CRS). In this study we explored the predictive validity of these instruments in a European sample of 119 stabilized outpatients with schizophrenia. Clinical outcome variables were relapse and admission to a psychiatric hospital during a follow-up period of 12 months. Results indicate that the predictive validity of all three measures was poor. The MAQ was the least problematic predictor for relapse (Nagelkerke R(2) = 0.09), and time to relapse (R(2) = 0.07) and had the best sensitivity for relapse (63.6%) as well as admission (87.5%). The MAQ and CRS were both moderate predictive for admission (Nagelkerke R(2) = 0.21, and R(2) = 0.29). We conclude that the validity of the instruments studied here is questionable and have limited clinical relevance. Given the feasibility and ease of most subjective instruments, researchers may be tempted to use them but should be aware of the serious drawbacks of these instruments. PMID- 21557379 TI - Childhood maltreatment and internalized shame in adults with a diagnosis of bipolar disorder. AB - Relatively little is understood regarding the aetiology of bipolar disorder (BD) other than for the influence of a large genetic component on the development of the disorder and the impact of stressful life events on changes in current mood. However, amongst a range of psychiatric diagnoses, research consistently demonstrates a higher frequency of reports of childhood abuse and neglect compared with individuals in the general population. In addition, those who report experiences of childhood maltreatment also report high levels of internalized shame in adulthood, although there is little research demonstrating this association amongst clinical populations. An adult sample of 35 participants with a diagnosis of BD and a control group of 35 participants with no psychiatric diagnoses completed measures of childhood abuse and neglect, and internalized shame. Participants in the BD group reported a significantly greater frequency of high levels of childhood trauma compared with participants in the control group, with the reported frequency of childhood emotional abuse and neglect being particularly high. Levels of current internalized shame were also significantly higher amongst participants in the BD group. Significant correlations were observed between current internalized shame and reports of childhood emotional abuse and neglect. Clinical implications of the study's findings are discussed, and limitations of the methodology are considered. KEY PRACTITIONER MESSAGE: The frequency of reports of childhood trauma would appear to be higher amongst adults with a diagnosis of BD compared with individuals with no psychiatric diagnoses. Levels of internalized shame in adulthood are also likely to be higher than those in the general population, although the current literature does not shed light on the relationship between childhood abuse and neglect, mood-related behaviour, and shame. Experiences of childhood abuse and neglect, particularly childhood emotional abuse and emotional neglect, are likely to be frequently reported by clients with a diagnosis of BD. Clinicians should therefore explicitly consider these experiences in their assessment, formulation and intervention with clients with a diagnosis of BD. PMID- 21557380 TI - Quantile regression analysis of body mass and wages. AB - Using the National Longitudinal Survey of Youth 1979, we explore the relationship between body mass and wages. We use quantile regression to provide a broad description of the relationship across the wage distribution. We also allow the relationship to vary by the degree of social skills involved in different jobs. Our results find that for female workers body mass and wages are negatively correlated at all points in their wage distribution. The strength of the relationship is larger at higher-wage levels. For male workers, the relationship is relatively constant across wage distribution but heterogeneous across ethnic groups. When controlling for the endogeneity of body mass, we find that additional body mass has a negative causal impact on the wages of white females earning more than the median wages and of white males around the median wages. Among these workers, the wage penalties are larger for those employed in jobs that require extensive social skills. These findings may suggest that labor markets reward white workers for good physical shape differently, depending on the level of wages and the type of job a worker has. PMID- 21557381 TI - Using qualitative methods for attribute development for discrete choice experiments: issues and recommendations. AB - Attribute generation for discrete choice experiments (DCEs) is often poorly reported, and it is unclear whether this element of research is conducted rigorously. This paper explores issues associated with developing attributes for DCEs and contrasts different qualitative approaches. The paper draws on eight studies, four developed attributes for measures, and four developed attributes for more ad hoc policy questions. Issues that have become apparent through these studies include the following: the theoretical framework for random utility theory and the need for attributes that are neither too close to the latent construct nor too intrinsic to people's personality; the need to think about attribute development as a two-stage process involving conceptual development followed by refinement of language to convey the intended meaning; and the difficulty in resolving tensions inherent in the reductiveness of condensing complex and nuanced qualitative findings into precise terms. The comparison of alternative qualitative approaches suggests that the nature of data collection will depend both on the characteristics of the question (its sensitivity, for example) and the availability of existing qualitative information. An iterative, constant comparative approach to analysis is recommended. Finally, the paper provides a series of recommendations for improving the reporting of this element of DCE studies. PMID- 21557382 TI - Economic consequences of maternal illness in rural Bangladesh. AB - We use panel data on household consumption combined with information taken from the medical records of women who gave birth in health facilities to explore the economic consequences of maternal ill health, in the context of a rural population in Bangladesh. The findings suggest that there is a large reduction in household resources associated with maternal illness, driven almost entirely by spending on health care. In spite of this loss of resources, we find that households are able to fully insure consumption against maternal ill health, although confidence intervals are unable to rule out a small effect. Households in our study area are shown to have good access to informal credit (whether it be from local money lenders or family relatives), and this appears critical in helping to smooth consumption in response to these health shocks, at least in the short term. PMID- 21557383 TI - What is a 'secure base' when death is approaching? A study applying attachment theory to adult patients' and family members' experiences of palliative home care. AB - OBJECTIVE: Attachment theory has received much interest lately in relation to how adults cope with stress and severe illness. The aim of this study was using the experiences of patients and family members to explore palliative home care as a 'secure base' (a central concept within the theory). METHODS: Twelve patients and 14 family members were interviewed during ongoing palliative home care. The interviews were analysed with deductive qualitative content analysis. RESULTS: Informants expressed the relevance of sensing security during palliative home care because death and dying were threats that contributed to vulnerability. Palliative home care could foster a feeling of security and provide a secure base. This was facilitated when informants had trust in staff (e.g. due to availability and competence in providing symptom relief), felt recognised as individuals and welcomed to contact the team in times of needs. Being comfortable, informed and having an everyday life also contributed to a perception of palliative home care as a secure base. Family members stressed the importance of being relieved from responsibilities that were too heavy. The underlying meanings of experiencing palliative home care as a secure base involved gaining a sense of control and of inner peace, perceiving that despite a demanding and changed life situation, one could continue partially being oneself and having something to hope for, even if this no longer concerned cure for the ill person. CONCLUSIONS: Important aspects of palliative home care as providing a secure base were identified and these have implications for clinical practice. PMID- 21557384 TI - Examining the role of trauma, personality, and meaning in young prolonged grievers. AB - PURPOSE: Younger spouses or partners have been understudied in the prolonged grief literature. The purpose of this study was to determine rates of prolonged grief in young spouses or partners and the associations between prolonged grief and personality styles (specifically, narcissistic, histrionic, and obsessive), trauma history, and the perceived meaning of the loss in the young conjugally bereaved. PARTICIPANTS AND METHOD: Participants between 20 and 50 years old who lost a spouse/partner to cancer 6 months-3 years prior to the study completed the following measures during one time point (via phone or in person interviews): Prolonged Grief-13, traumatic life events questionnaire, Millon clinical multiaxial inventory-III, and grief meaning reconstruction inventory. RESULTS: Fifty-six spouses and partners (51.8% women) completed the interviews (mean age: 44.54 +/- 4.20 years). The participants (49.1%) reported elevated rates of prolonged grief and 12.3% of the participants were diagnosed with prolonged grief with the recently published diagnostic algorithm. Bivariate analyses demonstrated an association between prolonged grief and negative meaning of the loss (r = 0.73; p < 0.01) and the frequency of the traumatic events (r = 0.23; p < 0.05). Multivariate analyses revealed that negative meaning of the loss was the only significant predictor of prolonged grief (Beta = 0.71; p = 0.0001). CONCLUSION: Elevated levels of prolonged grief were found in this population, suggesting a need for further research into young spousal grief. Young bereaved spouses may lack flexibility in reconstructing their view of the world as the death may invalidate their previously held world beliefs. PMID- 21557385 TI - Behind closed doors II: systematic analysis of prostate cancer patients' primary treatment consultations with radiation oncologists and predictors of satisfaction with communication. AB - OBJECTIVE: The purpose of this investigation was to explicate the content of primary treatment consultations in prostate oncology and examine the predictive relationships between patient, significant other, and oncologist consultation factors and patient satisfaction with communication. METHODS: The recorded consultations of 156 newly diagnosed prostate cancer patients from three Canadian cancer centers were examined using the Medical Interaction Process System (MIPS). The MIPS findings, independent observer ratings of patient, significant other, and oncologist affective behavior, and derived consultation ratios of patient centeredness, patient directedness, and psychosocial focus, were used to predict patient satisfaction with communication post-consultation and at 12-weeks post consultation. RESULTS: Biomedical content categories were predominant in the consultations, accounting for 86% of utterances, followed by administrative (9%) and psychosocial (5%) utterances. Post-consultation satisfaction with communication was significantly lower for patients whose significant others were rated as more assertive during the consultation, and those rated as more anxious during the consultation. Patients who were rated as more anxious during the consultation, those with lower satisfaction with communication immediately post consultation and those with shorter consultations were significantly less satisfied with communication at 12-weeks post-consultation. CONCLUSIONS: Adjuvant treatment consultations in prostate oncology are characterized by a high degree of information-giving by the physician, a predominance of biomedical discussion, and relatively minimal time addressing patients' psychosocial concerns. Patients may benefit from oncologists who address anxiety and emotional distress during the primary treatment consultation, allowing sufficient time to ensure that patients leave the consultation with their communication needs having been satisfied. PMID- 21557386 TI - Using the 12-item General Health Questionnaire to screen psychological distress from survivorship to end-of-life care: dimensionality and item quality. AB - OBJECTIVES: This study aimed (i) to determine the factor structure of the 12-item General Health Questionnaire (GHQ-12) across the cancer trajectory represented by samples from three cancer care settings and (ii) to appraise the item misfit and differential item functioning (DIF) of the GHQ-12. DATA AND METHODS: Data were from cancer outpatient (n = 200), general community (n = 364) and palliative care (n = 150) settings. The factor structure was tested using exploratory factor analysis followed by confirmatory factor analysis. The factors were assessed for correlation using Spearman's rho. The analyses were run separately for standard GHQ, Likert, modified Likert and chronic GHQ scoring and for the individual cancer settings. The best scoring method within the cancer setting was determined by Akaike's information criterion (AIC). Item misfit (mean square, MNSQ; standardised z-score, ZSTD) and DIF were assessed using the Rasch model. RESULTS: The best scoring method was the chronic GHQ for the cancer outpatient (AIC = 45.8), modified Likert for the general community (AIC = 9.6) and standard GHQ for the palliative care (AIC = -43.0). The GHQ-12 displayed a correlated two-factor structure ('social dysfunction' and 'distress'); Spearman rho values were 0.69, 0.82 and 0.88 in the cancer outpatient, the general community and the palliative care, respectively. One item in the palliative care indicated misfit (MNSQ = 1.62, ZSTD = 3.0). Five items in the cancer outpatient showed DIF by gender and age. Two items in the palliative care showed DIF by gender. CONCLUSIONS: The GHQ 12 was more problematic (less clear factor structure and evidence of item bias) for newly diagnosed patients, less problematic for patients approaching end-of life and satisfactory for patients between those times. PMID- 21557387 TI - Functional brain network efficiency predicts intelligence. AB - The neuronal causes of individual differences in mental abilities such as intelligence are complex and profoundly important. Understanding these abilities has the potential to facilitate their enhancement. The purpose of this study was to identify the functional brain network characteristics and their relation to psychometric intelligence. In particular, we examined whether the functional network exhibits efficient small-world network attributes (high clustering and short path length) and whether these small-world network parameters are associated with intellectual performance. High-density resting state electroencephalography (EEG) was recorded in 74 healthy subjects to analyze graph theoretical functional network characteristics at an intracortical level. Ravens advanced progressive matrices were used to assess intelligence. We found that the clustering coefficient and path length of the functional network are strongly related to intelligence. Thus, the more intelligent the subjects are the more the functional brain network resembles a small-world network. We further identified the parietal cortex as a main hub of this resting state network as indicated by increased degree centrality that is associated with higher intelligence. Taken together, this is the first study that substantiates the neural efficiency hypothesis as well as the Parieto-Frontal Integration Theory (P-FIT) of intelligence in the context of functional brain network characteristics. These theories are currently the most established intelligence theories in neuroscience. Our findings revealed robust evidence of an efficiently organized resting state functional brain network for highly productive cognitions. PMID- 21557388 TI - Evolution of crossmodal reorganization of the voice area in cochlear-implanted deaf patients. AB - Psychophysical and neuroimaging studies in both animal and human subjects have clearly demonstrated that cortical plasticity following sensory deprivation leads to a brain functional reorganization that favors the spared modalities. In postlingually deaf patients, the use of a cochlear implant (CI) allows a recovery of the auditory function, which will probably counteract the cortical crossmodal reorganization induced by hearing loss. To study the dynamics of such reversed crossmodal plasticity, we designed a longitudinal neuroimaging study involving the follow-up of 10 postlingually deaf adult CI users engaged in a visual speechreading task. While speechreading activates Broca's area in normally hearing subjects (NHS), the activity level elicited in this region in CI patients is abnormally low and increases progressively with post-implantation time. Furthermore, speechreading in CI patients induces abnormal crossmodal activations in right anterior regions of the superior temporal cortex normally devoted to processing human voice stimuli (temporal voice-sensitive areas-TVA). These abnormal activity levels diminish with post-implantation time and tend towards the levels observed in NHS. First, our study revealed that the neuroplasticity after cochlear implantation involves not only auditory but also visual and audiovisual speech processing networks. Second, our results suggest that during deafness, the functional links between cortical regions specialized in face and voice processing are reallocated to support speech-related visual processing through cross-modal reorganization. Such reorganization allows a more efficient audiovisual integration of speech after cochlear implantation. These compensatory sensory strategies are later completed by the progressive restoration of the visuo-audio-motor speech processing loop, including Broca's area. PMID- 21557389 TI - Concise review: Quiescent and active states of endogenous adult neural stem cells: identification and characterization. AB - The adult mammalian central nervous system (CNS) lacks the capacity for regeneration, making it a highly sought-after topic for researchers. The identification of neural stem cells (NSCs) in the adult CNS wiped out a long-held dogma that the adult brain contains a set number of neurons and is incapable of replacing them. The discovery of adult NSCs (aNSCs) stoked the fire for researchers who dream of brain self-repair. Unfortunately, the quiescent nature and limited plasticity of aNSCs diminish their regenerative potential. Recent studies evaluating aNSC plasticity under pathological conditions indicate that a switch from quiescent to active aNSCs in neurogenic regions plays an important role in both repairing the damaged tissue and preserving progenitor pools. Here, we summarize the most recent findings and present questions about characterizing the active and quiescent aNSCs in major neurogenic regions, and factors for maintaining their active and quiescent states, hoping to outline an emerging view for promoting the endogenous aNSC-based regeneration. PMID- 21557391 TI - Concise review: Transplantation of human hematopoietic cells for extracellular matrix protein deficiency in epidermolysis bullosa. AB - The skin is constantly exposed to environmental insults and requires effective repair processes to maintain its protective function. Wound healing is severely compromised in people with congenital absence of structural proteins of the skin, such as in dystrophic epidermolysis bullosa, a severe congenital mechanobullous disorder caused by mutations in collagen type VII. Remarkably, stem cell transplantation can ameliorate deficiency of this skin-specific structural protein in both animal models and in children with the disorder. Healthy donor cells from the hematopoietic graft migrate to the injured skin; simultaneously, there is an increase in the production of collagen type VII, increased skin integrity, and reduced tendency to blister formation. How hematogenous stem cells from bone marrow and cord blood can alter skin architecture and wound healing in a robust, clinically meaningful way is unclear. We review the data and the resulting hypotheses that have a potential to illuminate the mechanisms for these effects. Further modifications in the use of stem cell transplantation as a durable source of extracellular matrix proteins may make this regenerative medicine approach effective in other cutaneous and extracutaneous conditions. PMID- 21557390 TI - Concise review: Mesenchymal stem cell tumor-homing: detection methods in disease model systems. AB - Despite the decline in U.S. cancer incidence and mortality rates, cancer remains the number one cause of death for people under the age of 85 and one in four people in the U.S. will die of cancer, mainly because of metastasis. Recently, interest in mesenchymal stem cell (MSC) tumor-homing has led to inquires into: (a) why MSCs home to tumors, (b) what the inherent protumor and antitumor consequences are, and (c) how to best capitalize on MSC tumor-homing for cell based diagnostics and therapy. Here, these questions are reviewed and method for addressing them using animal models and tracking methodologies (or, synonymously, detection methodologies) are discussed. First, MSCs in a regenerative and tumor homing context are reviewed, followed by MSC delivery and genetic labeling methods for tissue model systems. Finally, the use of the nonoptical methods, magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, along with optical methods, fluorescence imaging and bioluminescent imaging, are reviewed related to tracking MSCs within disease model settings. The benefits and drawbacks of each detection method in animal models is reviewed along with the utility of each for therapeutic use. PMID- 21557392 TI - Consice review: Contribution of cancer stem cells to neovascularization. AB - Cancer stem cells (CSCs), a special subpopulation of tumor cells, are considered as tumor initiating cells. More recently, these cells have also been identified as initiators of tumor neovascularization. A better understanding of the contribution of CSCs to neovascularization should elucidate the mechanisms of cancer initiation and progression as well as establish new concepts for cancer diagnosis and treatment. In this review, we discuss the evidence for the roles of CSCs in tumor vascularization, including production of proangiogenic factors, transdifferentiation into vascular mural cells such as endothelial and smooth muscle-like cells, and formation of nonendothelium-lined vasculogenic mimicry. In addition, the potential therapeutic significance of targeting CSCs is envisaged. PMID- 21557393 TI - SAMP1/YitFc mouse strain: a spontaneous model of Crohn's disease-like ileitis. AB - The SAMP1/YitFc mouse strain represents a model of Crohn's disease (CD)-like ileitis that is ideal for investigating the pathogenesis of chronic intestinal inflammation. Different from the vast majority of animal models of colitis, the ileal-specific phenotype characteristic of SAMP1/YitFc mice occurs spontaneously, without genetic, chemical, or immunological manipulation. In addition, SAMP1/YitFc mice possess remarkable similarities to the human condition with regard to disease location, histologic features, incidence of extraintestinal manifestations, and response to conventional therapies. SAMP1/YitFc mice also display a well-defined time course of a predisease state and phases of acute and chronic ileitis. As such, the SAMP1/YitFc model is particularly suitable for elucidating pathways that precede the clinical phenotype that may lead to preventive, and therefore more efficacious, intervention with the natural course of disease, or alternatively, for the development of therapeutic strategies directed against chronic, established ileitis. In this review we summarize important contributions made by our group and others that uncover potential mechanisms in the pathogenesis of CD using this unique murine model of chronic intestinal inflammation. PMID- 21557394 TI - miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes. AB - BACKGROUND: miR-143 and miR-145 are believed to function as colon cancer tumor suppressors, as they inhibit colon cancer cell growth and are downregulated in sporadic colonic tumors. We speculated that miR-143 and miR-145 might also be downregulated and contribute to malignant transformation of colonic epithelium in longstanding ulcerative colitis (UC). METHODS: Biopsies were obtained 20 cm proximal to the anus from individuals with quiescent UC and from normal controls. RNA and proteins were extracted and measured. miR-143 and miR-145 were quantified by real-time polymerase chain reaction (PCR) and miR-145 was also assessed by in situ hybridization. Putative targets of these miRNAs, K-RAS, API5, MEK-2 (miR 143), and IRS-1 (miR-145) were determined by western blotting. To assess the effects of miR-143 and miR-145 on these predicted targets, HCT116 and HCA-7 colorectal cancer cells were transfected with miR-143 and miR-145 and expression levels of these proteins were measured. RESULTS: In UC, miR-143 and miR-145 were significantly downregulated 8.3-fold (3.4-20.1) (P < 0.0001) and 4.3-fold (2.3 7.8) (P < 0.0001), respectively, compared to normal colon. In contrast, IRS-1, K RAS, API5, and MEK-2 were upregulated in UC, consistent with their assignments as targets of these miRNAs. Furthermore, transfected miR-143 and miR-145 significantly downregulated these proteins in HCT116 or HCA-7 cells. CONCLUSIONS: Compared to normal colonic mucosa, in chronic UC miR-143 and miR-145 were significantly downregulated and their predicted targets, IRS-1, K-RAS, API5, and MEK-2 were upregulated. We postulate that loss of these tumor suppressor miRNAs predispose to chronic inflammation and neoplastic progression in IBD. PMID- 21557396 TI - Value in capsule retention in Crohn's disease. PMID- 21557395 TI - Loss of downregulated in adenoma (DRA) impairs mucosal HCO3(-) secretion in murine ileocolonic inflammation. AB - BACKGROUND: Ileocolonic luminal pH has been reported to be abnormally low in inflammatory bowel disease (IBD) patients, and one of the causative factors may be reduced epithelial HCO(3)(-) secretory rate (J(HCO3)(-)). Disturbances in J(HCO3)(-) may occur due to inflammation-induced changes in the crypt and villous architecture, or due to the effect of proinflammatory cytokines on epithelial ion transporters. METHODS: To discriminate between these possibilities, the tumor necrosis factor alpha (TNF-alpha) overexpressing (TNF(+/DeltaARE)) mouse model was chosen, which displays high proinflammatory cytokine levels in both ileum and colon, but develops only mild colonic histopathology and diarrhea. HCO(3)(-) secretion, mRNA expression, immunohistochemistry, and fluid absorptive capacity were measured in ileal and mid-colonic mucosa of TNF(+/DeltaARE) and wildtype (WT) (TNF(+/+)) mice in Ussing chambers, and in anesthetized mice in vivo. RESULTS: The high basal J(HCO3)(-) observed in WT ileal and mid-colonic mucosa were luminal Cl(-) -dependent and strongly decreased in TNF(+/DeltaARE) mice. Downregulated in adenoma (DRA) mRNA and protein expression was strongly decreased in TNF(+/DeltaARE) ileocolon, whereas cystic fibrosis transmembrane conductance regulator (CFTR), Na(+) /H(+) exchanger 3 (NHE3), Na(+) /HCO(3)(-) cotransporter (NBC), and epithelial sodium channel (ENaC) expression was not significantly altered. This indicates that the severe defect in ileocolonic J(HCO3)(-) was due to DRA downregulation. Fluid absorption was severely depressed in the ileum but only mildly affected in the mid-distal colon, preventing the development of overt diarrhea. CONCLUSIONS: Even mild ileocolonic inflammation may result in a decrease of epithelial HCO(3)(-) secretion, which may contribute to alterations in surface pH, intestinal flora, and mucus barrier properties. PMID- 21557397 TI - Role of genetic and environmental factors in British twins with inflammatory bowel disease. AB - BACKGROUND: Twin studies provide insight into the complex interaction between genetic and environmental factors in the development of inflammatory bowel disease (IBD). We assessed associations between childhood environmental factors and development of Crohn's disease (CD) and ulcerative colitis (UC) in twins. METHODS: Questionnaires on clinical demographics and exposure to environmental factors were sent to twins with IBD, their healthy co-twins, and their doctors. Kappa statistics were used to examine agreement between twin pairs and odds ratios were calculated by conditional logistic regression. RESULTS: In all, 250 IBD twin pairs (122 CD; 125 UC; 3 CD/UC; 28 concordant pairs) were analyzed. Concordant monozygotic twins with CD showed good agreement for disease location (kappa 0.88; 95% confidence interval [CI]: 0.45-1.00), disease behavior (kappa 1.00; 95% CI: 0.43-1.00), and moderate agreement for age at diagnosis and need for medical and surgical therapy. Concordant monozygotic twins with UC showed good agreement for disease extent (kappa 0.60; CI 0.13-1.00) and use of thiopurines (kappa 0.73; CI 0.10-1.00). In discordant twins, symptomatic childhood mumps infection (odds ratio [OR], 3.8; 95% CI, 1.2-11.3) and oral contraceptives (OR, 4.0; 1.1-14.2) were associated with CD. Smoking was associated with CD (OR, 4.3; 95% CI, 1.9-9.8) but inversely associated with UC (OR, 0.3; 95% CI, 0.1-0.9). Both CD and UC twins had suffered more "gastroenteritis" and spent more time with animals than their co-twins. CONCLUSIONS: Disease phenotype in CD and disease extent in UC appeared to be genetically influenced. Smoking is a risk factor for CD but is protective for UC. Early exposure to "infections" during childhood may be associated with the development of IBD. PMID- 21557398 TI - Complementary and alternative medicine use in inflammatory bowel disease. PMID- 21557399 TI - Information resources and inflammatory bowel disease. PMID- 21557400 TI - Adeno-associated virus-mediated human acidic fibroblast growth factor expression promotes functional recovery of spinal cord-contused rats. AB - BACKGROUND: Following spinal cord injury, the delivery of neurotrophic factors to the injured spinal cord has been shown to promote axonal regeneration and functional recovery. In previous studies, we showed that acidic fibroblast growth factor (aFGF) is a potent neurotrophic factor that promotes the regeneration of axotomized spinal cord or dorsal root ganglion neurones. METHODS: We constructed a recombinant adeno-associated virus (AAV) vector to express human aFGF and evaluated aFGF expression and function in AAV-aFGF-infected PC12 cells. We analyzed AAV-green fluorescent protein (GFP) tropism and AAV-mediated aFGF expression in contused spinal cords. Animals received behavioural testing to evaluate the functional recovery. RESULTS: Overexpression of aFGF was shown in AAV-aFGF-infected PC12 cells in a dose-dependent manner. Concurrently, neurite extension and cell number were significantly increased in AAV-aFGF infected cells. AAV-mediated GFP expression persisted for at least 5 weeks in contused spinal cords, and the most prominently transduced cells were neurones. Contusive injury reduced endogenous aFGF expression in spinal cords. Overexpression of aFGF was demonstrated in AAV-aFGF transduced spinal cords compared to AAV-GFP transduced spinal cords at 3 and 14 days post-injury. Evaluation of motor function revealed that the improvement of AAV-aFGF-treated rats was prominent. Both AAV-aFGF- and recombinant human aFGF-treated rats revealed significantly better recovery at 5 weeks post-injury, compared to vehicle- and AAV-GFP-treated rats. CONCLUSIONS: These data suggest that supplement of aFGF improve the functional recovery of spinal cord-contused rats and that AAV-aFGF-mediated gene transfer could be a clinically feasible therapeutic approach for patients after nervous system injuries. PMID- 21557402 TI - Cooperative assembly of binary molecular components into tubular structures for multiple photonic applications. PMID- 21557403 TI - Facile fabrication of stimuli-responsive polymer capsules with gated pores and tunable shell thickness and composite. PMID- 21557405 TI - Water-dispersed near-infrared-emitting quantum dots of ultrasmall sizes for in vitro and in vivo imaging. PMID- 21557406 TI - Nanoscale light-harvesting metal-organic frameworks. PMID- 21557407 TI - Cyclo[8]isoindoles: ring-expanded and annelated porphyrinoids. PMID- 21557408 TI - Tuning the spin state of cobalt in a Co-La heterometallic complex through controllable coordination sphere of La. PMID- 21557409 TI - Highly mobile palladium thin films on an elastomeric substrate: nanogap-based hydrogen gas sensors. PMID- 21557410 TI - Magnetochromatic polydiacetylene by incorporation of Fe3O4 nanoparticles. PMID- 21557411 TI - Graphene-based carbon nitride nanosheets as efficient metal-free electrocatalysts for oxygen reduction reactions. PMID- 21557412 TI - ortho-Selective nucleophilic addition of primary amines to silylbenzynes: synthesis of 2-silylanilines. PMID- 21557413 TI - Fluorescence nanoscopy of single DNA molecules by using stimulated emission depletion (STED). PMID- 21557414 TI - Transfer of preformed three-dimensional photonic crystals onto dye-sensitized solar cells. PMID- 21557415 TI - A fully delocalized mixed-valence bis-MU(thiolato) dicopper complex: a structural and functional model of the biological CuA center. PMID- 21557416 TI - Cold-ion spectroscopy reveals the intrinsic structure of a decapeptide. PMID- 21557417 TI - Carbon chain growth by formyl insertion on rhodium and cobalt catalysts in syngas conversion. PMID- 21557418 TI - Proton-driven switching between receptors for C60 and C70. PMID- 21557419 TI - From Maya Blue to "Maya Yellow": a connection between ancient nanostructured materials from the voltammetry of microparticles. PMID- 21557420 TI - Dinuclear palladium(III) complexes with a single unsupported bridging halide ligand: reversible formation from mononuclear palladium(II) or palladium(IV) precursors. PMID- 21557421 TI - Cassis odor through microwave eyes: olfactory properties and gas-phase structures of all the Cassyrane stereoisomers and its dihydro derivatives. PMID- 21557422 TI - Gold(I)-catalyzed formation of benzo[b]furans from 3-silyloxy-1,5-enynes. PMID- 21557423 TI - Complementary hydrogen bonding between a clicked C3-symmetric triazole derivative and carboxylic acids for columnar liquid-crystalline assemblies. PMID- 21557424 TI - The absence of redox reactions for palladium(II) and copper(II) on electrostatically charged Teflon: relevance to the concept of "cryptoelectrons". PMID- 21557425 TI - Hierarchical selectivity in fullerenes: site-, regio-, diastereo-, and enantiocontrol of the 1,3-dipolar cycloaddition to C70. PMID- 21557426 TI - Divergent regioselectivity in the synthesis of trisubstituted allylic alcohols by nickel- and ruthenium-catalyzed alkyne hydrohydroxymethylation with formaldehyde. PMID- 21557427 TI - Synthesis of 5,6-spiroethers and evaluation of their affinities for the bacterial A site. PMID- 21557428 TI - Colorimetric SNP genotyping based on allele-specific PCR by using a thiol-labeled primer. PMID- 21557429 TI - Ascorbate as an alternative to thiol additives in native chemical ligation. PMID- 21557430 TI - Azobenzene: an optical switch for in vivo experiments. PMID- 21557431 TI - Protein modification by strain-promoted alkyne-azide cycloaddition. PMID- 21557432 TI - Influence of the encapsulated clusters on the electrochemical behaviour of endohedral fullerene derivatives: comparative study of N-tritylpyrrolidino derivatives of Sc3N@I(h)-C80 and Lu3N@I(h)-C80. PMID- 21557433 TI - Acetylene???furan trimer formation at 0.37 K as a model for ultracold aggregation of non- and weakly polar molecules. AB - We have studied the aggregation process of (C(2)H(2))???furan trimers at ultracold temperatures (0.37 K) in helium nanodroplets. Computational sampling of the potential energy surface using the multiple-minima-hypersurface (MMH) approach yielded seven possible minimum structures, optimized at the MP2 level of theory with the cc-pVTZ and 6-311++G(d,p) basis sets. Experimentally, we could assign five transitions in the IR spectrum of acetylene-furan aggregates in the acetylene C-H(asym) stretch region between 3240 and 3300 cm(-1) to vibrational bands of the 2:1 acetylene-furan trimer. The transitions were assigned to three ring structures that all contain the T-shaped acetylene dimer as structural sub motif. Two of the structures form a nonplanar ring involving a C-H(Ac) ???pi(Fu) bond, the third is a nearly planar ring containing a C-H(Ac) ???O(Fu) bond. This assignment was corroborated by quantum mechanical/molecular dynamics (QM/MD) simulations mimicking in detail the aggregation process of precooled monomers. The simulations provided evidence for a transition from a higher level local minimum to the global minimum state over a small barrier during the aggregation process. The experimentally observed structures can be explained by a step-by step aggregation of moieties pre-cooled to 0.37 K that are steered by intermediate and short-range electrostatic interactions. Thus, we are able to unravel a special aggregation mechanism which differs from aggregation of molecules with large dipole moments where this aggregation process is dominated by long range 1/r(3) dipole-dipole interaction ("electrostatic steering"). This mechanism is expected to be a general mechanism in ultracold chemistry. PMID- 21557434 TI - Outer Helmholtz plane of the electrical double layer formed at the solid electrode-liquid interface. PMID- 21557435 TI - High-resolution electronic spectroscopy studies of meta-aminobenzoic acid in the gas phase reveal the origins of its solvatochromic behavior. AB - A theoretical and experimental investigation of meta-aminobenzoic acid (MABA) in the gas phase is presented, with the goal of understanding counterintuitive observations on the solvatochromism of this "push-pull" molecule. The adiabatic excitation energies, transition moments, and excited-state structures are examined using the complete active space self-consistent field approach (CASSCF and CASPT2), which shows the first excited electronic state of MABA to be of greater charge transfer character than was found in the para-isomer (PABA). The rotationally resolved electronic spectrum of MABA reveals the existence of two rotamers, owing to asymmetry in the carboxylic acid functional group. Stark measurements in a molecular beam show the change in permanent dipole moment upon excitation to be DeltaMU~3.5 D for both rotamers, more than three times larger than that found in PABA. The excited state measurements reported here, along with supporting data from theory, clearly demonstrate how the meta-directing effects of asymmetric substitution in aniline derivatives can drive charge transfer pathways in the isolated molecule. PMID- 21557436 TI - Do metal???water hydrogen bonds hold in solution? Insight from ab initio molecular dynamics simulations. PMID- 21557437 TI - Adsorption of formate and its role as intermediate in formic acid oxidation on platinum electrodes. PMID- 21557439 TI - Patient evaluation of a novel patient education leaflet about heart disease risk among people with rheumatoid arthritis. AB - OBJECTIVES: People with rheumatoid arthritis (RA) require access to clear and consistent information about their condition, and Arthritis Research UK produces a wide range of leaflets to meet this need. There is no patient information leaflet about cardiovascular disease (CVD) in the context of having RA, despite the fact that CVD accounts for 50% of the mortality in RA. A leaflet was developed; this paper describes the patient evaluation of this novel education resource. METHODS: A questionnaire was developed to evaluate the leaflet's content, literacy, graphics, layout and ability to stimulate learning. It was distributed, with the leaflet, to 500 National Rheumatoid Arthritis Society members. RESULTS: There was a 72.8% response rate. Of the respondents: 96% agreed that the purpose of the leaflet was clear; 78% agreed that the leaflet was relevant to them; 96% agreed that they understood the leaflet; 53% agreed that the leaflet cover was appealing; 81% agreed that the size of the typing was suitable; 71% agreed that the advice was appropriate for their lifestyle. Omissions included adequately describing any risks associated with its advice, what sources of information were used to compile the leaflet and when this information was produced. Eighty-four per cent of respondents said that they would recommend this leaflet to other people with RA. Qualitatively, many people felt more empowered as a result of reading the leaflet. CONCLUSIONS: Patient evaluation of new educational resources is important and ensures that materials meet patients' needs and are presented in a user-friendly style. Ultimately, the test of the effectiveness of the leaflet will be if patients change their behaviour appropriately. PMID- 21557440 TI - Basal insulin analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes. AB - As basal insulin analogues are being used off-label, there is a need to evaluate their safety (maternal hypoglycaemia and fetal and perinatal outcomes) and efficacy [haemoglobin A1c(HbA1c), fasting plasma glucose, and maternal weight gain]. The aim of this review is to provide an overview of the current literature concerning basal insulin analogue use in diabetic pregnancy, and to present the design and preliminary, non-validated baseline characteristics of a currently ongoing randomized, controlled, open-label, multicentre, multinational trial comparing insulin detemir with neutral protamine hagedorn insulin, both with insulin aspart, in women with type 1 diabetes planning a pregnancy (n = 306) or are already pregnant (n = 164). Inclusion criteria include type 1 diabetes > 12 months' duration; screening HbA1c <= 9.0% (women recruited prepregnancy), or pregnant with gestational age 8-12 weeks and HbA1c <= 8.0% at randomization. At confirmation of pregnancy all subjects must have HbA1c <= 8.0%. Exclusion criteria include impaired hepatic function, cardiac problems, and uncontrolled hypertension. Subjects are randomized to either insulin detemir or neutral protamine hagedorn insulin, both with prandial insulin aspart. The results are expected mid-2011 with full publications expected later this year. Baseline characteristics show that basal insulin analogues are already frequently used in pregnant women with type 1 diabetes. This study will hopefully elucidate the safety and efficacy of the basal insulin analogue detemir in diabetic pregnancy. PMID- 21557441 TI - Blue eyes as a risk factor for type 1 diabetes. AB - BACKGROUND: A high frequency of blue eyes and fair skin are reported in northern European Caucasians with type 1 diabetes (T1D). Also there is an inverse relationship between latitude and T1D incidence. We determined whether iris colour and skin pigmentation are risk factors in a Caucasian population living in two Mediterranean regions located at the same latitude with higher ultraviolet B irradiance, but with different T1D incidence. METHODS: We studied iris colour in 281 consecutive subjects with T1D and 298 controls. Skin type was evaluated by melanin quantification. RESULTS: In Lazio, blue eyes and fair skin type are significantly more common in T1D subjects than in controls (21 versus 9%, p = 0.002; 50 versus 35%, p < 0.001, respectively). In Sardinia, the frequency of blue eyes in T1D subjects is twice that in controls (5.8 versus 2.6% and significantly higher when compared to the expected calculated frequency in the entire population). By logistic regression analysis, only blue eyes are independent and significant predictors of T1D [odds ratio for blue eyes = 2.2; 95% confidence interval (1.1-4.4), p = 0.019]. CONCLUSIONS: As previously shown in a Caucasian population from northern Europe, blue eyes and a trend for fair skin increase the risk for T1D also in a Caucasian population born and residing in a Mediterranean region (Continental Italy). This finding may be relevant for explaining different T1D incidence as prevalence of blue eyes differ substantially between northern and southern European Caucasians. PMID- 21557442 TI - Serum prolactin concentrations determine whether they improve or impair beta-cell function and insulin sensitivity in diabetic rats. AB - BACKGROUND: Prolactin improves glucose homeostasis by increasing beta-cell mass under certain conditions such as pregnancy, whereas hyperprolactinaemia due to a pituitary gland adenoma tumour exacerbates insulin resistance. However, previous studies have not evaluated how prolactin modulates beta-cell function and insulin sensitivity at different dosages. Here, we determined that chronic intraperitoneal injections of different dosages of prolactin have opposite effects on insulin resistance and beta-cell function and mass in 90% pancreatectomized diabetic male rats, and the mechanisms were explored. METHODS: Diabetic rats were divided into three groups according to the dose of intraperitoneally injected prolactin for 4 weeks: (1) low dose of prolactin (25 ug/kg bw/12 h), (2) high dose of prolactin (250 ug/kg bw/12 h), and (3) vehicle. As a non-diabetic control group, sham-operated rats were injected with vehicle. RESULTS: Chronic high- and low-dose prolactin injections elevated serum prolactin levels by 2.5- and 11.8-fold, respectively. Both dosages promoted beta-cell mass by increasing beta-cell proliferation and neogenesis through the potentiation of phosphorylation of signal transducer and activator of transcription 5 and decreased menin expression in diabetic rats. However, only the low-dose prolactin injection potentiated glucose-stimulated insulin secretion though glucokinase and glucose transporter 2 induction in the diabetic rats. In addition, low-dose prolactin decreased hepatic glucose output in hyperinsulinaemic states, indicating an improvement in hepatic insulin resistance. However, the high-dose prolactin injection exacerbated whole-body and hepatic insulin resistance in diabetic rats. CONCLUSIONS: In contrast to the normal adaptive increases in glucose-stimulated insulin secretion through expanded beta-cell mass and insulin sensitivity realized with moderately increased prolactin levels, high levels of prolactin exacerbate insulin resistance and impair the insulin-secretory capacity in diabetic mice. PMID- 21557443 TI - PAR1 plays a role in epithelial malignancies: transcriptional regulation and novel signaling pathway. AB - Protease-activated receptor 1 (PAR(1)) is the first and prototype member of an established PAR family comprising four members. The role of PAR(1) in tumor biology has been established, and is characterized by a consistent direct correlation between overexpression of its levels and epithelial tumor aggressiveness. We have found that high expression of the human Par(1) (hPar(1)) gene in epithelial tumors is controlled largely at the transcriptional level. This led us to assign Egr-1, a transcription activator, as an inducer of hPar(1), and p53, a tumor suppressor gene, as an inhibitor, both acting to achieve fine tuning of hPar(1) in prostate carcinoma. High PAR(1) levels maintain prosurvival signals in tumor cells while silencing or ablation of the gene induce apoptosis. Studies of our hPar(1) transgenic mice, which overexpress hPar(1) in the mammary glands, revealed a novel PAR(1)-induced beta-catenin stabilization function. The components connecting PAR(1) to beta-catenin stabilization have been determined, assigning at first G(alpha)(13) as a selective immediate component. The PAR(1) G(alpha) (13) axis recruits disheveled (DVL), an upstream signaling partner of the canonical Wnt signaling pathway. Silencing of DVL by siRNA-DVL potently abrogates PAR(1)-induced beta-catenin stabilization, demonstrating its critical role in the process. We, thus, propose that transcriptional regulation of hPar(1) gene over expression in epithelia malignancies initiates a novel signaling pathway, directly connecting to beta-catenin stabilization, a core event in both tumorigenesis and developmental processes. PMID- 21557444 TI - Introduction to mini-theme issue on "protease-activated receptor signaling". PMID- 21557445 TI - Serine and metalloprotease signaling through PAR1 in arterial thrombosis and vascular injury. AB - Thrombin-dependent platelet activation has been shown to be important in the setting of angioplasty and stenting, which may cause ischemic complications including acute myocardial infarction and death. Inhibitors of the high-affinity thrombin receptor, protease-activated receptor 1 (PAR1), are now being evaluated in clinical trials for safety and efficacy in patients with atherothrombotic disease. However, it is unknown whether chronic inhibition of PAR1 in these large patient populations will have beneficial or possibly adverse effects on other biologic processes involved in blood vessel homeostasis and the response to vascular injury. Most recently, PAR1 was found to be cleaved at a distinct site by matrix metalloprotease-1 (MMP-1) to create a longer tethered ligand, which activates a distinct spectrum of G protein pathways in platelets. The differential activation by serine proteases such as thrombin and the metalloprotease MMP-1, places the protease receptor PAR1 at the junction of two major protease classes critically involved in thrombosis, matrix remodeling, and the response to vascular injury. PMID- 21557446 TI - Binding of delta9-tetrahydrocannabinol and diazepam to human serum albumin. AB - Cannabis is the most commonly used illicit drug worldwide. Cannabis users also appear to use other psychoactive drugs more frequently than noncannabis users. Here, Delta9-tetrahydrocannabinol (THC) and diazepam binding to human serum albumin (HSA) and HSA-heme is reported. THC binds to two different binding sites of HSA (K(d1) <= 10(-7) M and K(d2) = 10(-3)M) without affecting diazepam binding (K(d) = 1.2 * 10(-5) M). THC binding to the high-affinity site accounts for the low free fraction of the drug in plasma. Moreover, THC increases the affinity of heme for HSA. Accordingly, the affinity of THC for HSA-heme is higher than that for HSA. THC could bind to FA2 and FA7 sites, as substantiated by docking simulations; nevertheless, the observed allosteric effect(s) suggests that the primary binding site of THC is the FA2 cleft that positively modulates heme affinity. Possibly, the HSA conformational transition(s) induced by THC binding could account for drug delivery to the liver through receptor- mediated endocytosis. PMID- 21557447 TI - Diagnosis of hepatitis C virus infection by enzyme-linked immunosorbent assay and reverse transcriptase-nested polymerase chain reaction: a comparative evaluation. AB - Hepatitis C virus is one of the main causes of chronic hepatitis in developing countries. The current study was to evaluate the efficacy of the enzyme-linked immunosorbent assay third generation (ELISA-3) for detection of antibodies to hepatitis C virus (anti-HCV) in comparison with reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) to detect HCV RNA for the diagnosis of hepatitis C virus. Serum samples were collected from 151 chronic hepatitis C patients and 50 healthy individuals. All samples were tested for anti-HCV antibodies using ELISA-3 and HCV RNA by RT-nested PCR. Of the 151,120 (78.9%) were found to be seropositive by ELISA-3, and 148 (98%) patients were HCV RNA positive, 118 (78.1%) were positives for both, 30 (19.9%) were positive for ELISA 3 and negative for RT-PCR, and 2 cases (1.3%) were positive for RT-nested PCR and negative for ELISA-3. The sensitivity and the specificity for the detection of HCV were absolute when the two techniques were combined. In conclusion, ELISA-3 is a suitable assay for routine screening for anti-HCV. RT-nested PCR for HCV is a value for the early detection of viremic, anti-HCV negative cases; this may be of importance in treatment of hepatitis C. PMID- 21557449 TI - Transcatheter aortic valve implantation for severe aortic regurgitation in a stentless bioprosthetic valve with the Core Valve revalving system-technical tips and role of the Accutrak system. AB - Transcatheter aortic valve implantation may offer a less invasive alternate to surgical reoperation in patients with failed aortic bioprosthetic valves. Prior reports have focussed on successful transcatheter treatment of stented bioprosthesis. Newer stentless valves offer unique technical challenges. In the absence of radiopaque markers, the deployment is carried out under angiographic control. Device stability is also an important issue in cases of severe regurgitation. We report on the first case of percutaneous replacement of a severely regurgitant degenerated stentless bioprosthesis treated with the new iteration of the core valve system incorporating the Accutrak stability layer. Salient technical expedients have been mentioned and discussed in detail. PMID- 21557448 TI - Phylogenetic diversification of the globin gene superfamily in chordates. AB - Phylogenetic reconstructions provide a means of inferring the branching relationships among members of multigene families that have diversified via successive rounds of gene duplication and divergence. Such reconstructions can illuminate the pathways by which particular expression patterns and protein functions evolved. For example, phylogenetic analyses can reveal cases in which similar expression patterns or functional properties evolved independently in different lineages, either through convergence, parallelism, or evolutionary reversals. The purpose of this article is to provide a robust phylogenetic framework for interpreting experimental data and for generating hypotheses about the functional evolution of globin proteins in chordate animals. To do this, we present a consensus phylogeny of the chordate globin gene superfamily. We document the relative roles of gene duplication and whole-genome duplication in fueling the functional diversification of vertebrate globins, and we unravel patterns of shared ancestry among globin genes from representatives of the three chordate subphyla (Craniata, Urochordata, and Cephalochordata). Our results demonstrate the value of integrating phylogenetic analyses with genomic analyses of conserved synteny to infer the duplicative origins and evolutionary histories of globin genes. We also discuss a number of case studies that illustrate the importance of phylogenetic information when making inferences about the evolution of globin gene expression and protein function. Finally, we discuss why the globin gene superfamily presents special challenges for phylogenetic analysis, and we describe methodological approaches that can be used to meet those challenges. PMID- 21557450 TI - Cathodic electrochemiluminescence of the peroxydisulphate-ciprofloxacin system and its analytical applications. AB - The cathodic electrochemiluminescence (ECL) of peroxydisulphate (S(2)O(8)(2-)) ciprofloxacin (CPF) system at a wax-impregnated graphite electrode was studied. When CPF was absent, S(2)O(8)(2-) was electrochemically reduced to sulphate free radical (SO(4)(*-)), and dissolved oxygen absorbed on the electrode surface was reduced to protonated superoxide anion radical (HO(2)(*)). The HO(2)(*) was oxidized by SO(4)(*-) to produce molecular oxygen in both singlet and triplet states. Some of the singlet molecular oxygen ((1)O(2)) further combined through collision to be an energy-rich precursor singlet molecular oxygen pair ((1)O(2))(2). A weak ECL was produced when (1)O(2) or ((1)O(2))(2) was converted to ground-state molecular oxygen ((3)O(2)). When CPF was present, a stronger ECL was produced, which originated from two emitting species. The main emitting species was excited state CPF (CPF*), which was produced by accepting energy from ((1)O(2))(2). The other emitting species was excited singlet molecular oxygen pair [((1)O(2))(2)*], which originated from the chemical oxidation of CPF by SO(4)(*-) and dissolved oxygen. Based on the stronger ECL phenomenon, an ECL method for the determination of either S(2)O(8)(2-) or CPF was proposed. The proposed ECL method has been applied to the determination of CPF in pharmaceutical preparations. PMID- 21557451 TI - Analysis of fexofenadine in pharmaceutical formulations using tris(1,10 phenanthroline)-ruthenium(II) peroxydisulphate chemiluminescence system in a multichip device. AB - A simple, rapid and sensitive method has been developed for the analysis of fexofenadine (FEX) in pharmaceutical formulations, using a tris(1,10 phenanthroline)-ruthenium(II) [Ru(phen)(3)(2+)] peroxydisulphate chemiluminescence (CL) system in a multichip device. Various parameters that influence the CL signal intensity were optimized. These included pH, flow rates and concentration of reagents used. Under optimum conditions, a linear calibration curve in the range 0.05-5.0 ug/mL was obtained. The detection limit was found to be 0.001 ug/mL. The procedure was applied to the analysis of FEX in pharmaceutical products and was found to be free from interference from concomitants usually present in these preparations. PMID- 21557452 TI - Zebrafish heat shock protein a4 genes in the intestinal epithelium are up regulated during inflammation. AB - A number of heat shock proteins (HSPs), including Hsp70 and Hsp110, function as molecular chaperones within intestinal epithelial cells that line the mammalian digestive system. HSPs confer cellular protection against environmental stress induced by chemical toxins or pathogens. There is interest in how members of this protein family might influence the progression of inflammatory bowel disease. Using the zebrafish model system, we report the expression of the duplicated hspa4 genes within the intestinal epithelium. The hspa4 genes belong to the Hsp110 family. We show that under inflammatory stress conditions within the gut, expression of these genes is up-regulated in a similar manner to that previously observed for mammalian Hsp70. Because of the amenability of the zebrafish to whole-animal screening protocols, the hspa4 genes could be used as effective read outs for genetic, chemical and environmental factors that might influence intestinal inflammation. PMID- 21557453 TI - Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling. AB - Much is known regarding the role of Indian hedgehog (Ihh) in endochondral ossification, where Ihh regulates multiple steps of chondrocyte differentiation. The Ihh-/- phenotype is most notable for severely foreshortened limbs and a complete absence of mature osteoblasts. A far less explored phenotype in the Ihh /- mutant is found in the calvaria, where bones form predominately through intramembranous ossification. We investigated the role of Ihh in calvarial bone ossification, finding that proliferation was largely unaffected. Instead, our results indicate that Ihh is a pro-osteogenic factor that positively regulates intramembranous ossification. We confirmed through histologic and quantitative gene analysis that loss of Ihh results in reduction of cranial bone size and all markers of osteodifferentiation. Moreover, in vitro studies suggest that Ihh loss reduces Bmp expression within the calvaria, an observation that may underlie the Ihh-/- calvarial phenotype. In conjunction with the newly recognized roles of Hedgehog deregulation in craniosynostosis, our study defines Ihh as an important positive regulator of cranial bone ossification. PMID- 21557454 TI - Characterization of Pdgfrb-Cre transgenic mice reveals reduction of ROSA26 reporter activity in remodeling arteries. AB - With the intention to modulate gene expression in vascular mural cells of remodeling vessels, we generated and characterized transgenic mouse lines with Cre recombinase under the control of the platelet-derived growth factor receptor beta promoter, referred to as Tg(Pdgfrb-Cre)(35Vli) . Transgenic mice were crossed with the Gt(ROSA)26Sor(tm1Sor) strain and examined for Cre activation by beta-galactosidase activity, which was compared with endogenous Pdgfrb expression. In addition, Pdgfrb-Cre mice were used to drive expression of a conditional myc-tagged Cthrc1 transgene. There was good overlap of beta galactosidase activity with endogenous Pdgfrb immunoreactivity. However, dedifferentiation of vascular mural cells induced by carotid artery ligation revealed a dramatic discrepancy between ROSA26 reporter activity and Pdgfrb promoter driven Cre dependent myc-tagged Cthrc1 transgene expression. Our studies demonstrate the capability of the Pdgfrb-Cre mouse to drive conditional transgene expression as a result of prior Cre-mediated recombination in tissues known to express endogenous Pdgfrb. In addition, the study shows that ROSA26 promoter driven reporter mice are not suitable for lineage marking of smooth muscle in remodeling blood vessels. PMID- 21557456 TI - Continuous and high-dose cytarabine combined chemotherapy in children with down syndrome and acute myeloid leukemia: Report from the Japanese children's cancer and leukemia study group (JCCLSG) AML 9805 down study. AB - BACKGROUND: The aim of the JCCLSG AML 9805 Down study was to evaluate the effect of continuous and high-dose cytarabine combined chemotherapy on the survival outcome of acute myeloid leukemia (AML) with Down syndrome (DS). PROCEDURE: From May 1998 to December 2006, DS patients with newly diagnosed AML were enrolled. Remission induction therapy consisted of two courses of pirarubicin, vincristine, and continuous-dose cytarabine (AVC1). The patients who achieved complete remission (CR) after two courses of AVC1 were subsequently treated with mitoxantrone and continuous-dose cytarabine (MC), etoposide and high-dose cytarabine (EC) and pirarubicin, vincristine, and continuous-dose cytarabine (AVC2). RESULTS: Twenty-four patients were enrolled. All patients were younger than 4 years and diagnosed as having acute megakaryoblastic leukemia. Twenty-one patients achieved CR. Three patients died during remission induction therapy due to serious infection. No toxic deaths were observed during remission. All but one patient maintained CR without serious complications. The 5-year overall and event free survivals were 87.5% +/- 6.8% and 83.1% +/- 7.7%, respectively. CONCLUSIONS: Continuous and high-dose cytarabine combined chemotherapy with reduced intensity would be effective in DS children with AML. PMID- 21557455 TI - Notochordal and foregut abnormalities correlate with elevated neural crest apoptosis in Patch embryos. AB - Although Patch mutants show severe abnormalities in many neural crest-derived structures including the face and the heart, there is a paucity of information characterizing the mechanisms underlying these congenital defects. Via manipulating the genetic background to circumvent early embryonic lethality, our results revealed that Patch phenotypes are most likely due to a significant decrease in migratory neural crest lineage due to diminished neural crest survival and elevated apoptosis. Homozygous mutant neural crest precursors can undergo typical expansion within the neural tube, epithelial-to-mesenchymal transformation, and initiate normal neural crest emigration. Moreover, in vitro explant culture demonstrated that when isolated from the surrounding mesenchyme, Patch mutant neural crest cells (NCCs) can migrate appropriately. Additionally, Patch foregut, notochord and somitic morphogenesis, and Sonic hedgehog expression profiles were all perturbed. Significantly, the timing of lethality and extent of apoptosis correlated with the degree of severity of Patch mutant foregut, notochord, and somite dysfunction. Finally, analysis of Balb/c-enriched surviving Patch mutants revealed that not all the neural crest subpopulations are affected and that Patch mutant neural crest-derived sympathetic ganglia and dorsal root ganglia were unaffected. We hypothesize that loss of normal coordinated signaling from the notochord, foregut, and somites underlies the diminished survival of the neural crest lineage within Patch mutants resulting in subsequent neural crest deficient phenotypes. PMID- 21557457 TI - Feasibility and efficacy of repeated chemotherapy for progressive pediatric low grade gliomas. AB - BACKGROUND: Chemotherapy is widely accepted as first-line therapy for pediatric low-grade gliomas (LGG). Treatment modalities for further progression are not clearly established. The aim of the study was to determine the feasibility and long-term outcome of repeated chemotherapy for children with recurrent LGG. METHODS: The study group consisted of patients who received a second line of chemotherapy at progression of their LGG. We compared toxicity, progression-free survival (PFS), and overall survival (OS) of patients treated with chemotherapy at the time of initial diagnosis and patients who received another treatment with chemotherapy at further progression. RESULTS: Between 1985 and 2009, 118 patients received chemotherapy as primary treatment for LGG, 38 had repeated chemotherapy at further progression. Chemotherapy was tolerated extremely well. Ninety-two percent of patients completed their second line protocol and toxicity was comparable between initial and second line chemotherapy. Five-year OS and PFS were 86 +/- 6% and 37 +/- 8%, respectively, which were similar to first-line chemotherapy (P = 0.14). Repeated chemotherapy courses were not associated with worsening of visual, neuroendocrine, or other long-term organ sequelae. CONCLUSION: This study demonstrates high feasibility and low mortality of repeated chemotherapy treatment for progressive LGG. The chronic nature of LGG concerning tumor progression justifies consideration of non-toxic second-line treatment regimens at the time of recurrence. Prospective studies focusing on toxicity and long-term outcome are needed to substantiate this approach. PMID- 21557458 TI - Mannose-binding lectin (MBL) and the risk for febrile neutropenia and infection in pediatric oncology patients with chemotherapy. AB - BACKGROUND: We determined whether mannose-binding lectin (MBL) deficiency is associated with an increased risk of febrile neutropenia (FN) and/or infection in pediatric oncology patients. PROCEDURE: We systematically searched and reviewed all the literature on MBL and infections in children with cancer, identified from a literature search of Medline, Embase, and Central (1966-April 2010). We extracted information on the type of study, patient characteristics, definition of MBL deficiency, definition of infection and method of detection, follow-up period and the results of the outcome in different groups. The validity of each study was assessed. RESULTS: Six cohort studies were retrieved, consisting of 581 children with leukemia (n = 2) or varying types of cancer (n = 4). Many different outcome definitions were used. In only one out of three genotype studies, variant MBL2 genotypes, as well as MBL levels < 1,000 ug/L, were associated with an increased duration of FN. In one additional MBL level study the number of FN episodes, bacteremia and severe bacterial infection were increased in patients with MBL levels < 100 ug/L as compared to those with MBL levels of 100-999 ug/L. Sepsis, pneumonia, viral infection, and fungal infection were not associated with either MBL levels or genotypes in any of the studies. CONCLUSIONS: MBL deficiency could not be identified as an independent risk factor for FN or infection in pediatric oncology patients. A multicenter study of children with comparable chemotherapy regimens, relevant and equal outcome definitions and measuring both MBL levels and genotypes, will be required to avoid clinical and methodological inconsistencies. PMID- 21557459 TI - Transplant-associated thrombotic microangiopathy in pediatric patients treated with sirolimus and tacrolimus. AB - BACKGROUND: Transplant-associated thrombotic microangiopathy (TMA) syndromes are reported to occur with increased frequency in transplant patients treated with siroliumus combined with a calcineurin inhibitor. We performed a retrospective study of all pediatric transplant patients at City of Hope who were administered combined tacrolimus/sirolimus (TAC/SIR) to determine the occurrence of TMA. PROCEDURE: This analysis includes 41 consecutive patients between the ages of 2 and 20 (median age 9.1) who received an allogeneic hematopoietic stem cell transplant from any source and also received TAC/SIR for prevention or treatment of GVHD. Of those 41 patients, 20 received TAC/SIR as GVHD prohpylaxis and were designated the preventative group (PG), while 21 received TAC/SIR as treatment for GVHD and were designated the therapy group (TG). TMA occurrence in both groups was documented from day -1 of transplant to day 60 for the PG, and until 30 days after last dose for the TG. TMA was defined according to 2005 consensus criteria. RESULTS: Five of twenty patients in the PG, and five of twenty one in the TG, experienced TMA, with an overall rate of 23.8% for the population. All ten patients with TMA showed elevated levels of TAC, SIR or both and nine of ten suffered from organ injury due to regimen-related toxicity or GVHD. CONCLUSION: Physicians should exercise caution in the use of TAC/SIR in pediatric patients due to a high rate of TMA. It is not recommended for heavily pre-treated patients and peak levels of TAC/SIR must be very carefully controlled. PMID- 21557460 TI - Antiphospholid antibody syndrome and Hb E/Beta thalassemia disease post allogeneic stem cell transplantation. AB - We report a 10-year-old male with Hb E/Beta thalassemia disease who developed chronic graft-versus-host disease (cGVHD) of antiphospholipid antibody syndrome after successful allogeneic stem cell transplantation (SCT). He exhibited a recurrent ischemic stroke on day 368 post-SCT while on cyclosporine A, azathioprine, and prednisolone. The immunosuppressive agents were switched to pulse methylprednisolone, tacolimus, mycophenolate mofetil, and enoxaparin, but the patient was more confused. An additional plasma exchange which was aimed at the immediate removal of autoantibody was performed with a good response. The symptoms rapidly disappeared except for the complex partial seizure which persisted until seven years post-SCT. PMID- 21557461 TI - Nijmegen breakage syndrome (NBS) as a risk factor for CNS involvement in childhood acute lymphoblastic leukemia. AB - Central nervous system (CNS) involvement is an independent risk factor for poor event-free survival and relapse confined to the CNS. Knock-out mice deprived of RAG2, the protein involved in DNA repair, developed leukemic infiltration within leptomeninges. Therefore, we hypothesized that DNA repair deficiencies in humans, such as Nijmegen breakage syndrome (NBS), may constitute a risk factor for CNS dissemination of acute lymphoblastic leukemia (ALL). Having analyzed the incidence of CNS2/CNS3 status at diagnosis of ALL in two independent cohorts from the Polish Pediatric Leukemia/Lymphoma Study Group, we noticed that among children with NBS CNS involvement was significantly frequent. PMID- 21557462 TI - TSH suppression as a possible means of protection against hypothyroidism after irradiation for childhood Hodgkins lymphoma. AB - Hypothyroidism remains a common late effect after irradiation of the neck/mediastinum for Hodgkins lymphoma (HL). We evaluated the protective effect of TSH suppression during neck/mediastinum irradiation. From 1998 to 2001, 14 consecutive euthyroid children were given, before and until the end of their radiotherapy on neck/mediastinum, L-thyroxine at TSH-suppressive doses. The 14 patients had adequate TSH suppression during irradiation in 8, inadequate in 6. The 8-year hypothyroidism-free-survival after irradiation was 75 +/- 15% for the former group, 0% for the latter (P = 0.009). TSH suppression could have a protective effect on thyroid function as shown in a small group of patients with HL. PMID- 21557463 TI - Local control of metastatic sites with radiation therapy in metastatic Ewing sarcoma and rhabdomyosarcoma. AB - Approximately 20% of children with Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) present with metastatic disease at initial diagnosis. Overall, the outcome is poor, with an event-free survival of < 20%. Local control at metastatic sites has not been previously reported. We reviewed control of metastatic sites in children with EWS and RMS that received curative intent radiation therapy to each metastatic site. In 13 children, at a median follow-up of 18 months, a single local failure was seen. Toxicity was minimal. Our data suggest that radiation therapy is effective and tolerable in children with metastatic EWS and RMS. PMID- 21557464 TI - Risk factors and management of deep venous thrombosis in children following post surgical hypopituitarism in craniopharyngioma. PMID- 21557465 TI - Quantifying reduction in ecological risk in Penrhyn Estuary, Sydney, Australia, following groundwater remediation. AB - The environmental risk associated with discharge of contaminated groundwater containing a complex mixture of at least 14 volatile chlorinated hydrocarbons (VCHs) to Penrhyn Estuary, Sydney, Australia has previously been assessed. That probabilistic ecological risk assessment (ERA) was undertaken using surface water monitoring data from 2004 to 2005. Subsequently, in 2006, a groundwater remediation system was installed and commissioned to prevent further discharge of VCHs into the estuary. The present study assessed the ecological risk posed to the estuary after 2006 to evaluate the success of the remediation system. The ERA was undertaken using toxicity data derived from direct toxicity assessment (DTA) of preremediation contaminated groundwater using indigenous species, exposure data from surface water monitoring between 2007 and 2008 and the joint probability curve (JPC) methodology. The risk posed was measured in 4 zones of the entire site: source area (2), tributary (2), the inner estuary and outer estuary at high, low, and a combination of high and low tides. In the 2 source areas, risk decreased by over 2 and over 1 orders of magnitude to maximum values of less than 0.5%. In 1 estuary, risk decreased by over 1 order of magnitude, from a maximum of 36% to a maximum of 2.3%. At the other tributary and both the inner and outer estuaries, the risk decreased to less than 1%, regardless of the tide. This analysis revealed that the remediation system was very effective and that the standard level of protection required for slightly to moderately affected ecosystems (95% of species) by the Australian and New Zealand Guidelines for Fresh and Marine Water Quality was met postremediation. PMID- 21557466 TI - Anatomic and etiological classification of congenital limb deficiencies. AB - Limb deficiencies, the congenital absence or hypoplasia of a long bone and/or digits, vary greatly in their anatomy and etiology. Previous attempts to classify the range of possible phenotypes have not included all types of deficiencies. We present a new classification system, which includes all potential phenotypes. Infants with limb deficiencies were identified in the hospital-based Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, MA from the years 1972 to 1974 and 1979 to 2000. Affected infants were classified based on the anatomy and apparent cause of their deficiencies. The prevalence rate of all types of limb deficiency was 0.79/1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies. There was no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects; intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits, with normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects (0.22/1,000), such as amniotic band related limb deficiency. This new classification system includes deficiency of each long bone, as well as absence of any finger or toe. This system will make it possible to establish the prevalence of each specific phenotype. The large number of distinct apparent causes illustrates the marked etiologic heterogeneity of limb deficiencies. PMID- 21557467 TI - The familial association of tourette's disorder and ADHD: the impact of OCD symptoms. AB - Tourette's disorder (TD) frequently co-occurs with attention deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). While the relationship between TD and OCD suggests that they share etiological factors, the exact relationship between TD and ADHD is less clear. The goal of the current analyses was to understand better the familial relationship between DSM-IV ADHD and TD. Direct interview diagnostic data from a case-control study of 692 relatives of 75 comorbid TD and ADHD (TD + ADHD), 74 TD without ADHD (TD Only), 41 ADHD without TD (ADHD Only), and 49 control probands were analyzed. Hierarchical loglinear modeling was used to explore association patterns between TD, ADHD, and OCD or sub-clinical OCD (OCD/OCDsub) diagnoses among the 190 affected probands and their 538 relatives. The presence of OCD or OCDsub diagnosis in a proband was associated with a significantly increased risk of comorbid TD + ADHD in his/her relatives. The finding of an association between TD, ADHD and a proband OCD/OCDsub diagnosis was unexpected. The current results suggest that TD, ADHD, and OCD symptoms have overlapping neurobiology when occurring in families of TD and/or ADHD probands. PMID- 21557468 TI - Common genetic influences on depression, alcohol, and substance use disorders in Mexican-American families. AB - Multiple genetic and environmental factors influence the risk for both major depression and alcohol/substance use disorders. In addition, there is evidence that these illnesses share genetic factors. Although, the heritability of these illnesses is well established, relatively few studies have focused on ethnic minority populations. Here, we document the prevalence, heritability, and genetic correlations between major depression and alcohol and drug disorders in a large, community-ascertained sample of Mexican-American families. A total of 1,122 Mexican-American individuals from 71 extended pedigrees participated in the study. All subjects received in-person psychiatric interviews. Heritability, genetic, and environmental correlations were estimated using SOLAR. Thirty-five percent of the sample met criteria for DSM-IV lifetime major depression, 34% met lifetime criteria for alcohol use disorders, and 8% met criteria for lifetime drug use disorders. The heritability for major depression was estimated to be h(2) = 0.393 (P = 3.7 * 10(-6)). Heritability estimates were higher for recurrent depression (h(2) = 0.463, P = 4.0 * 10(-6)) and early onset depression (h(2) = 0.485, P = 8.5 * 10(-5)). While the genetic correlation between major depression and alcohol use disorders was significant (rho(g) = 0.58, P = 7 * 10(-3)), the environmental correlation between these traits was not significant. Although, there is evidence for increased rates of depression and substance use in US-born individuals of Mexican ancestry, our findings indicate that genetic control over major depression and alcohol/substance use disorders in the Mexican-American population is similar to that reported in other populations. PMID- 21557469 TI - Animal egg as evolutionary innovation: a solution to the "embryonic hourglass" puzzle. AB - The evolutionary origin of the egg stage of animal development presents several difficulties for conventional developmental and evolutionary narratives. If the egg's internal organization represents a template for key features of the developed organism, why can taxa within a given phylum exhibit very different egg types, pass through a common intermediate morphology (the so-called "phylotypic stage"), only to diverge again, thus exemplifying the embryonic "hourglass"? Moreover, if different egg types typically represent adaptations to different environmental conditions, why do birds and mammals, for example, have such vastly different eggs with respect to size, shape, and postfertilization dynamics, whereas all these features are more similar for ascidians and mammals? Here, I consider the possibility that different body plans had their origin in self organizing physical processes in ancient clusters of cells, and suggest that eggs represented a set of independent evolutionary innovations subsequently inserted into the developmental trajectories of such aggregates. I first describe how "dynamical patterning modules" (DPMs) associations between components of the metazoan developmental-genetic toolkit and certain physical processes and effects may have organized primitive animal body plans independently of an egg stage. Next, I describe how adaptive specialization of cells released from such aggregates could have become "proto-eggs," which regenerated the parental cell clusters by cleavage, conserving the characteristic DPMs available to a lineage. Then, I show how known processes of cytoplasmic reorganization following fertilization are often based on spontaneous, self-organizing physical effects ("egg-patterning processes": EPPs). I suggest that rather than acting as developmental blueprints or prepatterns, the EPPs refine the phylotypic body plans determined by the DPMs by setting the boundary and initial conditions under which these multicellular patterning mechanisms operate. Finally, I describe how this new perspective provides a resolution to the embryonic hourglass puzzle. PMID- 21557470 TI - Dual enlargement of gold nanoparticles: from mechanism to scanometric detection of pathogenic bacteria. AB - A mechanism of dual enlargement of gold nanoparticles (AuNPs) comprising two steps is described. In the first step, the AuNPs are enlarged by depositing Au atoms on their crystalline faces. In this process, the particles are not only enlarged but they are also observed to multiply: new Au nuclei are formed by the budding and division of the enlarged particles. In the second step, a silver enhancement is subsequently performed by the deposition of silver atoms on the enlarged and newly formed AuNPs to generate bimetallic Au@Ag core-shell structures. The dual nanocatalysis greatly enhances the electron density of the nanostructures, leading to a stronger intensity for colorimetric discrimination as well as better sensitivity for quantitative measurement. Based on this, a simple scanometric assay for the on-slide detection of the food-born pathogen Campylobacter jejuni is developed. After capturing the target bacteria, gold tagged immunoprobes are added to create a signal on a solid substrate. The signal is then amplified by the dual enlargement process, resulting in a strong color intensity that can easily be recognized by the unaided eye, or measured by an inexpensive flatbed scanner. In this paper, dual nanocatalysis is reported for the first time. It provides a valuable mechanistic insight into the development of a simple and cost-effective detection format. PMID- 21557471 TI - Sequential injection-bead injection-lab-on-valve coupled to high-performance liquid chromatography for online renewable micro-solid-phase extraction of carbamate residues in food and environmental samples. AB - A sequential injection-bead injection-lab-on-valve system was hyphenated to HPLC for online renewable micro-solid-phase extraction of carbamate insecticides. The carbamates studied were isoprocarb, methomyl, carbaryl, carbofuran, methiocarb, promecarb, and propoxur. LiChroprep((r)) RP-18 beads (25-40 MUm) were employed as renewable sorbent packing in a microcolumn situated inside the LOV platform mounted above the multiposition valve of the sequential injection system. The analytes sorbed by the microcolumn were eluted using 80% acetonitrile in 0.1% acetic acid before online introduction to the HPLC system. Separation was performed on an Atlantis C-18 column (4.6 * 150 mm, 5 MUm) utilizing gradient elution with a flow rate of 1.0 mL/min and a detection wavelength at 270 nm. The sequential injection system offers the means of performing automated handling of sample preconcentration and matrix removal. The enrichment factors ranged between 20 and 125, leading to limits of detection (LODs) in the range of 1-20 MUg/L. Good reproducibility was obtained with relative standard deviations of <0.7 and 5.4% for retention time and peak area, respectively. The developed method has been successfully applied to the determination of carbamate residues in fruit, vegetable, and water samples. PMID- 21557472 TI - A chiral HPLC-UV method for the quantification of dibenz[b,f]azepine-5 carboxamide derivatives in mouse plasma and brain tissue: eslicarbazepine acetate, carbamazepine and main metabolites. AB - For the first time, a selective and sensitive chiral HPLC-UV method was developed and fully validated for the simultaneous quantification of eslicarbazepine acetate (ESL), carbamazepine (CBZ), S-licarbazepine (S-Lic), R-licarbazepine (R Lic), oxcarbazepine (OXC) and carbamazepine-10,11-epoxide (CBZ-E), in mouse plasma and brain homogenate supernatant. After the addition of chloramphenicol as the internal standard, samples were processed using an SPE procedure. The chiral chromatographic analysis was carried out on a LiChroCART 250-4 ChiraDex column, employing a mobile phase of water and methanol (88:12, v/v) pumped at 0.9 mL/min and the UV detector set at 235 nm. The assay was linear (r(2) >=0.995) for ESL, CBZ, OXC, S-Lic, R-Lic and CBZ-E in the range of, respectively, 0.2-4, 0.4-30, 0.1-60, 0.2-60, 0.2-60 and 0.2-30 MUg/mL, in plasma, and of 0.06-1.5 MUg/mL for ESL, 0.12-15 MUg/mL for CBZ and CBZ-E and 0.06-15 MUg/mL for OXC and both licarbazepine (Lic) enantiomers in brain homogenate supernatant. The overall precision was within 8.71% and accuracy ranged from -7.55 to 8.97%. The recoveries of all the compounds were over 92.1%. Afterwards, the application of the method was demonstrated using real plasma and brain samples obtained from mice administered simultaneously with ESL and CBZ. PMID- 21557473 TI - Recent developments and applications of molecularly imprinted monolithic column for HPLC and CEC. AB - As a new generation of stationary phases, monolithic supports have attracted significant interest in high-performance liquid chromatography (HPLC) and capillary electrochromatography (CEC) because of their ease of preparation, high reproducibility, versatile surface chemistry and rapid mass transport. Molecularly imprinted polymers (MIPs) are synthetic materials with high specific recognition ability to template molecule. The combination of monolithic column and MIPs integrates the high efficiency of modern chromatography and the high selectivity provided by MIPs. This review focuses on the recent developments and applications of all kinds of monolithic matrix, i.e. organic polymer-based and silica-based MIP monolith in HPLC and CEC mode. PMID- 21557474 TI - HPLC determination of cefprozil in tablets using monolithic and C18 silica columns. AB - Cefprozil (CPZ) is a second-generation semi-synthetic cephalosporin antibiotic that commonly exists as the mixture of Z and E diastereoisomers, at the ratio of approximately 9:1. A novel reversed-phase HPLC method for the determination of CPZ in tablets was described. The separation of CPZ diastereoisomers and caffeine (internal standard) was carried out by applying the same analytical and instrumental conditions on two stationary phases, which have different surface chemistries. The columns used in the study were monolithic silica Merck Chromolith Performance RP-18e and conventional C18 silica Phenomenex Synergi Hydro RP columns. In total, 10 MUL aliquots of samples were injected into the system and eluted using water-acetonitrile (90:10, v/v) solution, which was pumped through the column at a flow rate of 1.0 mL/min. The analyte peaks were detected at 200 nm using diode array detector with high specificity. CPZ diastereoisomers and caffeine were measured within 13 min using the C18 column, whereas <5 min was required for the monolithic one. Validation studies were performed according to official recommendations. Value of a monolithic column for the assay of diastereoisomers in pharmaceutical tablets was evaluated for the first time and found as a powerful alternative to highly efficient C18 columns. PMID- 21557475 TI - Separation of adrenergic amines in Citrus aurantium L. var. amara by capillary electrochromatography using a novel monolithic stationary phase. AB - This manuscript reports on the use of capillary electrochromatography for the determination of tyramine, (+/-) synephrine, and (+/-) octopamine, the major alkaloids in bitter orange peel. A novel methacrylate-based monolithic stationary phase was prepared by UV-photopolymerization in 100 MUm id fused-silica capillaries. It facilitated the quantitative assessment of alkaloids with a mobile phase comprising aqueous 10 mM ammonium acetate in ACN and isopropanol. Applied voltage and temperature were 25 kV and 25 degrees C, and samples were injected in electrokinetic mode. The method reported herein revealed adequate sensitivity (LOD <=0.6 MUg/mL), repeatability (sigmarel <=4.1%), accuracy (recovery rates between 95.2 and 102.2%), and precision (intra-day variation <=5.7%, inter-day variation <=4.1%). The application of the CEC assay on C. aurantium var. amara plant material and dietary supplements, which usually are advertised for slimming properties, indicated that synephrine (0.17-0.82%) is the dominant alkaloid. PMID- 21557476 TI - DNA amplification via polymerase chain reaction inside miniemulsion droplets with subsequent poly(n-butylcyanoacrylate) shell formation and delivery of polymeric capsules into mammalian cells. AB - There is a growing interest in the development of stable nanocapsules that could deliver the bioactive compounds within the living organism, and to release them without causing any toxic effects. Here the miniemulsion droplets were first used as "nanoreactors" for the amplification of single-molecule dsDNA template (476 and 790 base pairs) through PCR. Afterwards, each droplet was surrounded with a biodegradable PBCA shell by interfacial anionic polymerization, enabling therefore to deliver the PCR products into the cells. The size of the initial miniemulsion droplets and the final polymeric capsules was in the range of 250 and 320 nm, mainly depending on the type of the continuous phase and presence of dsDNA template molecules. The formation of PCR products was resolved with gel electrophoresis and detected with fluorescence spectroscopy in the presence of DNA specific dye (SYBRGreen). TEM studies were performed to prove the formation of the polymeric shell. The shell thickness was measured to be within 5-15 nm and the average molecular weight of the formed PBCA polymer was around 75000 g . mol( 1) . For the cell uptake experiments, the obtained nanocapsules were transferred from the organic phase into aqueous medium containing a water-soluble surfactant. The effect of the surfactant type (anionic, cationic or non-ionic) on the HeLa cell viability and nanocapsule uptake behavior was studied by CLSM and FACS. Confocal analysis demonstrated that nanocapsules stabilized with cationic (CTMA Cl) and non-ionic (Lutensol AT50) surfactants show almost the same uptake, whereas capsules redispersed in anionic (SDS) surfactant possess a 30% higher uptake. The release of the encapsulated material within the cell was studied on the example of Cy5-labeled oligonucleotides showing the colocalization with mitochondria of MSCs cells. PMID- 21557477 TI - Interactions between a luminescent conjugated oligoelectrolyte and insulin during early phases of amyloid formation. AB - Aggregates of misfolded proteins play an important role in diseases such as Alzheimer's. Here it is demonstrated how the anionic oligothiophene p-FTAA interacts with and influences pre-fibrillar protein assemblies during the earlier stages of in vitro fibrillation. Conjugated polythiophenes have previously been demonstrated to detect and discriminate between different types of protein aggregates and also introduce luminescent or conductive properties to these nanoscale fiber structures. Fluorescence spectroscopy, DLS, TEM and FCS are employed to follow the interplay between p-FTAA and insulin during in vitro fibrillation. PMID- 21557478 TI - A thermoresponsive hydrogel based on telechelic PEG end-capped with hydrophobic dipeptides. AB - The self-assembly in aqueous solution of PEG (1500 Da) telechelically end-capped with hydrophobic dipeptides has been investigated using spectroscopic, microscopic, scattering, and rheological methods. A self-assembled beta-sheet fibril-based hydrogel has been identified (containing dityrosine end groups), which exhibits a gel-sol transition near body temperature. This thermo-responsive PEG-based biofunctional hydrogel is expected to have diverse potential uses in delivery or diagnostics for biomedical applications. PMID- 21557479 TI - Biofunctionalization of polyelectrolyte microcapsules with biotinylated polyethylene glycol-grafted liposomes. AB - Hollow polyelectrolyte microcapsules (PEMC) are prepared using layer-by-layer self-assembly of polyelectrolytes on melamine formaldehyde templates, followed by template dissolution, and subsequent coating with biotinylated polyethylene glycol-grafted liposomes. These potential site-specific carrier systems show a high specificity for NeutrAvidin binding and a strong resistance against unspecific protein binding. It is concluded that this design with NeutrAvidin as the outermost layer of such capsules provides an ideal platform for the biofunctionalization of PEMC as drug delivery systems or as artificial cell-like structures for biomimetic studies. PMID- 21557480 TI - Ionic liquids as active pharmaceutical ingredients. AB - Ionic liquids (ILs) are ionic compounds that possess a melting temperature below 100 degrees C. Their physical and chemical properties are attractive for various applications. Several organic materials that are now classified as ionic liquids were described as far back as the mid-19th century. The search for new and different ILs has led to the progressive development and application of three generations of ILs: 1) The focus of the first generation was mainly on their unique intrinsic physical and chemical properties, such as density, viscosity, conductivity, solubility, and high thermal and chemical stability. 2) The second generation of ILs offered the potential to tune some of these physical and chemical properties, allowing the formation of "task-specific ionic liquids" which can have application as lubricants, energetic materials (in the case of selective separation and extraction processes), and as more environmentally friendly (greener) reaction solvents, among others. 3) The third and most recent generation of ILs involve active pharmaceutical ingredients (API), which are being used to produce ILs with biological activity. Herein we summarize recent developments in the area of third-generation ionic liquids that are being used as APIs, with a particular focus on efforts to overcome current hurdles encountered by APIs. We also offer some innovative solutions in new medical treatment and delivery options. PMID- 21557481 TI - Polyaniline-intercalated molybdenum oxide nanocomposites: simultaneous synthesis and their enhanced application for supercapacitor. AB - A new and universal synthetic strategy to hybridize metal oxides and conduct polymer nanocomposites has been proposed in this work. The simultaneous reaction process, which includes the generation of metal oxide layers, the oxidation polymerization of monomers, and the in situ formation of polymer-metal oxides sandwich structure is successfully realized and results in the unique hybrid polyaniline (PANI)-intercalated molybdenum oxide nanocomposites. The peroxomolybdate proved to play a dual role as the precursor of the inorganic hosts and the oxidizing agent for polymerization. The as-obtained hybrid nanocomposites present a flexible lamellar structure by oriented assembly of conductive PANI chains in the MoO(3) interlayer, and thus inherit excellent electrical performance and possess the potential of active electrode materials for electrochemical energy storage. Such uniform lamellar structure together with the anticipated high conductivity of the hybrid PANI/MoO(3) nanocomposites afford high specific capacitance and good stability during the charge-discharge cycling for supercapacitor application. PMID- 21557482 TI - Synthesis of cyclic selenenate/seleninate esters stabilized by ortho-nitro coordination: their glutathione peroxidase-like activities. AB - The syntheses of selenenate/seleninate esters and related derivatives by aromatic nucleophilic substitution (S(N)Ar) reactions of 2-bromo-3-nitrobenzylalcohol (13) and 2-bromo-3-nitrobenzaldehyde (17) with Na(2)Se(2)/nBuSeNa are described. The reaction of 13 with Na(2)Se(2) at room temperature afforded 7-nitro-1,2 benzisoselenole(3H) (15) instead of the desired diaryl diselenide 14. Oxidation of selenenate ester 15 with hydrogen peroxide afforded the corresponding selenium(IV) derivative, 7-nitro-1,2-benzisoselenole(3H) selenium oxide (18). 2 (Butylselanyl)-3-nitrobenzaldehyde (19) was synthesized by treating compound 17 with in situ generated nBuSeNa. The bromination reaction of selenide 19 did not afford the expected arylselenenyl bromide 20, instead, it resulted in the formation of the unexpected 7-nitro-1,2-benzisoselenol(3H)-3-ol (21) and 3,3' oxybis(7-nitro-1,2-benzisoselenole(3H)) (22), respectively. The facile formation of heterocycles 21 and 22 is rationalized in terms of the aromatic ring strain in selenenyl bromide 20. The presence of intramolecular secondary Se...O interactions in esters 15, 18, 21, 22, and selenenic anhydride 29 has been confirmed by single-crystal X-ray diffraction studies as well as computational studies. The presence of an intramolecular Se...O interaction in esters 4b, 8, 15, 18, 21, and 22 has been further proved by natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Glutathione peroxidase-like (GPx) antioxidant activities of 15, 18, 21, 22, and related heterocycles such as 7 nitro-1,2-benzisoselenol(2H)-3-one selenium oxide (4b), 7-nitro-1,2 benzisoselenol(2H)-3-one (8), and 29 have been determined by the coupled reductase assay. PMID- 21557483 TI - A facile synthesis of highly substituted five-membered rings: Mukaiyama-aldol oxonoium-ene (MAOE) domino reaction. PMID- 21557484 TI - Theoretical investigation of 4,4',6,6'-tetra(azido)azo-1,3,5-triazine-N-oxides and the effects of N->O bonding on organic azides. AB - A family of 4,4',6,6'-tetra(azido)azo-1,3,5-triazine-N-oxides was designed and investigated by theoretical method. The effects of the N->O bond on the properties of TAAT-N-oxides, such as density, heat of formation, and detonation performance, were discussed. By comparison with the bond-dissociation energy of the weakest bond and the electrostatic potentials, the effects of the N->O bond on the stability and impact sensitivity of organic azides were also discussed. The results show that the introduction of N->O bonds at the appropriate positions increases the oxygen balance and density of the compounds, while it has little effect on the stability and impact sensitivity. Consequently, their introduction results in energetic compounds with improved detonation performances. PMID- 21557485 TI - The effect of the buffering capacity of the supporting electrolyte on the electrochemical oxidation of dopamine and 4-methylcatechol in aqueous and nonaqueous solvents. AB - Dopamine was electrochemically oxidized in aqueous solutions and in the organic solvents N,N-dimethyl-formamide and dimethylsulfoxide containing varying amounts of supporting electrolyte and water, to form dopamine ortho-quinone. It was found that the electrochemical oxidation mechanism in water and in organic solvents was strongly influenced by the buffering properties of the supporting electrolyte. In aqueous solutions close to pH 7, where buffers were not used, the protons released during the oxidation process were able to sufficiently change the localized pH at the electrode surface to reduce the deprotonation rate of dopamine ortho-quinone, thereby slowing the conversion into leucoaminochrome. In N,N-dimethylformamide and dimethylsulfoxide solutions, in the absence of buffers, dopamine was oxidized to dopamine ortho-quinone that survived without further reaction for several minutes at 25 degrees C. The voltammetric data obtained in the organic solvents were made more complicated by the presence of HCl in commercial sources of dopamine, which also underwent an oxidation process. PMID- 21557486 TI - New design tactics in OLEDs using functionalized 2-phenylpyridine-type cyclometalates of iridium(III) and platinum(II). AB - As a result of their outstanding attributes, organic light-emitting diodes (OLEDs) and white organic light-emitting diodes (WOLEDs) have been recognized in recent years as the most promising candidates for future flat-panel display technologies and next generation solid-state energy-saving lighting sources. New advancements in the area of high performance triplet emitters become vital for realizing more practical applications. In this regard, several critical issues must be carefully identified and addressed, and these include the ways to enhance device efficiency and suppress efficiency roll-off, to achieve versatile color tuning and simple device manufacture, as well as to obtain high-quality white light from WOLEDs. It has been shown that some functionalized phosphorescent Ir(III) and Pt(II) ppy-type cyclometalated complexes (ppy = 2-phenylpyridine) possess unique features that are suitable for solving these difficult and challenging tasks. In this Focus Review, we will highlight the recent design tactics adopted for these functional metallophosphors and the critical roles they may play in developing more realistic devices. PMID- 21557487 TI - DNA interstrand cross-links of an antitumor trinuclear platinum(II) complex: thermodynamic analysis and chemical probing. AB - The trinuclear platinum compound [{trans-PtCl(NH(3))(2)}(2)(MU-trans Pt(NH(3))(2){NH(2)(CH(2))(6)NH(2)}(2))](4+) (BBR3464) belongs to the polynuclear class of platinum-based anticancer agents. These agents form in DNA long-range (Pt,Pt) interstrand cross-links, whose role in the antitumor effects of BBR3464 predominates. Our results show for the first time that the interstrand cross links formed by BBR3464 between two guanine bases in opposite strands separated by two base pairs (1,4-interstrand cross-links) exist as two distinct conformers, which are not interconvertible, not only if these cross-links are formed in the 5'-5', but also in the less-usual 3'-3' direction. Analysis of the conformers by differential scanning calorimetry, chemical probes of DNA conformation, and minor groove binder Hoechst 33258 demonstrate that each of the four conformers affects DNA in a distinctly different way and adopts a different conformation. The results also support the thesis that the molecule of antitumor BBR3464 when forming DNA interstrand cross-links may adopt different global structures, including different configurations of the linker chain of BBR3464 in the minor groove of DNA. Our findings suggest that the multiple DNA interstrand cross-links available to BBR3464 may all contribute substantially to its cytotoxicity. PMID- 21557488 TI - Exploring new molecular architectures for anion recognition: synthesis and ATP binding properties of new cyclam-based ditopic polyammonium receptors. AB - Synthesis and characterization of three new polyamine receptors, composed of a cyclam unit (cyclam=1,4,8,11-tetraazacyclotetradecane) linked by a 2,6 dimethylpyridinyl spacer to the linear polyamines 1,4,8,11-tetraazaundecane (L1py), 1,4,7-triazaheptane (L2py), and to a quaternary ammonium group (L3py(+)), are reported. All receptors form highly charged polyammonium cations at neutral pH, suitable for anion recognition studies. ATP recognition was analyzed by using potentiometric, calorimetric, (1)H and (31)P NMR measurements in aqueous solution. All receptors form 1:1 adducts with ATP in aqueous solution, stabilized by charge-charge and hydrogen-bonding interactions between their ammonium groups and the anionic triphosphate chain of ATP. The binding ability of the three receptors for ATP increases in the order of L3py(+)=2.6 were eligible for retreatment. Physical function was assessed by Health Assessment Questionnaire (HAQ) disability index (DI) and Short Form 36 (SF-36) scores. Patients achieving a minimal clinically important difference (MCID) for PROs were determined. Additional PROs, including fatigue and pain, were assessed. RESULTS: A total of 748 patients were randomized and received the study drug. Patient characteristics were well balanced. At week 52, treatment with rituximab in both dose groups showed significant improvements in the HAQ DI compared to the MTX alone group (-0.905 and -0.916 in the rituximab 500 mg plus MTX and 1,000 mg plus MTX groups, respectively, versus -0.628 in the MTX alone group; P < 0.0001). Higher proportions of patients achieved MCID in the HAQ DI in the rituximab plus MTX groups compared to MTX alone. Treatment with rituximab plus MTX led to a significant reduction in the SF-36 physical component summary for both rituximab dose groups, but did not show statistically significant differences in the SF-36 mental component summary. Compared to the MTX alone group, both doses of rituximab plus MTX were associated with significant reductions in the patient global assessment of disease activity and pain, and a significantly higher improvement in Functional Assessment of Chronic Illness Therapy-Fatigue scores from baseline to 52 weeks. CONCLUSIONS: Rituximab plus MTX was associated with significant improvement in physical function and HRQOL outcomes compared with MTX alone in patients previously untreated with MTX. PMID- 21557526 TI - Patterns of medication use during pregnancy in rheumatoid arthritis. AB - OBJECTIVE: To characterize therapies prescribed during pregnancy to women with rheumatoid arthritis (RA). METHODS: We conducted a cohort study of women with RA with pregnancies using health care utilization data from 2002-2008. We examined the distribution of RA drugs by therapeutic classes, including nonsteroidal antiinflammatory drugs (NSAIDs)/coxibs, glucocorticoids, nonbiologic disease modifying antirheumatic drugs (DMARDs), and biologic DMARDs, during 90-day pregnancy trimesters and the 180 days prior to pregnancy. Drugs were characterized according to the Food and Drug Administration risk classification system. Differences in exposure by period were determined by chi-square tests. RESULTS: A total of 393 pregnancies were identified among 34,169 women with RA. Seventy-two percent of pregnancies ended in a delivery. Approximately 24% of women with RA received a DMARD during preconception. At any point during pregnancy, 23% of women with deliveries were dispensed >=1 DMARD and the proportion of use declined from the first to the third trimester (P = 0.03). Similar to DMARD therapy, use of NSAIDs/coxibs and exposure to category D/X medications were significantly lower compared to prepregnancy use (P < 0.05). In contrast, more women were prescribed glucocorticoids during pregnancy than before pregnancy. Use of biologics occurred in 12.5% of pregnancies. Compared to women with deliveries, women who experienced abortions were more frequently exposed to NSAIDs/coxibs (P < 0.05). Dispensing of category D/X medications was also higher in women with spontaneous abortions and primarily involved methotrexate (P < 0.05). CONCLUSION: Approximately 24% of women with RA received a DMARD in the 180 days before conception, and the proportion dropped during pregnancy. Glucocorticoid use remained high throughout pregnancy. Our results suggest that continued efforts directed at counseling women and their physicians about the potential risks/benefits of RA therapies during pregnancy are warranted. PMID- 21557528 TI - Initial evaluation of an ultrasound measure for assessing the activity of skin lesions in juvenile localized scleroderma. AB - OBJECTIVE: To evaluate the construct validity of 2 proposed measures (the Ultrasound Disease Activity [U-DA] and the Tissue Thickness Score [TTS]) for evaluating sonographic differences in juvenile localized scleroderma skin lesions. METHODS: We conducted a retrospective review of juvenile localized scleroderma patients who had ultrasound scans of their skin lesions between October 2005 and February 2009. Imaged lesions were classified as active or inactive based upon clinical assessment. Lesions had to have been imaged within 1 month of a clinic visit or have the same clinical assessment during both the visit before and the visit after the scan. Two physicians scored the scans using the U-DA, which scores for differences in lesion echogenicity and vascularity compared with normal tissue. Tissue thickness differences were evaluated by percent differences and by using the TTS. Wilcoxon's rank sum test was performed to assess differences. RESULTS: We studied 52 scans from 21 patients, 32 scans of active skin lesions and 20 scans of inactive skin lesions. Features reported by clinicians as indicative of active disease included erythema, warmth, violaceous color, new lesion, expansion of lesion, and induration. The U-DA was significantly different between active and inactive skin lesions (P = 0.0010) with significant differences found for the parameters of total echogenicity, hypodermis echogenicity, and deep tissue layer vascularity (P = 0.0014, P = 0.0023, and P = 0.0374, respectively). No significant differences were found for tissue layer thickness or TTS. CONCLUSION: The U-DA may be a useful tool in the identification of localized scleroderma activity. Further study is needed to prospectively evaluate the validity, reliability, and sensitivity of this potential monitoring tool. PMID- 21557530 TI - Cost-of-illness studies in systemic lupus erythematosus: A systematic review. AB - OBJECTIVE: To summarize the state of knowledge regarding the economic burden of systemic lupus erythematosus (SLE) and to evaluate the quality of cost-of-illness (COI) studies conducted to date. METHODS: Relevant literature was retrieved from the PubMed database in April 2010. The evaluation of identified articles was based on 7 key elements of COI studies derived from previous literature on health economics. Costs derived from each study were converted into 2008 US dollars using the Consumer Price Index and the purchasing power parity conversion rate. RESULTS: A total of 11 articles were included in the evaluation. The average direct costs per patient-year ranged from $3,735-$14,410. Costs of inpatient care were found to be the largest component of direct costs in most of the studies. The employment rate varied from 35.8-55%. The average duration of annual short term sick leave ranged from 7.0-64.8 days. The mean annual indirect costs per patient ranged from $1,093-$14,614, depending on the valuation method. CONCLUSION: There is a substantial economic burden, in terms of health care resource utilization, associated with SLE, as well as losses of productivity due to work capacity impairment. The cost estimates in this review should be used with caution due to significant discrepancies in methodologies across studies. Future studies should address several methodologic considerations in order to measure the true costs related to SLE. Incidence-based COI studies are needed to evaluate the lifetime costs of SLE. PMID- 21557533 TI - Macrophage activation syndrome revealing familial Mediterranean fever. PMID- 21557534 TI - A simplified Bethesda System for reporting thyroid cytopathology using only four categories improves intra- and inter-observer diagnostic agreement and provides non-overlapping estimates of malignancy risks. AB - Our previous study utilizing the 2008 NCI six-category system (also known as The Bethesda System) for reporting thyroid fine-needle aspirations (FNA) identified considerable overlap in diagnosis and in assigned malignancy risk estimates for the "follicular lesion of undetermined significance (FLUS)" and "follicular neoplasm (FN)" categories and for the "suspicious for malignancy (Susp)" and "malignant" categories. We proposed a simplified Bethesda System for reporting thyroid FNAs that provided four non-overlapping, statistically significant, and more clinically relevant diagnostic categories: unsatisfactory, benign, FLUS/FN, and Susp/malignant. In the current study, six cytopathologists participated in a blinded retrospective review of 60 thyroid FNAs and kappa statistics were utilized to compare the intra- and inter-observer diagnostic agreements obtained using the six-category and the simplified four-category schemes. Surgical follow up was used to determine which scheme provided more discrete malignancy risk estimates. Use of the simplified four-category scheme significantly improved intra- and inter-observer diagnostic agreement levels, significantly increased the sensitivity of FNA for a diagnosis of carcinoma in the subsequently resected thyroid glands, and provided non-overlapping malignancy risk estimates for each diagnostic category. PMID- 21557535 TI - Equivocal and weakly positive hybrid capture 2 tests in women aged 50 and older. AB - The performance of the Hybrid Capture 2 (HC2) test for human papilloma virus (HPV) detection depends on the prevalence of infection. However, the current HC2 manufacturer recommended interpretative algorithm is the same for all women. This test, which may be particularly useful in perimenopausal and postmenopausal women given the morphologic complexity of their Pap tests, could be affected by the overall lower prevalence of HPV infection in this age group. We investigated HC2 equivocal and weakly positive HPV tests in women 50 years and older and the detection of high-grade dysplasia (CIN2+) on their follow-up specimens. All HC2 test data from 1,067 consecutive specimens and 85 additional specimens from women >= 50-years-old with equivocal and weakly positive HC2 were analyzed. Follow-up specimens from women with HC2 tests within these ranges were reviewed. No CIN2+ was found on follow-up of 49 cases of women >= 50 with equivocal or weakly positive HC2 results. The current HC2 algorithm resulted in "positive" reports in 63% of specimens with initial equivocal HC2 due to retests mostly within the equivocal range. These results suggest that women 50 years and older may benefit from higher HC2 thresholds. The test could also be reported as HC2 values (RLU/CO) to be interpreted in view of risk factors. PMID- 21557536 TI - Redox-responsive polyphosphate nanosized assemblies: a smart drug delivery platform for cancer therapy. AB - Novel redox-responsive polyphosphate nanosized assemblies based on amphiphilic hyperbranched multiarm copolyphosphates (HPHSEP-star-PEP(x)) with backbone redox responsive, good biocompatibility, and biodegradability simultaneously have been designed and prepared successfully. The hydrophobic core and hydrophilic multiarm of HPHSEP-star-PEP(x) are composed of hyperbranched and linear polyphosphates, respectively. Benefiting from the amphiphilicity, HPHSEP-star-PEP(x) can self assemble into spherical micellar nanoparticles in aqueous media with tunable size from about 70 to 100 nm via adjusting the molecular weight of PEP multiarm. Moreover, HPHSEP-star-PEP(x) micellar structure can be destructed under reductive environment and result in a triggered drug release behavior. The glutathione mediated intracellular drug delivery was investigated against a HeLa human cervical carcinoma cell line, and the results indicate that doxorubicin-loaded (DOX-loaded) HPHSEP-star-PEP(x) micelles show higher cellular proliferation inhibition against glutathione monoester pretreated HeLa cells than that of the nonpretreated ones. In contrast, the DOX-loaded micelles exhibit lower inhibition against buthionine sulfoximine pretreated HeLa cells. These results suggest that such redox-responsive polyphosphate micelles can rapidly deliver anticancer drugs into the nuclei of tumor cells enhancing the inhibition of cell proliferation and provide a favorable platform to construct excellent drug delivery systems for cancer therapy. PMID- 21557537 TI - Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. AB - C57BL/6 mice are widely used in biomedical research for the background of genetically engineered mice (GEM) and wild-type controls with the belief that the genetic background of GEM and control mice differ significantly by only one or more altered genes. This principle, however, does have limitations due in part to the existence of multiple substrains of C57BL/6 mice that should not be used interchangeably as they can differ both genetically and phenotypically. We show here that these mispairings do occur frequently and can lead to inaccurate and conflicting findings. PMID- 21557538 TI - Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl thiazoles analogues as potent and orally bioavailable anticancer agents. AB - In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)). PMID- 21557539 TI - Development of an optical biosensor based immunoassay to screen infant formula milk samples for adulteration with melamine. AB - The illegal adulteration of milk with melamine in 2008 in China led to adverse kidney and urinary tract effects in hundreds of thousands of children and the reported deaths of six. The milk had been deliberately adulterated to elevate the apparent protein content, and subsequently melamine was detected in many milk related products which had been exported. This led to the banning of imports of milk and milk products from China intended for the nutritional use of children and to the implementation of analytical methods to test products containing milk products. An optical biosensor inhibition immunoassay has been developed as a rapid and robust method for the analysis of infant formula and infant liquid milk samples. A compound with a chemical structure similar to that of melamine was employed as a hapten to raise a polyclonal antibody and as the immobilized antigen on the surface of a biosensor chip. The sensitivity of the assay, given as an IC(50), was calculated to be 67.9 ng mL(-1) in buffer. The antibody did not cross-react with any of the byproducts of melamine manufacture; however, significant cross-reactivity was observed with the insecticide cyromazine of which melamine is a metabolite. When sample matrix was applied to the assay, a limit of detection of <0.5 MUg mL(-1) was determined in both infant formula and infant liquid milk. The development of the immunoassay and validation data for the detection of melamine is presented together with the results obtained following the analysis of melamine-contaminated milk powder. PMID- 21557540 TI - Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor gamma. AB - Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-gamma (PPARgamma) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPARgamma confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARgamma activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2 ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC(50) = 1.6 nM) with partial PPARgamma agonism (EC(50) = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat. PMID- 21557541 TI - Mechanical reinforcement of nanoparticle thin films using atomic layer deposition. AB - Thin films composed of nanoparticles exhibit synergistic properties, making them useful for numerous advanced applications. Nanoparticle thin films (NTFs), however, have a very low resistance to mechanical loading and abrasion, presenting a major bottleneck to their widespread use and commercialization. High temperature sintering has been shown to improve the mechanical durability of NTFs on inorganic substrates; however, these high-temperature processes are not amenable to organic substrates. In this study, we demonstrate that the mechanical durability of TiO(2)/SiO(2) nanoparticle layer-by-layer (LbL) films on glass and polycarbonate substrates can be drastically improved using atomic layer deposition (ALD) at a relatively low temperature. The structure and physical properties of ALD-treated TiO(2)/SiO(2) nanoparticle LbL films are studied using spectroscopic ellipsometry, UV-vis spectroscopy, contact angle measurements, and nanoindentation. The composition of TiO(2)/SiO(2) LbL films as a function of ALD cycle number is determined through solution ellipsometry, enabling the determination of the characteristic pore size of nanoparticle thin films. Mechanical durability is also investigated by abrasion tests, showing that the robustness of ALD-treated nanoparticle films is comparable to that of thermally calcined films. More importantly, ALD-treated nanoparticle films retain the original functionality of the TiO(2)/SiO(2) LbL films, such as superhydrophilicity and antireflection properties, demonstrating the utility of ALD as a reinforcement method for nanoparticle thin films. PMID- 21557542 TI - Electrical conductivity, chemistry, and bonding alternations under graphene oxide to graphene transition as revealed by in situ TEM. AB - A suspended graphene oxide device is fabricated and investigated using a transmission electron microscope (TEM) scanning tunneling microscope (STM) setup. A detailed study of step-by-step reduction of an individual graphene oxide sheet under current flow and Joule heating in tandem with conductivity measurements, atomic structure imaging, chemical composition, and bonding alternations tracing is performed. As monitored by electron energy loss spectroscopy, the oxygen content is tuned from that peculiar to a pristine graphene oxide (i.e., 23.8 at %) to oxygen-free pure graphene. Six orders of magnitude conductance rise is observed during this process with the final conductivity reaching 1.5 * 10(5) S/m. Quantification of plasma energy losses of the starting graphene oxide shows that ~40% of the oxygen atoms are in the form of epoxy, and ~60% oxygen atoms are in the form of hydroxyl. The total portion of sp(3) bonds in pristine graphene oxide is estimated to be ~45%. The epoxy groups show a larger influence on the conductivity of graphene oxide than hydroxyl ones. Through analyzing consecutive plasma-loss energy spectra under gradual graphene oxide to graphene transformation, it is found that the oxygen atoms in epoxy groups decompose prior to those in hydroxyl groups. PMID- 21557544 TI - Curved silicon nanowires with ribbon-like cross sections by metal-assisted chemical etching. AB - A generic process for the preparation of curved silicon nanowires (SiNWs) with ribbon-like cross sections was developed. The present synthetic approach is based on chemical etching of (100)-oriented silicon wafers in mixture solutions of HF and H(2)O(2) by using patterned thin gold films as catalyst and provides a unique opportunity for the fabrication of extended arrays of zigzag SiNWs, ultrathin straight [111] SiNWs, and curved SiNWs with controlled turning angles. On the basis of our experiments performed under various etching conditions, the factors governing the axial crystal orientation and morphology of SiNWs were systematically analyzed. We proposed a model that explains the formation of the present novel silicon nanostructures during chemical etching of silicon. PMID- 21557543 TI - Lipoprotein-inspired nanoparticles for cancer theranostics. AB - Over hundreds of millions of years, animals have evolved endogenous lipoprotein nanoparticles for shuttling hydrophobic molecules to different parts of the body. In the last 70 years, scientists have developed an understanding of lipoprotein function, often in relationship to lipid transport and heart disease. Such biocompatible, lipid-protein complexes are also ideal for loading and delivering cancer therapeutic and diagnostic agents, which means that lipoprotein and lipoprotein-inspired nanoparticles also offer opportunities for cancer theranostics. By mimicking the endogenous shape and structure of lipoproteins, the nanocarrier can remain in circulation for an extended period of time, while largely evading the reticuloendothelial cells in the body's defenses. The small size (less than 30 nm) of the low-density (LDL) and high-density (HDL) classes of lipoproteins allows them to maneuver deeply into tumors. Furthermore, lipoproteins can be targeted to their endogenous receptors, when those are implicated in cancer, or to other cancer receptors. In this Account, we review the field of lipoprotein-inspired nanoparticles related to the delivery of cancer imaging and therapy agents. LDL has innate cancer targeting potential and has been used to incorporate diverse hydrophobic molecules and deliver them to tumors. Nature's method of rerouting LDL in atherosclerosis provides a strategy to extend the cancer targeting potential of lipoproteins beyond its narrow purview. Although LDL has shown promise as a drug nanocarrier for cancer imaging and therapy, increasing evidence indicates that HDL, the smallest lipoprotein, may also be of use for drug targeting and uptake into cancer cells. We also discuss how synthetic HDL-like nanoparticles, which do not include human or recombinant proteins, can deliver molecules directly to the cytoplasm of certain cancer cells, effectively bypassing the endosomal compartment. This strategy could allow HDL-like nanoparticles to be used to deliver drugs that have increased activity in the cytoplasm. Lipoprotein nanoparticles have evolved to be ideal delivery vehicles, and because of that specialized function, they have the potential to improve cancer theranostics. PMID- 21557545 TI - Preparation of an ion-imprinted fiber for the selective removal of Cu2+. AB - A novel Cu(2+)-imprinted fiber (IIF) was prepared by grafting acrylic acid (AA) onto the surface of a polypropylene (PP) fiber and subsequently modified with polyethylenimine (PEI). An examination by infrared spectroscopy and scanning electron microscopy confirmed that the ion-imprinted polymer was successfully introduced onto the surface of a PP fiber. The modification of PP fibers with AA was beneficial to the grafting of PEI onto the fibers. The highest grafting degree of PEI could reach 120 wt % under optimal grafting conditions. This IIF showed excellent tensile and chemical stability in acid solution, which qualified the IIF for practical applications. Besides having a high adsorption capacity for Cu(2+) (120 mg/g), the IIF adsorbent showed a high selectivity for Cu(2+) as compared with that of the non-ion-imprinted fiber (NIF). The dynamic adsorption results indicated that IIF can thoroughly remove Cu(2+) from the solution in a relatively short contact time. The effective treatment volume was about 910 bed volumes. The selectivity coefficient of IIF for Cu(2+) with respect to Zn(2+) could reach 76.4. IIF also has good regeneration performance and could maintain almost the same adsorption capacity for copper ions after 10 adsorption desorption cycles. PMID- 21557546 TI - Cellular responses to patterned poly(acrylic acid) brushes. AB - We use patterned poly(acrylic acid) (PAA) polymer brushes to explore the effects of surface chemistry and topography on cell-surface interactions. Most past studies of surface topography effects on cell adhesion have focused on patterned feature sizes that are larger than the dimensions of a cell, and PAA brushes have been characterized as cell repellent. Here we report cell adhesion studies for RBL mast cells incubated on PAA brush surfaces patterned with a variety of different feature sizes. We find that when patterned at subcellular dimensions on silicon surfaces, PAA brushes that are 30 or 15 nm thick facilitate cell adhesion. This appears to be mediated by fibronectin, which is secreted by the cells, adsorbing to the brushes and then engaging cell-surface integrins. The result is detectable accumulation of plasma membrane within the brushes, and this involves cytoskeletal remodeling at the cell-surface interface. By decreasing brush thickness, we find that PAA can be 'tuned' to promote cell adhesion with down-modulated membrane accumulation. We exemplify the utility of patterned PAA brush arrays for spatially controlling the activation of cells by modifying brushes with ligands that specifically engage IgE bound to high-affinity receptors on mast cells. PMID- 21557547 TI - Surface pressure-dependent interactions of secretory phospholipase A2 with zwitterionic phospholipid membranes. AB - The hydrolytic activity of secretory phospholipase A(2) (PLA(2)) is regulated by many factors, including the physical state of substrate aggregates and the chemical nature of phospholipid molecules. In order to achieve strong binding of PLA(2) on its substrates, many previous works have used anionic lipid dispersion to characterize the orientation and penetration depth of PLA(2) molecules on membrane surfaces. In this study, we applied monolayer technique with controllable surface area to investigate the PLA(2)s of Taiwan cobra venom and bee venom on zwitterionic phophatidylcholine monolayers and demonstrated an optimum hydrolytic activity at a surface pressure of 18 and 24 mN/m, respectively. By combining polarized attenuated total reflection Fourier transform infrared spectroscopy and monolayer-binding experiments, we found that the amount of membrane-bound PLA(2) decreased markedly as the surface pressure of the monolayer was increased. Interestingly, the insertion area of the PLA(2)s decreased to near zero as the surface pressure increased to the optimum pressure for hydrolytic activity. On the basis of the measured infrared dichroic ratio, the orientation of the PLA(2)s bound to zwitterionic membranes was similar to that observed on a negatively charged membrane and was independent of the surface pressure. Our findings suggest that both PLA(2)s were located on the membrane surface rather than penetrating the membrane bilayer and that the deeply inserted mode is not a favorable condition for the hydrolysis of phospholipids in zwitterionic phospholipid membranes. The results are discussed in terms of the easy access of catalytic water for the PLA(2) activity and the mobilization of its substrate and product to facilitate the catalytic process. PMID- 21557548 TI - Single-walled carbon nanotubes/polymer composite electrodes patterned directly from solution. AB - This work describes a simple technique for direct patterning of single-walled carbon nanotube (SWNT)/poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) composite electrodes in a large area on a substrate based on the solution transfer process by microcontact printing using poly(dimethylsiloxane) (PDMS) stamps. Various shapes of SWNT/PEDOT-PSS composite patterns, such as line, circle, and square, can be easily fabricated with high pattern fidelity and structural integrity. The single parallel line pattern device exhibits high electrical conductivity (0.75 * 10(5) S/m) and electronic stability because of alignment of nanotubes and big-size SWNT bundles (~5 nm). The electromechanical study reveals that the composite patterns show ~1% resistance change along SWNT alignment direction and ~5% resistance change along vertical alignment direction after 200 bend cycles. Our approach provides a facile, low-cost method to pattern transparent conductive SWNT/polymer composite electrodes and demonstrates a novel platform for future integration of conducting SWNT/polymer composite patterns for optoelectronic applications. PMID- 21557550 TI - Equation of state of colloidal dispersions. AB - We present a comparison of experimentally and theoretically determined osmotic pressures for various colloidal dispersions. Experimental data is collected from several different silica and polystyrene dispersions. The theoretical pressure determinations are based on the primitive model combined with the cell model, and the physical quantities are calculated exactly using Monte Carlo simulations in the canonical and grand canonical ensemble. The input to the simulations in terms of colloidal particle size, surface charge density, and so forth are taken directly from experiments, and the approach does not contain any adjustable parameters. The agreement between theory and experiment is very good without any fitting parameters, showing that the simplifications behind the primitive model and the cell model are physically sound. The results reveal a surprising correspondence between the equations of state in spherical and planar geometries, indicating that the particle shape is of secondary importance in dispersions dominated by repulsive interactions. For one of the silica dispersions, we have also investigated how various monovalent counterions influence the swelling properties. Within experimental error, we are unable to detect any ion specificity, which is further support for the theoretical models used. PMID- 21557551 TI - Tandem "click" reactions at acetylene-terminated Si(100) monolayers. AB - We demonstrate a simple method for coupling alkynes to alkynes. The method involves tandem azide-alkyne cycloaddition reactions ("click" chemistry) for the immobilization of 1-alkyne species onto an alkyne modified surface in a one-pot procedure. In the case presented, these reactions take place on a nonoxidized Si(100) surface although the approach is general for linking alkynes to alkynes. The applicability of the method in the preparation of electrically well-behaved functionalized surfaces is demonstrated by coupling an alkyne-tagged ferrocene species onto alkyne-terminated Si(100) surfaces. The utility of the approach in biotechnology is shown by constructing a DNA sensing interface by derivatization of the acetylenyl surface with commercially available alkyne-tagged oligonucleotides. Cyclic voltametry, electrochemical impedance spectroscopy, X ray photoelectron spectroscopy, and X-ray reflectometry are used to characterize the coupling reactions and performance of the final modified surfaces. These data show that this synthetic protocol gives chemically well-defined, electronically well-behaved, and robust (bio)functionalized monolayers on silicon semiconducting surfaces. PMID- 21557552 TI - Evidence for side-chain pi-delocalization in a planar substituted benzene: an experimental and theoretical charge density study on 2,5-dimethoxybenzaldehyde thiosemicarbazone. AB - The charge density in 2,5-dimethoxybenzaldehyde thiosemicarbazone (1) has been studied experimentally using Mo-K(alpha) X-ray diffraction at 100 K, and by theory using DFT calculations at the B3LYP/6-311++G(2d,2p) level. The quantum theory of atoms in molecules (QTAIM) was used to investigate the extent of pi delocalization in the thioamide side-chain, which is virtually coplanar with the benzene ring. The experimental and theoretical ellipticity profiles along the bond paths were in excellent agreement, and showed that some of the formal single bonds in the side-chain have significant pi-bond character. This view was supported by the magnitudes of the topological bond orders and by the delocalization indices delta(Omega(A), Omega(B)). An orbital decomposition of delta(Omega(A), Omega(B)) demonstrated that there was significant pi-character in all the interchain non-H chemical bonds. On the other hand, the source function referenced at the interchain bond critical points could not provide any evidence for pi-delocalization, showing instead only limited sigma-delocalization between nearest neighbors. Overall, the topological evidence and the atomic graphs of the oxygen atoms did not provide convincing evidence for pi-delocalization involving the methoxy substituents. PMID- 21557553 TI - Accurate determination of the structure of cyclohexane by femtosecond rotational coherence spectroscopy and ab initio calculations. AB - We combine femtosecond time-resolved rotational coherence spectroscopy with high level ab initio theory to obtain accurate structural information for the nonpolar molecules cyclohexane (C(6)H(12)) and cyclohexane-d(12) (C(6)D(12)). We measured the rotational B(0) and centrifugal distortion constants D(J), D(JK) of the v = 0 states of C(6)H(12) and C(6)D(12) to high accuracy, for example, B(0)(C(6)H(12)) = 4306.08(5) MHz, as well as B(v) for the vibrationally excited states nu(32), nu(6), nu(16) and nu(24) of C(6)H(12) and additionally nu(15) for C(6)D(12). To successfully reproduce the experimental RCS transient, the overtone and combination levels 2nu(32), 3nu(32), nu(32) + nu(6), and nu(32) + nu(16) had to be included in the RCS model calculations. The experimental rotational constants are compared to those obtained at the second-order Moller-Plesset (MP2) level. Combining the experimental and calculated rotational constants with the calculated equilibrium bond lengths and angles allows determination of accurate semiexperimental equilibrium structure parameters, for example, r(e)(C-C) = 1.526 +/- 0.001 A, r(e)(C-H(axial)) = 1.098 +/- 0.001 A, and r(e)(C-H(equatorial)) = 1.093 +/- 0.001 A. The equilibrium C-C bond length of C(6)H(12) is only 0.004 A longer than that of ethane. The effect of ring strain due to the unfavorable gauche interactions is mainly manifested as small deviations from the C-C-C, C-C H(axial), and C-C-H(equatorial) angles from the tetrahedral value. PMID- 21557554 TI - Dielectric relaxation spectroscopy of lysozyme aqueous solutions: analysis of the delta-dispersion and the contribution of the hydration water. AB - The dielectric properties of lysozyme aqueous solutions have been investigated over a wide frequency range, from 1 MHz to 50 GHz, where different polarization mechanisms, at a molecular level, manifest. The dielectric relaxation spectra show a multimodal structure, reflecting the complexity of the protein-water interactions, made even more intricate with the increase of the protein concentration. The deconvolution of the spectra into their different components is not unambiguous and is generally a delicate process which requires caution. We have analyzed the whole relaxation region, on the basis of the sum of simple Debye-type relaxation functions, considering three main contributions. Particular attention has been payed to the delta-dispersion, intermediate between the beta dispersion (rotational dynamics of the protein) and the gamma-dispersion (orientational polarization of the water molecules). This intermediate contribution to the dielectric spectrum is attributed to the orientational polarization of water molecules in the immediate vicinity of the protein surface (hydration water). Our measurements clearly demonstrate that, at least at high protein concentrations, the delta-dispersion has a bimodal structure associated with two kinds of hydration water, i.e., tightly bound and loosely bound hydration water. In the concentration range investigated, the existence of a three-modal delta-dispersion, as recently suggested, is not supported, on the basis of statistical tests, by the analysis of the dielectric relaxations we have performed and a bimodal dispersion is accurate enough to describe the experimental data. The amount of the hydration water has been evaluated both from the dielectric parameters associated with the delta-dispersion and from the decrement of the loss peak of the gamma-dispersion. The relative weight of tightly bound and loosely bound hydration water is briefly discussed. PMID- 21557555 TI - Ring currents in polycyclic sodium clusters. AB - In the recent work by Khatua et al. (Khatua, S.; Roy, D. R.; Bultinck, P.; Bhattacharjee, M.; Chattaraj, P. K. Phys. Chem. Chem. Phys.2008, 10, 2461-2474) the synthesis and structure of a fac-trioxo molybdenum metalloligand and its sodium complex containing 1D hexagonal chains of sodium ions was reported. In the same paper, the aromaticity of hexagonal Na clusters was quantified by means of the nucleus-independent chemical shift and electronic multicenter indices. It was shown that the aromaticity of hexagonal Na-clusters is of the same order as the aromaticity of analogous benzenoid hydrocarbons. In the present study current density maps are used to rationalize the aromaticity of polycyclic Na clusters. It is shown that although polycyclic Na systems sustain a diatropic ring current, the induced current density is several times weaker than in analogous benzenoid hydrocarbons. A detailed analysis indicates that the current density in hexagonal Na systems is almost completely determined by four HOMO sigma electrons. PMID- 21557556 TI - Effect of gel network on pattern formation in the ferrocyanide-iodate-sulfite reaction. AB - Stationary patterns have been researched experimentally since the discovery of the Turing pattern in the chlorite-iodide-malonic acid (CIMA) reaction and the self-replicating spot pattern in the ferrocyanide-iodate-sulfite (FIS) reaction. In this study, we reproduced the pattern formation in the FIS reaction by using poly(acrylamide) gels. Gels with different swelling ratios were prepared to use as a medium. The effect of the swelling ratio was compared with the effect of thickness. It was found that the swelling ratio greatly influenced pattern formation. Oscillating spot patterns appeared at high swelling ratios, and lamellar patterns appeared at a low swelling ratio. Self-replicating spot patterns appeared in between the two areas. The front velocities, which were observed in the initial stage of pattern formation, depended on the swelling ratio. Furthermore, this dependence obeys the free volume theory of diffusion. These results provide evidence that the change in front velocities is caused by a change in diffusion. Pattern formation can be controlled not only by thickness but also by swelling ratio, which may be useful for creating novel pattern templates. PMID- 21557557 TI - Improved high-efficiency organic solar cells via incorporation of a conjugated polyelectrolyte interlayer. AB - The power conversion efficiencies of bulk heterojunction (BHJ) solar cells can be increased from 5 to 6.5% by incorporating an ultrathin conjugated polyelectrolyte (CPE) layer between the active layer and the metal cathode. Poly[N-9'' heptadecanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3' benzothiadiazole)] (PCDTBT) and [6,6]-phenyl C(71) butyric acid methyl ester (PC(71)BM) were chosen for the photoactive layer. CPEs with cationic polythiophenes, in both homopolymer and block copolymer configurations, were used to improve the electronic characteristics. The significant improvement in device performance and the simplicity of fabrication by solution processing suggest a promising and practical pathway for improving polymer solar cells with high efficiencies. PMID- 21557558 TI - Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model. AB - The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 +/- 2.30% and 160.20 +/- 0.99 nm, respectively, and freeze dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC(50) of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs. PMID- 21557559 TI - Lanthanoid-containing open Wells-Dawson silicotungstates: synthesis, crystal structures, and properties. AB - Five novel lanthanoid-containing silicotungstates with polymeric crystal structures [Ln(2)(H(2)O)(7)Si(2)W(18)O(66)](n)(10n-) [Ln = Gd(III) (Gd-1 and Gd 2), Tb(III), Ho(III)] and [Dy(2)(H(2)O)(6.5)(C(2)H(4)O(2))(0.5)Si(2)W(18)O(66)](n)(10n-) were obtained from the one-step reaction of Na(10)[SiW(9)O(34)].nH(2)O with Ln(NO(3))(3).nH(2)O in a sodium acetate buffer. The compounds were characterized by single-crystal X-ray diffraction and a wide range of analytical methods, including FT-IR, UV/vis, and photoluminescence spectroscopy as well as electrochemistry and thermogravimetric analysis. This new polyoxotungstate series is the first example of lanthanoids embedded in the open Wells-Dawson silicotungstate anion [alpha Si(2)W(18)O(66)](16-). The lanthanoid-containing Wells-Dawson-type polyoxoanions [Ln(2)(H(2)O)(7)Si(2)W(18)O(66)](10-) [Ln = Gd(III) (Gd-1 and Gd-2), Tb(III), Ho(III)] and [Dy(2)(H(2)O)(6.5)(C(2)H(4)O(2))(0.5)Si(2)W(18)O(66)](10-) are linked by Ln(3+) cations to form 3D architectures for Gd-1 or 2D frameworks for the isostructural compounds Tb-2, Dy-2, Ho-2, and Gd-2. The structure-directing influence of the lanthanoid cation on the local structure of the dimeric building blocks and on the crystal packing motifs is investigated in detail. The photoluminescence properties of Tb-2 and Dy-2 were investigated at room temperature, and Ho-2 exhibits an interesting photochromic behavior. The magnetic susceptibility of Gd-1 and Gd-2 was studied in the temperature range between 2 and 300 K for its effective magnetic moment. PMID- 21557560 TI - Synthesis and structure of ruthenium(IV) complexes featuring N-heterocyclic ligands with an N-H group as the hydrogen-bond donor: hydrogen interactions in solution and in the solid state. AB - The synthesis and characterization of novel ruthenium(IV) complexes [Ru(eta(3):eta(3)-C(10)H(16))Cl(2)L] [L = 3-methylpyrazole (2b), 3,5 dimethylpyrazole (2c), 3-methyl-5-phenylpyrazole (2d), 2-(1H-pyrazol-5-yl)phenol (2e), 6-azauracile (3), and 1H-indazol-3-ol (4)] are reported. Complex 2e is converted to the chelated complex [Ru(eta(3):eta(3)-C(10)H(16))Cl(kappa(2)-N,O-2 (1H-pyrazol-3-yl)phenoxy)] (5) by treatment with an excess of NaOH. All of the ligands feature N-H, O-H, or C?O as the potential hydrogen-bonding group. The structures of complexes 2a-2c, 2e, 3, and 5 in the solid state have been determined by X-ray diffraction. Complexes 2a-2c and 3, which contain the pyrazole N-H group, exhibit intra- and intermolecular hydrogen bonds with chloride ligands [N-H...Cl distances (A): intramolecular, 2.30-2.78; intermolecular, 2.59-2.77]. Complexes 2e and 3 bearing respectively O-H and C?O groups also feature N-H...O interactions [intramolecular (2e), 2.27 A; intermolecular (3), 2.00 A]. Chelated complex 5, lacking the O-H group, only shows an intramolecular N-H...Cl hydrogen bonding of 2.42 A. The structure of complex 3, which turns out to be a dimer in the solid state through a double intermolecular N-H...O hydrogen bonding, has also been investigated in solution (CD(2)Cl(2)) by NMR diffusion studies. Diffusion-ordered spectroscopy experiments reveal an equilibrium between monomer and dimer species in solution whose extension depends on the temperature, concentration, and coordinating properties of the solvent. Preliminary catalytic studies show that complex 3 is highly active in the redox isomerization of the allylic alcohols in an aqueous medium under very mild reaction conditions (35 degrees C) and in the absence of a base. PMID- 21557561 TI - Mercaptothiazolinyl functionalized hexapodal and tripodal receptors on benzene platform: formation of silver ion assisted hexanuclear metallocage vs metal organic polymer. AB - Mercaptothiazolinyl functionalized hexapodal (L(1)) and tripodal (L(2)) receptors on the benzene platform have been synthesized easily in good yields and structurally characterized by a single-crystal X-ray crystallographic study. In the solid state, L(1) shows an orientation of six arms in 1,3,5 vs 2,4,6 facial steric gearing fashion, whereas L(2) adopted C(2v) symmetry where two of its thiazolinyl arms are oriented in one direction and the third arm in the another direction. Two silver complexes of L(1), 1 ([2(L(1)).6(AgClO(4)).2(CHCl(3)).HClO(4)]) and 2 ([2(L(1)).6(AgClO(4))]), that are suitable for single-crystal X-ray studies are isolated upon the slow diffusion of a dimethylformamide solution of AgClO(4) to the solution of L(1) in chloroform and dichloromethane, respectively. Similarly, upon the slow diffusion of an acetonitrile solution of AgClO(4) to the chloroform solution of L(2), colorless crystals of the silver complex of L(2), 3, are successfully isolated. The structural analyses of 1 and 2 show the formation of a silver ion assisted hexanuclear metallocage Ag(6)(L(1))(2) via dimeric assembly of L(1) with multiple clefts and pockets toward guests binding. In 1, two chloroform molecules sit in top and bottom pockets, whereas six perchlorate counteranions are bound in six clefts between the silver ion pillared side arms of the metallocage. Though complex 2 shows the formation of a metallocage like 1, the single crystal structural analysis depicts perchlorate counteranions bonded to the silver atoms of the metallocage. On the contrary, the silver complex of tripodal receptor L(2), 3, shows the formation of a metallo-organic polymeric network of L(2) and Ag(+). To the best of our knowledge, this work represents the first report on the formation of an M(6)L(2) type metallosupramolecular cage topology with multiple clefts for guest binding by a semirigid hexapodal receptor. PMID- 21557562 TI - Noble reaction features of bromoborane in oxidative addition of B-Br sigma-bond to [M(PMe3)2] (M=Pt or Pd): theoretical study. AB - Through detailed calculations by density functional theory and second-order Moller-Plesset perturbation theory (MP2) to fourth-order Moller-Plesset perturbation theory including single, double, and quadruple excitations [MP4(SDQ)] methods, we investigated the oxidative addition of the B-Br bond of dibromo(trimethylsiloxy)borane [Br(2)B(OSiMe(3))] to Pt(0) and Pd(0) complexes [M(PMe(3))(2)] (M = Pt or Pd) directly yielding a trans bromoboryl complex trans [MBr{BBr(OSiMe(3))}(PMe(3))(2)]. Two reaction pathways are found for this reaction: One is a nucleophilic attack pathway which directly leads to the trans product, and the other is a stepwise reaction pathway which occurs through successive cis oxidative addition of the B-Br bond to [M(PMe(3))(2)] and thermal cis-trans isomerization. In the Pt system, the former course occurs with a much smaller energy barrier (E(a) = 5.8 kcal/mol) than the latter one (E(a) = 20.7 kcal/mol), where the DFT-calculated E(a) value is presented hereafter. In the Pd system, only the latter course is found in which the rate-determining steps is the cis-trans isomerization with the E(a) of 15.1 kcal/mol. Interestingly, the thermal cis-trans isomerization occurs on the singlet potential energy surface against our expectation. This unexpected result is understood in terms of the strong donation ability of the boryl group. Detailed analyses of electronic processes in all these reaction steps as well as remarkable characteristic features of [Br(2)B(OSiMe(3))] are also provided. PMID- 21557563 TI - Noncontact sub-10 nm temperature measurement in near-field laser heating. AB - An extremely focused optical field down to sub-10 nm in an apertureless near field scanning optical microscope has been used widely in surface nanostructuring and structure characterization. The involved sub-10 nm near-field heating has not been characterized quantitatively due to the extremely small heating region. In this work, we present the first noncontact thermal probing of silicon under nanotip focused laser heating at a sub-10 nm scale. A more than 200 degrees C temperature rise is observed under an incident laser of 1.2 * 10(7) W/m(2), while the laser polarization is well aligned with the tip axis. To explore the mechanism of heating and thermal transport at sub-10 nm scale, a simulation is conducted on the enhanced optical field by the AFM tip. The high intensity of the optical field generated in this region results in nonlinear photon absorption. The optical field intensity under low polarization angles (~10(14) W/m(2) within 1 nm region for 15 degrees and 30 degrees ) exceeds the threshold for avalanche breakdown in silicon. The measured high-temperature rise is a combined effect of the low thermal conductivity due to ballistic thermal transport and the nonlinear photon absorption in the enhanced optical field. Quantitative analysis reveals that under the experimental conditions the temperature rise can be about 235 and 105 degrees C for 15 degrees and 30 degrees laser polarization angles, agreeing well with the measurement result. Evaluation of the thermal resistances of the tip-substrate system concludes that little heat in the substrate can be transferred to the tip because of the very large thermal contact resistance between them. PMID- 21557564 TI - Redox chemistry, acid reactivity, and hydrogenation reactions of two-electron mixed valence diiridium and dirhodium complexes. AB - The syntheses and reaction chemistry of two electron mixed-valence diphosphazane bridged dirhodium and diiridium complexes M(2)(0,II)(tfepma)(2)(CN(t)Bu)(2)Cl(2) [M = Rh (1), Ir (2); tfepma = MeN[P(OCH(2)CF(3))(2)](2), CN(t)Bu = tert-butyl isocyanide] are described. 1 and 2 undergo addition and two-electron oxidation and reduction chemistries. In the presence of CN(t)Bu, the addition product with the stoichiometry M(2)(0,II)(tfepma)(2)(CN(t)Bu)(3)Cl(2) [M = Rh (3), Ir (3)] is generated; in the presence of 1 equiv of CN(t)Bu and 2 equiv of bis(pentamethyl cyclopentadienyl)cobalt(II), 1 and 2 are reduced to furnish M(2)(0,0)(tfepma)(2)(CN(t)Bu)(3) [M = Rh (5), Ir (6)], which feature both four- and five-coordinate M(0) centers. Complexes 1, 2, 5, and 6 all possess coordinatively unsaturated square planar M(0) centers that are reactive: (1) 2 reacts with PhICl(2) to produce Ir(2)(II,II)(tfepma)(2)(CN(t)Bu)(2)Cl(4) (7); (2) protonation of 2 with HX yields Ir(2)(II,II)(tfepma)(2)(CN(t)Bu)(2)Cl(2)HX [X = Cl(-) (8), OTs(-) (9)]; (3) protonation of 5 with HOTs produces [Rh(2)(I,I)(tfepma)(2)(CN(t)Bu)(3)(MU-H)](OTs); and (4) the reversible hydrogenation of 2 proceeds smoothly, furnishing the cis-dihydride complex Ir(2)(II,II)(tfepma)(2)(CN(t)Bu)(2)(H)(2)Cl(2) (11). Substitution of tfepma in 2 with bis(diphenylphsophino)methane (dppm) yields the orthometalated complex Ir(2)(II,II)(dppm)(PPh(o-C(6)H(4))CH(2)PPh(2))(CN(t)Bu)(2)Cl(2)H (12). The X-ray crystal structures of 11 compounds are presented and discussed, and spectroscopic characterization by multinuclear and variable temperature NMR provides details about solution structures and in some cases the formation of isomeric products. The electronic spectra of the new complexes are also described briefly, with absorption and emission features derived from the bimetallic core. PMID- 21557565 TI - Synthesis, characterization, and structure-property relationships in two new polar oxides: Zn2(MoO4)(SeO3) and Zn2(MoO4)(TeO3). AB - Two new noncentrosymmetric (NCS) polar oxide materials, Zn(2)(MoO(4))(AO(3)) (A = Se(4+) or Te(4+)), have been synthesized by hydrothermal and solid-state techniques. Their crystal structures have been determined, and characterization of their functional properties (second-harmonic generation, piezoelectricity, and polarization) has been performed. The isostructural materials exhibit a three dimensional network consisting of ZnO(4), ZnO(6), MoO(4), and AO(3) polyhedra that share edges and corners. Powder second-harmonic generation (SHG) measurements using 1064 nm radiation indicate the materials exhibit moderate SHG efficiencies of 100 * and 80 * alpha-SiO(2) for Zn(2)(MoO(4))(SeO(3)) and Zn(2)(MoO(4))(TeO(3)), respectively. Particle size vs SHG efficiency measurements indicate the materials are type 1 non-phase-matchable. Converse piezoelectric measurements resulted in d(33) values of ~14 and ~30 pm/V for Zn(2)(MoO(4))(SeO(3)) and Zn(2)(MoO(4))(TeO(3)), respectively, whereas pyroelectric measurements revealed coefficients of -0.31 and -0.64 MUC/m(2) K at 55 degrees C for Zn(2)(MoO(4))(SeO(3)) and Zn(2)(MoO(4))(TeO(3)), respectively. Frequency-dependent polarization measurements confirmed that all of the materials are nonferroelectric; that is, the macroscopic polarization is not reversible, or "switchable". Infrared, UV-vis, thermogravimetric, and differential thermal analysis measurements were also performed. First-principles density functional theory (DFT) electronic structure calculations were also done. Crystal data: Zn(2)(MoO(4))(SeO(3)), monoclinic, space group P2(1) (No. 4), a = 5.1809(4) A, b = 8.3238(7) A, c = 7.1541(6) A, beta = 99.413(1) degrees , V = 305.2(1) A(3), Z = 2; Zn(2)(MoO(4))(TeO(3)), monoclinic, space group P2(1) (No. 4), a = 5.178(4) A, b = 8.409(6) A, c = 7.241(5) A, beta = 99.351(8) degrees , V = 311.1(4) A(3), Z = 2. PMID- 21557566 TI - A vanadium (VO2+) metal-organic framework: selective vapor adsorption, magnetic properties, and use as a precursor for a polyoxovanadate. AB - The reaction of VOSO(4) with 2-carboxyethylphosphonic acid (H(2)-CEP) in presence of piperazine (PIP) produces a 3D inorganic-organic hybrid framework, {(H(2)PIP)(0.5)[VO(CEP)].H(2)O} (1) with bidirectional channels occupied by the H(2)PIP cations and H(2)O molecules. The PO(3)(2-) unit of CEP connects three V(IV) centers to generate a 1D ladder, which is further linked to four such ladders by the CEP linkers to form a 3D hybrid framework. The dehydrated framework, {(H(2)PIP)(0.5)[VO(CEP)]} (1') shows selective and gated adsorption behavior with H(2)O but not with methanol and ethanol. Very interestingly, when 1 is treated with an aqueous solution of LiNO(3)/NaNO(3), the framework breaks down and results in a new polyoxovanadate (POV) cluster, [H(5)(H(2)PIP)(3)][V(V)(12)V(IV)(2)O(38)(PO(4))].8H(2)O (2) at pH ~ 2.1. The cluster has been characterized by single-crystal X-ray diffraction, (31)P NMR, EPR, and magnetic studies. The temperature-dependent magnetic susceptibility measurement suggests antiferromagnetic ordering in 1 with T(N) ~ 3.8 K. PMID- 21557567 TI - Nanoparticles electrostatically coated with folic acid for effective gene therapy. AB - We developed a novel vector, electrostatically coated poly(ethylenimine) (PEI)/pDNA complexes with folic acid (FA). Without covalent binding, the FA molecules could coat the PEI/pDNA complexes, and stable anionic nanoparticles were formed at a charge ratio greater than 60. The addition of FA markedly decreased the cytotoxicity of the cationic PEI/pDNA complexes to the melanoma cell line, B16-F10 cells, which regularly expressed FA-specific receptor (FR). Furthermore, the anionic FA60/PEI/pDNA complexes showed high transgene efficiency via the FR-mediated pathway in B16-F10 cells. The FA60/PEI/pDNA complexes did not show agglutination with erythrocytes. After the intravenous injection of FA60/PEI/pDNA complexes into mice, a higher transgene efficiency than PEI/pDNA complexes was observed in the liver, kidney, spleen, and lung with FR. The gene expressions of FA60/PEI/pDNA complexes were significantly inhibited by preadministration of FA. Thus, the FA60/PEI/pDNA complexes were useful for effective gene therapy. PMID- 21557568 TI - Comparison of the spectroscopic properties of pi-conjugated, fused salphen triads embedded with Zn-homo-, Ni-homo-, and Ni/Zn-heteronuclei. AB - Stepwise condensation reactions of 2,6-dihydroxynaphthalene-1,5-dicarbaldehyde and a phenylenediamine with concomitant binding of metal ions afforded a trinuclear complex of a fully pi-conjugated, fused salphen ligand. By changing the synthetic pathway, we obtained a series of homo- and heteronuclear complexes containing selected combinations of nickel(II) and zinc(II) ions. Comparison of the trinuclear complexes' spectroscopic features with those of analogous dinuclear complexes revealed that the absorption spectrum of each trinuclear complex is composed of a salphen-centered absorption at 400 nm and a naphthalene centered absorption around 500-600 nm, suggesting that the pi-conjugated system is divided into several compartments, each of which independently undergoes electronic excitation. Molecular orbital calculations revealed that the formal fusion of the salphen moieties increases the highest occupied molecular orbital (HOMO) level by ~0.4 eV, which in turn causes the low-energy absorption observed in the spectra. In contrast, interorbital interactions mediated by the N(2)O(2) metal coordination site are small, even though this site is bridged by an o phenylene linkage. These results suggest that the coordination site effectively breaks electronic communication between the compartments, which in turn affect various spectroscopic properties of the pi-conjugated metallo-polysalphens. PMID- 21557569 TI - Boron-bridged pi-conjugated ladders as efficient electron-transporting emitters. AB - Four diboron-bridged ladder molecules 1-4 have been designed and synthesized. X ray diffraction analysis revealed that the bulky phenyl substituents on boron centers efficiently prevented pi stacking of the luminescent ladder unit. Characterizations of these complexes demonstrated that the construction of diboron-containing ladder-type skeletons endowed these materials with good thermal stability, high fluorescence quantum yields, and strong electron affinity. The highly efficient nondoped organic light-emitting diodes using complexes 1 and 2 as electron-transporting emitters exhibited maximum luminance values of 16,930 and 18,060 cd/m(2) with turn-on voltages of 3.5 and 2.5 V as well as maximum luminous efficiencies of 6.4 and 5.4 cd/A, respectively. PMID- 21557570 TI - Stretchable magnetoelectronics. AB - We fabricated [Co/Cu] multilayers revealing a giant magnetoresistance (GMR) effect on free-standing elastic poly(dimethylsiloxane) (PDMS) membranes. The GMR performance of [Co/Cu] multilayers on rigid silicon and on free-standing PDMS is similar and does not change with tensile deformations up to 4.5%. Mechanical deformations imposed on the sensor are totally reversible, due to the elasticity of the PDMS membranes. This remarkable performance upon stretching relies on a wrinkling of GMR layers on top of the PDMS membrane. PMID- 21557571 TI - Enantioconvergent synthesis of (+)-aphanorphine via asymmetric Pd-catalyzed alkene carboamination. AB - A concise asymmetric synthesis of (+)-aphanorphine has been achieved via a new enantioconvergent strategy. A racemic gamma-aminoalkene derivative is transformed into a 1:1 mixture of enantiomerically enriched diastereomers using an asymmetric Pd-catalyzed carboamination. This mixture is then converted to an enantiomerically enriched protected aphanorphine derivative by a Friedel-Crafts reaction, which generates a quaternary all-carbon stereocenter. The natural product is obtained in three additional steps. PMID- 21557572 TI - Thermodynamic stabilization of hydrous ferric oxide by adsorption of phosphate and arsenate. AB - Hydrous ferric oxide (HFO) is an X-ray amorphous compound with a high affinity for anions under strongly or mildly acidic conditions. Because of the usually small particle size of HFO, the adsorption capacity is high and adsorption may significantly impact the thermodynamic properties of such materials. Here we show that adsorption of phosphate and arsenate stabilizes HFO by experimental determination of enthalpies of formation (by acid-solution calorimetry) and estimates of standard entropies for six phosphate- or arsenate-enriched HFO samples. At pH values lower than ~5, the phosphate-doped HFO is not only less soluble than ferrihydrite (anion-free HFO) but also crystalline FeOOH polymorphs feroxyhyte and lepidocrocite. The arsenate-doped HFO is also stabilized with respect to the ferrihydrite. Phosphate availability in soils can be controlled by the phosphate-enriched HFO which is many orders of magnitude less soluble than apatite or crystalline Fe(III) phosphates, for example strengite (FePO(4).2H(2)O). Thermodynamic dissolution models for scorodite (FeAsO(4).2H(2)O) and As-enriched HFO show that under mildly acidic or circumneutral conditions, scorodite dissolves, As-HFO precipitates, and a substantial amount of As(V) is released into the aqueous solution (at pH 7, log m(As) ~ -2.5). The data presented in this paper can be used to model the equilibrium concentration of Fe(III), P(V), or As(V) in soil solutions or in natural or anthropogenic sediments polluted by arsenic. PMID- 21557573 TI - Monitoring network design for phytoremediation systems using primary and secondary data sources. AB - Phytoremediation, or contaminant removal using plants, has been deployed at many sites to remediate contaminated soil and groundwater. Research has shown that trees are low-cost, rapid, and relatively simple-to-use monitoring systems as well as inexpensive alternatives to traditional pump-and-treat systems. However, tree monitoring is also an indirect measure of subsurface contamination and inherently more uncertain than conventional techniques such as wells or soil borings that measure contaminant concentrations directly. This study explores the implications for monitoring network design at real-world sites where scarce primary data such as monitoring wells or soil borings are supplemented by extensive secondary data such as trees. In this study, we combined secondary and primary data into a composite data set using models to transform secondary data to primary, as primary data were too sparse to attempt cokriging. Optimal monitoring networks using both trees and conventional techniques were determined using genetic algorithms, and trade-off curves between cost and uncertainty are presented for a phytoremediation system at Argonne National Laboratory. Optimal solutions found at this site indicate that increasing the number of secondary data sampled resulted in a significant decrease in global uncertainty with a minimal increase in cost. The choice of the data transformation model had an impact on the optimal designs and uncertainty estimated at the site. Using a data transformation model with a higher error resulted in monitoring network designs where primary data were favored over colocated secondary data. The spatial configuration of the monitoring network design was similar with regard to the areas sampled, irrespective of the data transformation model used. Overall, this study shows that using a composite data set, with primary and secondary data, results in effective monitoring designs, even at sites where the only data transformation model available is one with significant error. PMID- 21557575 TI - Quantitative health risk assessment of Cryptosporidium in rivers of southern China based on continuous monitoring. AB - The concentrations of Cryptosporidium in the source water of several cities of Zhejiang Province, China were determined to be in the range of 0-17 oocysts/10 L in the rainy season in 2008, with a mean value of 7 oocysts/10 L. Based on the investigation data, comprehensive risk assessment of Cryptosporidium infection was performed by considering different water intake routes as well as water consumption. Intakes of unboiled tapwater (including drinking and tooth-brushing and food and dish washing) and source water (through swimming in rivers) were estimated to be 2.59-25.9 and 0.32-0.74 L/year-person, respectively. The mortality due to Cryptosporidium infection for people in this region, excluding HIV-infected patients, was calculated as 0-0.0146 per 10(5) persons using a conditional probability formula. Disability-adjusted life years (DALYs) were used to quantify the risk of Cryptosporidium infection, for which uncertainty was analyzed. For people who consumed conventionally treated water, the DALYs due to Cryptosporidium infection were 6.51 per 10(5) (95% CI: 2.16 * 10(-5)-22.35 * 10( 5)) persons, which were higher than a risk judged acceptable by some (1.97 * 10( 5) DALYs per year), and the risk for those consuming ozone-treated water became 0.0689 * 10(-5) DALYs per year. The major risk of infection resulted from swimming in the river. This study provides a method to establish the risk of Cryptosporidium infection and optimize the scheme for reducing the risk effectively, which is useful for the modification of water quality standards based on cost utility analysis given use of DALYs. PMID- 21557574 TI - Dehalogenation of polybrominated diphenyl ethers and polychlorinated biphenyl by bimetallic, impregnated, and nanoscale zerovalent iron. AB - Nanoscale zerovalent iron particles (nZVI), bimetallic nanoparticles (nZVI/Pd), and nZVI/Pd impregnated activated carbon (nZVI/Pd-AC) composite particles were synthesized and investigated for their effectiveness to remove polybrominated diphenyl ethers (PBDEs) and/or polychlorinated biphenyls (PCBs). Palladization of nZVI promoted the dehalogenation kinetics for mono- to tri-BDEs and 2,3,4 trichlorobiphenyl (PCB 21). Compared to nZVI, the iron-normalized rate constants for nZVI/Pd were about 2-, 3-, and 4-orders of magnitude greater for tri-, di-, and mono-BDEs, respectively, with diphenyl ether as a main reaction product. The reaction kinetics and pathways suggest an H-atom transfer mechanism. The reaction pathways with nZVI/Pd favor preferential removal of para-halogens on PBDEs and PCBs. X-ray fluorescence mapping of nZVI/Pd-AC showed that Pd mainly deposits on the outer part of particles, while Fe was present throughout the activated carbon particles. While BDE 21 was sorbed onto activated carbon composites quickly, debromination was slower compared to reaction with freely dispersed nZVI/Pd. Our XPS and chemical data suggest about 7% of the total iron within the activated carbon was zerovalent, which shows the difficulty with in-situ synthesis of a significant fraction of zerovalent iron in the microporous material. Related factors that likely hinder the reaction with nZVI/Pd-AC are the heterogeneous distribution of nZVI and Pd on activated carbon and/or immobilization of hydrophobic organic contaminants at the adsorption sites thereby inhibiting contact with nZVI. PMID- 21557576 TI - Dynamic solid phase DNA extraction and PCR amplification in polyester-toner based microchip. AB - A variety of substrates have been used for fabrication of microchips for DNA extraction, PCR amplification, and DNA fragment separation, including the more conventional glass and silicon as well as alternative polymer-based materials. Polyester represents one such polymer, and the laser-printing of toner onto polyester films has been shown to be effective for generating polyester-toner (PeT) microfluidic devices with channel depths on the order of tens of micrometers. Here, we describe a novel and simple process that allows for the production of multilayer, high aspect-ratio PeT microdevices with substantially larger channel depths. This innovative process utilizes a CO(2) laser to create the microchannel in polyester sheets containing a uniform layer of printed toner, and multilayer devices can easily be constructed by sandwiching the channel layer between uncoated cover sheets of polyester containing precut access holes. The process allows the fabrication of deep channels, with ~270 MUm, and we demonstrate the effectiveness of multilayer PeT microchips for dynamic solid phase extraction (dSPE) and PCR amplification. With the former, we found that (i) more than 65% of DNA from 0.6 MUL of blood was recovered, (ii) the resultant DNA was concentrated to greater than 3 ng/MUL (which was better than other chip-based extraction methods), and (iii) the DNA recovered was compatible with downstream microchip-based PCR amplification. Illustrative of the compatibility of PeT microchips with the PCR process, the successful amplification of a 520 bp fragment of lambda-phage DNA in a conventional thermocycler is shown. The ability to handle the diverse chemistries associated with DNA purification and extraction is a testimony to the potential utility of PeT microchips beyond separations and presents a promising new disposable platform for genetic analysis that is low cost and easy to fabricate. PMID- 21557577 TI - Catalyst-controlled torquoselectivity switch in the 4pi ring-opening reaction of 2-amino-2-azetines giving beta-substituted alpha,beta-unsaturated amidines. AB - The torquoselectivity of the 4pi electrocyclic ring-opening reaction of 2 azetines can be controlled by the Bronsted acidity of the catalyst and the polarity of the solvent. DFT calculations provided insight into the mechanism of this remarkable switch. Anti and syn stereoisomers of alpha,beta-unsaturated amidines were selectively synthesized from ynamides and aldimines in the presence of Tf(2)NH and CSA, respectively. PMID- 21557578 TI - Deactivation of ferrylmyoglobin by vanillin as affected by vanillin binding to beta-lactoglobulin. AB - Vanillin was found to be efficient as a deactivator of ferrylmyoglobin with a second-order rate constant of k(2) = 57 +/- 1 L mol(-1) s(-1) for reduction to metmyoglobin with DeltaH(?) = 58.3 +/- 0.3 kJ mol(-1) and DeltaS(?) = -14 +/- 1 J mol(-1) K(-1) in aqueous pH 7.4 solution at 25 degrees C. Binding to beta lactoglobulin (betaLG) was found to affect the reactivity of vanillin at 25 degrees C only slightly to k(2) = 48 +/- 2 L mol(-1) s(-1) (DeltaH(?) = 68.4 +/- 0.4 kJ mol(-1) and DeltaS(?) = 17 +/- 1 J mol(-1) K(-1)) for deactivation of ferrylmyoglobin. Binding of vanillin to betaLG was found to have a binding stoichiometry vanillin/betaLG > 10 with K(A) = 6 * 10(2) L mol(-1) and an apparent total DeltaH degrees of approximately -38 kJ mol(-1) and DeltaS degrees = -55.4 +/- 4 J mol(-1) K(-1) at 25 degrees C and DeltaC(p, obs) = -1.02 kJ mol(-1) K(-1) indicative of increasing ordering in the complex, as determined by isothermal titration microcalorimetry. From tryptophan fluorescence quenching for betaLG by vanillin, approximately one vanillin was found to bind to each betaLG far stronger with K(A) = 5 * 10(4) L mol(-1) and a DeltaH degrees = -10.2 kJ mol(-1) and DeltaS degrees = 55 J mol(-1) K(-1) at 25 degrees C. The kinetic entropy/enthalpy compensation effect seen for vanillin reactivity by binding to betaLG is concluded to relate to the weakly bound vanillin oriented through hydrogen bonds on the betaLG surface with the phenolic group pointing toward the solvent, in effect making both DeltaH(?) and DeltaS(?) more positive. The more strongly bound vanillin capable of tryptophan quenching in the betaLG calyx seems less or nonreactive. PMID- 21557579 TI - Bisphosphonate-derivatized liposomes to control drug release from collagen/hydroxyapatite scaffolds. AB - A drug delivery system was developed by combining composite scaffolds made up of collagen and hydroxyapatite (Col/HA) with bisphosphonate (BP)-derivatized liposomes. The Col/HA scaffold was prepared by a freeze-drying method to yield a porous scaffold. The liposomes were composed of distearoylphosphocholine, cholesterol, distearoylphosphoethanolamine-poly(ethylene glycol) (DSPE-PEG), and a bone-binding bisphosphonate (BP) attached to the DSPE-PEG (DSPE-PEG-BP). By taking advantage of the specific interaction between the liposomal BP and the HA incorporated into the scaffold, the BP-decorated liposomes (BP-liposomes) were shown to display a strong affinity to Col/HA scaffolds. Three different model drugs, carboxyfluorescein (CF), doxorubicin (DOX), and lysozyme (LYZ) were entrapped in liposomes; there were no differences in drug release from the liposomes whether the liposomes were BP decorated or not. Whereas unencapsulated drugs and drugs encapsulated in PEG-liposomes displayed rapid release from the scaffolds, the drugs entrapped in BP-liposomes showed a slower release from the Col/HA scaffolds. We conclude that the proposed system can prolong the in situ residence of model drugs and has the potential to provide a sustained drug release platform in bone regeneration and repair. PMID- 21557581 TI - Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6 (N-acetylcystein-S-yl) conjugate. AB - The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6 NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined. A single intraventricular injection of THMA produced a significant lasting depletion of regional rat brain 5-HT and 5 hydroxyindoleacetic acid (5-HIAA), consistent with previous reports that THMA harbors 5-HT neurotoxic potential. The lasting effect of THMA on brain 5-HT markers was blocked by the 5-HT uptake inhibitor fluoxetine, indicating that persistent effects of THMA on 5-HT markers, like those of MDMA, are dependent on intact 5-HT transporter function. Efforts to identify THMA in the brains of animals treated with a high, neurotoxic dose (80 mg/kg) of MDMA were unsuccessful. Inability to identify THMA in the brains of these animals was not related to the unstable nature of the THMA molecule because exogenous THMA administered intracerebroventricularly could be readily detected in the rat brain for several hours. The thioether conjugate of THMA, 6-NAC-THMA, led to no detectable lasting alterations of cortical 5-HT or 5-HIAA levels, indicating that it lacks significant 5-HT neurotoxic activity. The present results cast doubt on the role of either THMA or 6-NAC-THMA in the lasting serotonergic effects of MDMA. The possibility remains that different conjugated forms of THMA or oxidized cyclic forms (e.g., the indole of THMA) play a role in MDMA-induced 5-HT neurotoxicity in vivo. PMID- 21557582 TI - Iron-catalyzed cycloaddition of alkynenitriles and alkynes. AB - The combination of Fe(OAc)(2) and an electron-donating, sterically hindered pyridyl bisimine ligand catalyzes the cycloaddition of alkynenitriles and alkynes. A variety of substituted pyridines were obtained in good yields. PMID- 21557583 TI - Structures, energetics, and aromaticities of the tetrasilacyclobutadiene dianion and related compounds: (Si4H4)(2-), (Si4H4)(2-).2Li+, [Si4(SiH3)4](2-).2Li+, [Si4(SiH3)4](2-).2Na+, and [Si4(SiH3)4](2-).2K+. AB - In light of the important recent synthesis of a stable tetrasilacyclobutadiene dianion compound by Sekiguchi and co-workers and the absence of theoretical studies, ab initio methods have been used to investigate this dianion and a number of related species. These theoretical methods predict multiple minima for each compound, and most minima contain folded and bicyclic silicon rings. For (Si(4)H(4))(2-), (Si(4)H(4))(2-).2Li(+), [Si(4)(SiH(3))(4)](2-).2Li(+), [Si(4)(SiH(3))(4)](2-).2Na(+), and [Si(4)(SiH(3))(4)](2-).2K(+), respectively, the energetically lowest-lying structures are designated A-3 (C(2v) symmetry), B 8 (C(1) symmetry), C-1 (C(2) symmetry), D-1 (C(2) symmetry), and E-1 (C(2h) symmetry). None of these structures satisfies both the ring planarity and the cyclic bond equalization criteria of aromaticity. However, all of the representative NICS values of these lowest-lying structures are negative, indicating some aromatic character. Especially, structures C-1 and D-1 of C(2) symmetry effectively satisfy the criteria of aromaticity due to the slightly trapezoidal silicon rings, which are nearly planar with nearly equal bond lengths. SiH(3) substitution for hydrogen in (Si(4)H(4))(2-).2Li(+) significantly reduces the degree of aromaticity, as reflected in the substantially smaller NICS absolute values for [Si(4)(SiH(3))(4)](2-).2Li(+) than those of (Si(4)H(4))(2-) and (Si(4)H(4))(2-).2Li(+). The aromaticity is further weakened in [Si(4)(SiH(3))(4)](2-).2Na(+) and [Si(4)(SiH(3))(4)](2-).2K(+) by replacing lithium with the sodium and potassium cations. PMID- 21557584 TI - [2+2] Photocycloaddition reaction dynamics of triplet pyrimidines. AB - Taking the 266 nm excited pyrimidine (uracil or thymine) with cyclopentene as model reaction systems, we have examined the photoproduct formation dynamics from the [2 + 2] photocycloaddition reactions of triplet pyrimidines in solution and provided mechanistic insights into this important DNA photodamage reaction. By combining two compliment methods of nanosecond time-resolved transient IR and UV vis laser flash-photolysis spectroscopy, the photoproduct formation dynamics as well as the triplet quenching kinetics are measured. Characteristic IR absorption bands due to photoproduct formation have been observed and product quantum yields are determined to be ~0.91% for uracil and ~0.41% for thymine. Compared to the measured large quenching rate constants of triplet uracil (1.5 * 10(9) M(-1)s( 1)) or thymine (0.6 * 10(9) M(-1)s(-1)) by cyclopentene, the inefficiency in formation of photoproducts indicates competitive physical quenching processes may exist on the route leading to photoproducts, resulting in very small product yields eventually. Such an energy wasting process is found to be resulted from T(1)/S(0) surface crossings by the hybrid density functional calculations, which compliments the experiments and reveals the reaction mechanism. PMID- 21557585 TI - Vibrational spectroscopy of N-methyliminodiacetic acid (MIDA)-protected boronate ester: examination of the B-N dative bond. AB - N-methyliminodiacetic acid (MIDA)-protected boronate esters are a new class of reagents that offer great promise in iterative Suzuki-Miyaura cross-coupling reactions. Compared to earlier reagents, MIDA esters are easily handled and are benchtop stable under air indefinitely. The success of this new species is tied to its unique molecular architecture. Compared to the simpler B-N containing molecules ammonia borane and trimethylamine borane, MIDA esters are much larger, and the sp(3) hybridized boron atom is secured by two five membered rings, making this molecular class stable for spectroscopic study. Here, we present infrared, Raman, and surface enhanced Raman (SERS) spectra of methylboronic acid MIDA ester. Comparisons of the spectroscopic results to those from electronic structure calculations suggest that the B-N stretching mode in this molecule lies in the range 560-650 cm(-1), making it among the lowest energy vibrations observed to date that can be primarily attributed to B-N stretching. PMID- 21557586 TI - Dispersion-corrected energy decomposition analysis for intermolecular interactions based on the BLW and dDXDM methods. AB - As the simplest variant of the valence bond (VB) theory, the block-localized wave function (BLW) method defines the intermediate electron-localized state self consistently at the DFT level and can be used to explore the nature of intermolecular interactions in terms of several physically intuitive energy components. Yet, it is unclear how the dispersion interaction affects such a kind of energy decomposition analysis (EDA) as standard density functional approximations neglect the long-range dispersion attractive interactions. Three electron densities corresponding to the initial electron-localized state, optimal electron-localized state, and final electron-delocalized state are involved in the BLW-ED approach; a density-dependent dispersion correction, such as the recently proposed dDXDM approach, can thus uniquely probe the impact of the long range dispersion effect on EDA results computed at the DFT level. In this paper, we incorporate the dDXDM dispersion corrections into the BLW-ED approach and investigate a range of representative systems such as hydrogen-bonding systems, acid-base pairs, and van der Waals complexes. Results show that both the polarization and charge-transfer energies are little affected by the inclusion of the long-range dispersion effect, which thus can be regarded as an independent energy component in EDA. PMID- 21557588 TI - Spanning set of silica cluster isomer topologies from QTAIM. AB - Structural and chemical properties of the building block of silica nanowires, (SiO(2))(6), are investigated with the theory of atoms and molecules (QTAIM). Twenty-five conformers have been analyzed, ten of which have not been reported before. We extend the silica (SiO(2))(6) topology phase space using QTAIM; the Poincare-Hopf topological sum rules are applied and used to identify the spanning set of topologies, and this includes finding eight new distinct topologies that satisfy the Poincare-Hopf relation. A simple phase diagram of the solutions of the Poincare-Hopf relation is created with the aid of a new classification scheme to determine the boundary between topological stability and instability. Sum rules are then found to be applicable to any set of isomers. We determine that O O bonding interactions exist for the silica (SiO(2))(6) conformers in regions where the energy surface is flattest. In addition, we identify unstable local minima in the topology of the charge density in order to further compare conformer instabilities. We quantify the dimensionality of a molecule using the Poincare-Hopf relation instead of Euclidean geometry. This quantum topological definition of geometry shows that the four most energetically stable (SiO(2))(6) conformers are quantified as two-dimensional within the new quantum topology. PMID- 21557587 TI - Intense visible and near-infrared upconversion photoluminescence in colloidal LiYF4:Er3+ nanocrystals under excitation at 1490 nm. AB - We report intense upconversion photoluminescence (PL) in colloidal LiYF(4):Er(3+) nanocrystals under excitation with telecom-wavelength at 1490 nm. The intensities of two- and three-photon anti-Stokes upconversion PL bands are higher than or comparable to that of the Stokes emission under excitation with low power density in the range 5-120 W/cm(2). The quantum yield of the upconversion PL was measured to be as high as ~1.2 +/- 0.1%, which is almost 4 times higher than the highest upconversion PL quantum yield reported to date for lanthanide-doped nanocrystals in 100 nm sized hexagonal NaYF(4):Yb(3+)20%, Er(3+)2% using excitation at ~980 nm. A power dependence study revealed that the intensities of all PL bands have linear dependence on the excitation power density, which was explained by saturation effects in the intermediate energy states. PMID- 21557589 TI - Theoretical study of the formation of naphthalene from the radical/pi-bond addition between single-ring aromatic hydrocarbons. AB - The experimental investigations performed in the 1960s on the o-benzyne + benzene reaction as well as the more recent studies on reactions involving pi-electrons highlight the importance of pi-bonding for different combustion processes related to PAH's and soot formation. In the present investigation radical/pi-bond addition reactions between single-ring aromatic compounds have been proposed and computationally investigated as possible pathways for the formation of two-ring fused compounds, such as naphthalene, which serve as precursors to soot formation. The computationally generated optimized structures for the stationary points were obtained with uB3LYP/6-311+G(d,p) calculations, while the energies of the optimized complexes were refined using the uCCSD(T) method and the cc-pVDZ basis set. The computations have addressed the relevance of a number of radical/pi-bond addition reactions including the singlet benzene + o-benzyne reaction, which leads to formation of naphthalene and acetylene through fragmentation of the benzobicyclo[2,2,2]octatriene intermediate. For this reaction, the high-pressure limit rate constants for the individual elementary reactions involved in the overall process were evaluated using transition state theory analysis. Other radical/pi-bond addition reactions studied were between benzene and triplet o-benzyne, between benzene and phenyl radical, and between phenyl radicals, for all of which potential energy surfaces were produced. On the basis of the results of these reaction studies, it was found necessary to propose and subsequently confirm additional, alternative pathways for the formation of the types of PAH compounds found in combustion systems. The potential energy surface for one reaction in particular, the phenyl + phenyl addition, is shown to contain a low-energy channel leading to formation of naphthalene that is energetically comparable to the other examined conventional pathways leading to formation of biphenyl compounds. This channel is the first evidence of a reaction which involves an aromatic radical adding to the nonradical pi-bond site of another aromatic radical which leads directly to a fused ring structure. PMID- 21557590 TI - Advanced control for photoautotrophic growth and CO2-utilization efficiency using a membrane carbonation photobioreactor (MCPBR). AB - A membrane carbonation (MC) module uses bubbleless gas-transfer membranes to supply inorganic carbon (C(i)) for photoautotrophic cyanobacterial growth in a photobioreactor (PBR); this creates the novel MCPBR system, which allows precise control of the CO(2)-delivery rate and minimal loss of CO(2) to the atmosphere. Experiments controlled the supply rate of C(i) to the main PBR by regulating the recirculation rate (Q(R)) between the module of MC chamber and the main PBR. The experiments evaluated how Q(R) controls the CO(2) mass transport in MC chamber and how it connects with the biomass production rate, C(i) concentration, pH in the PBR, and CO(2)-utilization efficiency. The biomass production rate and C(i) concentration increased in response to the C(i) supply rate (controlled by Q(R)), but not in linear proportion. The biomass production rate increased less than C(i) due to increased light limitation. Except for the highest Q(R), when the higher C(i) concentration caused the pH to decrease, CO(2) loss to gas ventilation was negligible. The results demonstrate that this MCPBR offers independent control over the growth of photoautotrophic biomass, pH control, and minimal loss of CO(2) to the atmosphere. PMID- 21557591 TI - Collision-induced dissociation and density functional theory studies of CO adsorption over zirconium oxide cluster ions: oxidative and nonoxidative adsorption. AB - Zirconium oxide cluster cations and anions are produced by laser ablation and reacted with CO in a fast flow reactor. The CO adsorption products Zr(x)O(y)CO(+) are observed for most of the generated cationic clusters (Zr(x)O(y)(+) = Zr(2)O(5,6)(+), Zr(3)O(7,8)(+), Zr(4)O(9,10)(+)...) while only specific anionic systems (Zr(x)O(y)(-) = Zr(3)O(7)(-), Zr(4)O(9)(-)...) absorb CO to produce Zr(x)O(y)CO(-). To study how the CO molecule is adsorbed on the clusters, the Zr(x)O(y)CO(+/-) products are mass-selected by a time-of-flight mass spectrometer (TOF-MS) and collided with a crossed helium beam. The fragment ions from collision-induced dissociation (CID) are detected by a secondary TOF-MS. Loss of CO and CO(2) is observed upon the collision of the helium beam with Zr(x)O(y)CO(+) and Zr(x)O(2x+1)CO(-), respectively. Density functional theory calculations indicate that oxidative and nonoxidative adsorption of CO takes place over Zr(3)O(7)(-) and Zr(3)O(7)(+), respectively. This is consistent with the CID experiments. PMID- 21557592 TI - Axial chirality of donor-donor, donor-acceptor, and tethered 1,1'-binaphthyls: a theoretical revisit with dynamics trajectories. AB - The circular dichroism (CD) spectra of (R)-2,2'-dimethoxy-1,1'-binaphthyl (DD) and its untethered and tethered donor-acceptor analogues (DA and DA7-DA9) were investigated experimentally and theoretically. The experimental CD spectra of DD and DA resembled each other in several aspects, displaying a positive-positive negative Cotton effect pattern in the (1)L(b)-(1)L(a) region and a strong negative couplet at the (1)B(b) band, but significantly differed in transition energy and rotatory strength. The couplet amplitude (A) of the main band was 1.6 times larger in DA than in DD, despite the comparable extinction coefficients and seemingly analogous conformations. An additional positive Cotton effect was observed at the CT (CT) band for donor-acceptor binaphthyl DA. Our theoretical prediction of the CD spectra of binaphthyls involves three sequential first principle quantum mechanics (QM) calculations. Thus, the geometry optimizations of a series of conformers with varying dihedral angles were performed by the dispersion-corrected DFT-D method using the B97-D functional and the TZV2P basis set. The potential curve as a function of the dihedral angle (theta) was obtained by using the SCS-MP2/TZVPP single-point energy calculations with and without application of the solvent correction. The CD spectrum of each conformer was independently calculated by the second-order approximate coupled cluster calculation (CC2 method) using the TZVPP basis sets and the resolution of the identity (RI-J) approximation. The (net) theoretical CD spectrum was obtained by averaging over all possible conformers, where the dynamics trajectories based on the relative SCS-MP2 energies were taken into account. By using 17 possible conformers at theta varying from 50 to 130 degrees by 5 degrees intervals, the experimental CD spectra were successfully reproduced in a quantitative manner, enabling us to characterize properly almost all of the important spectral features and chiroptical properties. The two-state model, reported previously, turned out to have led to the right answer with wrong reasons. The couplet sign and amplitude A are critical functions of theta and can be used not only for (qualitatively) determining the absolute configuration but also for quantitatively analyzing the binaphthyl conformations. The angle dependence of A was already argued in the classical coupled oscillator and exciton chirality theories to provide reasonable structure elucidations but only in a qualitative or semiquantitative manner. Our method is able to predict the A value quantitatively as a function of theta. For tethered binaphthyls DA7-DA9, particular care should be exercised in the conformational assessment based on the classical treatment because the amplitude A was shown to be significantly affected by the existence of the tether itself. In the present method, the couplet amplitude A was nicely related to the dihedral angle theta of DA and DD by the state-of-the-art ab initio calculations, enabling us to gain the quantitative information about the conformation of axially chiral binaphthyls. The Cotton effect at the CT band also serves as a complementary clue for elucidating the conformation of donor-acceptor binaphthyls. PMID- 21557593 TI - Dynamical mechanisms of direct three-body recombination. AB - Despite the ubiquity of recombination processes in nature and various technologies, presently little is known about the dynamics of these processes. This article reports on a quasi-classical trajectory study of the dynamics of the direct three-body recombination of Cs(+) and Br(-) ions in the presence of a Xe atom at energies of the ion encounter and that of the third body ranging from 0.2 to 10 eV. Several dynamical mechanisms of stabilization of the recombining ion pair have been found. Head-on ion encounters are characterized by two mechanisms of removing the energy from the recombining pair. In the case of nonzero impact parameters of ion encounters, the dynamics leading to the stabilization of the nascent CsBr molecule becomes much more complicated and three new mechanisms appear. They depend mainly on the energy of the ion encounter, on the energy of the collision of the ion pair with the third body, and on the impact parameter of the ion encounter and the impact parameter of the third body. The common feature of all the three mechanisms is the transfer of a fraction of the rotational energy of the recombining pair to the third body. This transfer plays a key role in the stabilization of the molecule. The dynamical peculiarities observed are expected to be common for the recombination of the charged and neutral particles. PMID- 21557594 TI - Rotational spectra and computational analysis of two conformers of leucinamide. AB - Rotational spectra were recorded for two isotopic species of two conformers of the amide derivative of leucine in the range of 10.5-21 GHz and fit to a rigid rotor Hamiltonian. Ab initio calculations at the MP2/6-311++G(d,p) level identified the low energy conformations with different side chain configurations; the rotational spectra were assigned to the two lowest energy ab initio structures. We recorded 16 a- and b-type rotational transitions for conformer 1; the rotational constants of the normal species are A = 2275.6(2), B = 1033.37(2) and C = 911.71(5) MHz. We recorded 23 a- and b-type rotational transitions for conformer 2; the rotational constants of the normal species are A = 2752.775(8), B = 843.502(1) and C = 796.721(1) MHz. The rotational spectra of the (15)N(amide) isotopomer of each conformer were recorded and the atomic coordinates of the amide nitrogen were determined by Kraitchman's method of isotopic substitution. The experimentally observed structures are significantly different from the crystal structures of leucinamide and the gas-phase structures of leucine, and a natural bond orbital analysis revealed the donor-acceptor interactions governing side chain configuration. PMID- 21557595 TI - New theoretical method for rapid prediction of solvation free energy in water. AB - We present a new theoretical method for rapid calculation of the solvation free energy in water by combining molecular simulation and the classical density functional theory (DFT). The DFT calculation is based on an accurate free-energy functional for water that incorporates the simulation results for long-range correlations and the fundamental measure theory for the molecular excluded-volume effects. The numerical performance of the theoretical method has been validated with simulation results and experimental data for the solvation free energies of halide (F(-), Cl(-), Br(-), and I(-)) and alkali (Li(+), Na(+), K(+), Rb(+), and Cs(+)) ions in water at ambient conditions. Because simulation is applied only to the particular thermodynamic condition of interest, the hybrid method is computationally much more efficient than conventional ways of solvation free energy calculations. PMID- 21557596 TI - Effect of aggregation on the photophysical properties of three fluorene-phenylene based cationic conjugated polyelectrolytes. AB - The effect of aggregation on the photophysical properties of three cationic poly{9,9-bis[N,N-(trimethylammonium)hexyl] fluorene-co-l,4-phenylene} polymers with average chain lengths of ~6, 12, and 100 repeat units (PFP NR3(6(I),12(Br),100(Br))) has been studied by steady-state and time-resolved fluorescence techniques. Conjugated polyelectrolytes are known to aggregate in solution and for these PFP-NR3 polymers this causes a decrease in the fluorescence quantum yield. The use of acetonitrile as a cosolvent leads to the breakup of aggregates of PFP-NR3 in water; for PFP-NR3(6(I)), this results in an ~10-fold increase in fluorescence quantum yield, a ca. 2-fold increase in the molar extinction coefficient at 380 nm, and an increase in the emission lifetime, as compared with polymer behavior in water. Fluorescence anisotropy also decreases with increasing aggregation, and this is attributed to increased fluorescence depolarization by interchain energy transfer in aggregate PFP-NR3 clusters. Forster resonance energy transfer along the polymer chain is expected to be very fast, with a calculated FRET rate constant of 7.3 * 10(12) s(-1) and a Forster distance of 2.83 nm (cf. the polymer repeat unit separation of 0.840 nm) for PFP-NR3(100(Br)). The complex polymer excited-state decay kinetics in aggregated PFP-NR3 systems have been successfully modeled in terms of intrachain energy transfer via migration and trapping at interchain aggregate trap sites, with model parameters in good agreement with data from picosecond time-resolved studies and the calculated theoretical Forster energy-transfer rates. PMID- 21557597 TI - Spin-selective correlation experiment for measurement of long-range J couplings and for assignment of (R/S) enantiomers from the residual dipolar couplings and DFT. AB - We report the C-HETSERF experiment for determination of long- and short-range homo- and heteronuclear scalar couplings ((n)J(HH) and (n)J(XH), n >= 1) of organic molecules with a low sensitivity dilute heteronucleus in natural abundance. The method finds significant advantage in measurement of relative signs of long-range heteronuclear total couplings in chiral organic liquid crystal. The advantage of the method is demonstrated for the measurement of residual dipolar couplings (RDCs) in enantiomers oriented in the chiral liquid crystal with a focus to unambiguously assign R/S designation in a 2D spectrum. The alignment tensor calculated from the experimental RDCs and with the computed structures of enantiomers obtained by DFT calculations provides the size of the back-calculated RDCs. Smaller root-mean-square deviations (rmsd) between experimental and calculated RDCs indicate better agreement with the input structure and its correct designation of the stereogenic center. PMID- 21557598 TI - Electrochemistry of cytochrome c1, cytochrome c552, and CuA from the respiratory chain of Thermus thermophilus immobilized on gold nanoparticles. AB - The electrochemical behavior of three proteins fragments from the respiratory chain of the extremophilic bacterium Thermus thermophilus , namely, cytochrome c(1) (Cyt-c(1)), cytochrome c(552) (Cyt-c(552)), and Cu(A), immobilized on three dimensional gold nanoparticles electrodes was investigated by cyclic voltammetry. The gold nanoparticles were modified by either dithiobissuccinimidyl propionate (DTSP) or a mixed self-assembled monolayer of 6-mercaptohexan-1-ol and hexanethiol, depending on the surface of the protein. High surface coverages with enzymes and good electron transfer rates were achieved in the case of Cyt-c(1) immobilized on DTSP-modified gold nanoparticles and Cyt-c(552) or Cu(A) immobilized on mixed SAMs-modified gold nanoparticles. Interestingly, high surface coverages with Cu(A) were also observed on DTSP-modified gold nanoparticles, but a slower electron transfer rate was determined in this case. The gold nanoparticle/protein assemblies were characterized by surface-enhanced IR spectroscopy and transmission electron microscopy. PMID- 21557599 TI - Tailoring (bio)chemical activity of semiconducting nanoparticles: critical role of deposition and aggregation. AB - The impact of deposition and aggregation on (bio)chemical properties of semiconducting nanoparticles (NPs) is perhaps among the least studied aspects of aquatic chemistry of solids. Employing a combination of in situ FTIR and ex situ X-ray photoelectron spectroscopy (XPS) and using the Mn(II) oxygenation on hematite (alpha-Fe(2)O(3)) and anatase (TiO(2)) NPs as a model catalytic reaction, we discovered that the catalytic and sorption performance of the semiconducting NPs in the dark can be manipulated by depositing them on different supports or mixing them with other NPs. We introduce the electrochemical concept of the catalytic redox activity to explain the findings and to predict the effects of (co)aggregation and deposition on the catalytic and corrosion properties of ferric (hydr)oxides. These results offer new possibilities for rationally tailoring the technological performance of semiconducting metal oxide NPs, provide a new framework for modeling their fate and transport in the environment and living organisms, and can be helpful in discriminating between weakly and strongly adsorbed species in spectra. PMID- 21557600 TI - Effect of filler choice on a binary frontal polymerization system. AB - Binary frontal polymerization is a process that involves two different systems polymerizing simultaneously but independently of each other. Various factors including filler choice and initiator concentration can affect front temperature and velocity. Like thermal frontal polymerization systems, binary frontal polymerization of a cyanate ester system and multifunctional acrylate is affected by initiator (amine) concentration and filler choice. Systems with higher viscosities and higher initiator concentrations resulted in higher velocities. Front temperature was rarely affected by filler choice. Aniline concentration and initial monomer ratios had a greater effect on front temperature than filler choice does. PMID- 21557601 TI - Optimization of coarse-grained interaction potential: inside inherent limitations of coarse-graining methods. AB - We studied the inherent limitations of coarse-grained (CG) potentials within the recently developed approach (Kowalczyk et al. J. Phys. Chem. B2009, 113, 12988 12998). For all studied fluids, the spherically symmetric CG potential constructed according to our scheme modified in this work balances the reproduction of various equilibrium properties (i.e., structural and thermodynamic) measured in CG simulations. The inherent loss of atomistic information at the CG level correlates with the contribution from short-range directional interactions. The highest loss of atomistic information at 298 K and 1 bar is reported for protic liquids (i.e., methanol and acetamide), while the best description at the CG level was obtained for molecular hydrogen and carbon dioxide. The investigated aprotic liquids (i.e., benzene, toluene, and acetone) can be CG into spherically symmetric interaction potentials with some loss of atomistic details. Interestingly, we show that the proposed optimal CG potential reproduces also the interfacial properties of vapor-liquid coexistence for aprotic benzene at 298 K. For all studied fluids, we find that one can easily reproduce structural properties without preserving their cohesive properties or vice versa. However, a general conclusion from our study is the following: an increase in the protic character of a fluid leads to an increase of inherent loss of atomistic details at the CG level. PMID- 21557602 TI - Immobilization of 99-technetium (VII) by Fe(II)-goethite and limited reoxidation. AB - During the nuclear waste vitrification process volatilized (99)Tc will be trapped by melter off-gas scrubbers and then washed out into caustic solutions, and plans are currently being contemplated for the disposal of such secondary waste. Solutions containing pertechnetate [(99)Tc(VII)O(4)(-)] were mixed with precipitating goethite and dissolved Fe(II) to determine if an iron (oxy)hydroxide-based waste form can reduce Tc(VII) and isolate Tc(IV) from oxygen. The results of these experiments demonstrate that Fe(II) with goethite efficiently catalyzes the reduction of technetium in deionized water and complex solutions that mimic the chemical composition of caustic waste scrubber media. Identification of the phases, goethite + magnetite, was performed using XRD, SEM and TEM methods. Analyses of the Tc-bearing solid products by XAFS indicate that all of the Tc(VII) was reduced to Tc(IV) and that the latter is incorporated into goethite or magnetite as octahedral Tc(IV). Batch dissolution experiments, conducted under ambient oxidizing conditions for more than 180 days, demonstrated a very limited release of Tc to solution (2-7 MUg Tc/g solid). Incorporation of Tc(IV) into the goethite lattice thus provides significant advantages for limiting reoxidation and curtailing release of Tc disposed in nuclear waste repositories. PMID- 21557603 TI - Tailoring charge density and hydrogen bonding of imidazolium copolymers for efficient gene delivery. AB - Conventional free radical polymerization with subsequent postpolymerization modification afforded imidazolium copolymers with controlled charge density and side chain hydroxyl number. Novel imidazolium-containing copolymers where each permanent cation contained one or two adjacent hydroxyls allowed precise structure-transfection efficiency studies. The degree of polymerization was identical for all copolymers to eliminate the influence of molecular weight on transfection efficiency. DNA binding, cytotoxicity, and in vitro gene transfection in African green monkey COS-7 cells revealed structure-property transfection relationships for the copolymers. DNA gel shift assays indicated that higher charge densities and hydroxyl concentrations increased DNA binding. As the charge density of the copolymers increased, toxicity of the copolymers also increased; however, as hydroxyl concentration increased, cytotoxicity remained constant. Changing both charge density and hydroxyl levels in a systematic fashion revealed a dramatic influence on transfection efficiency. Dynamic light scattering of the polyplexes, which were composed of copolymer concentrations required for the highest luciferase expression, showed an intermediate DNA-copolymer binding affinity. Our studies supported the conclusion that cationic copolymer binding affinity significantly impacts overall transfection efficiency of DNA delivery vehicles, and the incorporation of hydroxyl sites offers a less toxic and effective alternative to more conventional highly charged copolymers. PMID- 21557604 TI - Ultrathin gold nanoframes through surfactant-free templating of faceted pentagonal silver nanoparticles. AB - Ultrathin gold nanoframes (up to 1.6 nm) were prepared via templating upon well defined faceted silver morphologies. Starting with silver decahedra, small quantities of gold (1-10 mol% relative to the amount of silver) were selectively deposited on the nanoparticle edges under optimized reducing conditions. Silver dissolution in hydrogen peroxide yielded well-defined gold frames that retained their structural integrity in the ultrathin nanowire regime below 2 nm. The frame formation protocol was also successfully applied to other silver nanoparticle shapes featuring pentagonal twinning and (111) facets (e.g., pentagonal faceted rods and icosahedra). The demonstrated approach can be applied in the controlled preparation of ultrathin metal nanowires complementary to lithography and in the production of ultrafine noble-metal nanostructures for catalytic applications. PMID- 21557605 TI - 2,7-Diaminofluorene-based organic dyes for dye-sensitized solar cells: effect of auxiliary donor on optical and electrochemical properties. AB - New organic dyes containing a diarylaminofluorene unit as an electron donor and cyanoacrylic acid as acceptor and anchoring group in a donor-pi-donor-pi-acceptor architecture have been synthesized and characterized as sensitizers for nanocrystalline TiO(2)-based dye-sensitized solar cells. They have shown three major electronic absorptions originating from the pi-pi* and charge-transfer transitions covering the broad visible range (250-550 nm) in solution. The charge transfer transition of the dyes exhibited negative solvatochromism, suggesting a polarized ground state. They have also displayed acidochromism in solution owing to the presence of a protonation-deprotonation equilibrium. On comparison with the triphenylamine and carbazole-based parent dyes (E)-2-cyano-3-(4 (diphenylamino)phenyl)acrylic acid and (E)-2-cyano-3-(9-ethyl-9H-carbazol-3 yl)acrylic acid they exhibited longer wavelength absorptions and facile oxidation, indicating the stronger electron-donating ability of the auxiliary chromophores. In addition, they exhibited nearly two times larger light-to electron conversion efficiency under simulated AM 1.5 G irradiation (100 mW cm( 2)) with an aperture mask when compared to the parent dyes. Among the new dyes, the one containing the naphthylphenylamine segment showed better device characteristics attributable to the higher HOMO energy level which probably facilitates the regeneration of the dye and effective suppression of the back reaction of the injected electrons with the I(3)(-) in the electrolyte. The optical properties of the dyes were modeled using TDDFT simulations employing different theoretical models (B3LYP, CAM-B3LYP, and MPW1K), and the best correlations with the observed parameters have been found for CAM-B3LYP and MPW1K calculations. The electron lifetimes extracted from the electrochemical impedance measurements of the dye-sensitized solar cells were used to interpret the solar cell efficiency alternations. PMID- 21557606 TI - Anomalous electronic transport in dual-nanostructured lead telluride. AB - The Pb- and Sb- dual nanostructured PbTe system exhibits anomalous electronic transport behavior wherein the carrier mobility first increases and then decreases with increase in temperature. By combining in situ transmission electron microscopy observations and theoretical calculations based on energy filtering of charge carriers, we propose a plausible mechanism of charge transport based on interphase potential that is mediated by interdiffusion between coexisting Pb and Sb precipitates. These findings promise new strategies to enhance thermoelectric figure of merit via dual and multinanostructuring of miscible precipitates. PMID- 21557607 TI - Probing conformational states of modified helix 69 in 50S ribosomes. AB - The movement of the small ribosomal subunit (30S) relative to the large ribosomal subunit (50S) during translation is widely known, but many molecular details and roles of rRNA and proteins in this process are still undefined, especially in solution models. The functional relationship of modified nucleotides to ribosome activity is one such enigma. To better understand ribosome dynamics and the influence of modified nucleotides on such processes, the focus of this work was helix 69 of 23S rRNA, which contains three pseudouridine residues in its loop region. Ribosome probing experiments with dimethylsulfate revealed that specific base accessibilities and individual nucleotide conformations in helix 69 are influenced differently by pH, temperature, magnesium, and the presence of pseudouridine modifications. PMID- 21557608 TI - Hydrogen generation by hangman metalloporphyrins. AB - A cobalt(II) hangman porphyrin with a xanthene backbone and a carboxylic acid hanging group catalyzes the electrochemical production of hydrogen from benzoic and tosic acid in acetonitrile solutions. We show that Co(II)H is exclusively involved in the generation of H(2) from weak acids. In a stronger acid, a Co(III)H species is observed electrochemically, but it still needs to be further reduced to Co(II)H before H(2) generation occurs. Overpotentials for H(2) generation are lowered as a result of the hangman effect. PMID- 21557609 TI - Prussian blue nanocontainers: selectively permeable hollow metal-organic capsules from block ionomer emulsion-induced assembly. AB - Hollow polymer-based particles are useful for the encapsulation, protection, and release of active compounds. Adding a metal-organic coordination framework shell to nanocontainers is an attractive goal because it should help control their stability and permeability while yielding new properties and functions. We have discovered that polymer capsules with a Prussian blue analogue inner shell can be synthesized by emulsion-induced assembly of a metal-containing amphiphilic block ionomer. The capsules are selectively permeable and were used as nanocontainers to encapsulate and release a model compound. Further, these nanomaterials are tunable in size and organize into 2-D close-packed arrays in the solid state. Potential applications for these materials include the encapsulation and nanopatterning of pharmaceutical, biological, and catalytic compounds. PMID- 21557610 TI - Controlled synthesis of vertically aligned hematite on conducting substrate for photoelectrochemical cells: nanorods versus nanotubes. AB - This paper describes two different processes to synthesize vertically aligned hematite nanorod and nanotube arrays, respectively, on a conductive substrate by the electrochemical deposition method with the help of an anodized aluminum oxide nanotemplate. The two types of nanostructured hematite were used as the photoanode for photoelectrochemical cells. The hematite nanotubes exhibited much higher photoelectrochemical activity than the hematite nanorods, including an improved photocurrent density, more negative onset potential, better photon harvesting, and better charge carrier transfer ability. The observed behavior may offer new information to enhance the photocatalytic ability of hematite, which is considered to be one of the best photoanode materials in the research field of photoelectrochemical cells. PMID- 21557612 TI - Enhancement of gas sensing properties of CdS nanowire/ZnO nanosphere composite materials at room temperature by visible-light activation. AB - CdS nanowire/ZnO nanosphere materials (CdS/ZnO) with hierarchical structure were synthesized by a three-step solvothermal process. XRD, FESEM and TEM analysis confirmed the growth of ZnO nanospheres on the surface of CdS nanowires (NWs). The transient photovoltage (TPV) measurements revealed that the interface between CdS and ZnO can inhibit the recombination of photogenerated excess carriers and prolong the lifetime of excess carriers in CdS/ZnO materials. Moreover, the CdS/ZnO materials exhibit a dramatic improvement in optoelectronic performance and visible-light-irradiation gas sensing activity, which gave 1 order of magnitude larger than that of CdS NWs in response to formaldehyde. The enhancement of sensing properties is attributed to the interfacial transport of excess carriers. PMID- 21557611 TI - Multifunctional nanoemulsion platform for imaging guided therapy evaluated in experimental cancer. AB - Nanoparticle applications in medicine have seen a tremendous growth in the past decade. In addition to their drug targeting application and their ability to improve bioavailability of drugs, nanoparticles can be designed to allow their detection with a variety of imaging methodologies. In the current study, we developed a multimodal nanoparticle platform to enable imaging guided therapy, which was evaluated in a colon cancer mouse model. This "theranostic" platform is based on oil-in-water nanoemulsions and carries iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for NIRF imaging, and the hydrophobic glucocorticoid prednisolone acetate valerate (PAV) for therapeutic purposes. Angiogenesis targeted nanoemulsions functionalized with alphavbeta(3)-specific RGD peptides were evaluated, as well. When subcutaneous tumors were palpable, the nanoemulsions were administered at a dose of 30 mg of FeO/kg and 10 mg of PAV/kg. MRI and NIRF imaging showed significant nanoparticle accumulation in the tumors, while tumor growth profiles revealed a potent inhibitory effect in all of the PAV nanoemulsion-treated animals as compared to the ones treated with control nanoemulsions, the free drug, or saline. This study demonstrated that our nanoemulsions, when loaded with PAV, iron oxide nanocrystals, and Cy7, represent a flexible and unique theranostic nanoparticle platform that can be applied for imaging guided therapy of cancer. PMID- 21557613 TI - High-yield synthesis of few-layer graphene flakes through electrochemical expansion of graphite in propylene carbonate electrolyte. AB - High-yield production of few-layer graphene flakes from graphite is important for the scalable synthesis and industrial application of graphene. However, high yield exfoliation of graphite to form graphene sheets without using any oxidation process or super-strong acid is challenging. Here we demonstrate a solution route inspired by the lithium rechargeable battery for the high-yield (>70%) exfoliation of graphite into highly conductive few-layer graphene flakes (average thickness <5 layers). A negative graphite electrode can be electrochemically charged and expanded in an electrolyte of Li salts and organic solvents under high current density and exfoliated efficiently into few-layer graphene sheets with the aid of sonication. The dispersible graphene can be ink-brushed to form highly conformal coatings of conductive films (15 ohm/square at a graphene loading of <1 mg/cm(2)) on commercial paper. PMID- 21557614 TI - Pinpointing biomarkers in proteomic LC/MS data by moving-window discriminant analysis. AB - The identification of differential patterns in data originating from combined measurement techniques such as LC/MS is pivotal to proteomics. Although "shotgun proteomics" has been employed successfully to this end, this method also has severe drawbacks, because of its dependence on largely untargeted MS/MS sequencing and databases for statistical analyses. Alternatively, several MS signal-based (MS/MS-independent) methods have been published that are mainly based on (univariate) Student's t-tests. Here, we present a more robust multivariate alternative employing linear discriminant analysis. Like the t-test based methods, it is applied directly to LC/MS data, instead of using MS/MS measurements. We demonstrate the method on a number of simulated data sets, as well as on a spike-in LC/MS data set, and show its superior performance over t tests. PMID- 21557615 TI - Template-free synthesis of hierarchical TiO2 structures and their application in dye-sensitized solar cells. AB - We demonstrate here the synthesis of a hierarchical TiO(2) architecture without any surfactants or templates. Two kinds of structure existed simultaneously, the ordered nanoarrays at bottom provided direct conduction pathway for photo generated electrons, while the upper micro-flowers consisted of nanobelt as building units increased the light harvesting ability as the scattering part. The formation mechanism of the hierarchical architecture has been proposed by studying the morphology evolution processes upon reaction time. The performance of dye-sensitized solar cells based on the obtained hierarchical anatase TiO(2) has been also studied, giving a J(SC) = 12.44 mA cm(-2), V(OC) = 0.64 V, FF = 69.05%, and eta = 5.53%, which is superior than commercial TiO(2) (P25). The UV vis results prove that the obtained morphology is beneficial to light-scattering and thus increases the light harvesting ability. This hierarchical TiO(2) structure offers great potential for the development of high-efficiency DSSCs. PMID- 21557616 TI - Synthesis of nickel bowl-like nanoparticles and their doping for inducing planar alignment of a nematic liquid crystal. AB - Nickel bowl-like nanoparticles have first been synthesized by a magnetic self assembly process stabilized by polyvinyl pyrrolidone (PVP) without any sphere like materials as templates. A trace of doped bowls can induce liquid crystal (LC) molecules into a perfect planar alignment, attributable to their bowl-like shape and magnetic self-assembly into a 1D structure. It would provide a novel method of establishing LCs alignment by doping special nanostructured materials. PMID- 21557617 TI - Reversible and covalent binding of 5-(hydroxymethyl)-2-furaldehyde (HMF) with lysine and selected amino acids. AB - The chemical reactivity of 5-(hydroxymethyl)-2-furaldehyde (HMF) with lysine, glycine, and proline was studied using isotope labeling technique. To confirm the formation of HMF adducts in glucose amino acid model systems, a useful strategy was developed in which products simultaneously possessing six glucose (HMF moiety) and any number of amino acid carbon atoms in addition to nitrogen were targeted using specifically labeled precursors such as [(15)N(alpha)]lysine.2HCl, [(15)N(epsilon)]lysine.2HCl, [U-(13)C(6)]lysine.2HCl, [(13)C(6)]lysine.2HCl, and [U-(13)C(6)]glucose in the case of lysine model system. In addition, model systems containing HMF and amino acids were also studied to confirm specific adduct formation. Complete labeling studies along with structural analysis using appropriate synthetic precursors such as HMF Schiff base adducts of piperidine and glycine have indicated that HMF generated in the glucose/amino acid model systems initially forms a Schiff base adduct that can undergo decarboxylation through an oxazolidin-5-one intermediate and form two isomeric decarboxylated Schiff bases. Unlike the Schiff bases resulting from primary amines or amino acids such as glycine or lysine, those resulting from secondary amino acids such as proline or secondary amines such as piperidine can further undergo vinylogous Amadori rearrangement, forming N-substituted 5-(aminomethyl)furan-2-carbaldehyde derivatives. PMID- 21557618 TI - Lipid stability and antioxidant profile of microsomal fraction of broiler meat enriched with alpha-lipoic acid and alpha-tocopherol acetate. AB - The importance of the linkage between nutrition and health is a hot issue. Like other food-related sectors, the meat industry is undergoing foremost transformations, driven among other things by changes in consumer requirements. The present study was designed to evaluate the lipid stability and antioxidative potential of leg and breast microsomal fraction of broiler meat fed on ALA and ATA. For the first 3 weeks of growth, broilers were fed on feed supplemented with ATA (200 mg/kg of feed) and during the last 3 weeks broilers were fed on feed supplemented with ALA (25, 75, 150 mg/kg of feed) and a constant level of ATA (200 mg/kg of feed). The body weight of the carcass was measured after every week of growth until 6 weeks. Positive correlation between the antioxidant activity and the TPC was observed. Higher values of TBARS were detected in leg muscles than in breast muscles. HPLC data revealed ALA and ATA contents were higher in T(4) (leg, 5.55 +/- 0.19 and 3.87 +/- 0.15 MUg/mg of protein; breast, 5.63 +/- 0.20 and 2.03 +/- 0.10 MUg/mg of protein, respectively) and lowest in T(5) (ALA, leg, 1.40 +/- 0.06 MUg/mg of protein; breast, 1.54 +/- 0.05 MUg/mg of protein; ATA, leg, 1.25 +/- 0.06 MUg/mg of protein; breast, 0.63 +/- 0.008 MUg/mg of protein), in which the only oxidized oil was used. Oxidized oil in feed reduced weight gain and increased TBARS, whereas TPC, DPPH, ALA, and ATA values decreased in both leg and breast meat. PMID- 21557619 TI - Effect of macerating enzymes on the oligosaccharide profiles of Merlot red wines. AB - Commercial pectinase preparations are applied in winemaking to improve wine processing and final quality. These preparations contain pectolytic enzyme activities such as polygalacturonases, pectin esterases, pectin lyases, and rhamnogalacturonases. These enzymes modify the polysaccharide and oligosaccharide composition of wines. The influence of various commercial enzyme preparations on wine oligosaccharide composition was studied, on Merlot wines from the Bordeaux area. Wine oligosaccharides were isolated by high-resolution size-exclusion chromatography on a Superdex-30 HR column. The glycosyl residue and glycosyl linkage compositions of the oligosaccharide fractions obtained were determined. The MS spectra of the Merlot oligosaccharide fractions from control and enzyme treated wines were recorded on an AccuTOF mass spectrometer equipped with an electrospray ionization (ESI) source and a time-of-flight (TOF) mass analyzer. Oligosaccharides in the control wines were partly methylated homogalacturonans, corresponding to smooth regions of pectins, whereas those of the enzyme-treated wines were mostly rhamnogalacturonan-like structures linked with neutral lateral chains, arising from the hairy regions. The enzyme preparations used thus cleaved the rhamnogalacturonan backbone of the hairy zones and demethylated and hydrolyzed the smooth regions. Besides, different structures were detected, depending on the enzyme preparation used, indicating that they contained rhamnogalacturonase activities with different specificities. The oligosaccharide profiles can serve as a marker of enzymatic treatments. PMID- 21557620 TI - Update 1 of: Synthesis and functionalization of indoles through palladium catalyzed reactions. PMID- 21557621 TI - Seed-dependent deposition behavior of Abeta peptides studied with wireless quartz crystal-microbalance biosensor. AB - Real-time monitoring of the deposition processes of Abeta1-40 and Abeta1-42 peptides on various seeds has been performed using a 55 MHz wireless quartz crystal microbalance (QCM) over long-time periods (~40 h). Dissolved peptide solutions were stirred for nucleation and growth of seeds at pH = 7.4 and 4.6, which were immobilized on the sensor chips. The isolated Abeta peptides were then flowed at the neutral pH, focusing on the interaction between the seeds and the monomers (or small multimers), excluding other interactions among seeds and other aggregates. The thioflavin-T fluorescence assay and atomic-force microscopy were used for evaluating structures of the seeds and deposited aggregates. The deposition rate, determined by the frequency decrease, is about 100 monomers/nm(2)/year in the case of fibril formation. The notable deposition behavior was observed in the deposition of Abeta1-40 peptide on Abeta1-42 seeds grown at the lower pH, which can be an important model for Alzheimer's disease. PMID- 21557622 TI - Scientific reviewing--a moral responsibility. PMID- 21557623 TI - Purification and properties of a novel phenolic antioxidant from Radix astragali fermented by Aspergillus oryzae M29. AB - The Chinese herb Radix astragalus (RA) has been widely used as a dietary supplement in Asia, and there are numerous reports on its bioactivities. However, there are no reports to date regarding the use of Aspergillus spp. in the culture medium of the RA plant for the production of phenolic antioxidants. In this study, utilizing the fungus Aspergillus to ferment the native RA has successfully resulted in a significant increase in the phenolic contents of RA, and the fermented RA also revealed much better antioxidant activity toward 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals, hydroxyl radical, superoxide radical and peroxyl radical than those of unfermented RA. Among these phenolics, a potent novel antioxidant was isolated and identified as 3,4-di(4' hydroxyphenyl) isobutyric acid with a molecular weight of 272, by ESI-MS (electrospray ionization mass), 1H NMR (nuclear magnetic resonance), 13C NMR, DEPT (distortionless enhancement by polarization transfer)-NMR, HMQC (heteronuclear multiple quantum coherence), and HMBC (heteronuclear multiple bond correlation) spectra. These data demonstrated that the solid-state bioprocessing strategy could be an innovative approach to enhance the antioxidant activity of RA. PMID- 21557624 TI - Fluorescent beta-cyclodextrins modified by isomeric aminobenzamides: synthesis, conformational analysis, and fluorescent behaviors. AB - Three isomeric fluorescent beta-cyclodextrins bearing 2-, 3-, and 4-(2 aminoethyl)amino-N-butylbenzamide, respectively (1-3) have been synthesized. The conformations of these fluorescent CDs have been investigated by 2D NMR and induced circular dichromism. It is confirmed that the ortho isomer 1 takes a butyl-included conformation, while the other two isomers 2 and 3 display a phenyl included conformation, respectively. The three fluorescent CDs 1-3 exhibited totally different self- and guest-inclusion fluorescence behavior. In the presence of adamantane carboxylate sodium (ADA) or deoxycholate sodium (DCA), the fluorescence intensity of 1 showed an enhancement over 1-fold, while 2 exhibited dramatic fluorescence quenching. Interestingly, the fluorescent responses of 3 toward two guests respectively were highly distinguishable. The fluorescence intensity of 3 only showed a slight increase upon the addition of ADA, but the addition of DCA led to a large decrease in fluorescence intensity. The investigations have been further carried out by 2D NMR, induced circular dichromism, fluorescence spectroscopy and molecular modeling to explore the relationships between the conformations and the fluorescence characteristics of CDs 1-3 in the absence and presence of guest molecules. On the basis of the above investigations, the origins for the different fluorescence behaviors have been proposed. PMID- 21557625 TI - Control of olefin geometry in macrocyclic ring-closing metathesis using a removable silyl group. AB - Introducing a silyl group at one of the internal olefin positions in diolefinic substrates results in E-selective olefin formation in macrocyclic ring-forming metathesis. The application of this method to a range of macrocyclic (E) alkenylsiloxanes is described. Protodesilylation of alkenylsiloxane products yields novel Z-configured macrocycles. PMID- 21557626 TI - Enantiocontrolled total syntheses of breviones A, B, and C. AB - Enantiocontrolled total syntheses of the breviones A, B, and C have been accomplished using a highly diastereoselective oxidative coupling of an alpha pyrone with a tricyclic diene prepared from an optically pure Wieland-Miescher ketone derivative through the 7-endo-trig mode of acyl radical cyclization. PMID- 21557627 TI - A new strategy for the synthesis of chiral beta-alkynyl esters via sequential palladium and copper catalysis. AB - A new strategy for the synthesis of chiral beta-alkynyl esters which relies on sequential Pd and Cu catalysis is reported. Terminal alkynes bearing aryl, alkyl, and silyl groups can be employed without prior activation yielding a wide range of important chiral building blocks. The reaction sequence utilizes a robust Pd(II)-catalyzed hydroalkynylation of ynoates with terminal alkynes providing geometrically pure ynenoates which are readily reduced by CuH. In contrast to previous reports, where additions to ynenoates proceed with marginal preference for the 1,6-pathway, this conjugate reduction occurs with high 1,4-selectivity yielding beta-alkynyl esters with excellent levels of enantioselectivity. Importantly, the method tolerates a wide range of functionality, including allylic carbonates and carbamates, and thus allows for rapid elaboration of the beta-alkynyl esters into a variety of chiral, substituted heterocycles. PMID- 21557628 TI - Site-directed methyl group labeling as an NMR probe of structure and dynamics in supramolecular protein systems: applications to the proteasome and to the ClpP protease. AB - Methyl groups are powerful reporters of structure, motion, and function in NMR studies of supramolecular protein assemblies. Their utility can be hindered, however, by spectral overlap, difficulties with assignment or lack of probes in biologically important regions of the molecule studied. Here we show that (13)CH(3)-S- labeling of Cys side chains using (13)C-methyl-methanethiosulfonate ((13)C-MMTS) (IUPAC name: methylsulfonylsulfanylmethane) provides a convenient probe of molecular structure and dynamics. The methodology is demonstrated with an application focusing on the gating residues of the Thermoplasma acidophilum proteasome, where it is shown that the (13)CH(3)-S- label reports faithfully on the conformational heterogeneity and dynamics in this region of the complex. A second and related application involves labeling with (13)C-MMTS at the N-termini of the subunits comprising the E. coli ClpP protease that reveals multiple conformations of gating residues in this complex as well. These N-terminal residues adopt a single conformation upon gate opening. PMID- 21557629 TI - Non-DLVO silica interaction forces in NMP-water mixtures. I. A symmetric system. AB - Despite the success of DLVO theory, there exist numerous examples of interactions that do not follow its predictions. One prominent example is the interaction between hydrophilic surfaces in mixtures of water with another polar, associating solvent. Interactions of such surfaces are still poorly understood yet play a key role in a wide variety of processes in nature, biology, and industry. The interaction forces between a silica sphere and a glass plate in N-methyl-2 pyrrolidone (NMP)-water binary mixtures were measured using the AFM technique. The interactions in pure NMP and pure water agreed qualitatively with DLVO theory. In contrast, the addition of NMP to water drastically altered the interactions, which no longer followed DLVO predictions. An unusually strong, long-range (50-80 nm), multistepped attractive force was observed on the approach of hydrophilic surfaces in the NMP concentration range of 30-50 vol %, where the adhesive pull-off force was also maximized. The maximum attractive force was observed at an NMP concentration near 30 vol %, consistent with the formation of a strong hydrogen-bonded complex between NMP and water near the solid surface. The analysis of force profiles, zeta potentials, solution viscosity, and contact angles suggests that attraction arises from the bridging of surface-adsorbed macrocluster layers known to form on hydrophilic surfaces in mixtures of associating liquids. PMID- 21557630 TI - Heteroatom as a promotor: synthesis of polyfunctionalized benzenes and naphthalenes. AB - Construction of a new benzene via the electrocyclization of diene-allene is an efficient protocol to access polysubstituted benzenes from simple, readily available starting materials. In this paper, we present a comprehensive study of a heteroatom-promoted propargyl-allenyl isomerization and electrocyclization for the facile and efficient synthesis of polyfunctionalized benzenes and naphthalenes. As a result of the readily accessible starting materials, simple operation, and mild conditions, this reaction should be an appealing strategy in organic synthesis. PMID- 21557631 TI - Accurate double many-body expansion potential energy surface for ground-state HS2 based on ab initio data extrapolated to the complete basis set limit. AB - A double many-body expansion potential energy surface is reported for the electronic ground state of HS(2) by fitting accurate multireference configuration interaction energies calculated with aug-cc-pVTdZ and aug-cc-pVQdZ basis sets upon separate extrapolation of the complete-active-space self-consistent field and dynamical correlation components of the total energy to the complete basis set limit. The major topographical features of the potential energy surface are examined in detail, and the model function is used for thermalized calculations of the rate constants for the S + SH -> H + S(2) reaction at 298 and 400 K. A value of (1.44 +/- 0.06) * 10(-11) cm(3) s(-1) is obtained at 298 K, providing perhaps the most reliable estimate of the rate constant known thus far for such a reaction. PMID- 21557632 TI - Decision-analytic models to simulate health outcomes and costs in heart failure: a systematic review. AB - Chronic heart failure (CHF) is a critical public health issue with increasing effect on the healthcare budgets of developed countries. Various decision analytic modelling approaches exist to estimate the cost effectiveness of health technologies for CHF. We sought to systematically identify these models and describe their structures. We performed a systematic literature review in MEDLINE/PreMEDLINE, EMBASE, EconLit and the Cost-Effectiveness Analysis Registry using a combination of search terms for CHF and decision-analytic models. The inclusion criterion required 'use of a mathematical model evaluating both costs and health consequences for CHF management strategies'. Studies that were only economic evaluations alongside a clinical trial or that were purely descriptive studies were excluded. We identified 34 modelling studies investigating different interventions including screening (n = 1), diagnostics (n = 1), pharmaceuticals (n = 15), devices (n = 13), disease management programmes (n = 3) and cardiac transplantation (n = 1) in CHF. The identified models primarily focused on middle aged to elderly patients with stable but progressed heart failure with systolic left ventricular dysfunction. Modelling approaches varied substantially and included 27 Markov models, three discrete-event simulation models and four mathematical equation sets models; 19 studies reported QALYs. Three models were externally validated. In addition to a detailed description of study characteristics, the model structure and output, the manuscript also contains a synthesis and critical appraisal for each of the modelling approaches. Well designed decision models are available for the evaluation of different CHF health technologies. Most models depend on New York Heart Association (NYHA) classes or number of hospitalizations as proxy for disease severity and progression. As the diagnostics and biomarkers evolve, there is the hope for better intermediate endpoints for modelling disease progression as those that are currently in use all have limitations. PMID- 21557633 TI - Symptoms and signs of tear film dysfunction in glaucomatous patients. AB - PURPOSE: The purposes of this study were to evaluate the presence of symptoms of tear film dysfunction by using the Ocular Surface Disease Index (OSDI) questionnaire in glaucomatous patients and to examine whether they have ocular surface signs. METHODS: Fifty patients with ocular hypertension or open-angle glaucoma were sequentially examined. All patients used preserved antiglaucomatous drops once, twice, 3 times, or 4 times a day. Each patient filled out an OSDI questionnaire. Fluorescein corneal staining, lissamine green conjunctival staining, break-up time, and Schirmer I test were performed in patients with positive OSDI. RESULTS: Using the OSDI, 26 of 50 patients (52%) showed at least mild symptoms of tear film dysfunction (score >12); of them, 17 (34%) had severe OSDI (Score >32). Decrease in tear production was seen in only 8 glaucomatous patients. The break-up time was <7 s in 18 patients. Lissamine green conjunctival staining was positive in at least one eye of all the 26 patients, whereas fluorescein corneal staining was positive in at least one eye of 22 patients. A statistically significant (P<0.05) difference was found for lissamine green conjunctival staining between 16 patients using ipotensive drops once or twice a day and 10 patients using drops 3 or 4 times a day. In the group of patients using only beta-blocker agents, we found a positive correlation between symptoms and vital staining of the ocular surface. CONCLUSION: Fifty-two percent of patients in therapy with preserved antiglaucomatous drops showed symptoms of tear film dysfunction. Signs of ocular surface diseases seemed to be greater in patients under >2 medications. Symptoms correlated to signs only in patients in monotherapy with beta-blockers drops. PMID- 21557634 TI - Prospects and challenges for immunotherapy of ovarian cancer--what can we learn from the tumor microenvironment? AB - Although there has been a marked resurgence of optimism that tumor vaccination or active immunotherapy may hold the prospect of clinical benefit for ovarian cancer patients, this optimism has been tempered by an appreciation that ovarian cancer represents a paradigm for the art of immunological defense. The pathogenesis of ovarian cancer is characterized by the evolution of multiple immunosuppressive mechanisms in the tumor microenvironment, several of which correlate with increased morbidity and mortality in ovarian cancer patients. This issue of International Reviews of Immunology focuses on the immunology of ovarian cancer, with a particular emphasis on the role of antigen-presenting cells in shaping immunological stasis within the tumor microenvironment. An understanding of these mechanisms will likely guide the development of novel adjuvants to alleviate local immune suppression in support of clinically effective ovarian tumor vaccination. PMID- 21557635 TI - Understanding the cross-talk between ovarian tumors and immune cells: mechanisms for effective immunotherapies. AB - Despite decades of research, ovarian cancer remains a lethal disease. Recent studies have reported the critical role played by the immune system in controlling growth and spread of ovarian tumors. Accordingly, immunotherapy has been indicated as the most likely successful new approach in the treatment of the disease. Unfortunately, ovarian cancer triggers immune inhibitory mechanisms that hamper anti-tumor responses. Therefore, future immunotherapies should be able to overcome these obstacles. Here we review the basic mechanisms of tumor immune surveillance with a particular focus on ovarian cancer, and we discuss cutting edge strategies to promote immune system eradication of ovarian tumors. PMID- 21557636 TI - Peritoneal immune system in patients with advance epithelial ovarian cancer. AB - The development of epithelial ovarian cancer is associated with changes in the peritoneal cavity microenvironment. Tumor cells produce different factors, which impairs differentiation, maturation, and function of antigen-presenting cells. In this review, we focus on selected cell populations in the peritoneal cavity immune system and their potential role in epithelial ovarian cancer immunopathogenesis. We devote most attention to dendritic cells because they are considered to be superior in their antigen-presenting ability, compared with both macrophages and B lymphocytes. We also present a brief characterization of tumor infiltraiting cells in epithelial ovarian cancer patients. PMID- 21557637 TI - Immune therapy for ovarian cancer: promise and pitfalls. AB - This review covers immune and anatomic considerations specific for ovarian cancer immune therapy. Prior approaches and potential reasons for lack of better efficacy are discussed, along with newer approaches in pre-clinical and early clinical development. Potential means for future investigations and means to integrate immune with other approaches are discussed. PMID- 21557638 TI - Antigen-presenting cell (APC) subsets in ovarian cancer. AB - The major human antigen-presenting cells (APCs) include monocytes/macrophages, myeloid dendritic cells (mDC), plasmacytoid dendritic cells (pDC), and B cells. These APC subsets have been observed in ovarian tumor environments. Their phenotypes and functionalities are subjected to alteration by multiple factors in the tumor environment. In this review, we summarize the nature, cellular interactions, and prognostic significance of the main APC populations in ovarian cancer, and discuss the relevance of manipulating APC subsets for patient treatment. PMID- 21557639 TI - Cancer testis antigens: novel biomarkers and targetable proteins for ovarian cancer. AB - Ovarian cancer is the fifth leading cause of cancer death in women and the leading cause from gynecological malignancies. Despite the recently improved outcomes of new chemotherapeutical agents in the therapy of ovarian cancer and the increased 5-year survival rate, the mortality of this malignancy disease remains unchanged. Ovarian cancer therapy is often correlated to the stage of the tumor, but the first step is usually surgical treatment. Afterward, various courses of chemotherapy and radiation are suggested. Obviously, the higher the developmental stage of the tumor, the less the probability is in eradicating it surgically, especially in relation to metastasis. It is clear that an early diagnosis of ovarian cancer is important for the survival of these patients. In order to identify ovarian cancer patients in the early stages, a number of studies are focusing on a particular class of antigens called cancer testis antigens. These antigens display high expression in tumors of different histology, but are normally restricted to the testis and have low or no expression in normal tissues. The testes are an immunologically-privileged site due to the presence of tight junctions between adjacent Sertoli cells that constitute the blood-testis barrier, which prevents auto-immune reactions. In the past few years, some of these antigens were demonstrated to be very promising for the early diagnosis and development of vaccines for ovarian cancer. This review aims to underline the most reliable cancer testis antigens under investigation at this moment. PMID- 21557640 TI - Sperm protein 17: clinical relevance of a cancer/testis antigen, from contraception to cancer immunotherapy, and beyond. AB - Sperm protein 17 belongs to the cancer/testis antigen family and was found to play a key role in the cell fusion process between the mammalian spermatozoa and egg. Sperm protein 17-specific autoantibodies in vasectomized males suggest its high expression in the testis. Sperm protein 17 expression levels are low or absent in normal tissues, other than the testis. Sperm protein 17 is expressed by tumors, including ovarian cancer, indicating that it is an ideal target for cancer immunotherapy, and plays a role in tumorigenesis and drug resistance. This review recapitulates the milestones of sperm protein 17 research and highlights its potential use in translational medicine. PMID- 21557641 TI - Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. AB - Whole tumor cell lysates can serve as excellent multivalent vaccines for priming tumor-specific CD8(+) and CD4(+) T cells. Whole cell vaccines can be prepared with hypochlorous acid oxidation, UVB-irradiation and repeat cycles of freeze and thaw. One major obstacle to successful immunotherapy is breaking self-tolerance to tumor antigens. Clinically approved adjuvants, including MontanideTM ISA-51 and 720, and keyhole-limpet proteins can be used to enhance tumor cell immunogenicity by stimulating both humoral and cellular anti-tumor responses. Other potential adjuvants, such as Toll-like receptor agonists (e.g., CpG, MPLA and PolyI:C), and cytokines (e.g., granulocyte-macrophage colony stimulating factor), have also been investigated. PMID- 21557642 TI - Effect of opponent type on moral emotions and responses to video game play. AB - This study suggests that fighting against different types of opponents in video games (e.g., human opponents vs. monster opponents) may lead to different emotional responses and moral judgments toward game characters. Based on Bandura's moral disengagement theory, this study proposes that shooting at monster opponents makes game players feel less guilty and judge the player controlled character as more morally justified. An experiment was conducted in which participants played shooting games with either human opponents or monster opponents. The results show that when playing against monster opponents, participants felt both less ashamed and less guilty, reported enjoying the game more, and judged their character as more justified than participants who played against human opponents. PMID- 21557643 TI - Immune response in patients receiving a bioprosthetic heart valve: lack of response with decellularized valves. AB - Conventional biological heart valves treated with glutaraldehyde (GA) reveal a limited lifespan due to calcification. This is assumed to be an immune response initiated process, which is not seen with decellularized valves. However, their immunological potential is still a matter of debate. Therefore, serum samples from patients undergoing heart valve surgery were obtained before (Pre), after (Post), and 9-12 months after operation (Follow Up). Immunoglobulin G (IgG) and M (IgM) antibodies against porcine collagen I and alpha-Gal (Gal-alpha1,3-Gal beta1,4-GlcNac-R) were determined for decellularized and GA treated valves. Antibody titers for collagen type I revealed no significant alteration for both types of valves. However, a considerable anti-alpha-Gal antibody response was observed in patients with GA-treated porcine valves. In detail, IgM antibodies were increased during follow up (p<0.05), whereas decellularized valves revealed a minor decrease in the IgM response (p<0.001). IgG antibodies were considerably increased with GA-treated porcine (p<0.05) and bovine (p<0.01) xenografts, whereas there was lack of response with decellularized valves. This indicates that GA treatment is not sufficient to eliminate immune response to the alpha-Gal epitope completely. Future investigations will have to verify whether immune response to alpha-Gal can be linked to the limited durability of conventional valves. PMID- 21557644 TI - Act quickly, decide later: long-latency visual processing underlies perceptual decisions but not reflexive behavior. AB - Humans largely guide their behavior by their visual representation of the world. Recent studies have shown that visual information can trigger behavior within 150 msec, suggesting that visually guided responses to external events, in fact, precede conscious awareness of those events. However, is such a view correct? By using a texture discrimination task, we show that the brain relies on long latency visual processing in order to guide perceptual decisions. Decreasing stimulus saliency leads to selective changes in long-latency visually evoked potential components reflecting scene segmentation. These latency changes are accompanied by almost equal changes in simple RTs and points of subjective simultaneity. Furthermore, we find a strong correlation between individual RTs and the latencies of scene segmentation related components in the visually evoked potentials, showing that the processes underlying these late brain potentials are critical in triggering a response. However, using the same texture stimuli in an antisaccade task, we found that reflexive, but erroneous, prosaccades, but not antisaccades, can be triggered by earlier visual processes. In other words: The brain can act quickly, but decides late. Differences between our study and earlier findings suggesting that action precedes conscious awareness can be explained by assuming that task demands determine whether a fast and unconscious, or a slower and conscious, representation is used to initiate a visually guided response. PMID- 21557645 TI - Evidence for early morphological decomposition: combining masked priming with magnetoencephalography. AB - Are words stored as morphologically structured representations? If so, when during word recognition are morphological pieces accessed? Recent masked priming studies support models that assume early decomposition of (potentially) morphologically complex words. The electrophysiological evidence, however, is inconsistent. We combined masked morphological priming with magneto encephalography (MEG), a technique particularly adept at indexing processes involved in lexical access. The latency of an MEG component peaking, on average, 220 msec post-onset of the target in left occipito-temporal brain regions was found to be sensitive to the morphological prime-target relationship under masked priming conditions in a visual lexical decision task. Shorter latencies for related than unrelated conditions were observed both for semantically transparent (cleaner-CLEAN) and opaque (corner-CORN) prime-target pairs, but not for prime target pairs with only an orthographic relationship (brothel-BROTH). These effects are likely to reflect a prelexical level of processing where form-based representations of stems and affixes are represented and are in contrast to models positing no morphological structure in lexical representations. Moreover, we present data regarding the transitional probability from stem to affix in a post hoc comparison, which suggests that this factor may modulate early morphological decomposition, particularly for opaque words. The timing of a robust MEG component sensitive to the morphological relatedness of prime-target pairs can be used to further understand the neural substrates and the time course of lexical processing. PMID- 21557646 TI - Putting a name to a face: the role of name labels in the formation of face memories. AB - Although previous research in ERPs has focused on the conditions under which faces are recognized, less research has focused on the process by which face representations are acquired and maintained. In Experiment 1, participants were required to monitor for a target "Joe" face that was shown among a series of nontarget "Other" faces. At the halfway point, participants were instructed to switch targets from the Joe face to a previous nontarget face that is now labeled "Bob." The ERP analysis focused on the posterior N250 component known to index face familiarity and the P300 component associated with context updating and response decision. Results showed that, in the first half of the experiment, there was increase in N250 negativity to the target Joe face compared with the nontarget Bob and designated Other face. In the second half of the experiment, an enhanced N250 negativity was produced to the now-target Bob face compared with the Other face. Critically, the enhanced N250 negativity to the Joe face was maintained, although Joe was no longer the target. The P300 component followed a similar pattern of brain response, where the Joe face elicited a significantly larger P300 amplitude than the Other face and the Bob face. In the Bob half of the experiment, the Bob face elicited a reliably larger P300 than the Other faces, and the heightened P300 to the Joe face was sustained. In Experiment 2, we examined whether the increased N250 and P300 to Joe was because of simple naming effects. Participants were introduced to both Joe and Bob faces and names at the beginning of the experiment. In the first half of the experiment, participants monitored for the target Joe face and at the halfway point, they were instructed to switch targets to the Bob face. Findings show that N250 negativity significantly increased to the Joe face relative to the Bob and Other faces in the first half of the experiment and an enhanced N250 negativity was found for the target Bob face and the nontarget Joe face in the second half. An increased P300 amplitude was demonstrated to the target Joe and Bob faces in the first and second halves of the experiment, respectively. Importantly, the P300 amplitude elicited by the Joe face equaled the P300 amplitude to the Bob face, although it was no longer the target face. The findings from Experiments 1 and 2 suggest that the N250 component is not solely determined by name labeling, exposure, or task relevancy, but it is the combination of these factors that contribute to the acquisition of enduring face representations. PMID- 21557647 TI - Neural basis of linearization in speech production. AB - An initial stage of speech production is conceptual planning, where a speaker determines which information to convey first (the linearization problem). This fMRI study investigated the linearization process during the production of "before" and "after" sentences. In "after" sentences, a series of events is expressed in the order of event occurrence. In "before" sentences, however, the order of event mention is achieved by reversing the chronological order. We suggested that the linearization process may be supported by a neural network connecting the left middle temporal gyrus (MTG) with the medial superior frontal gyrus, left middle frontal gyrus, and left angular gyrus/inferior parietal gyrus. Within this network, regions were more activated and interregional interactions were strongly enhanced for producing "before" than "after" sentences. The left MTG was also functionally connected with the left orbital inferior frontal gyrus, contributing to the retrieval of necessary world knowledge and linguistic knowledge. Connectivity between these two regions was not different between conditions. PMID- 21557649 TI - The detection and the neural correlates of behavioral (prior) intentions. AB - Prior intentions are abstract mental representations that are believed to be the prime cause of our intentional actions. To date, only a few studies have focused on the possibility that single prior intentions could be identified in people's minds. Here, for the first time, we used the autobiographical Implicit Association Test (aIAT) in order to identify a specific prior intention on the basis of a pattern of associations derived from reaction times (Experiment 1). The aIAT is based on two critical blocks: the block associating intentions with true sentences (congruent block) gave rise to faster reaction times (RTs) than the block associating intentions with false sentences (incongruent block). Furthermore, when comparing intentions with hopes, it was revealed that the reported effect was intention-specific: The pattern of associations reflected a congruency effect when intentions and the logical category "True" were paired, but not when hopes and the "True" category were paired (Experiment 2). Finally, we investigated the neural bases of the congruency effect that leads to the identification of an intention (Experiment 3). We found a reduced late positive component (LPC) for the incongruent with respect to the congruent block, suggesting that the incongruent block needs additional resources of cognitive control with respect to the congruent block. PMID- 21557648 TI - Brain regions engaged by part- and whole-task performance in a video game: a model-based test of the decomposition hypothesis. AB - Part- and whole-task conditions were created by manipulating the presence of certain components of the Space Fortress video game. A cognitive model was created for two-part games that could be combined into a model that performed the whole game. The model generated predictions both for behavioral patterns and activation patterns in various brain regions. The activation predictions concerned both tonic activation that was constant in these regions during performance of the game and phasic activation that occurred when there was resource competition. The model's predictions were confirmed about how tonic and phasic activation in different regions would vary with condition. These results support the Decomposition Hypothesis that the execution of a complex task can be decomposed into a set of information-processing components and that these components combine unchanged in different task conditions. In addition, individual differences in learning gains were predicted by individual differences in phasic activation in those regions that displayed highest tonic activity. This individual difference pattern suggests that the rate of learning of a complex skill is determined by capacity limits. PMID- 21557650 TI - Using complement coercion to understand the neural basis of semantic composition: evidence from an fMRI study. AB - Previous research regarding the neural basis of semantic composition has relied heavily on violation paradigms, which often compare implausible sentences that violate world knowledge to plausible sentences that do not violate world knowledge. This comparison is problematic as it may involve extralinguistic operations such as contextual repair and processes that ultimately lead to the rejection of an anomalous sentence, and these processes may not be part of the core language system. Also, it is unclear if violations of world knowledge actually affect the linguistic operations for semantic composition. Here, we compared two types of sentences that were grammatical, plausible, and acceptable and differed only in the number of semantic operations required for comprehension without the confound of implausible sentences. Specifically, we compared complement coercion sentences (the novelist began the book), which require an extra compositional operation to arrive at their meaning, to control sentences (the novelist wrote the book), which do not have this extra compositional operation, and found that the neural response to complement coercion sentences activated Brodmann's area 45 in the left inferior frontal gyrus more than control sentences. Furthermore, the processing of complement coercion recruited different brain regions than more traditional semantic and syntactic violations (the novelist astonished/write the book, respectively), suggesting that coercion processes are a part of the core of the language faculty but do not recruit the wider network of brain regions underlying semantic and syntactic violations. PMID- 21557651 TI - Is it a baby? Perceived age affects brain processing of faces differently in women and men. AB - It is known that infant faces stimulate visual and anterior brain regions belonging to the mesocortical limbic system (orbito-frontal cortex, anterior cingulate cortex, and nucleus accumbens) as well as the fusiform gyrus during face coding, suggesting a preferential response to baby schema. In the present investigation, faces of infants, children, and adults were presented to 40 male and female right-handed university students with technological objects (and inanimate scenarios to serve as targets) in a randomly mixed fashion. EEG was recorded from 128 scalp sites. In both sexes, the N1 response to infant faces was larger than the response to adult faces; however, the baby-specific N1 response was much larger in women than in men across the left hemisphere. The anterior N2 response to infants was greater than the response to children only in women, whereas the response to children of any age was larger than the response to adults in men. LORETA identified the intracranial sources of N2 response to infants in the left fusiform gyrus (FG), as well as the uncus, cingulate, and orbito-frontal cortices. The FG, the limbic, and especially the orbito-frontal sources were much larger in women than in men. The data suggest a sex difference in the brain response to faces of different ages and in the preferential response to infants, especially with regard to activation of the mesocorticolimbic system. PMID- 21557652 TI - Mine and me: exploring the neural basis of object ownership. AB - Previous research has shown that encoding information in the context of self evaluation leads to memory enhancement, supported by activation in ventromedial pFC. Recent evidence suggests that similar self-memory advantages can be obtained under nonevaluative encoding conditions, such as when object ownership is used to evoke self-reference. Using fMRI, the current study explored the neural correlates of object ownership. During scanning, participants sorted everyday objects into self-owned or other-owned categories. Replicating previous research, a significant self-memory advantage for the objects was observed (i.e., self owned > other-owned). In addition, encoding self-owned items was associated with unique activation in posterior dorsomedial pFC (dMPFC), left insula, and bilateral supramarginal gyri (SMG). Subsequent analysis showed that activation in a subset of these regions (dMPFC and left SMG) correlated with the magnitude of the self-memory advantage. Analysis of the time-to-peak data suggested a temporal model for processing ownership in which initial activation of dMPFC spreads to SMG and insula. These results indicate that a self-memory advantage can be elicited by object ownership and that this effect is underpinned by activity in a neural network that supports attentional, reward, and motor processing. PMID- 21557653 TI - Life cycle of the multiarmed sea star Coscinasterias acutispina (Stimpson, 1862) in laboratory culture: sexual and asexual reproductive pathways. AB - The multiarmed sea star Coscinasterias acutispina generally has 7-10 arms and 2-5 madreporites. It is known to be able to reproduce by asexual fission, and we have previously observed that this species also has the ability to reproduce sexually; however, there has been no report until now of spawning in this species. We succeeded in establishing a long-term culture of juveniles produced by artificial fertilization. Twelve months after the completion of metamorphosis, three individuals had six arms of the same length and a madreporite. At this time, fission occurred in two of these individuals, while the remaining individual underwent fission four months later. Each sea star divided into two halves, provided with three arms each. Thereafter, four or five new arms and two or four madreporites were formed anew in each of the six daughter sea-stars, so that by 30 days after the first fission the number of arms and madreporites in each was similar to that in adults. A second fission occurred in four of these six individuals, four or five months after the first fission, and in three of them the plane of division was the same as that of the first fission. The original three individuals eventually proliferated to 12 by undergoing fission. All individuals had fully developed gonads by 1-3 months after the second fission. Some of them eventually spawned under laboratory culture, and the resulting larvae metamorphosed into juveniles. Our observations demonstrate that individuals of C. acutispina possess the potential for both sexual and asexual reproduction. PMID- 21557654 TI - Are plumatellid statoblasts in freshwater bryozoans phylogenetically informative? AB - Morphological characters of statoblasts (including floatoblasts and sessoblasts) in freshwater bryozoans have been important in phylactolaemate systematics and identification in that older phylogenetic hypotheses relied heavily on statoblast morphology. To assess the reliability of statoblast characters in drawing conclusions about phylogeny, we examined the phylogenetic distribution of metric and proportional floatoblast characters, floatoblast symmetry, and floatoblast and sessoblast microsculpture in Plumatellidae, the largest family of phylactolaemates, in the context of molecular phylogenetic reconstructions based on nucleotide sequences of parts of the mitochondrial 12S rRNA, 16S rRNA, and cytochrome b (cytb) genes. Adding cytb sequences to a previous phylogeny based on 12S and 16S increased support only for a node including Plumatella vaihiriae in the P. repens clade. Characters of gross floatoblast morphology were generally not phylogenetically informative individually, but collectively discriminated among members of three relatively well-supported clades that were analyzed as pre defined groups in a discriminant analysis. Two characters of floatoblast microsculpture (reticulation and hypertubercles) were restricted to particular clades; other characters (e.g., villi) were clearly convergent. In nine of 11 cases, fenestral microsculpture was identical or partly correlated between the floatoblast and sessoblast of a species. Overall, our results indicate that statoblast morphology is not highly phylogenetically constrained. PMID- 21557655 TI - The importance of workers for queen hibernation survival in Camponotus ants. AB - The higher proportion of polygynous ant species in northern areas indicates that cold climates influence queen number per colony. It is unclear, however, what ecological and physiological factors facilitate the dominance of polygynous species in cold climates. This is the case in two common arboreal ants in Japan Camponotus yamaokai and C. nawai-which are quite similar in morphology, but different in social structure and geographical distribution. Polygynous C. yamaokai inhabits colder areas, whereas monogynyous C. nawai inhabits warmer climates. We compared queen survival in both ants at low temperature to evaluate whether interspecific difference in cold tolerance can explain the geographical distribution. We examined the influence of cohabitation with other individuals, as well as individual cold tolerance. Experimental groups with different caste compositions were prepared and maintained under conditions simulating in the laboratory climates of the northern limit of C. nawai. Wintering experiments revealed that C. yamaokai queens survived longer than C. nawai queens under solitary conditions, although half of the queens died in less than a month, even in C. yamaokai. Queens hibernating with workers survived longer than solitary queens, but queen number did not affect queen survival. Cohabitation with workers allowed 80% of C. yamaokai queens to survive more than two months. Under field conditions, monogynous C. nawai foundresses overwinter without workers, whereas new queens of polygynous C. yamaokai always overwinter with many workers. Thus, the geographical distribution of these ants appears to depend on the overwintering behavior of new queens. PMID- 21557656 TI - Life-history variation with respect to experienced thermal environments in the lizard, Eremias multiocellata (Lacertidae). AB - We compared adult size, female reproductive traits, and offspring phenotypes between multiocellated racerunners (Eremias multiocellata) from two thermally different sites (populations) in Inner Mongolia (North China): the colder one in Wulatehouqi (WQ) and the warmer one in Dalateqi (DQ). Both adults and neonates were smaller in the colder site. Females from the two sites both produced a single litter of 2-5 young per season, and did not differ in allocation of energy to reproduction after accounting for differences in body size. Female neonates had more ventral scales than did males, and the WQ neonates had fewer ventral scales than did the DQ neonates. The WQ neonates were slower than the DQ neonates. When body length was normalized across populations, we found that (1) hindlimb length correlated positively with sprint speed in both WQ and DQ neonates, (2) forelimb length correlated positively with sprint speed only in the DQ neonates, and (3) tail length correlated positively with sprint speed only in the WQ neonates. Hindlimb length played a more important role in locomotion than did tail length or forelimb length. Though differing in size and morphology, neonates from the two sites did not differ in early growth and survival under identical laboratory conditions. Our data are consistent with many studies that have shown countergradient variation in physiological traits (growth rate and reproductive output) and cogradient variation in morphological traits. PMID- 21557657 TI - Molecular cloning and characterization of cDNAs encoding biosynthetic precursors for the antimicrobial peptides japonicin-1Ja, japonicin-2Ja, and temporin-1Ja in the Japanese brown frog, Rana japonica. AB - Using a combination of reverse-transcription polymerase chain reaction and the 5' and/or 3'-rapid amplification of cDNA ends, we cloned, from a Japanese brown frog (Rana japonica) skin total RNA preparation, cDNAs encoding biosynthetic precursors for the antimicrobial peptides (AMPs) japonicin-1Ja (FFPIGVFCKIFKTC), japonicin-2Ja (FGLPMLSILPKALCILLKRKC), and temporin-1Ja (ILPLVGNLLNDLL.NH2). These peptides were previously isolated from an extract of R. japonica skin. The present study is the first report to describe the molecular cloning of the cDNA encoding a japonicin-2 family peptide. The nucleotide and deduced amino acid sequence analyses revealed that the hypothetical precursor protein of japonicin 2Ja, as well as japonicin-1Ja and temporin-1Ja, is organized similarly to those of typical amphibian AMP precursors, with a highly conserved signal peptide, a relatively well conserved intervening sequence, and a hypervariable AMP mature region. Antimicrobial assays for synthetic replicates of cyclic and linear japonicin-2Ja revealed that the intramolecular disulfide bond is necessary for activity. A semi-quantitative analysis by real-time RTPCR using TaqMan probes revealed that the relative values of preprojaponicin-2Ja mRNA expression levels in the skin, skeletal muscle of hind leg, kidney, testis, small intestine, and stomach total RNA sample specimens in adult R. japonica were 6.5*10(5), 9.6, 2.0, 1.6, 1.6, and 1.0, respectively. The presence of preprojaponicin-2Ja mRNAs in the cytoplasm of glandular cells in R. japonica dorsal skin glands was demonstrated by means of in situ hybridization using digoxigenin-labeled cRNA probes for the precursor. PMID- 21557658 TI - Exaggerated asymmetric head morphology of female Doubledaya bucculenta (Coleoptera: Erotylidae: Languriinae) and ovipositional preference for bamboo internodes. AB - The lizard beetle Doubledaya bucculenta (Coleoptera: Erotylidae: Languriinae) female has evident asymmetric head morphology. The females excavate small holes in host bamboo internodes for the deposition of eggs. To understand the asymmetry and allometry of male and female adults and larvae of D. bucculenta, mandibular length, genal and head width, and elytral length were measured, and the oviposition preference for different-sized internodes of the bamboo Pleioblastus simonii and the relationship between internode size and emerging adult size were examined. Larval mandibles exhibited no clear asymmetry pattern, and genae showed fluctuating asymmetry in length. Adult male mandibles showed left-directional asymmetry, but genae showed fluctuating asymmetry. Adult female mandibles and genae exhibited marked left-directional asymmetry. The degree of asymmetry of mandibles and genae remained constant regardless of body size. Large females tended to choose large-diameter internodes of P. simonii and to lay eggs successfully, whereas small females tended to choose intermediate-diameter internodes, but to fail in oviposition, suggesting that small females pay a high cost on oviposition. There was a positive correlation between internode size and emerging adult size. Marked directional asymmetry of female mandibles and genae are discussed in relation to greater frequency of cutting bamboo fibers compared with adult males, and the traits of bamboo internode. PMID- 21557659 TI - Effects of co-administration of estrogen and androgen on induction of sex reversal in the medaka Oryzias latipes. AB - To investigate how estrogen and androgen affect each other in inducing sex reversal in the medaka, O. Iatipes, 17beta-estradiol (E2) and 17alpha methyldihydrotestosterone (MDHT) were co-administered by a convenient method for hormonal treatment, in which freshly fertilized eggs were immersed for 24 h in saline containing either or both of the two sex steroids in different concentrations and/or ratios. The minimal concentrations of E2 and MDHT sufficient to induce the maximal rate of sex reversal from male to female and from female to male were 500 ng/ml and 2.5 ng/ml, respectively, both of which were referred to as the most efficacious dose (MED), and each equivalent for the inducing potency in sex reversal. E2 and MDHT, when simultaneously administered at MED, greatly suppressed each other to induce each corresponding sex reversal. Thus, the present experimental results indicate that E2 and DMHT are antagonists that induce corresponding sex reversal, and suggest that genotypic sex in the medaka might be modified through an unknown factor of common affinity to both sex steroids, by which the pathway of differentiation of either sex could be switched at the early stages of development far before gonadal sex differentiation. PMID- 21557660 TI - Mating system and size advantage of male mating in the protogynous swamp eel Monopterus albus with paternal care. AB - In fish with paternal care, protogynous sex change (female to male) is rare and has only been reported from species with haremic polygyny. The swamp eel, Monopterus albus, is a protogynous fish with paternal care, but little is known about its mating system. To understand protogyny in this species, we examined the mating system and male size advantage in mating in M. albus under semi-natural condition. Females swam over wide ranges and visited multiple male nests. Males defended a narrow territory around nests against other males that approached nests; at these nests, males courted and accepted visiting females. After spawning inside nests, caring males continued to perform courtship activities, and multiple breeding was observed. These observations suggest that the M. albus mating system is male-territory-visiting (MTV)-polygamy. Larger males had nests, and mated more frequently compared with small males. Because small initial males of this species are not found in nature, and because M. albus does not engage in sneaking tactics, larger nesting males do not suffer from reproductive parasitism. Thus, protogyny in this fish is likely consistent with the predictions of the size-advantage model. Biting attacks by territorial males of this predatory fish seriously wounded intruding males, occasionally resulting in the death of the intruder. We discuss the possibility that sexual differences in mortality rates in small fish may facilitate the evolution of protogyny in this species. Protogyny of the swamp eel is, to our knowledge, the first example of an MTV-polygamous mating system in a fish with paternal care. PMID- 21557661 TI - Redescriptions of Spirosperma apapillatus and Embolocephalus nikolskyi (Annelida, Clitellata, Tubificinae) from Japan, with reference to distribution of papillate tubificines in Japanese freshwaters. AB - Based on new specimens, two freshwater papillate tubificines, Spirosperma apapillatus (Lastockin in Lastockin and Sokolskaja, 1953) and Embolocephalus nikolskyi (Lastockin in Lastockin and Sokolskaja, 1953) are redescribed, and geographic distributions are shown for these two species and E. yamaguchii (Brinkhurst, 1971) in the Japanese archipelago. A geographic cline from northern Hokkaido to northern Honshu is suggested by the distribution of simple-pointed ventral chaetae in Japanese E. nikoslkyi. That species is replaced by E. yamaguchii in the south, beginning in northern Honshu. Tubifex (Peloscolex) nomurai Yamatoto and Okada, 1940 , which was described from deep profundal bottoms in Lake Tazawa, Japan, may be ascribed to E. nikolskyi, or may be closely related; the definitive status is not settled. PMID- 21557662 TI - Review of the oriental leafhopper genus Lampridius (Hemiptera: Cicadellidae: Deltocephalinae), with description of a related new genus. AB - The leafhopper genus Lampridius Distant, 1918 (type species: L. spectabilis Distant, 1918 ) is redescribed, and a second species, L. cuspidatus sp. nov. (Thailand: Loei), is described. A related new genus Paralampridius gen. nov. and four new species are described: P. mimicus sp. nov. (China: Guangdong, Hainan), P. rotundatus sp. nov. (Thailand: Loei), P. sinuatus sp. nov. (Thailand: Loei, Suphanburi, Petchaburi), and P. truncatus sp. nov. (Thailand: Chaiyaphum, Ubon Ratchathani). Both genera are tentatively included in the tribe Opsiini, although only Lampridius has paired aedeagal shafts with separate gonopores. All six species are illustrated, and a key is provided for their identification. Problems with the current tribal classification are discussed in light of the present discovery of closely related species that show variation in characters previously assumed to be stable at the tribal level in the subfamily Deltocephalinae. PMID- 21557663 TI - Novel cholesteryl ester transfer protein inhibitors: promising therapy for dyslipidemia? PMID- 21557664 TI - Arm restraints. PMID- 21557666 TI - Loss of HSF1 results in defective radiation-induced G(2) arrest and DNA repair. AB - HSF1 is a transcription factor that plays a key role in the response to heat stress and was previously shown by us to also be essential for importation of p53 into the nucleus. Here we extend these studies and show that loss of HSF1 renders cells more sensitive to killing by ionizing radiation. Cells that lack a functional HSF1 were unable to arrest in G(2) after exposure to ionizing radiation, suggesting that HSF1 activity was essential for activation of this cell cycle checkpoint. In addition, cells with no HSF1 showed a reduced capacity to repair radiation-induced double-stranded DNA breaks. We found that in these cells 53BP1 did not accumulate at sites of DNA damage, suggesting that HSF1 was also essential for the functioning of this DNA damage mediator. Taken together our results indicate that HSF1 plays an important role in checkpoint activation and DNA repair and suggest that there is overlap between the heat stress response pathway and the pathway that responds to ionizing radiation. PMID- 21557667 TI - Response of primary human fibroblasts exposed to solar particle event protons. AB - Solar particle events (SPEs) present a major radiation-related risk for manned exploratory missions in deep space. Within a short period the astronauts may absorb doses that engender acute effects, in addition to the risk of late effects, such as the induction of cancer. Using primary human cells, we studied clonogenic survival and the induction of neoplastic transformation after exposure to a worst case scenario SPE. We simulated such an SPE with monoenergetic protons (50, 100, 1000 MeV) delivered at a dose rate of 1.65 cGy min-1 in a dose range from 0 to 3 Gy. For comparison, we exposed the cells to a high dose rate of 33.3 cGy min-1. X rays (100 kVp, 8 mA, 1.7 mm Al filter) were used as a reference radiation. Overall, we observed a significant sparing effect of the SPE dose rate on cell survival. High-dose-rate protons were also more efficient in induction of transformation in the dose range below 30 cGy. However, as dose accumulated at high dose rate, the transformation levels declined, while at the SPE dose rate, the number of transformants continued to increase up to about 1 Gy. These findings suggest that considering dose-rate effects may be important in evaluating the biological effects of exposure to space radiation. Our analyses of the data based on particle fluence showed that lethality and transforming potential per particle clearly increased with increasing linear energy transfer (LET) and thus with the decreasing energy of protons. Further, we found that the biological response was determined not only by LET but also type of radiation, e.g. particles and photons. This suggests that using gamma or X rays may not be ideal for assessing risk associated with SPE exposures. PMID- 21557668 TI - Approaching parents to take part in a cleft gene bank: a qualitative pilot study. AB - OBJECTIVE: A gene bank, comprising genetic material and environmental and family history data, is being established in the United Kingdom to improve the understanding of the etiology of orofacial clefting (OFC). This study aimed to identify factors that might contribute to participation in a cleft gene bank and what issues need to be considered in approaching parents to be included. DESIGN: A qualitative approach was adopted, using focus groups and interviews. Transcripts of audio recordings were analyzed using inductive thematic analysis. PARTICIPANTS: A UK cleft center invited 100 families of children born with OFC to participate. Inclusion criteria included any parent of a child aged between 6 months and 16 years willing to take part. Sixteen parents participated. RESULTS: Participants were generally motivated to take part in a cleft gene bank because they value the discovery of new knowledge of the etiology of OFC. They wanted reassurance about the purpose and integrity of the project. Many conveyed shock at the diagnosis of cleft and offered mixed accounts of experiences with health care professionals. They suggested an individualized approach from a trustworthy and sensitive professional when being invited to join the gene bank, avoiding difficult times associated with new-baby challenges and issues related to the cleft. CONCLUSIONS: This pilot study indicates that parents of children born with OFC would be supportive of developing a cleft gene bank, but sensitive issues need to be considered. PMID- 21557669 TI - Short communication prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States. AB - Abstract The prevalence of susceptibility to etravirine was investigated among clinical samples submitted for routine clinical testing in the United States using two separate weighted genotypic scoring systems. The presence of etravirine mutations and susceptibility to etravirine by phenotype of clinical samples from HIV-1-infected patients, submitted to Monogram Biosciences for routine resistance testing between June 2008 and June 2009, were analyzed. Susceptibility by genotype was determined using the Monogram and Tibotec etravirine-weighted genotypic scoring systems, with scores of <=3 and <=2, respectively, indicating full susceptibility. Susceptibility by phenotype was determined using the PhenoSense HIV assay, with lower and higher clinical cut-offs of 2.9 and 10, respectively. The frequency of individual etravirine mutations and the impact of the K103N mutation on susceptibility to etravirine by genotype were also determined. Among the 5482 samples with >=1 defined nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations associated with resistance, 67% were classed as susceptible to etravirine by genotype by both scoring systems. Susceptibility to etravirine by phenotype was higher (76%). The proportion of first-generation NNRTI-resistant samples with (n=3598) and without (n=1884) K103N with susceptibility to etravirine by genotype was 77% and 49%, respectively. Among samples susceptible to first-generation NNRTIs (n=9458), >99% of samples were susceptible to etravirine by phenotype (FC <2.9); the remaining samples had FC >=2.9-10. In summary, among samples submitted for routine clinical testing in the United States, a high proportion of samples with first-generation NNRTI resistance was susceptible to etravirine by genotype and phenotype. A higher proportion of NNRTI-resistant samples with K103N than without was susceptible to etravirine. PMID- 21557670 TI - A novel nonoperative technique in the initial management and treatment of congenital microstomia. AB - Congenital microstomia in the newborn can result in poor functional and aesthetic outcomes. In the past, treatment options have included surgical methods such as commissurotomies and z-plasties as well as nonsurgical treatments using oral splints. In severe microstomia, a surgical release may be required to permit splint placement. Because of the small diameter of the stoma, such surgical releases are not optimal and frequently must be repeated. We devised a nonoperative technique for the initial treatment of congenital microstomia that will slowly enlarge the stomal diameter without the need for surgical release. The patient is a newborn male born with multiple congenital anomalies including severe mandibular hypoplasia and retrusion, microstomia, and microglossia. The size of his oral cavity was less than 1 cm at birth with no clinical signs of a tongue. After initial dilation in the operating room with Hagar dilators, the oral stoma was serially dilated using Boston Scientific esophageal balloons. Once full dilation was achieved, we fabricated oral splints to continue the dilation process while maintaining oral competence with no surgical intervention. PMID- 21557672 TI - Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine. AB - Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients. PMID- 21557673 TI - Effect of apolipoprotein E polymorphism on statin-induced decreases in plasma lipids and cardiovascular events. AB - Hypercholesterolemia or dyslipidemia is an independent risk factor for cardiovascular disease and statins (inhibitors of a key enzyme of cholesterol synthesis, 3-hydroxymethyl glutaryl coenzyme A reductase) are the drugs of choice for decreasing plasma cholesterol. It has been estimated that genetic factors can explain 40%-60% of final cholesterol concentrations and approximately 70% of the efficacy of statin treatment. The gene most often analyzed in the context of statin efficacy is the gene for apolipoprotein E (APOE). This review summarizes evidence of the association between variations in the APOE gene locus and the response of plasma lipids to statin therapy. Although the results are not consistent, carriers of the APOE4 allele seems to be less responsive to statins than carriers of APOE2 and APOE3 alleles. This effect is partially context dependent (gene-gender interactions; gene-nutrition and gene-smoking interactions have not yet been studied) and the absolute differences vary between different population groups. PMID- 21557674 TI - Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions. AB - Epilepsy is a common neurological disorder. About one-third of epilepsy patients have a multidrug resistance (MDR) phenotype and develop refractory epilepsy (RE). Changes in the properties of the antiepileptic drugs (AEDs) targets resulting in reduced drug sensitivity, can't explain the MDR phenotype. This particular refractoriness is now attributed to overexpression of multidrug transporters in brain, leading to impaired access of AEDs to CNS targets, and it was documented in both human as well as in experimental models of RE. Single nucleotide polymorphism (SNP) identified in the MDR1-ABCB1 gene (C3435T/CC-genotype) is associated with increased intestinal expression of P-glycoprotein (P-gp) that affects levels of AEDs in plasma. The functional studies of P-gp using P-gp inhibitors could show the still unclear clinical impact of ABCB1 polymorphisms on AEDs resistance. Some drug-drug interactions previously believed to be cytochrome P450 (CYP) mediated are now also considered to be due to the modulation of multidrug-transporters. Because in certain cases pharmacoresistance can be overcome by add-on therapy, co-administered P-gp inhibitors could contribute to the effectiveness of AEDs treatment in RE. And in this regard, perhaps we can postulate to P-gp as a new clinical therapeutic target in multidrug-refractory epilepsy. PMID- 21557675 TI - Status of research on MMPs in India. AB - INTRODUCTION: MMPs are metal-dependant endopeptidases capable of degrading any one of the components of the extracellular matrix. In normal physiological conditions it is regulated by tissue inhibitors of metalloproteinases, and any alteration in this regulatory process leads to pathological conditions. AREAS COVERED: This review discusses the status of MMP research in India. The first research paper was published in 1998; the subsequent developments in this field led to an increase in the number of publications. This review highlights the growth of MMP research in India based on the research papers published from 1998 to 2010. We identify four major subject areas: cancer, arthritis, ulcer and quantitative structure-activity relationship. The diseases involved are discussed along with the required steps for improving treatments. EXPERT OPINION: Indian researchers need to work on new molecules with specific MMP inhibitory activity for cancer and communicable and geriatric diseases. Although several publications on natural products have appeared from India, they are very few considering the number of medicinal plants available in the country. Inhibiting MMPs could be both beneficial and detrimental to cells, owing to the inter-relationship between normal physiology and pathology; thus, targeting MMPs with broad MMP inhibitors can have mixed blessings. PMID- 21557676 TI - Characterization of discriminatory urinary proteomic biomarkers for severe preeclampsia using SELDI-TOF mass spectrometry. AB - OBJECTIVE: To analyze the proteomic pattern in urine for distinguishing severe preeclampsia from mild preeclampsia and normotensive controls using surface enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). STUDY DESIGN: Urine samples were collected from women with severe preeclampsia (n=11 [sPE]), mild preeclampsia (n=7 [mPE]), and normotensive controls (n=8) and analyzed by SELDI-TOF-MS to identify discriminatory protein peaks in the sPE cohort. A scoring system was constructed--designated as Preeclampsia Proteomic Score of Urine (PPSU)--to differentiate sPE from mPE and normotensive controls. RESULTS: Four discriminatory protein peaks were identified (m/z ratio: 4155, 6044, 6663, and 7971), all of which were down-regulated in women with sPE. PPSU scores in women with sPE were significantly lower than that in both mPE and controls (sPE 0 [0-4] vs. mPE 3 [0-4] vs. controls 4 [2-4]; median [range]; P<0.05). PPSU<2 had a sensitivity of 90.9% and specificity of 93.3% in discriminating patients with sPE from mPE and controls. CONCLUSION: Proteomic analysis of urine can accurately distinguish sPE from mPE and normotensive controls. PMID- 21557677 TI - Colonization, serotypes and transmission rates of group B streptococci in pregnant women and their infants born at a single University Center in Germany. AB - OBJECTIVE: To evaluate colonization, transmission rate and serotype distribution of group B streptococci (GBS) in pregnant women and infants born in a single University Center in Germany. METHODS: In a prospective study we collected cultures from pregnant women and ear cultures from newborns. We performed serotyping and susceptibility testing. Obstetrical factors associated with mother to infant transmission were analyzed using logistic regression. RESULTS: We evaluated cultures of 869 pregnant women and 845 neonates including 657 paired maternal-neonatal cultures. Maternal colonization occurred in 21.1% (183/869), transmission from mother to newborn in 11.2% (17/152). Intrapartum antimicrobial prophylaxis (IAP) and cesarean delivery were associated with reduction of transmission rate (P=0.014 and 0.019, respectively). The incidence for early onset disease (EOD) was 1.71 per 1000 live births. Of GBS positive women IAP was administered in only 39% (59/152). Serotype III was the most prevalent isolate (28% maternal; 52% neonatal) and transmission occurred more frequently compared to other serotypes. CONCLUSIONS: The incidence of EOD and distribution of serotypes in Germany are similar to published data from the USA prior to 1996. Despite national guidelines with universal GBS screening, our study demonstrated a lack of adherence to this recommendation. There is a need for enhanced compliance. PMID- 21557681 TI - Posttraumatic stress following childbirth in homelike- and hospital settings. AB - OBJECTIVE: To assess the prevalence of posttraumatic stress disorder (PTSD) following childbirth in homelike versus hospital settings and to determine risk factors for the development of posttraumatic stress symptoms. METHODS.: Multi center cross-sectional study at midwifery practices, general hospitals and a tertiary (university) referral center. An unselected population of 907 women was invited to complete questionnaires on PTSD, demographic, psychosocial, and obstetric characteristics 2 to 6 months after delivery. Prevalence of PTSD was based on women who met all criteria of the diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV), whereas risk factors were determined using the severity (sum-score) of posttraumatic stress symptoms. RESULTS: PTSD following childbirth was found in 1.2% of the respondents (5/428 women, response rate 47%), while 9.1% of women (39/428) had experienced the delivery as traumatic. Posttraumatic stress symptoms were associated with unplanned cesarean section, low sense of coherence (coping skills), and high intensity of pain. Initial differences in posttraumatic stress symptoms between home and hospital deliveries disappeared after taking into account the (by definition) uncomplicated nature of home births. CONCLUSION: In this Dutch study, 1 in 100 women had PTSD following childbirth, with no differences between home- and hospital deliveries after controlling for complications and interventions. Emergency cesarean section, severe labor pain, and poor coping skills were associated with more posttraumatic stress symptoms. PMID- 21557682 TI - Are bone defects in rare patients with Glanzmann's thrombasthenia associated with ITGB3 or ITGA2B mutations? AB - The question as to whether Glanzmann thrombasthenia patients with ITGB3 defects and deficiencies of both alphaIIbbeta3 and alphavbeta3 show phenotypic differences to those with abnormalities exclusive to alphaIIbbeta3 is unresolved. Studies on beta3-deficient mice have shown an increased bone mass. Here we review the literature on bone defects in thrombasthenia patients and report the molecular analysis of a patient associating a lifelong thrombasthenia-like syndrome with skeletal defects. We show that the patient is compound heterozygote for Arg327His and Gly391Arg mutations in alphaIIb, with one mutation inherited from each parent. Modelling strongly suggested that both mutations act by destabilizing the alphaIIb beta propeller. So it appears likely that this patient has a combination of co-expressed genetic defects. PMID- 21557683 TI - Short-term exposure of platelets to glucose impairs inhibition of platelet aggregation by cyclooxygenase inhibitors. AB - Aspirin treatment reduces cardiovascular events and deaths in high-risk non diabetic patients, but not in patients suffering from diabetes. In these patients, hyperglycemia has been found to cause reduced platelet sensitivity to aspirin. It is supposed that long-term exposure of platelets to glucose leads to non-enzymatic glycosylation and impairs aspirin inhibition of platelet aggregation. On the other hand, short-term exposure of platelets to glucose also attenuates the effect of aspirin on platelets. The aim of the present work was to analyse the effect of short-term exposure of glucose on the inhibition of platelet aggregation by aspirin and other cyclooxygenase (COX) inhibitors. Already a 15 min exposure of platelets to glucose impaired aspirin inhibition of the platelet aggregation induced by collagen, thrombin, adenosine diphosphate (ADP), and arachidonic acid (AA). Aspirin inhibition of platelet aggregation in platelet-rich plasma (PRP) was attenuated by 5.6, 11.2, 16.8, and 22.4 mM of glucose in a concentration-dependent way. The same effect was observed with indomethacin and acetaminophen used as cyclooxygenase inhibitors instead of aspirin. N-methyl-L-arginine, an inhibitor of nitric oxide synthase, prevented the effect of glucose on aspirin, indomethacin and acetaminophen inhibition of platelet aggregation. Other monosaccharides, for example fructose and galactose, impaired aspirin inhibition as did glucose. Lactic acid (0.1, 0.2, 0.4, 0.8 mM), the end product of anaerobic glycolysis in platelets, impaired the inhibition of platelet aggregation with aspirin in a concentration-dependent way but did not affect indomethacin. It is suggested that lactic acid might be a mediator of the effect of glucose on aspirin inhibition in platelets. PMID- 21557684 TI - Can thrombelastography be a new tool to assess bleeding risk in patients with idiopathic thrombocytopenic purpura? AB - Thrombelastography (TEG) analyses the status of blood coagulation including abnormalities associated with low platelet count. The aim of this study was to investigate the changes in TEG parameters in idiopathic thrombocytopenic purpura (ITP) patients. Thirty nine patients with ITP (platelet count < 100 * 103 ul-1) were included in the study. Age-matched 17 patients with thrombocytopenia due to chemotherapy were selected as a control group. Platelet count was positively correlated with maximum clot formation (MCF) in INTEM (r = 0.716, p < 0.001) and MCF in EXTEM (r = 0.679, p < 0.001); negatively correlated with clot formation time (CFT) in INTEM (r = -0.755, p < 0.001) and CFT in EXTEM (r = -0.585, p < 0.001) in ITP patients. Platelet count was positively correlated with MCF in INTEM (r = 0.776, p < 0.001) and MCF in EXTEM (r = 0.878, p < 0.001); negatively correlated with CFT in INTEM (r = -0.627, p < 0.001) in control group. Receiver operating characteristic curves to describe the critical platelet count and fibrinogen level that affect MCF revealed 31 * 103 ul-1 and 375 mg dl-1 as cut off values, respectively. In conclusion, ROTEM determines the contribution of fibrinogen and platelets to clot strength in patients with ITP. MCF appears to be the most important TEG parameter in predicting bleeding in ITP patients that makes TEG superior to other hemostatic tests. PMID- 21557685 TI - Platelet-monocyte cross talk and tissue factor expression in stable angina vs. unstable angina/non ST-elevation myocardial infarction. AB - Tissue factor (TF), the major procoagulant in vivo, is usually absent from blood cells. However, since both monocyte TF (MoTF) expression and platelet activation are present in acute coronary syndrome we hypothesized that MoTF expression may in part depend on monocyte platelet aggregate (MPA) formation in coronary artery disease (CAD). Patients with unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI, n = 20) had significantly higher levels of MoTF (17.4 +/- 3.1MFI) and MPAs (CD42b:273 +/- 183MFI; CD62P:256.3 +/- 48.5MFI) than patients with stable angina (SA, n = 40; MoTF:13.2 +/- 2.2MFI, p = 0.001; CD42b:160 +/- 113MFI, p = 0.025; CD62P:118.7 +/- 24.5MFI, p = 0.018) as measured by whole blood flow cytometry on CD14+-cells. TF-activity of isolated mononuclear cells (MNC) was elevated in UA/NSTEMI (75 +/- 27 pg/mL) in comparison to SA (47 +/- 17 pg/mL, p = 0.001) as determined by chromogenic assay, and TF mRNA expression in isolated MNC was more frequent in UA/NSTEMI than in SA (50% vs. 18.2%; p = 0.017). MoTF expression significantly correlated with the constitutive platelet marker CD42b (r = 0.69, p < 0.001) and the platelet activation marker CD62P (r = 0.47, p = 0.001) on CD14+-cells suggesting its association with MPAs in UA/NSTEMI. In addition, MoTF expression correlated with MoTF activity of isolated MNC (r = 0.41, p = 0.01) and plasma levels of the F1.2 prothrombin fragment (r = 0.35, p = 0.02). In conclusion, MoTF and MPAs are elevated in UA/NSTEMI compared with SA. MoTF expression correlates with platelet mass and activity attached to monocytes. PMID- 21557686 TI - Symptomatic change in Japanese hypogonadal patients several years after androgen replacement therapy. AB - OBJECTIVE: There are few reports on the prognosis of patients receiving androgen replacement therapy (ART). In this study, we evaluated the subsequent symptoms of Japanese hypogonadal patients who had received ART, within several years previously by mail-in survey. METHODS: Thirty-three aged men with symptoms of hypogonadism and testosterone deficiency who had received ART for 6 months responded to this survey. The survey consisted of questions associated with present physical and mental status and desire to resume ART. The Aging male's symptoms (AMS) scale, IIEF-5 and SF-36 were also evaluated at pre-initiation, termination of ART and the time of the survey. RESULTS: The mean duration from the last treatment was 55 months. Compared with the treatment period, more than half of patients (57.5%) answered that their present condition was better. Scores on the AMS scale, IIEF and SF-36 were all improved significantly in the early stages of treatment and not worsened a long period of time after ART was discontinued. CONCLUSIONS: For symptomatic Japanese hypogonadal patients, subjective effects of treatment were observed during the early treatment period and remained unchanged after discontinuation of ART. A short treatment period may thus be adequate in Japanese hypogonadal patients as regards symptomatic changes. PMID- 21557687 TI - Characterization of AbetapN3 deposition in the brains of dogs of various ages and other animal species. AB - Senile plaques (SP) are characteristic histopathological manifestations of Alzheimer's disease (AD), but are also found in normal aging (NA). Recent studies have demonstrated that beta amyloid (Abeta) proteins that have been truncated at the N-terminal position 3 (AbetapN3) are the predominant component of SP in AD, but not in NA. The present study revealed that AbetapN3 was deposited in an age dependent manner in canine brains. Moreover, AbetapN3 was the main component of the SP that developed in very old dogs. The deposition of AbetapN3 increased in accordance with the number of SP, but that of N-terminally intact Abeta (AbetaN1) did not. In addition, AbetapN3 was also deposited in the SP of a Japanese macaque and an American black bear, but not in a feline brain. Focal microvascular cerebral amyloid angiopathy was also observed in the deep cortices and the white matter of the dogs and a woodpecker. Those were always composed of both AbetapN3 and AbetaN1. In conclusion, though non-human animals do not develop full pathology of AD of the human type, AbetapN3 is widely deposited in the brains of senescent vertebrates. PMID- 21557688 TI - Outcome of monochorionic twin pregnancies with abnormal umbilical artery Doppler between 16 and 20 weeks of gestation. AB - OBJECTIVES: To study the perinatal outcome among monochorionic diamniotic (MCDA) twin pregnancies with absent or reversed end-diastolic flow of the umbilical artery (UA-AREDF) at 16-20 weeks of gestation. METHODS: This was a retrospective study of 84 MCDA twin pregnancies, which were followed up since first trimester in a single obstetric unit. Pregnancies with fetal structural anomalies or genetic syndromes, and those with single intrauterine death before 16 weeks were excluded. The study group was divided into four groups based on the finding of UA AREDF at the routine follow-up scan at 16-20 week, and the presence of complications at the same time of recruitment. The perinatal outcome between these groups was compared. RESULTS: AREDF was present in 56.7% of the 30 monochorionic (MC) twins with complications at recruitment. The mortality was significantly higher among those with AREDF. Among the 54 uncomplicated cases at recruitment, only 7.41% had AREDF. The presence of isolated AREDF was associated with significantly higher incidence of growth discordance (25.0% vs. 2%). The incidence of perinatal mortality and twin-to-twin transfusion syndrome was almost doubled (25.0% vs. 9% and 25.0% vs. 14%). CONCLUSIONS: AREDF of the umbilical artery is uncommon in normal MC twin in mid-trimester. Once AREDF is present, the perinatal outcome is much worse. Doppler assessment of the umbilical artery should be considered in all MC twin pregnancies for risk assessment. PMID- 21557689 TI - Neonatal chemical hypoglycemia in newborns from pregnancies complicated by type 2 and gestational diabetes mellitus - the importance of neonatal ponderal index. AB - OBJECTIVE: To determine the frequency and risk factors associated with neonatal chemical hypoglycemia in neonates of mothers with type 2 diabetes and gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: A retrospective cohort study of women with type 2 diabetes or GDM and their singleton neonates. The primary outcome measure was the presence of neonatal chemical hypoglycemia (capillary plasma equivalent glucose <45 mg/dl) within 1 h of birth. Statistical methods included bivariate and multivariate analyses. RESULTS: 242 mother infant dyads were identified. Sixty-eight (28%) were treated with diet, 110 (46%) with glyburide, and 64 (26%) with insulin. The incidence of neonatal chemical hypoglycemia was 18% (44/242). The incidence was significantly higher in those requiring pharmacotherapy (25% vs. 3%, p < 0.001). The frequency of neonatal chemical hypoglycemia between the glyburide and insulin-treated pregnancies did not differ significantly (23% vs. 27%, p = 0.58). The frequency of neonatal chemical hypoglycemia was statistically associated with birth weight, macrosomia and ponderal index (p < 0.001). Neonatal ponderal index was the strongest predictor of hypoglycemia (adjusted Odds ratio 5.59). CONCLUSION: Neonatal chemical hypoglycemia occurs more frequently in infants from women with type 2 diabetes and GDM treated with glyburide or insulin. An increased neonatal ponderal index is a strong predictor of significant neonatal chemical hypoglycemia. PMID- 21557690 TI - Maternal psychosocial outcome after early onset preeclampsia and preterm birth. AB - OBJECTIVE: To evaluate the impact of severe, early onset preeclampsia on long term maternal psychosocial outcome after preterm birth. METHODS: Women with severe, early onset preeclampsia before 32 weeks' gestation (cases) admitted in a tertiary university referral center between 1993 and 2004, and women with preterm delivery without preeclampsia (controls), matched for age, parity, gestational age at delivery, ethnicity, and year of delivery. Women who consented to participation received three questionnaires in 2008 concerning depression (Zung Depression Scale: score range 0-20; 20 items with 2-point frequency scale: no = 0 and yes = 1), posttraumatic stress symptoms (Impact of Event Scale: score range 0 75; 15 items with 4-point frequency scale: not at all = 0, rarely = 1, sometimes = 3 and often = 5. Scores > 19 are regarded as high symptom levels), and social aspects (Social Readjustment Rating Scale: selection of six items concerning relational aspects with husband/partner, employer, or future family planning). RESULTS: Included in the study were 104 cases and 78 controls (response rate 79% and 58%, respectively). There was no difference in depression scores between cases (5.4 +/- 4.0) and controls (5.4 +/- 4.3). Patients with severe, early onset preeclampsia had significantly higher scores of posttraumatic stress symptoms (28.7 +/- 8.6 vs. 25.7 +/- 7.9). The majority of women among both cases and controls had high-posttraumatic stress symptom levels (88% vs. 79%). No differences could be found in relational aspects. CONCLUSION: Women with preterm birth due to severe, early onset preeclampsia experience more often posttraumatic stress symptoms on average 7 years after the pregnancy compared to women with preterm birth without preeclampsia. PMID- 21557691 TI - Potential utility of melatonin as an antioxidant during pregnancy and in the perinatal period. AB - Reactive oxygen species (ROS) play a critical role in the pathogenesis of various diseases during pregnancy and the perinatal period. Newborns are more prone to oxidative stress than individuals later in life. During pregnancy, increased oxygen demand augments the rate of production of ROS and women, even during normal pregnancies, experience elevated oxidative stress compared with non pregnant women. ROS generation is also increased in the placenta during preeclampsia. Melatonin is a highly effective direct free-radical scavenger, indirect antioxidant, and cytoprotective agent in human pregnancy and it appears to be essential for successful pregnancy. This suggests a role for melatonin in human reproduction and in neonatal pathologies (asphyxia, respiratory distress syndrome, sepsis, etc.). This review summarizes current knowledge concerning the role for melatonin in human pregnancy and in the newborn. Numerous studies agree that short-term melatonin therapy is highly effective in reducing complications during pregnancy and in the neonatal period. No significant toxicity or treatment related side effects with long-term melatonin therapy in children and adults have been reported. Treatment with melatonin might result in a wide range of health benefits, including improved quality of life and reduced healthcare costs. PMID- 21557692 TI - The effectiveness of bilateral hypogastric artery ligation for obstetric hemorrhage in three different underlying conditions and its impact on future fertility. AB - OBJECTIVE: To evaluate the effectiveness of bilateral hypogastric artery ligation (BHAL) according to the underlying cause and future fertility in these women. METHOD: Fifty-eight women who underwent BHAL operation in our department between 1997 and 2008 were further divided into three subgroups in accordance with the underlying disease. Group 1: Severe preeclampsia with coagulapathy (n:24). Group 2: Postpartum hemorrhage (PPH) due to uterine atony (n:24). Group 3: Massive hemorrhage due to inadequate surgical control of bleeding and/or uterine rupture (n:10). Effectiveness of BHAL according to the underlying cause and future fertility after BHAL were evaluated. RESULTS: Success rate of BHAL was found to be 87.9% (51 out of 58 patients). Complication rates of the groups were 25%, 12.5%, and 10%, respectively. There was one maternal death in each group. Mean hospital stay, blood and blood products transfusion need were similar for all groups. Thirty women out of 58 had desired future fertility, and 17/30 (56.7%) of them became pregnant within less than 1 year. CONCLUSION: BHAL is a safe, effective, life-saving procedure in controlling massive PPH. It preserves future fertility and must be the first choice operation for PPH in young women whichever the underlying condition is. PMID- 21557693 TI - Association of bacterial vaginosis with adverse fetomaternal outcome in women with spontaneous preterm labor: a prospective cohort study. AB - OBJECTIVE: To compare the fetomaternal outcome in women with spontaneous preterm labor, with or without bacterial vaginosis (BV). METHODS: One hundred and fifty two pregnant patients presenting with spontaneous preterm labor between 28 and 35 weeks of gestation were screened for BV using Amsel's criteria and Nugent score, and were divided into two groups of 30 patients each, based on the BV positive or negative screen. Both the groups were followed till puerperium, and the fetal maternal outcome was studied. The data was analyzed using Chi-square test and Man Whitney test. RESULTS: BV was detected in 37 out of 152 women with preterm labor (24.34%). There was a significant increase in the incidence of respiratory distress (14% vs. 6%), requirement of intermittent positive pressure ventilation (IPPV) (14% vs. 5%), admission in neonatal intensive care unit (NICU) (15% vs. 6%), and duration of NICU stay >2 days (15% vs. 6%) in patients with BV. No significant difference was found in the mean birth weight, Apgar score, incidence of neonatal sepsis, perinatal mortality, and postpartum fever between the two groups. CONCLUSIONS: BV is a risk factor for increased neonatal morbidity. More research is needed for designing appropriate screening and treatment guidelines for prevention of adverse outcomes associated with BV. PMID- 21557694 TI - Trace elements' concentrations in maternal and umbilical cord plasma at term gestation: a comparison between active labor and elective cesarean delivery. AB - OBJECTIVE: Trace elements are minerals required in minute quantities to maintain proper physical functioning. The role of trace elements in the process of parturition is poorly understood. This study was aimed to determine levels of trace elements' concentration in maternal plasma and umbilical venous and arterial plasma at term during active labor vs elective cesarean delivery (CD). STUDY DESIGN: A prospective case-control study was conducted. Forty healthy parturients in active labor at term with their newborns were compared to 40 healthy parturients matched for maternal age, parity, and gestational age, who delivered by elective CD (before commencement of labor). Samples of maternal venous blood and umbilical cord arterial and venous blood were drawn immediately following delivery. Trace elements' concentrations were measured using the inductively coupled plasma mass spectrometer (ICP-MS). RESULTS: Significant higher levels of manganese (Mn) and selenium were found in maternal venous plasma during active labor vs elective CD. Magnesium (Mg) levels were significantly higher in maternal venous blood during elective CD compared to active labor. Umbilical cord artery levels of Mg, Mn, and zinc (Zn) were significantly higher in active term labor vs elective CD. Also, significant higher levels of copper and Zn were found in umbilical cord vein between active labor and elective CD. CONCLUSION: Trace elements' concentrations differ significantly in fetal blood during active labor vs elective CD. Hence, trace elements may play a crucial role in the process of human parturition. PMID- 21557695 TI - Late pregnancy associated plasma protein A levels decrease in preterm labor. AB - OBJECTIVE: The purpose of the present study is to evaluate late, 'at admission', Pregnancy-associated plasma protein-A (PAPP-A) levels as a predictor of preterm birth in women with complaints of preterm labor or preterm painful contractions. METHODS: Prospective cohort study of singleton gestations, 23-37 weeks, and symptoms of preterm labor. Primary end point was delivery < 37 weeks. Predictive PAPP-A values were calculated both for preterm delivery and threatened preterm delivery on receiver operator curve. RESULTS: In all, 41 women (38.3%) delivered before 37 weeks (Group 1); 32 women (30.7%) had symptoms of preterm labor but did not deliver preterm (Group 2); 31 women (29.7%) delivered term (Group 3, control). Mean PAPP-A levels in preterm-labor and its matched control were 33.4 +/- 19.9 and 52.5 +/- 25.4 mIU/ml, respectively, and difference was statistically significant (p = 0.003). Mean PAPP-A level in threatened preterm labor group was 47.6 +/- 25.3 mIU/ml and difference was significant compared to preterm-labor, but not significant compared to control group (p = 0.028 and p = 0.74, respectively). CONCLUSION: Late PAPP-A levels decreased in preterm labor, levels < 29.8 mIU/ml was associated with increased risk for preterm birth, supporting active management whereas cutoff value of 33.6 mIU/ml is useful for discrimination of preterm birth from threatened preterm birth reaching to term. PMID- 21557696 TI - Paraoxonase-1 is not affected in polycystic ovary syndrome without metabolic syndrome and insulin resistance, but oxidative stress is altered. AB - Paraoxonase-1 (PON1) activity is decreased in polycystic ovary syndrome (PCOS) having metabolic syndrome (MetS) or insulin resistance (IR). We aimed to assess PON1 activity and oxidative stress in PCOS without MetS or IR. Metabolic and hormonal parameters, high-sensitive C-reactive protein (hs-CRP), oxidative stress parameters (total antioxidant status (TAS), total oxidative stress (TOS), oxidative stress index (OSI), lipid hydroperoxide (LOOH), total free sulfhydryl ( -SH) groups), PON and arylesterase were analyzed in 30 normal weighed patients with PCOS without MetS or IR and 20 normal controls. Hs-CRP, PON, arylesterase, and TAS levels of PCOS and control groups were similar. LOOH, TOS, and OSI of PCOS group were higher than in the controls (p < 0.05; p < 0.001, and p < 0.001, respectively). - SH group levels showed a positive correlation with free testosterone (fT). TOS positively correlated with free androgen index (FAI), body mass index (BMI), waist-to-hip ratio (WHR), LOOH, and OSI. This study showed that oxidative stress is increased in PCOS even in the absence of MetS or IR. PON1 activity appears not to be affected in PCOS without MetS and IR. Several metabolic and antropometric risk factors may aggravate this altered oxidative state in PCOS. PMID- 21557697 TI - The plasma level and gene expression of resistin in polycystic ovary syndrome. AB - OBJECTIVES: To investigate the relationship between plasma resistin, polycystic ovary syndrome (PCOS), and insulin resistance (IR). To compare the mRNA level of resistin in mononuclear cells and monocyte-derived macrophages in women with PCOS and controls. MATERIALS AND METHODS: Patients with PCOS and controls were enrolled and IR was considered as the stratified factor for subgroups. Fasting blood was collected to determine the levels of sex hormones, insulin, glucose, blood lipid, and resistin. Resistin gene expression was evaluated by quantitative real-time RT-PCR in mononuclear cells and monocyte-derived macrophages cultured with or without rosiglitazone for 96 h. RESULTS: No significant difference of plasma resistin levels was found among PCOS-IR, PCOS-non-IR, control-IR, and control-non-IR groups. There were no significant differences in resistin mRNA expression between participants with and without PCOS and with and without IR. Resistin mRNA expression in monocyte-derived macrophages was higher than that in mononuclear cells (p = 0.04), and could be reduced by rosiglitazone (p < 0.001). CONCLUSIONS: Plasma resistin does not correlate with normal weight PCOS or IR. Resistin gene expression in mononuclear cells and monocyte-derived macrophages in PCOS and IR is the same as controls. Further researches on the role of resistin in the pathogenesis of PCOS or IR should concentrate on the tissue level. PMID- 21557698 TI - Involvement of GDF-9, leptin, and IGF1 receptors associated with adipose tissue transplantation on fertility restoration in obese anovulatory mice. AB - The aim was to analyze the effect of adipose tissue transplantation on growth differentiation factor-9 (GDF-9), insulin growth factor 1 receptor (IGF1R), and leptin receptor (LEPR) protein expression in ovaries of obese anovulatory mice. Leptin-deficient female (ob/ob) and wild-type mice were divided into untreated ob/ob mice and gonadal white adipose tissue transplanted ob/ob mice, with evaluation after 7, 15, and 45 days and compared to control wild-type mice. The corporal weight and glycemia levels increased in the obese group concomitant with polymicrocyst formation and abundant estrone, mimicking anovulatory disease. In the treated group after 45 days, glycemia, weight, ovarian size, and number of follicles were decreased and corpora lutea were decreased. The analysis of GDF-9 revealed that, whereas control ovaries presented follicular localization, the obese ovary lacked this protein. On the other hand, obese ovaries showed elevated expression of IGF1R that was normalized after the transplantation. Finally, LEPR was reduced in obese ovaries, and adipose tissue transplantation was efficient in returning it to normal levels. In conclusion, the adipose tissue transplantation, especially after 45 days, seems to stimulate ovulation, supported by the fact that several proteins involved in ovulation returned to basal levels. PMID- 21557699 TI - A flow bio-reactor for studying the effects of haemodynamic forces on the morphology and rheology of cylindrically cultured endothelial cells. AB - This study reports on the development and validation of an integrated experimental system for quantitative monitoring of the effects of vascular dynamic and static forces on endothelial cells (ECs), in terms of their morphological remodelling and rheological properties. The system consists of a microscope-based flow bio-reactor which imposes controlled individual and combined haemodynamic forces on ECs cultured on the inner surface of cylindrical transparent substrate tubes. EC morphology is monitored by optical microscopy. Micro-rheological alterations are measured by optical magnetic twisting cytometry (OMTC) using ferromagnetic micro-beads adherent to the EC cytoskeleton. System validation tests ascertained the capability for imposing controlled flow conditions and for real-time monitoring of morphological and rheological changes. PMID- 21557700 TI - Using a fuzzy controller optimized by a genetic algorithm to regulate blood glucose level in type 1 diabetes. AB - In this paper a closed-loop control algorithm for blood glucose regulation in type 1 diabetic patients is proposed by using the Mamdani-type fuzzy method. Because of the presence of high-pass proportional derivatives in fuzzy designing, optimal values are applied for two inputs and one output membership functions in order to prevent the fluctuations due to derivatives in fuzzy design. Therefore, 19 values which are related to membership functions of the two inputs and one output are obtained by using a genetic algorithm (GA). The new model, termed the Augmented Minimal Model (AMM), is used in simulations. This controller is capable of stabilizing the blood glucose concentration at a normoglycaemic level of 90 mg dl(-1). The operation of the controller under various situations including multiple meal disturbances, and noise due to inaccurate effects of measuring blood glucose level are considered. Uncertainties in the meal disturbance function and variations of model parameters were also taken into consideration in simulations and the controller was found to be robust to such uncertainties. PMID- 21557701 TI - Collagen fibers constructed by gravity filament forming process. AB - Fibers comprised of reconstituted type I collagen were prepared by a gravity filament forming process and crosslinked with 0.1% glutaraldehyde. These fibers have a crosslinking index of about 90% (89.89 +/- 1.82%) with higher denature temperature (74.43 +/- 0.08 degrees C) as compared to that without glutaraldehyde treatment (52.1 +/- 0.17 degrees C). The ultimate tensile strength of the collagen fibers increases from 99.4 +/- 12.9 to 174.4 +/- 9.0 MPa after glutaraldehyde-crosslinking. L929 fibroblast cells were seeded and cultured using these newly developed collagen fibers. The fibroblast cells proliferated well and covered all surface areas of the collagen fiber. These collagen fibers have a great potential for application in 3-D tissue engineering. PMID- 21557702 TI - Abscopal mutagenic effect of low-energy-ions in Arabidopsis thaliana seeds. AB - PURPOSE: To demonstrate the abscopal mutagenic effect of low-energy-ion irradiation in dormant plant seeds, and its dependence on the targeted portion of seeds. MATERIALS AND METHODS: Arabidopsis thaliana-lines transgenic for b glucuronidase (GUS) recombination substrates and A. thaliana RADiation54 (AtRAD54) promoter::GUS were adopted. The seeds were irradiated from four specialised orientations with 30 KeV (40)Ar(+) ions. The homologous recombination frequency (HRF) and the expression levels of the AtRAD54 genein non-irradiated aerial plants were measured. Moreover, several post-embryonic developments, such as growth of primary roots, differentiation of root hairs, and germination of seeds and growth of true leaves, were also analysed. RESULTS: It was shown that low-energy-ion irradiation of seeds led to significant increases in HRF in the non-irradiated aerial parts of irradiated plants and the aerial parts of naive plants from irradiated progenitors. The low-energy-ion irradiation was also shown to induce an elevated expression of AtRAD54 gene in aerial plants, and to inhibit the post-embryonic developments of seeds. Moreover, the changes in HRF, expression level of the AtRAD54 gene and post-embryonic developments depended largely on the orientation of seeds with regard to low-energy-ion irradiation; and the root apical meristem (RAM)-orientated irradiation exhibited the largest effects on all biological endpoints assayed here. CONCLUSIONS: Low-energy-ion irradiation can induce an abscopal mutagenic effect in dormant plant seeds, the extent of which depends greatly on the targeted portion of seeds. PMID- 21557703 TI - The RABiT: a rapid automated biodosimetry tool for radiological triage. II. Technological developments. AB - PURPOSE: Over the past five years the Center for Minimally Invasive Radiation Biodosimetry at Columbia University has developed the Rapid Automated Biodosimetry Tool (RABiT), a completely automated, ultra-high throughput biodosimetry workstation. This paper describes recent upgrades and reliability testing of the RABiT. MATERIALS AND METHODS: The RABiT analyses fingerstick derived blood samples to estimate past radiation exposure or to identify individuals exposed above or below a cut-off dose. Through automated robotics, lymphocytes are extracted from fingerstick blood samples into filter-bottomed multi-well plates. Depending on the time since exposure, the RABiT scores either micronuclei or phosphorylation of the histone H2AX, in an automated robotic system, using filter-bottomed multi-well plates. Following lymphocyte culturing, fixation and staining, the filter bottoms are removed from the multi-well plates and sealed prior to automated high-speed imaging. Image analysis is performed online using dedicated image processing hardware. Both the sealed filters and the images are archived. RESULTS: We have developed a new robotic system for lymphocyte processing, making use of an upgraded laser power and parallel processing of four capillaries at once. This system has allowed acceleration of lymphocyte isolation, the main bottleneck of the RABiT operation, from 12 to 2 sec/sample. Reliability tests have been performed on all robotic subsystems. CONCLUSIONS: Parallel handling of multiple samples through the use of dedicated, purpose-built, robotics and high speed imaging allows analysis of up to 30,000 samples per day. PMID- 21557704 TI - Induction of adaptive response in human blood lymphocytes exposed to 900 MHz radiofrequency fields: influence of cell cycle. AB - PURPOSE: To investigate the influence of cell cycle on the adaptive response (AR) induced by the exposure of human blood lymphocytes to radiofrequency fields (RF). MATERIALS AND METHODS: Human peripheral blood lymphocytes in G(0)-, G(1)- or S phase of the cell cycle were exposed for 20 hours to an adaptive dose (AD) of 900 MHz RF at an average specific absorption rate of 1.25 W/kg and then treated with a challenge dose (CD) of 100 ng/ml mitomycin C (MMC). Un-exposed and sham-exposed controls as well as cells treated with MMC alone were included in the study. The incidence of micronuclei (MN) was evaluated to determine the induction of AR. RESULTS: The results indicated that the cells which were exposed to AD of RF in G(0)- and G(1)-phase of the cell cycle did not exhibit AR while such a response was observed when the cells were exposed to AD of RF in S-phase of the cell cycle. CONCLUSIONS: These results confirmed the observations reported in our previous investigation where AR was observed in human blood lymphocytes exposed to AD of RF in S-phase of the cell cycle and further suggested that the timing of AD exposure of RF is important to elicit AR. PMID- 21557705 TI - Targeting miR-375 in gastric cancer. AB - INTRODUCTION: Gastric cancer remains a major cancer burden in the world, with a poor 5-year survival rate. It is necessary to develop new effective therapeutic strategies to improve the long-term clinical outcome. MicroRNA (miRNA), a class of small non-coding RNA, has been identified as a key regulator of gene expression, and is implicated in the pathogenesis of gastric cancer. AREAS COVERED: This review summarizes the role of miRNAs in gastric carcinogenesis, with an emphasis on the expression and function of miR-375 in gastric cancer and beyond. It also discusses the opportunities and challenges of miR-375 as a potential therapeutic target for gastric cancer. The genes targeted by miR-375, including JAK2 and 3'-phosphoinositide dependent protein kinase-1 (PDK1), are also candidates for gastric cancer therapy. EXPERT OPINION: Although radical surgery and rational chemotherapy are still the main treatment for gastric cancer, targeting miRNAs, in combination with other conventional therapies, may serve as a promising therapy strategy to improve the clinical outcome. PMID- 21557706 TI - Charged liposomes as carriers to enhance the permeation through the skin. AB - INTRODUCTION: In recent years, there has been increased interest in developing charged liposomes as carriers for transdermal drug delivery. It is necessary to modify the basic composition of the liposomes in order to enhance the penetration properties of the vesicles through the skin. Charged liposomes offer several advantages compared with previous drug delivery systems. AREAS COVERED: This paper provides a brief overview of the different drug delivery systems that exist which aim to improve the permeation of drugs through the skin, focusing on the use of charged liposomes for transdermal delivery. We propose a classification of such liposomes based on the origin of the charge given to the vesicles. EXPERT OPINION: Despite the advances that are occurring in the design of charged liposomes for transdermal drug delivery, the long-term stability continues to be a drawback in such systems. The presence of charge on the surface of the vesicles favors the electrostatic repulsion among them, creating a zeta potential positive or negative that prevents their aggregation and flocculation. However, there is loss of the encapsulated drug, which limits the in vivo use of these systems. It should be emphasized that charged liposomes are indeed a promising candidate for use in gene therapy and vaccine targeting, in a great diversity of diseases, for which drugs are administered by the percutaneous route. PMID- 21557707 TI - The importance of interfaces in protein drug delivery - why is protein adsorption of interest in pharmaceutical formulations? AB - INTRODUCTION: In the area of peptide and protein drug products, interfaces are present as part of the basic liquid formulation, when freeze-dried formulations are reconstituted and when particulate delivery systems are prepared. Proteins are known to interact with these interfaces, and the effects seen are often irreversible adsorption and structural changes. AREAS COVERED: This review focuses on the ways in which peptides and proteins interact with surfaces and interfaces, and the effect these interactions have on the stability and safety of the active protein in pharmaceutical formulations. It illustrates, through examples, what can be determined by an adsorption study, and what can change when either the protein or the interfaces are modified. Last but not least, it addresses the value of these studies. The reader will gain an update on the basics of protein adsorption, with a focus on pharmaceutically relevant interfaces and recent advances in the field. EXPERT OPINION: Protein adsorption is widely studied; however, a more unified approach is still needed, especially on the adsorption of pharmaceutically relevant proteins, modified proteins and surfaces. PMID- 21557708 TI - Cetuximab in the treatment of patients with colorectal cancer. AB - INTRODUCTION: Cetuximab is a chimeric mAb with avidity for the EGFR higher than that of the natural ligands of the receptor. Preclinical studies showed that cetuximab demonstrated synergy with topoisomerase I inhibitors in the treatment of human colorectal cancer (CRC) cell lines in vivo. Subsequent clinical trials have shown that cetuximab can reverse resistance to topoisomerase I inhibitors in addition to having modest monotherapy activity. These studies led to accelerated provisional FDA approval of the drug for the treatment of patients with irinotecan-refractory metastatic CRC. Its clinical utility has been improved with the discovery of negative predictive biomarkers; these have shown that there is a lack of cetuximab benefit for patients whose tumors generally harbor a KRAS mutation, thus sparing these patients the toxicity of the agent which would not be of treatment benefit. AREAS COVERED: This review covers the last decade of clinical trials that have determined the toxicity and efficacy of cetuximab when given to patients with CRC, as well as some of the molecular subgroups tumors from patients with CRC who appear to not derive benefit from this mAb. EXPERT OPINION: Cetuximab has modest single-agent efficacy in the treatment of patients with metastatic CRC whose tumors do not harbor a KRAS mutation. In combination with irinotecan, it is associated with an overall survival (OS) and progression free survival (PFS) advantage in first-line therapy in patients with KRAS non mutant metastatic CRC; it can be combined with irinotecan to overcome resistance in patients with KRAS non mutant CRC who have previously progressed on prior irinotecan chemotherapy. Future studies of putative biomarkers are likely to give additional information to clearly define which patients with metastatic CRC receive therapeutic benefit from cetuximab and other monoclonal anti-EGFR therapies. PMID- 21557712 TI - Toxicity spectrum of inhibitors of mammalian target of rapamycin in organ transplantation: etiology, pathogenesis and treatment. AB - INTRODUCTION: Control of the immune responses is critical for body homeostasis. Immunosuppressive strategies have been critical to this enterprise as they reveal molecular and cellular mechanisms of immune-mediated tissue destruction. AREAS COVERED: While exerting potent effects to blockade critical processes during cell maturation prior to division and effector functions, the novel drug class of mammalian target of rapamycin inhibitors (mTORi) consequently exert adverse reactions due to disruption of pleiotropic physiologic pathways. This review includes selected clinical and preclinical materials from the time of the author's own first-in-human experience in 1993 through to 2009. The goal of this contribution is to provide a foundation in basic biochemical processes to allow the reader to understand the pathophysiology of adverse clinical reactions. EXPERT OPINION: mTORi, as potent agents for clinical immunosuppression, inevitably, disrupt multiple cellular pathways as well as important vectors of host resistance. Judicious use of this pharmacologic class demands dedication to learning strategies of individualization for patient needs and reactions in the manner of clinicians previously committed on the introduction of calcineurin inhibitors 3 decades ago. PMID- 21557713 TI - Misinformation on abortion. AB - OBJECTIVE: To find the latest and most accurate information on aspects of induced abortion. METHODS: A literature survey was carried out in which five aspects of abortion were scrutinised: risk to life, risk of breast cancer, risk to mental health, risk to future fertility, and fetal pain. FINDINGS: Abortion is clearly safer than childbirth. There is no evidence of an association between abortion and breast cancer. Women who have abortions are not at increased risk of mental health problems over and above women who deliver an unwanted pregnancy. There is no negative effect of abortion on a woman's subsequent fertility. It is not possible for a fetus to perceive pain before 24 weeks' gestation. Misinformation on abortion is widespread. Literature and websites are cited to demonstrate how data have been manipulated and misquoted or just ignored. Citation of non-peer reviewed articles is also common. Mandates insisting on provision of inaccurate information in some US State laws are presented. Attention is drawn to how women can be misled by Crisis Pregnancy Centres. CONCLUSION: There is extensive promulgation of misinformation on abortion by those who oppose abortion. Much of this misinformation is based on distorted interpretation of the scientific literature. PMID- 21557709 TI - Reversible and irreversible protein glutathionylation: biological and clinical aspects. AB - INTRODUCTION: Depending in part on the glutathione:glutathione disulfide ratio, reversible protein glutathionylation to a mixed disulfide may occur. Reversible glutathionylation is important in protecting proteins against oxidative stress, guiding correct protein folding, regulating protein activity and modulating proteins critical to redox signaling. The potential also exists for irreversible protein glutathionylation via Michael addition of an -SH group to a dehydroalanyl residue, resulting in formation of a stable, non-reducible thioether linkage. AREAS COVERED: This article reviews factors contributing to reversible and irreversible protein glutathionylation and their biomedical implications. It also examines the possibility that certain drugs such as busulfan may be toxic by promoting irreversible glutathionylation. The reader will gain an appreciation of the protective nature and control of function resulting from reversible protein glutathionylation. The reader is also introduced to the recently identified phenomenon of irreversible protein glutathionylation and its possible deleterious effects. EXPERT OPINION: The process of reversible protein glutathionylation is now well established but these findings need to be substantiated at the tissue and organ levels, and also with disease state. That being said, irreversible protein glutathionylation can also occur and this has implications in disease and aging. Toxicologists should consider this when evaluating the possible side effects of certain drugs such as busulfan that may generate a glutathionylating species in vivo. PMID- 21557714 TI - Response of blood platelets to resveratrol during a model of hyperhomocysteinemia. AB - Resveratrol (3,4',5-trihydroxystilben), a phenolic antioxidant synthesized in grapes and other plants, and also present in wine, has been suggested to help prevent cardiovascular events. In this study the influence of resveratrol on platelet aggregation during a model of hyperhomocysteinemia was investigated. We induced hyperhomocysteinemia using a reduced form of Hcys (final dose, 0.1 mM) and the most reactive form of Hcys, its cyclic thioester, homocysteine thiolactone (HTL, 1 uM). The aim of our study in vitro was also to investigate superoxide anion radical (O(2)(-)) generation after incubation of platelets with Hcys, HTL, and resveratrol. We have observed that HTL, like its precursor Hcys, stimulated the generation of (O(2)(-) in platelets and caused an augmentation of platelet aggregation induced by the strong physiological agonist thrombin. Our results in vitro also demonstrated that resveratrol reduced the toxic action of Hcys and HTL on blood platelet aggregation and superoxide anion radical production in platelets, suggesting its potential protective effects on hemostasis are negatively influenced by homocysteine and its derivatives. PMID- 21557716 TI - Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid. AB - It was the aim of this study to develop a nanoparticulate oral drug delivery system for leuprolide based on polyacrylic acid (PAA). In order to achieve formation of nanoparticles in a mild, aqueous environment, two different techniques were combined, namely hydrophobic ion pairing between leuprolide and sodium dodecyl sulphate in a first step, followed by encapsulation into nanoparticles gained by interpolymer complexation between polyacrylic acid and Pluronic F68. The obtained nanoparticles were characterized regarding particle size distribution, drug encapsulation efficiency and in vitro release profile. Additionally, the pharmacokinetic profiles of leuprolide after oral administration of PAA-nanoparticulate and PAA-control tablets to male Sprague Dawley rats were assessed and compared. It could be shown, that hydrophobic ion pairing increased encapsulation efficacy of leuprolide and leads to a slowed drug release of nanoparticulate suspensions. Relative oral bioavailability of leuprolide could be increased by nanoparticulate tablets up to 4.2-fold. Results verify that the suggested approach is a promising strategy for the design of oral delivery systems for oral administration of peptide drugs. PMID- 21557717 TI - Fully covered, retrievable self-expanding metal stents (Niti-S) in palliation of malignant dysphagia: long-term results of a prospective study. AB - BACKGROUND: In the palliative treatment of malignant dysphagia, fully covered, retrievable metal stents are not commonly used, mainly due to the high risk of migration. Therefore, we performed a prospective study to evaluate the clinical efficacy of a fully covered, retrievable self-expanding metal stent (Niti-S). METHOD: Between October 1998 and February 2009, 100 consecutive patients with malignant esophageal obstruction treated with the fully covered Niti-S stent (Niti-S, Taewoong Medical, Seoul, South Korea) were included. Data collected contained functional outcome, feasibility of endoscopic stent retrieval, recurrent dysphagia, complications, and survival. RESULT: At 4 weeks after stent placement, dysphagia significantly improved in all patients (p = 0.000). Recurrent dysphagia occurred in 19 of 100 patients treated with Niti-S stents (19%) mainly due to tumor overgrowth (7/100, 7%), stent migration (6/100, 6%), and food impaction (6/100, 6%). Endoscopic stent retrieval was successful in all the attempted 17 patients (17/100, 17%)--7 overgrowth, 6 stent migration, 2 stent degradation, and 2 severe pain. Major complications were 2 hemorrhage, 2 severe pain, and 1 tracheal compression (5/100, 5%), and minor complications were 10 retrosternal pain and 7 symptomatic gastroesophageal reflux (17/100, 17%). After a median follow-up of 142 days, 97 patients had expired. There was no stent related mortality or 30-day mortality. CONCLUSION: The fully covered, retrievable Niti-S stent has proved its effectiveness for palliation of malignant dysphagia and feasibility of endoscopic retrieval. We estimate its dog-bone shaped flanges at both ends and it being completely covered provide good resistance to migration and overgrowth. PMID- 21557718 TI - Fecal eosinophil cationic protein as a marker of active disease and treatment outcome in collagenous colitis: a pilot study. AB - BACKGROUND AND AIMS: Fecal calprotectin (FC) is used as a marker for intestinal inflammation in inflammatory bowel disease (IBD) but there is no reliable marker for collagenous colitis (CC). We have previously demonstrated that the mucosal inflammation in CC is characterized by eosinophil activation, which is restored during budesonide treatment, but there is no enhanced neutrophil activity. The aim of this study was to evaluate the use of fecal eosinophil cationic protein (F ECP) and eosinophil protein X (F-EPX) compared with the neutrophil-derived myeloperoxidase (F-MPO) and FC in patients treated for active CC. METHODS: Patients with active CC (n = 12) were studied before and after 3, 7, 28 and 56 days of budesonide treatment. Clinical symptoms and stool frequency were recorded, fecal samples were collected, and F-ECP, F-EPX, F-MPO and FC were measured at each occasion. RESULTS: All but one patient achieved remission. On inclusion 92%, 67%, 67% and 75% of the patients had elevated F-ECP, F-EPX, F-MPO and FC levels, respectively. All markers decreased during the treatment, particularly F-ECP and F-EPX, which decreased after only 3 days. At the end of the study 100%, 92%, 83% and 75% of the patients had normal F-ECP, F-EPX, F-MPO and FC values, respectively. CONCLUSION: F-ECP demonstrated the best discriminating capacity in detecting active CC. A normalized F-ECP and F-EPX may further be studied as a marker for successful treatment. During budesonide treatment there is a rapid fall in F-ECP and F-EPX, accompanied by clinical improvement, indicating an essential role for the eosinophil participating in the pathophysiology of CC. PMID- 21557719 TI - Tolfenamic acid interrupts the de novo synthesis of the beta-amyloid precursor protein and lowers amyloid beta via a transcriptional pathway. AB - Amyloid beta (Abeta) peptides are related to the pathogenesis of Alzheimer's disease (AD). The search for therapeutic strategies that lower these peptides has mainly focused on the proteolytic processing of the beta-amyloid precursor protein (APP), and other post-transcriptional pathways. The transcription factor specificity protein 1 (Sp1) is vital for the regulation of several genes involved in AD including APP and the beta site APP cleaving enzyme 1 (BACE1). We have previously reported that tolfenamic acid promotes the degradation of Sp1 protein (SP1) in pancreatic human cancer cells and mice tumors. This study examines the ability of tolfenamic acid to reduce SP1 levels, and thereby decrease APP transcription and Abeta levels in rodent brains. Tolfenamic acid was administered by oral gavage to C57BL/6 mice at variable dosages and for different time periods. Results have shown that tolfenamic acid was able to down regulate brain protein levels of SP1, APP, and Abeta. These findings demonstrate that interference with upstream transcriptional pathways can lower pathogenic intermediates associated with AD, and thus tolfenamic acid represents a novel approach for the development of a therapeutic intervention for AD. PMID- 21557720 TI - Errors in ADAS-cog administration and scoring may undermine clinical trials results. AB - BACKGROUND: The Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS cog) is the most widely used cognitive outcome measure in AD trials. Although errors in administration and scoring have been suggested as factors masking accurate estimates and potential effects of treatments, there have been few formal examinations of errors with the ADAS-cog. METHODS: We provided ADAS-cog administration training using standard methods to raters who were designated as experienced, potential raters by sponsors or contract research organizations for two clinical trials. Training included 1 hour sessions on test administration, scoring, question periods, and required that raters individually view and score a model ADAS-cog administration. Raters scores were compared to the criterion scores established for the model administration. RESULTS: A total of 108 errors were made by 80.6% of the 72 raters; 37.5% made 1 error, 25.0% made 2 errors and 18.0% made 3 or more. Errors were made in all ADAS-cog subsections. The most common were in word finding difficulty (67% of the raters), word recognition (22%), and orientation (22%). For the raters who made 1, 2, or >= 3 errors the ADAS-cog score was 17.5 (95% CI, 17.3 - 17.8), 17.8 (17.0 - 18.5), and 18.8 (17.6 - 20.0), respectively, and compared to the criterion score, 18.3. ADAS-cog means differed significantly and the variances were more than twice as large between those who made errors on word finding and those who did not, 17.6 (SD=1.4) vs. 18.8 (SD=0.9), respectively (chi(2) = 37.2, P < .001). CONCLUSIONS: Most experienced raters made at least one error that may affect ADAS-cog scores and clinical trials outcomes. These errors may undermine detection of medication effects by contributing both to a biased point estimate and increased variance of the outcome. PMID- 21557721 TI - Vascular dementia: atherosclerosis, cognition and Alzheimer's disease. AB - Both Alzheimer's disease type pathology (neuritic plaques and neurofibrillary tangles) and evidence of atherosclerosis and infarcts are common in autopsy specimens from the brains of patients enrolled in longitudinal prospective cohorts; the relative contribution of each of these to overall cognitive function is unclear. In addition whether each of these two forms of brain pathology can accelerate the appearance of the other is also unclear. In this paper we examine the relationship among Alzheimer's brain pathology, cerebral infarcts and cerebral atherosclerosis. We conclude that each is an independent predictor of dementia. Moreover we do not find that atherosclerosis increases Alzheimer's type brain pathology or vice versa. PMID- 21557722 TI - Brain resilience and plasticity in the face of Alzheimer pathology. PMID- 21557723 TI - Immune responses to AAV in clinical trials. AB - Findings in the first clinical trial in which an adeno-associated virus (AAV) vector was introduced into the liver of human subjects highlighted an issue not previously identified in animal studies. Upon AAV gene transfer to liver, two subjects developed transient elevation of liver enzymes, likely as a consequence of immune rejection of transduced hepatocytes mediated by AAV capsid-specific CD8(+) T cells. Studies in healthy donors showed that humans carry a population of antigen-specific memory CD8(+) T cells probably arising from wild-type AAV infections. The hypothesis formulated at that time was that these cells expanded upon re-exposure to capsid, i.e. upon AAV-2 hepatic gene transfer, and cleared AAV epitope-bearing transduced hepatocytes. Other hypotheses have been formulated which include specific receptor-binding properties of AAV-2 capsid, presence of capsid-expressing DNA in AAV vector preparations, and expression of alternate open reading frames from the transgene; emerging data from clinical trials however fail to support these competing hypotheses. Possible solutions to the problem are discussed, including the administration of a short-term immunosuppression regimen concomitant with gene transfer, or the development of more efficient vectors that can be administered at lower doses. While more studies will be necessary to define mechanisms and risks associated with capsid specific immune responses in humans, monitoring of these responses in clinical trials will be essential to achieving the goal of long-term therapeutic gene transfer in humans. PMID- 21557724 TI - Functional analysis of hyperthermophilic endocellulase from Pyrococcus horikoshii by crystallographic snapshots. AB - A hyperthermophilic membrane-related beta-1,4-endoglucanase (family 5, cellulase) of the archaeon Pyrococcus horikoshii was found to be capable of hydrolysing cellulose at high temperatures. The hyperthermophilic cellulase has promise for applications in biomass utilization. To clarify its detailed function, we determined the crystal structures of mutants of the enzyme in complex with either the substrate or product ligands. We were able to resolve different kinds of complex structures at 1.65-2.01 A (1 A=0.1 nm). The structural analysis of various mutant enzymes yielded a sequence of crystallographic snapshots, which could be used to explain the catalytic process of the enzyme. The substrate position is fixed by the alignment of one cellobiose unit between the two aromatic amino acid residues at subsites +1 and +2. During the enzyme reaction, the glucose structure of cellulose substrates is distorted at subsite -1, and the beta-1,4-glucoside bond between glucose moieties is twisted between subsites -1 and +1. Subsite -2 specifically recognizes the glucose residue, but recognition by subsites +1 and +2 is loose during the enzyme reaction. This type of recognition is important for creation of the distorted boat form of the substrate at subsite -1. A rare enzyme-substrate complex was observed within the low activity mutant Y299F, which suggested the existence of a trapped ligand structure before the formation by covalent bonding of the proposed intermediate structure. Analysis of the enzyme-substrate structure suggested that an incoming water molecule, essential for hydrolysis during the retention process, might be introduced to the cleavage position after the cellobiose product at subsites +1 and +2 was released from the active site. PMID- 21557725 TI - Evidence that ACN1 (acetate non-utilizing 1) prevents carbon leakage from peroxisomes during lipid mobilization in Arabidopsis seedlings. AB - ACN1 (acetate non-utilizing 1) is a short-chain acyl-CoA synthetase which recycles free acetate to acetyl-CoA in peroxisomes of Arabidopsis. Pulse-chase [2 (13)C]acetate feeding of the mutant acn1-2 revealed that acetate accumulation and assimilation were no different to that of wild-type, Col-7. However, the lack of acn1-2 led to a decrease of nearly 50% in (13)C-labelling of glutamine, a major carbon sink in seedlings, and large decreases in primary metabolite levels. In contrast, acetyl-CoA levels were higher in acn1-2 compared with Col-7. The disappearance of eicosenoic acid was slightly delayed in acn1-2 indicating only a small effect on the rate of lipid breakdown. A comparison of transcript levels in acn1-2 and Col-7 showed that induced genes included a number of metabolic genes and also a large number of signalling-related genes. Genes repressed in the mutant were represented primarily by embryogenesis-related genes. Transcript levels of glyoxylate cycle genes also were lower in acn1-2 than in Col-7. We conclude that deficiency in peroxisomal acetate assimilation comprises only a small proportion of total acetate use, but this affects both primary metabolism and gene expression. We discuss the possibility that ACN1 safeguards against the loss of carbon as acetate from peroxisomes during lipid mobilization. PMID- 21557726 TI - Down-regulation of c-Myc expression inhibits the invasion of bile duct carcinoma cells. AB - Cholangiocarcinoma is the second most common primary hepatic tumour originating from biliary tract epithelial cells with poor prognosis. Enhanced c-Myc protein expression contributes to many aspects of tumour cell biology. Although the ability of c-Myc to drive unrestricted cell proliferation and to inhibit cell differentiation had been well recognized, whether down-regulated c-Myc expression can inhibit tumour cell invasion still remains to be explored. The c-Myc ASODN (antisense oligodeoxyribonucleotide) and NSODN (nonsense oligodeoxyribonucleotide) were designed, synthesized and transfected into human QBC939 bile duct carcinoma cells using the Lipofectamine 2000 reagent. The protein expression of c-Myc was detected by Western blot. A transwell experiment was applied to evaluate the invasive capacity of the QBC939 cells. c-Myc ASODN could significantly suppress the c-Myc protein expression (P<0.05) and the invasion (P<0.01) of QBC939 cells transfected with c-Myc ASODN compared with that in the control and c-Myc NSODN-transfected group. Thus in the present study we show that down-regulation of c-Myc expression can inhibit the invasion of QBC939 cells in vitro. PMID- 21557727 TI - Radiosensitization in human breast carcinoma cells by thymoquinone: role of cell cycle and apoptosis. AB - TQ (thymoquinone), the bioactive constituent of black seed (Nigella sativa), has been shown to inhibit the growth of various human cancers both in vitro and in vivo. This study reports the radiosensitizing effect of TQ on human breast carcinoma cells (MCF7 and T47D). TQ in combination with single dose of ionizing radiation (2.5 Gy) was found to exert supra-additive cytotoxic effects on both the carcinomas as measured by cell proliferation and colony-formation assays. Annexin V binding and FACS analysis revealed the role of enhanced apoptosis and cell cycle modulation in the mechanism of TQ-mediated radiosensitization, thus supporting TQ as an adjuvant for preclinical testing in cancer chemo radiotherapy. PMID- 21557728 TI - Facilitation of transmitter release from rat sympathetic neurons via presynaptic P2Y(1) receptors. AB - BACKGROUND AND PURPOSE: P2Y(1) , P2Y(2) , P2Y(4) , P2Y(12) and P2Y(13) receptors for nucleotides have been reported to mediate presynaptic inhibition, but unequivocal evidence for facilitatory presynaptic P2Y receptors is not available. The search for such receptors was the purpose of this study. EXPERIMENTAL APPROACH: In primary cultures of rat superior cervical ganglion neurons and in PC12 cell cultures, currents were recorded via the perforated patch clamp technique, and the release of [(3) H]-noradrenaline was determined. KEY RESULTS: ADP, 2-methylthio-ATP and ATP enhanced stimulation-evoked (3) H overflow from superior cervical ganglion neurons, treated with pertussis toxin to prevent the signalling of inhibitory G proteins. This effect was abolished by P2Y(1) antagonists and by inhibition of phospholipase C, but not by inhibition of protein kinase C or depletion of intracellular Ca(2+) stores. ADP and a specific P2Y(1) agonist caused inhibition of Kv7 channels, and this was prevented by a respective antagonist. In neurons not treated with pertussis toxin, (3) H overflow was also enhanced by a specific P2Y(1) agonist and by ADP, but only when the P2Y(12) receptors were blocked. ADP also enhanced K(+) -evoked (3) H overflow from PC12 cells treated with pertussis toxin, but only in a clone expressing recombinant P2Y(1) receptors. CONCLUSIONS AND IMPLICATIONS: These results demonstrate that presynaptic P2Y(1) receptors mediate facilitation of transmitter release from sympathetic neurons most likely through inhibition of Kv7 channels. PMID- 21557729 TI - The anandamide transport inhibitor AM404 reduces the rewarding effects of nicotine and nicotine-induced dopamine elevations in the nucleus accumbens shell in rats. AB - BACKGROUND AND PURPOSE: The fatty acid amide hydrolase inhibitor URB597 can reverse the abuse-related behavioural and neurochemical effects of nicotine in rats. Fatty acid amide hydrolase inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptors alpha (PPAR-alpha). Since recent evidence indicates that PPAR-alpha can modulate nicotine reward, it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward. EXPERIMENTAL APPROACH: A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404). To clarify AEA's role in nicotine reward, we investigated the effect of AM404 on conditioned place preference (CPP), reinstatement of abolished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague-Dawley rats. KEY RESULTS: AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of the abolished CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine. CONCLUSIONS AND IMPLICATIONS: These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21557730 TI - Adrenoceptor activity of muscarinic toxins identified from mamba venoms. AB - BACKGROUND AND PURPOSE: Muscarinic toxins (MTs) are snake venom peptides named for their ability to interfere with ligand binding to muscarinic acetylcholine receptors (mAChRs). Recent data infer that these toxins may have other G-protein coupled receptor targets than the mAChRs. The purpose of this study was to systematically investigate the interactions of MTs with the adrenoceptor family members. EXPERIMENTAL APPROACH: We studied the interaction of four common MTs, MT1, MT3, MT7 and MTalpha, with cloned receptors expressed in insect cells by radioligand binding. Toxins showing modest to high-affinity interactions with adrenoceptors were additionally tested for effects on functional receptor responses by way of inhibition of agonist-induced Ca2+ increases. KEY RESULTS: All MTs behaved non-competitively in radioligand displacement binding. MT1 displayed higher binding affinity for the human alpha(2B)-adrenoceptor (IC50 = 2.3 nM) as compared with muscarinic receptors (IC50 >= 100 nM). MT3 appeared to have a broad spectrum of targets showing high-affinity binding (IC50 = 1-10 nM) to M4 mAChR, alpha(1A)-, alpha(1D)- and alpha(2A)-adrenoceptors and lower affinity binding (IC50 >= 25 nM) to alpha(1B)- and alpha(2C)-adrenoceptors and M1 mAChR. MT7 did not detectably bind to other receptors than M1, and MTalpha was specific for the alpha(2B)-adrenoceptor. None of the toxins showed effects on beta1- or beta2-adrenoceptors. CONCLUSIONS AND IMPLICATIONS: Some of the MTs previously found to interact predominantly with mAChRs were shown to bind with high affinity to selected adrenoceptor subtypes. This renders these peptide toxins useful for engineering selective ligands to target various adrenoceptors. PMID- 21557731 TI - Tadalafil analgesia in experimental arthritis involves suppression of intra articular TNF release. AB - BACKGROUND AND PURPOSE: We investigated the effect of the phosphodiesterase-5 inhibitor, tadalafil, on the acute hypernociception in rat models of arthritis. EXPERIMENTAL APPROACH: Rats were treated with either an intra-articular injection of zymosan (1 mg) or surgical transection of the anterior cruciate ligament (as an osteoarthritis model). Controls received saline intra-articular or sham operation respectively. Joint pain was evaluated using the articular incapacitation test measured over 6 h following zymosan or between 4 and 7 days after anterior cruciate ligament transection. Cell counts, tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and the chemokine, cytokine-induced neutrophil chemoattractant-1 (CINC-1) were measured in joint exudates 6 h after zymosan. Groups received tadalafil (0.02-0.5 mg.kg-1 per os) or saline 2 h after intra-articular zymosan. Other groups received the u-opioid receptor antagonist naloxone or the cGMP inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) before tadalafil. KEY RESULTS: Tadalafil dose-dependently inhibited hypernociception in zymosan and osteoarthritis models. In zymosan-induced arthritis, tadalafil significantly decreased cell influx and TNF-alpha release but did not alter IL-1 or CINC-1 levels. Pretreatment with ODQ but not with naloxone prevented the anti-inflammatory effects of tadalafil. CONCLUSIONS AND IMPLICATIONS: Therapeutic oral administration of tadalafil provided analgesia mediated by guanylyl cyclase and was independent of the release of endogenous opioids. This effect of tadalafil was associated with a decrease in neutrophil influx and TNF-alpha release in inflamed joints. PMID- 21557732 TI - Constitutive formation of an RXFP1-signalosome: a novel paradigm in GPCR function and regulation. AB - The classical second messenger cAMP is important in diverse physiological processes, where its spatial and temporal compartmentalization allows precise control over multiple cellular events. Within this context, G-protein-coupled receptors (GPCRs) govern specialized pools of cAMP, which are functionally specific for the unique cellular effects attributed to a particular system. The relaxin receptor, RXFP1, is a GPCR that exerts pleiotropic physiological effects including a potent anti-fibrotic response, increased cancer metastases, and has efficacy as a vasodilator in heart failure. On a cellular level, relaxin stimulation of RXFP1 results in the activation of multiple G-protein pathways affecting cAMP accumulation. Specificity and diversity in the cAMP signal generated by RXFP1 is controlled by differential G-protein coupling dependent upon the background of cellular expression, and cAMP compartmentalization. Further complexity in cAMP signalling results from the constitutive assembly of an RXFP1-signalosome, which specifically responds to low concentrations of relaxin, and activates a distinct cAMP pathway. The RXFP1-signalosome is a higher order protein complex that facilitates receptor sensitivity to attomolar concentration of peptide, exhibits constitutive activity and dual coupling to G proteins and beta-arrestins and reveals a concentration-biased agonism mediated by relaxin. The specific and directed formation of GPCR-centered signalosomes allows an even greater spatial and temporal control of cAMP, thus rationalizing the considerable physiological scope of this ubiquitous second messenger. PMID- 21557733 TI - Allosteric modulation of glycine receptors. AB - Inhibitory (or strychnine sensitive) glycine receptors (GlyRs) are anion selective transmitter-gated ion channels of the cys-loop superfamily, which includes among others also the inhibitory gamma-aminobutyric acid receptors (GABA(A) receptors). While GABA mediates fast inhibitory neurotransmission throughout the CNS, the action of glycine as a fast inhibitory neurotransmitter is more restricted. This probably explains why GABA(A) receptors constitute a group of extremely successful drug targets in the treatment of a wide variety of CNS diseases, including anxiety, sleep disorders and epilepsy, while drugs specifically targeting GlyRs are virtually lacking. However, the spatially more restricted distribution of glycinergic inhibition may be advantageous in situations when a more localized enhancement of inhibition is sought. Inhibitory GlyRs are particularly relevant for the control of excitability in the mammalian spinal cord, brain stem and a few selected brain areas, such as the cerebellum and the retina. At these sites, GlyRs regulate important physiological functions, including respiratory rhythms, motor control, muscle tone and sensory as well as pain processing. In the hippocampus, RNA-edited high affinity extrasynaptic GlyRs may contribute to the pathology of temporal lobe epilepsy. Although specific modulators have not yet been identified, GlyRs still possess sites for allosteric modulation by a number of structurally diverse molecules, including alcohols, neurosteroids, cannabinoids, tropeines, general anaesthetics, certain neurotransmitters and cations. This review summarizes the present knowledge about this modulation and the molecular bases of the interactions involved. PMID- 21557734 TI - Obesity and risk of vascular disease: importance of endothelium-dependent vasoconstriction. AB - Obesity has become a serious global health issue affecting both adults and children. Recent devolopments in world demographics and declining health status of the world's population indicate that the prevalence of obesity will continue to increase in the next decades. As a disease, obesity has deleterious effects on metabolic homeostasis, and affects numerous organ systems including heart, kidney and the vascular system. Thus, obesity is now regarded as an independent risk factor for atherosclerosis-related diseases such as coronary artery disease, myocardial infarction and stroke. In the arterial system, endothelial cells are both the source and target of factors contributing to atherosclerosis. Endothelial vasoactive factors regulate vascular homeostasis under physiological conditions and maintain basal vascular tone. Obesity results in an imbalance between endothelium-derived vasoactive factors favouring vasoconstriction, cell growth and inflammatory activation. Abnormal regulation of these factors due to endothelial cell dysfunction is both a consequence and a cause of vascular disease processes. Finally, because of the similarities of the vascular pathomechanisms activated, obesity can be considered to cause accelerated, 'premature' vascular aging. Here, we will review some of the pathomechanisms involved in obesity-related activation of endothelium-dependent vasoconstriction, the clinical relevance of obesity-associated vascular risk, and therapeutic interventions using 'endothelial therapy' aiming at maintaining or restoring vascular endothelial health. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3. PMID- 21557735 TI - VS-105: a novel vitamin D receptor modulator with cardiovascular protective effects. AB - BACKGROUND AND PURPOSE: Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells. KEY RESULTS: VS-105 induced HL-60 cell differentiation with an EC50 value at 11.8 nM. Treatment (i.p., 3* a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS 105 (0.004-0.64 ug.kg-1) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS 105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage. CONCLUSIONS AND IMPLICATIONS: VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation. PMID- 21557736 TI - Skeletal lipidomics: regulation of bone metabolism by fatty acid amide family. AB - There is increasing evidence demonstrating that fatty acid derivatives play a key regulatory role in a variety of tissues. However, the study of skeletal lipidomics is just emerging and global strategies, such as targeted lipidomics, have not been applied to bone tissue. Such strategies hold great promises as in the case of genomics and proteomics. A partial profile of endocannabinoids and endocannabinoid-like compounds has demonstrated the presence of several long chain fatty acid amides (FAAs), some of which displaying potent effects on osteoblasts, the bone forming cells and osteoclasts, the bone resorbing cells. In the skeleton, the FAAs activate the CB(1) cannabinoid receptor present in sympathetic nerve terminals as well as CB(2) cannabinoid receptor, the Gi-protein coupled receptor GPR55, and the transient receptor potential vanilloid type ion channel expressed by osteoblasts and/or osteoclasts. This review on the skeletal FAA system focuses on the production of FAAs in the skeleton and their net bone anabolic and anti-catabolic activity resulting from the stimulation of bone formation and inhibition of bone resorption. As the FAA family holds great promise as a basis for the treatment of osteoporosis and other diseases involving bone, further studies should aim towards the complete profiling of these lipids and their receptors in bone tissue, followed by elucidation of their function and mechanism of action. PMID- 21557737 TI - Depletion and recovery of lymphoid subsets following morphine administration. AB - BACKGROUND AND PURPOSE: Opioid use and abuse has been linked to significant immunosuppression, which has been attributed, in part, to drug-induced depletion of lymphocytes. We sought to define the mechanisms by which lymphocyte populations are depleted and recover following morphine treatment in mice. EXPERIMENTAL APPROACH: Mice were implanted with morphine pellets and B- and T cell subsets in the bone marrow, thymus, spleen and lymph nodes were analysed at various time points. We also examined the effects of morphine on T-cell development using an ex vivo assay. KEY RESULTS: The lymphocyte populations most susceptible to morphine-induced depletion were the precursor cells undergoing selection. As the lymphocytes recovered, more lymphocyte precursors proliferated than in control mice. In addition, peripheral T-cells displayed evidence that they had undergone homeostatic proliferation during the recovery phase of the experiments. CONCLUSIONS AND IMPLICATIONS: The recovery of lymphocytes following morphine-induced depletion occurred in the presence of morphine and via increased proliferation of lymphoid precursors and homeostatic proliferation of T-cells. PMID- 21557738 TI - The flavonoid scaffold as a template for the design of modulators of the vascular Ca(v) 1.2 channels. AB - BACKGROUND AND PURPOSE: Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Ca(v) 1.2 channel current (I(Ca1.2) ). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Ca(v) 1.2 channels. EXPERIMENTAL APPROACH: Twenty-four flavonoids were analysed for their effects on I(Ca1.2) in rat tail artery myocytes, using the whole-cell patch-clamp method. KEY RESULTS: Most of the flavonoids stimulated or inhibited I(Ca1.2) in a concentration- and voltage-dependent manner with EC(50) values ranging between 4.4 uM (kaempferol) and 16.0 uM (myricetin) for the stimulators and IC(50) values between 13.4 uM (galangin) and 100 uM [(+/-)-naringenin] for the inhibitors. Key structural requirements for I(Ca1.2) stimulatory activity were the double bond between C2 and C3 and the hydroxylation pattern on the flavonoid scaffold, the latter also determining the molecular charge, as shown by molecular modelling techniques. Absence of OH groups in the B ring was key in I(Ca1.2) inhibition. The functional interaction between quercetin and either the stimulator myricetin or the antagonists resokaempferol, crysin, genistein, and 5,7,2' trihydroxyflavone revealed that quercetin expressed the highest apparent affinity, in the low uM range, for Ca(v) 1.2 channels. Neither protein tyrosine kinase nor protein kinase Calpha were involved in quercetin-induced stimulation of I(Ca1.2). CONCLUSIONS AND IMPLICATIONS: Quercetin-like plant flavonoids were active on vascular Ca(v)1.2 channels. Thus, the flavonoid scaffold may be a template for the design of novel modulators of vascular smooth muscle Ca(v)1.2 channels, valuable for the treatment of hypertension and stroke. PMID- 21557739 TI - Reduction of body weight, liver steatosis and expression of stearoyl-CoA desaturase 1 by the isoflavone daidzein in diet-induced obesity. AB - BACKGROUND AND PURPOSE: The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats. EXPERIMENTAL APPROACH: Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg.kg(-1)) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism. KEY RESULTS: A single treatment (acute) with daidzein dose dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment. CONCLUSIONS AND IMPLICATIONS: These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products. PMID- 21557740 TI - Longitudinal associations between marital instability and child sleep problems across infancy and toddlerhood in adoptive families. AB - This study examined the longitudinal association between marital instability and child sleep problems at ages 9 and 18 months in 357 families with a genetically unrelated infant adopted at birth. This design eliminates shared genes as an explanation for similarities between parent and child. Structural equation modeling indicated that T1 marital instability predicted T2 child sleep problems, but T1 child sleep problems did not predict T2 marital instability. This result was replicated when models were estimated separately for mothers and fathers. Thus, even after controlling for stability in sleep problems and marital instability and eliminating shared genetic influences on associations using a longitudinal adoption design, marital instability prospectively predicts early childhood sleep patterns. PMID- 21557741 TI - Infantile amnesia across the years: a 2-year follow-up of children's earliest memories. AB - Although infantile amnesia has been investigated for many years in adults, only recently has it been investigated in children. This study was a 2-year follow-up and extension of an earlier study. Children (4-13 years old) were asked initially and 2 years later for their earliest 3 memories. At follow-up, their age at the time of these memories shifted to several months later, with younger children unlikely to provide the same memories. Moreover, when given cues about memories recalled 2 years previously, many were still not recalled. In contrast, older children were more likely to recall the same memories, and cues to former memories were successful. Thus, older children were becoming consistent in terms of recalling very early memories. PMID- 21557742 TI - The genetic and environmental covariation among psychopathic personality traits, and reactive and proactive aggression in childhood. AB - The present study investigated the genetic and environmental covariance between psychopathic personality traits with reactive and proactive aggression in 9- to 10-year-old twins (N = 1,219). Psychopathic personality traits were assessed with the Child Psychopathy Scale (D. R. Lynam, 1997), while aggressive behaviors were assessed using the Reactive Proactive Questionnaire (A. Raine et al., 2006). Significant common genetic influences were found to be shared by psychopathic personality traits and aggressive behaviors using both caregiver (mainly mother) and child self-reports. Significant genetic and nonshared environmental influences specific to psychopathic personality traits and reactive and proactive aggression were also found, suggesting etiological independence among these phenotypes. Additionally, the genetic relation between psychopathic personality traits and aggression was significantly stronger for proactive than reactive aggression when using child self-reports. PMID- 21557743 TI - Structure mapping and relational language support children's learning of relational categories. AB - Learning relational categories--whose membership is defined not by intrinsic properties but by extrinsic relations with other entities--poses a challenge to young children. The current work showed 3-, 4- to 5-, and 6-year-olds pairs of cards exemplifying familiar relations (e.g., a nest and a bird exemplifying home for) and then tested whether they could extend the relational concept to another category (e.g., choose the barn as a home for a horse). It found that children benefited from (a) hearing a (novel) category name in a relational construction and (b) comparing category members. The youngest group--3-year-olds--learned the category only when given a combination of relational language and a series of comparisons in a progressive alignment sequence. PMID- 21557744 TI - Narrative elaboration and participation: two dimensions of maternal elicitation style. AB - This study investigated the narrative scaffolding styles of Spanish-speaking and English-speaking mothers as they engaged their preschool-aged children in family reminiscing and book sharing interactions. Specifically, the study examined the dimensions of narrative elaboration and participation in mothers' scaffolding styles across the 2 narrative tasks. Cluster analyses identified 2 styles of maternal scaffolding for each context, differing in the degree to which mothers elaborated, the manner in which they did so, and the extent to which they encouraged child participation. Findings highlight the importance of both narrative elaboration and narrative participation as defining dimensions of maternal scaffolding styles. Results are discussed in relation to variations in socialization practices and the role these practices might play in children's development. PMID- 21557745 TI - Carpal-metacarpal specializations for burrowing in South American octodontoid rodents. AB - Among the ecomorphologically diverse Octodontoidea rodents, fossorial habits are prevalent in Ctenomyidae and Octodontidae and occur in some members of Echimyidae. To detect traits linked to scratch-digging, we analyzed morpho structural variation in the carpus and metacarpus of 27 species of extinct and living octodontoids with epigean, fossorial and subterranean habits. Within a context of relative morphological uniformity, we detected the following specialized traits in the burrowing Clyomys (Echimyidae), Spalacopus (Octodontidae), Ctenomys and ?Eucelophorus (Ctenomyidae): broad shortened carpus, robust metacarpals, markedly broad and short metacarpal V, and predominance of ray III (mesaxony, incipient in Spalacopus). In addition, the specialized subterranean Ctenomys presented an enlarged scapholunar in extensive contact with the unciform, and with a complex-shaped proximal articular surface. These features are interpreted as responses to mechanical requirements of scratch digging, providing greater carpal rigidity and resistance to direct forces exerted during the digging stroke. In Ctenomys, the radius-scapholunar joint restricts movement at wrist level. The phylogenetic distribution of traits shows that the most derived carpal and metacarpal morphologies occur among subterranean octodontoids, also possessing important craniodental adaptations, and supports the hypothesis that the acquisition of digging specializations would have been linked to increasing burrowing frequency in some lineages. Nevertheless, octodontoids with less morphological specializations have metacarpal modifications advantageous for digging, suggesting that scratch-digging specialization preceded the acquisition of tooth-digging traits, in agreement with the general claim that scratch-digging is the primary digging strategy in burrowing mammals. PMID- 21557746 TI - Petal-specific subfunctionalization of an APETALA3 paralog in the Ranunculales and its implications for petal evolution. AB - * The petals of the lower eudicot family Ranunculaceae are thought to have been derived many times independently from stamens. However, investigation of the genetic basis of their identity has suggested an alternative hypothesis: that they share a commonly inherited petal identity program. This theory is based on the fact that an ancient paralogous lineage of APETALA3 (AP3) in the Ranunculaceae appears to have a conserved, petal-specific expression pattern. * Here, we have used a combination of approaches, including RNAi, comparative gene expression and molecular evolutionary studies, to understand the function of this petal-specific AP3 lineage. * Functional analysis of the Aquilegia locus AqAP3-3 has demonstrated that the paralog is required for petal identity with little contribution to the identity of the other floral organs. Expanded expression studies and analyses of molecular evolutionary patterns provide further evidence that orthologs of AqAP3-3 are primarily expressed in petals and are under higher purifying selection across the family than the other AP3 paralogs. * Taken together, these findings suggest that the AqAP3-3 lineage underwent progressive subfunctionalization within the order Ranunculales, ultimately yielding a specific role in petal identity that has probably been conserved, in stark contrast with the multiple independent origins predicted by botanical theories. PMID- 21557747 TI - The evolution of RNA editing and pentatricopeptide repeat genes. AB - The pentatricopeptide repeat (PPR) is a degenerate 35-amino-acid structural motif identified from analysis of the sequenced genome of the model plant Arabidopsis thaliana. From the wealth of sequence information now available from plant genomes, the PPR protein family is now known to be one of the largest families in angiosperm species, as most genomes encode 400-600 members. As the number of PPR genes is generally only c. 10-20 in other eukaryotic organisms, including green algae, the family has obviously greatly expanded during land plant evolution. This provides a rare opportunity to study selection pressures driving a 50-fold expansion of a single gene family. PPR proteins are sequence-specific RNA-binding proteins involved in many aspects of RNA processing in organelles. In this review, we will summarize our current knowledge about the evolution of PPR genes, and will discuss the relevance of the dramatic expansion in the family to the functional diversification of plant organelles, focusing primarily on RNA editing. PMID- 21557748 TI - Arbuscular mycorrhizal-like fungi in Carboniferous arborescent lycopsids. PMID- 21557749 TI - Towards standardization of the description and publication of next-generation sequencing datasets of fungal communities. PMID- 21557750 TI - A potential new target for asthma therapy: a disintegrin and metalloprotease 10 (ADAM10) involvement in murine experimental asthma. AB - BACKGROUND: Elevated levels of CD23, a natural regulator of IgE production, have been shown to decrease the signs of lung inflammation in mice. The aim of this study was to study the involvement of ADAM10, the primary CD23 sheddase, in experimental asthma. METHODS: ADAM10 was blocked either by using mice with a B cell-specific deletion of the protease or pharmacologically by intranasal administration of selective ADAM10 inhibitors. Airway hypersensitivity (AHR) and bronchoaveolar lavage fluid (BALF) eosinophilia and select BALF cytokine/chemokine levels were then determined. RESULTS: Using an IgE and mast cell-dependent mouse model, B-cell-specific ADAM10(-/-) mice (C57B/6 background) exhibited decreased eosinophilia and AHR when compared with littermate (LM) controls. Treatment of C57B/6 mice with selective inhibitors of ADAM10 resulted in an even further decrease in BALF eosinophilia, as compared with the ADAM10(-/ ) animals. Even in the Th2 selective strain, Balb/c, BALF eosinophilia was reduced from 60% to 23% respectively. In contrast, when an IgE/mast cell independent model of lung inflammation was used, the B-cell ADAM10(-/-) animals and ADAM10 inhibitor treated animals had lung inflammation levels that were similar to the controls. CONCLUSIONS: These results thus show that ADAM10 is important in the progression of IgE-dependent lung inflammation. The use of the inhibitor further suggested that ADAM10 was important for maintaining Th2 levels in the lung. These results thus suggest that decreasing ADAM10 activity could be beneficial in controlling asthma and possibly other IgE-dependent diseases. PMID- 21557751 TI - EAACI position paper: prevention of work-related respiratory allergies among pre apprentices or apprentices and young workers. AB - Apprenticeship is a period of increased risk of developing work-related respiratory allergic diseases. There is a need for documents to provide appropriate professional advice to young adults aiming to reduce unsuitable job choices and prevent impairment from their careers. The present document is the result of a consensus reached by a panel of experts from European and non European countries addressed to allergologists, pneumologists, occupational physicians, primary care physicians, and other specialists interested in this field, which aims to reduce work-related respiratory allergies (rhinoconjunctivitis and asthma) among allergic or nonallergic apprentices and other young adults entering the workforce. The main objective of the document is to issue consensus suggestions for good clinical practice based on existing scientific evidence and the expertise of a panel of physicians. PMID- 21557752 TI - Human lung mast cells modulate the functions of airway smooth muscle cells in asthma. AB - BACKGROUND: Activated mast cell densities are increased on the airway smooth muscle in asthma where they may modulate muscle functions and thus contribute to airway inflammation, remodelling and airflow obstruction. OBJECTIVES: To determine the effects of human lung mast cells on the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. METHODS: Freshly isolated human lung mast cells were stimulated with IgE/anti IgE. Culture supernatants were collected after 2 and 24 h and the mast cells lysed. The supernatants/lysates were added to serum-deprived, subconfluent airway smooth muscle cells for up to 48 h. Released chemokines and extracellular matrix were measured by ELISA, proliferation was quantified by [(3) H]-thymidine incorporation and cell counting, and intracellular signalling by phospho-arrays. RESULTS: Mast cell 2-h supernatants reduced CCL11 and increased CXCL8 and fibronectin production from both asthmatic and nonasthmatic muscle cells. Leupeptin reversed these effects. Mast cell 24-h supernatants and lysates reduced CCL11 release from both muscle cell types but increased CXCL8 release by nonasthmatic cells. The 24-h supernatants also reduced asthmatic, but not nonasthmatic, muscle cell DNA synthesis and asthmatic cell numbers over 5 days through inhibiting extracellular signal-regulated kinase (ERK) and phosphatidylinositol (PI3)-kinase pathways. However, prostaglandins, thromboxanes, IL-4 and IL-13 were not involved in reducing the proliferation. CONCLUSIONS: Mast cell proteases and newly synthesized products differentially modulated the secretory and proliferative functions of airway smooth muscle cells from donors with and without asthma. Thus, mast cells may modulate their own recruitment and airway smooth muscle functions locally in asthma. PMID- 21557753 TI - Multiple wheat flour allergens and cross-reactive carbohydrate determinants bind IgE in baker's asthma. AB - BACKGROUND: Several wheat flour allergens relevant to baker's asthma have been identified in the last 25 years. The aim of this study was to determine the frequency of sensitization to these allergens in German bakers. METHODS: Using recombinant DNA technology, the following wheat flour allergens were cloned, expressed in Escherichia coli and purified: five subunits of the wheat alpha amylase inhibitors (WTAI-CM1, WTAI-CM2, WTAI-CM3, WDAI-0.19 and WMAI-0.28), thioredoxin, thiol reductase or 1-cys-peroxiredoxin homologues, triosephosphate isomerase, alphabeta-gliadin, serpin, glyceraldehyde-3-phosphate-dehydrogenase, a nonspecific lipid transfer protein (nsLTP), dehydrin, profilin and peroxidase. In addition, ImmunoCAPs with the recombinant allergen omega-5-gliadin and two cross reactive carbohydrate determinants (CCDs), horse radish peroxidase (HRP) and the N-glycan of bromelain (MUXF), were used. Specific IgE was measured in wheat flour positive sera from 40 German bakers with work-related asthma/rhinitis and 10 controls with pollinosis. RESULTS: Thirty bakers (75%) had IgE to at least one of the 19 single allergens. Most frequent was IgE to WDAI-0.19, HRP and MUXF (25% each), followed by WTAI-CM1 (20%), thiol reductase (16%), WTAI-CM3 (15%), WTAI CM2 and thioredoxin (12.5%), WMAI-28, triosephosphate-isomerase, alphabeta gliadin (10%), 1-cys-peroxiredoxin (7.5%), dehydrin, serpin, glyceraldehyde-3 phosphate-dehydrogenase (5%), omega-5-gliadin, nsLTP and profilin (2.5%). Fifteen bakers (38%) had IgE to any alpha-amylase inhibitor and 12 (30%) to at least one CCD. The controls reacted exclusively to CCDs (80%), profilin (60%), thioredoxin (30%), triosephosphate isomerase and nsLTP (10%). CONCLUSIONS: The single allergen sensitization profiles obtained with 17 recombinant wheat flour allergens and two CCDs revealed no major allergen for German bakers. The highest frequencies were found for alpha-amylase inhibitors and CCDs. PMID- 21557754 TI - Factors influencing fluoride ingestion from dentifrice by children. AB - OBJECTIVE: This study assessed the percentage of the amount of dentifrice loaded onto the toothbrush that is ingested by children, taking into account age, the amount of dentifrice used during toothbrushing, and the dentifrice flavor. METHODS: The sample consisted of 155 children of both genders attending public kindergartens and schools in Bauru, Brazil, divided into 5 groups (n = 30-32) of children aged 2, 3, 4, 5 and 6 years old. The dentifrices used were SorrisoTM (1219 ppm F, peppermint-flavored) and TandyTM (959 ppm F, tutti-frutti-flavored). The assessment of fluoride intake from dentifrices was carried out six times for each child, using 0.3, 0.6, and 1.2 g of each dentifrice, following a random, crossover distribution. Brushing was performed by the children or their parents/caregivers according to the home habits and under the observation of the examiner. Fluoride present in the expectorant and on toothbrush was analyzed with an ion-specific electrode after HMDS-facilitated diffusion. Fluoride ingestion was indirectly derived. Results were analyzed by 3-way repeated-measures anova and Tukey's tests (P < 0.05) using the percent dentifrice ingested as response variable. RESULTS: Age and percent dentifrice ingested for both dentifrices, and the three amounts used were inversely related (P < 0.0001). Percent dentifrice ingested was significantly higher after the use of TandyTM under all conditions of the study when compared with SorrisoTM (P < 0.0001). Significant differences were observed when brushing with 0.3 g when compared with 1.2 g, for both dentifrices tested (P < 0.05). CONCLUSIONS: The results indicate that all variables tested must be considered in preventive measures aiming to reduce the amount of fluoride ingested by young children. PMID- 21557755 TI - Association between tooth extraction due to infection and myocardial infarction. AB - OBJECTIVE: To explore whether the association between tooth extraction and nonfatal myocardial infarction (MI) varies by reason for extraction. METHODS: Men of the Oslo study of 1972/73 took part in the health survey in 2000 (n=6530) then aged 48-77 years. The present analysis is a nested case-control study of the men with a self-reported history of MI as cases (n=548) and randomly drawn controls (n=625). Reasons for extraction (self-reported) were recorded as periodontal infections (marginal periodontitis) or apical infection of a single tooth, and these were grouped as infection due to extractions. Extractions due to trauma or other causes were grouped as noninfection extractions. RESULTS: More men with a history of MI had extracted teeth than controls (92.7% versus 88.6%; P=0.020). The prospective logistic regression analysis predicting nonfatal MI showed strength of association between infection extraction, no extraction, or noninfection extractions combined [odds ratio (OR)=1.64; 95% confidence interval (CI): 1.24, 2.16] in adjusted analysis and crude analysis (OR=1.73; 95% CI: 1.34, 2.23). Adjustment was made for known risk factors for MI and periodontitis in 1972/73, such as systolic blood pressure, smoking, total cholesterol, BMI, and education recorded in the 2000 screening. CONCLUSIONS: Extractions due to dental infections were associated with nonfatal MI in elderly men. PMID- 21557756 TI - Healing of peri-implant tissues after flapless and flapped implant installation. AB - AIM: The aim of this study was to investigate the consequences of different flapless procedures for the installation of dental implants on peri-implant bone response. MATERIALS AND METHODS: After bilateral extraction of the mandibular second and third premolars and a 3-month healing period, 30 SLActive((r)) implants were installed for 3 months in 10 Beagle dogs according to three different surgical approaches, i.e.: (1) flapped (F), (2) tissue punch flapless (P), and (3) direct flapless (DF). RESULTS: At harvesting, 29 implants were analysed. Micro-computed tomography and histomorphometrical evaluation (which also included the mobile implants) showed comparable results in bone volume (F=55 +/- 9, P=51 +/- 4, DF=54 +/- 5) and crestal bone level (F=3420 +/- 762, P=5358 +/ 1681, DF=3843 +/- 433). However, the implants inserted using the punch approach revealed a significantly lower first bone contact (F=3420 +/- 762, P=5358 +/- 1681, DF=3843 +/- 433) and bone-to-implant contact percentage (F=70 +/- 12, P=48 +/- 23, DF=73 +/- 12). Considering the gingival response, the barrier epithelium was also significantly deeper around the implants installed using the punch approach (F=1383 +/- 332, P=2278 +/- 1154, DF=1107 +/- 300). CONCLUSIONS: The results indicate that a flapless surgical technique can be used for the installation of oral implants. In addition, using a tissue punch wider than the implant diameter should be avoided, as it can jeopardize the outcome of the implantation procedure. PMID- 21557757 TI - Randomized controlled trial on lateral augmentation using two collagen membranes: morphometric results on mineralized tissue compound. AB - BACKGROUND: Guided bone regeneration is considered an effective tool for gaining mineralized tissue either at exposed implant surface or in deficient alveolar ridge areas before implant placement. MATERIAL AND METHODS: Customized casts obtained following impression taking at surgery and re-entry allowed for morphometric assessment of alveolar ridge alterations 6 months after one-stage augmentation of bone dehiscences. In a randomized pilot study using biphasic calcium phosphate tests (n=17) received treatment with ribose cross-linked collagen membranes (RCLM), whereas controls (n=20) received non-cross-linked membranes. The primary endpoint was to quantify the effect of membrane type on dimensional changes in bone margins at crestal level of endosseous implants. RESULTS: Soft tissue dehiscencies occurred at 70.5% and 55% frequency for tests and controls, respectively. Gain in clinically hard newly mineralized tissue at the crestal level was significantly higher in test group in lateral (1.8 versus 0.7 mm; p=.046) and in vertical dimensions (1.1 versus 0.2 mm; p=.035) compared with controls. Second measurement obtained at the border of reflected flap revealed no significant difference between groups (3.0 versus 2.1 mm; p=0.57) for lateral dimension. CONCLUSIONS: Both collagen devices were effective in bone augmentation. RCLMs supported mineralization process and remodelling even in sites showing compromised healing as indicated by morphometric outcome. PMID- 21557758 TI - The effect of selective serotonin re-uptake inhibitors on the risk of myocardial infarction in a cohort of patients with depression. AB - AIM: To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression. METHODS: This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR). RESULTS: SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05). CONCLUSIONS: Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk. PMID- 21557759 TI - Memory disorders associated with consumption of drugs: updating through a case/noncase study in the French PharmacoVigilance Database. AB - AIMS: To investigate putative associations of reports of memory disorders and suspected drugs. METHODS: We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval. RESULTS: Among the 188,284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4-93). The maximal number of cases occurred between 40-49 and 50-59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin. CONCLUSIONS: Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature. Taking account of the limits of this study in the FPVD (under-reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations. PMID- 21557760 TI - Potentially inappropriate medications in geriatric outpatients with polypharmacy: application of six sets of published explicit criteria. AB - AIM: Our aim was to compare the practicability of six different potentially inappropriate medication (PIM) criteria in geriatric outpatients with polypharmacy. METHODS: We analysed baseline data from the Medication Safety Review Clinic in Taiwanese Elders (MSRC-Taiwan) study. The prevalence and correlates of PIMs were determined on the basis of criteria developed in the USA, Canada, France, Norway, Ireland and Thailand. The percentage of PIMs considered as drug-related problems and the problem-solving rate are reported. RESULTS: In the 193 participants, the prevalence of PIM varied from 24 to 73%. Application of the criteria revealed that a high number of chronic medications was a common risk factor for having at least one PIM. Of the 1713 medications reviewed, 5.6-14.8% were considered PIMs. Only 30-40% of the identified PIMs were reported as drug related problems by the MSRC team experts. Criteria with a higher number of statements and a higher percentage of local market/institution drug availability tended to detect more PIMs. CONCLUSIONS: The prevalence of PIM varied significantly when different criteria were applied. Caution should be exercised in applying PIM criteria developed in other regions when medication availability in the local market is limited. PMID- 21557761 TI - The association between renal function and tooth loss in Japanese community dwelling postmenopausal women. AB - OBJECTIVES: This study examined whether low renal function is associated with the number of remaining teeth among community-dwelling elderly Japanese. BACKGROUND DATA: Many elderly individuals display both low renal function and tooth loss. MATERIALS AND METHODS: Subjects comprised 405 randomly selected women (55-74 years old). Serum cystatin C level was used to assess renal dysfunction. Multiple linear regression analysis was used to evaluate the relationship between number of remaining teeth and serum cystatin C level, with number of remaining teeth as the dependent variable. Six variables were selected as independent variables in the final model: serum cystatin C; age; mean clinical attachment level; serum cross-linked N-telopeptide of type I collagen level; body mass index and smoking habits. RESULTS: Multiple linear regression analysis revealed a significant relationship between number of remaining teeth and serum cystatin C level. The beta value for serum cystatin C level for the number of remaining teeth was -0.11 (p = 0.018). CONCLUSION: This study indicates a relationship between serum cystatin C level and number of remaining teeth, suggesting that low renal function could be associated with tooth loss. PMID- 21557762 TI - A cross-sectional study of oral health and oral health-related quality of life among frail elderly persons on admission to a special oral health care programme in Copenhagen City, Denmark. AB - AIM: To describe the oral health and the oral-health-related quality of life (OHRQoL) of citizens in Copenhagen City on admission to a specific oral health care programme for disabled elderly persons. Further, to analyse how various factors influence the oral health and the OHRQoL among these patients. METHODS: A cross-sectional study of 189 persons (average 85 years) consecutively admitted to a special oral health-care programme. Clinical data and data from interviews comprising social factors, life-style, dental visit habits, oral hygiene practices and self-perceived oral health were collected. A modified index on perceived dysfunction, discomfort and disability due to oral disorders was used. RESULTS: Sixty-eight per cent had natural teeth, among those 57% had decayed teeth and two out of three wore dentures. Smoking habits influence the number of teeth present and the OHRQoL (p < 0.05) of the patients. Edentulousness, decayed teeth, and presence of dentures did not seem to cause OHRQoL problems, while higher OHRQoL scores (more problems) were reported by those with 1-9 teeth and tooth mobility. CONCLUSION: OHRQoL of these patients can be increased by removal of loose teeth and provision of dentures to those with very few teeth rather than focus on traditional caries treatment. PMID- 21557763 TI - Resonance frequency analysis of overdenture retainer implants with immediate loading. AB - OBJECTIVE: To evaluate 16 patients of both sexes with lower overdenture and upper complete dentures, by analysing the resonance frequency of the initial and late stability of implants used to retain the overdenture under immediate loading. BACKGROUND: Oral rehabilitation treatment with complete dentures using implants has been increasingly more common among the specialists in the oral rehabilitation area. This is an alternative for obtaining retention and stability in treatments involving conventional complete dentures, where two implants are enough to retain the overdenture satisfactorily. MATERIALS AND METHODS: The OsstellTM Mentor device was used for the analysis in the initial period (primary stability), 3 and 15 months after the installation of the lower overdenture (secondary stability). The statistical analysis was performed with the repeated measures model (p < 0.01). RESULTS: The implant stability quotients were observed to increase after 15 months of the rehabilitating treatment. CONCLUSION: The use of overdentures over two lower implants should become the treatment of choice for individuals who have a fully edentulous mandible. PMID- 21557764 TI - Central nervous system processing of emotions in children with faecal incontinence. AB - AIM: Faecal incontinence (FI) is a common disorder involving both the enteric (ENS) and central nervous systems (CNS). The aim of the study is to analyze neurophysiologically the central processing of emotions in children with FI, healthy controls and children with Attention-deficit hyperactivity disorder (ADHD). METHODS: Fourteen children with FI and constipation, nine with non retentive FI, 15 controls and 13 children with ADHD were examined. The methods included a physical exam, sonography, Child Behavior Checklist, a psychiatric interview and intelligence test. Acoustic evoked potentials were recorded according to standardized methodology. For the event-related potentials, 80 neutral, 40 positive and 40 negative pictures from the International Affective Picture System (IAPS), and 40 pictures depicting faeces were presented. RESULTS: Children with FI had significantly more intense responses for most stimuli over the frontal, central and parietal regions compared to controls. Stool pictures did not evoke stronger responses than other stimuli. Children with constipation elicited stronger responses. Children with ADHD did not differ from controls. Acoustic evoked potentials were comparable in all groups. CONCLUSIONS: Children with FI have increased responses in the processing of emotions. These can be interpreted as a neurobiological vulnerability, possibly due to the association of the ENS and CNS. PMID- 21557765 TI - Paediatric functional abdominal pain: significance of child and maternal health. A prospective study. AB - AIM: First, to what extent do general paediatric outpatients with functional abdominal pain experience other somatic and mental health symptoms compared with children in a population-based sample? Second, to what extent are such symptoms in both patients and their mothers associated with persistent child abdominal pain and functional disability? METHODS: Ninety-four referred patients [mean age (SD) 11.1 (1.9) years, 62% girls] were assessed by questionnaires and a paediatric consultation at baseline and at follow-up after 6-9 months (94% follow up participation). At baseline, somatic and mental health symptoms in the patients were compared with a population-based sample of 14,000 school children. Outcome at follow-up was patient self-reported abdominal pain and disability. Prognostic factors explored included patient and maternal somatic and mental health symptoms. RESULTS: The patients experienced significantly more somatic [e.g. headache (OR: 9.2; 95% CI: 5.9-14.6)] and emotional symptoms than the school children. Patient's older age and peer problems at baseline were significantly associated with more abdominal pain at follow-up, whereas patient's older age, emotional symptoms, prosocial behaviour and maternal somatic symptoms were associated with disability. CONCLUSION: Our results highlight the importance of focusing wider than just the patient's symptoms of abdominal pain in clinical practice and research. PMID- 21557766 TI - Underexpressed microRNA-199b-5p targets hypoxia-inducible factor-1alpha in hepatocellular carcinoma and predicts prognosis of hepatocellular carcinoma patients. AB - BACKGROUND AND AIM: MicroRNAs are short noncoding RNA molecules that are responsible for the posttranscriptional regulation of target genes. The aim of this study was to determine whether microRNA-199b-5p (miR-199b) plays a role in the progression and prognosis of hepatocellular carcinoma (HCC), and to elucidate whether hypoxia-inducible factor-1alpha (Hif1alpha) is regulated by miR-199b. METHODS: In this study, 35 matched HCCs and cirrhosis tissues were assayed for miR-199b and Hif1alpha expression. To evaluate the role of miR-199b, we assessed cell proliferation rate and clonogenic survival of miR-199b- or negative control transfected cells by MTT and clone formation assay, respectively. In addition, the regulation of Hif1alpha by miR-199b was evaluated by Western blotting and luciferase assay. MiR-199b was downregulated in 77% of HCCs, whereas Hif1alpha protein was upregulated in 69% of cases. A significant inverse correlation between miR-199b and Hif1alpha was observed in HCCs. RESULTS: Patients with lower levels of miR-199b expression had poorer overall survival and progression-free survival rates, whereas patients with higher levels of miR-199b expression had better survival. Moreover, miR-199b could restrain cell growth and obviously enhance the radiosensitizing effect of HepG2 cells. MiR-199b and pGL3-Hif1alpha vector-transfected cells showed suppressed Hif1alpha protein expression and significant reduced luciferase activity. CONCLUSIONS: Underexpressed miR-199b, which may be via the upregulation of Hif1alpha in HCCs, is inversely correlated with survival and directly correlated with the malignant status of HCC patients. PMID- 21557767 TI - Endoscopic, clinicopathological features and prognosis of very young patients with gastric cancer. AB - BACKGROUND AND AIM: The number of clinical reports of very young (<35 years) patients with gastric cancer are limited. We aimed to investigate the endoscopic and clinicopathological features and long-term prognosis of this unique group of patients. METHODS: A prospective endoscopy database review of all consecutive very young patients with gastric cancer was performed. The gender, age, clinical features, endoscopic and pathologic findings, and long-term survival of these very young patients were analyzed and compared with those of elderly patients. RESULTS: A total of 210 patients were included with a median age of 31 year, 60.0% was female, and 34.3% presented with alarm features, 19.0% reported family history of gastric cancer. 58.1% of these cancers were located in gastric body, 33.8% were located in the antrum. 63.8% of these cancers were found to be diffuse type; 18.1% of patients underwent curative surgical treatment, and the 5-year survival rate was 42.1%. CONCLUSIONS: The study describes that very young patients with gastric cancer were mainly females, who were less likely to present with alarm features, but had a high frequency of family history of gastric cancer; and the majority of these cancers were located in gastric body, and they had similar long-term prognosis compared with elderly counterparts if curative surgical resection was performed. PMID- 21557768 TI - Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test. AB - BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 +/- 0.71 Delta0/00 per 100 mg caffeine) to controls (2.31 +/- 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 +/- 0.65, P = 0.005) and cirrhosis (1.00 +/- 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = 0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F >= 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition. PMID- 21557769 TI - Conflicting clinical environment about the management of antithrombotic agents during the periendoscopic period in Japan. AB - BACKGROUND AND AIMS: Although there are guidelines for the management of antithrombotic agents during the periendoscopic period, gaps between various guidelines create a confusing situation in daily clinical practice. The purpose of this study was to examine the current management of antithrombotic agents during the periendoscopic period in Japan. METHODS: This is a prospective cohort study in 12 high-volume endoscopy centers in Japan. A total of 970 outpatients receiving antithrombotic agents underwent endoscopies (705 esophagogastroduodenoscopies and 265 colonoscopies) with or without invasive procedures. Main outcome measures are adverse events in these patients. RESULTS: Need for cessation of antithrombotics before endoscopy was mostly determined by non-gastroenterologists (51%) who are unfamiliar with the Japan Gastroenterological Endoscopy Society (JGES) guideline, although cessation periods after endoscopy for most patients were determined by endoscopists (78%). Consequently, most patients underwent endoscopy without cessation (25%) or after a cessation period of 6-7 days (33%), indicating low permeation of the JGES guideline in Japan. Among 970 patients, two patients experienced major complications that may be related to thromboembolic events or gastrointestinal bleeding (95% confidence interval [CI]: 0-0.7%). One of these patients died due to sudden onset ventricular tachycardia. Invasive procedures, including 40 biopsies and two mucosal resections, were performed in 42 patients without cessation of antithrombotics, and no patients experienced major complications (95% CI: 0-8.4%). CONCLUSIONS: This study revealed a conflicting clinical environment due to absence of a unified guideline in Japan. Further accumulation of data is mandatory to establish a unified guideline based upon solid evidence. PMID- 21557770 TI - Biology of hepatic cancer stem cells. AB - Hepatocellular carcinoma (HCC) is the most commonly diagnosed malignancy of the liver and is the third most frequent cause of cancer death worldwide. Although advances in HCC detection and treatment have increased the likelihood of a cure at early stages of the disease, HCC remains largely incurable because of late presentation and tumor recurrence. Only 25% of HCC patients are deemed suitable for curative treatment, with the overall survival at just a few months for inoperable patients. Additionally, this disease is particularly difficult to treat because of the high recurrence rate, its chemotherapy-resistant nature and the premalignant nature of surrounding cirrhotic liver disease. In the past few years, compelling evidence has emerged in support of the hierarchic cancer stem cell (CSC)/tumor-initiating cell (T-IC) model for solid tumors, including HCC. Understanding the characteristics and function of CSCs in the liver has also shed light on HCC management and treatment, including the implications for prognosis, prediction and treatment resistance. In this review, a detailed summary of the recent progress in liver CSC research with regard to identification, regulation and therapeutic implications will be discussed. PMID- 21557771 TI - Endosonographic findings of gastric ectopic pancreas: a single center experience. AB - BACKGROUND AND AIM: Ectopic pancreas is a common submucosal lesion in the stomach, but its histological diagnosis is usually difficult when tissue samples are obtained with a conventional biopsy forceps. The aim of this study was to describe the endosonographic features of gastric ectopic pancreas. METHODS: We retrospectively analyzed a database of all patients who underwent endoscopic ultrasonography (EUS) at Pusan National University Hospital from July 2006 to August 2010. A total of 26 patients with histologically confirmed ectopic pancreas were included in the study. The EUS features of their lesions were analyzed. RESULTS: Ten lesions were located in the antrum, and 16 lesions were located in the body. Nine lesions (34.6%) showed an umbilication or central dimpling on the surface, and a mural growth pattern was most commonly observed (61.5%). Twenty-four lesions (92.3%) showed hypoechoic echogenicity, and 13 lesions (50.0%) were heterogeneous. The borders were indistinct in 16 lesions (61.5%) and lobulated margins were observed in 16 lesions (61.5%). Anechoic cystic or tubular structures appeared in 17 lesions (65.4%), and 20 lesions (76.9%) involved two or more sonographic layers. CONCLUSIONS: The characteristic EUS features of ectopic pancreas are indistinct borders, lobulated margins, presence of anechoic duct-like structures, a mural growth pattern, and localization within two or more layers. These EUS features are potentially useful for differentiating ectopic pancreas from other mesenchymal tumors in the stomach. PMID- 21557772 TI - Increased CD4(+) CD69(+) CD25(-) T cells in patients with hepatocellular carcinoma are associated with tumor progression. AB - BACKGROUND AND AIM: A new subset of Treg cells, CD4(+) CD69(+) CD25(-) T cells, has been identified in mice. Herein, we aimed to identify this subset of T cells and to evaluate its function in patients with hepatocellular carcinoma (HCC). METHODS: We detected CD4(+) CD69(+) CD25(-) T cells and its expression of CCR6 and transforming growth factor-beta1 (TGF-beta1) in peripheral blood of 91 HCC patients, 38 chronic hepatitis patients and 34 healthy donors by flow cytometry. CD4(+) CD69(+) CD25(-) T cells in HCC tissues were also analyzed. RESULTS: CD4(+) CD69(+) CD25(-) T cells were significantly increased in peripheral blood of HCC patients compared with healthy persons and chronic hepatitis patients (8.74% +/- 0.42% vs 4.55% +/- 0.33% and 5.15% +/- 0.36%, P < 0.0001). The percentage of peripheral CD4(+) CD69(+) CD25(-) T cells was significantly higher in HCC patients with Tumor Node Metastasis (TNM) stage III plus IV (P < 0.05). Patients with large tumor size and tumor vascular invasion were inclined to obtain high percentage of CD4(+) CD69(+) CD25(-) T cells (P < 0.05). The frequency of membrane-bound TGF-beta1 positive cells in CD4(+) CD69(+) CD25(-) T cells from HCC patients was higher than that from the other two groups (P < 0.0001). A considerable proportion of CD4(+) CD69(+) CD25(-) T cells were present in HCC tissues, which has significant correlation with tumor size and TNM stage. Few CD4(+) CD69(+) CD25(-) T cells express CCR6 both in peripheral blood and tumor tissues from HCC patients. CONCLUSIONS: Increased CD4(+) CD69(+) CD25(-) T cells in HCC patients are significantly correlated with tumor size, vascular invasion and TNM stage. Thus, increased CD4(+) CD69(+) CD25(-) T cells exert a critical role in HCC progression and might be a clinically aggressive phenotype of HCC. PMID- 21557773 TI - Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir. AB - BACKGROUND AND AIM: We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg-interferon and adefovir for 48 weeks. METHODS: Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment. RESULTS: Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA < 2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow-up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg <= 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%. CONCLUSIONS: At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of < 7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR. PMID- 21557774 TI - Pregnancy and risk of acute myeloid leukaemia--a case-control study. AB - Although maternal haematopoiesis is characterised by rapid proliferation and immunological adjustment, leukaemia seldom occurs in pregnant women. In this case control study, we investigated pregnancy and risk of acute myeloid leukaemia (AML). A total of 785 women with AML diagnosed in ages 15-50 were compared with 1576 age- and sex-matched controls. At the time of diagnosis, 13 cases and 53 controls were pregnant (1.3% and 3.4%, respectively), resulting in a significantly reduced odds ratio of 0.44 (95% confidence interval 0.22-0.85). Odds ratios of AML during the years following childbirth were close to unity. The results suggest that pregnancy conveys a strong short-term protection against AML. PMID- 21557775 TI - Lenalidomide is effective for extramedullary disease in relapsed or refractory multiple myeloma. PMID- 21557776 TI - The utility of positron emission tomography/computed tomography in the staging of extranodal natural killer/T-cell lymphoma. AB - Natural killer (NK)/T-cell lymphoma cases are rarely discovered using positron emission tomography/computed tomography (PET/CT). We compared the utility of PET/CT and that of conventional methods (CMs; CT with IV contrast, biopsies from primary sites, and bone marrow examinations) in the staging of extranodal NK/T cell lymphoma. Nineteen untreated patients with extranodal NK/T-cell lymphoma at three institutions were analyzed. PET/CT and CMs were applied for initial workups following diagnosis. PET/CT and CMs were compared and evaluated for their ability to detect tumor lesions and their influence on the staging and treatment strategies. In total, 116 lesions were detected by CM and PET/CT. Using PET/CT, 108 lesions (93%) were discovered. The number of nodal lesions was 28: all were positive by PET/CT and 26 (93%) by CMs. The number of extranodal lesions was 89: 84 (94%) and 54 (61%) lesions were positive by PET/CT and CMs, respectively. PET/CT was superior to CMs in detecting cutaneous lesions [31/31 lesions (100%) vs. 20/31 lesions (65%), respectively; P=0.042]. Bone marrow involvement was confirmed pathologically in only seven patients; four cases (57%) were positive by PET/CT. Using CMs, ten patients (53%) were stages I-II and nine (47%) were stages III-IV. Using PET/CT, eight patients (42%) were in stages I-II and 11 (58%) were in stages III-IV. PET/CT findings altered the stage and treatment strategy in two cases (11%). Our study demonstrated that PET/CT is a useful tool for detecting extranodal lesions in NK/T-cell lymphoma, particularly cutaneous lesions. PET/CT may therefore influence future staging and treatment strategies. PMID- 21557777 TI - Pain evaluation and control during and following the treatment of hypertrophic scars and keloids by contact and intralesional cryosurgery--a preliminary study. AB - BACKGROUND: Intralesional cryosurgery effectively treats hypertrophic scars and keloids (HSK), but pain experienced by the patient during treatment can limit the application of cryosurgery. OBJECTIVES: To characterize the pain response during cryosurgical treatment of HSK, and to evaluate the pain experienced during contact and intralesional cryosurgery that employs a pain-control protocol. METHODS: Twenty-nine patients (17 women, 12 men) aged 17 years and older (mean ages 31.9+/-12.5 and 38.9+/-18.6 years, respectively, P=0.24), who were treated for a total of 36 HSKs by intralesional (n=20; 22 cryotreatments) or contact (n=9; 14 cryotreatments) cryosurgery were evaluated. The pain-control protocol involved oral pain-relief tablets (Dipyrone) and translesional local anaesthesia with Bupivacaine hydrochloride 0.5%. Pain evaluation according to the Visual Analogue Scale (VAS) (0-10 cm) was compared between the two groups at three time points: during cryosurgery, immediately after it, and 4 h later. Scores <=3 cm were considered to define the 'zone of analgesic success'. These results were compared with control data (contact cryosurgery without a pain-control protocol; n=56). RESULTS: Pain in the intralesional group was significantly lower than that in the contact group during and immediately after cryotreatment. During: mean VAS=1.68+/-2.21 vs. 5.07+/-4.01 cm; median VAS=0.5 vs. 5.5 cm, respectively; P<0.0001. Immediately after: mean VAS=1.22+/-1.77 vs. 5.38+/-3.81 cm; median VAS=0 vs. 6.0 cm, respectively; P=0.001. The control group had more pain during treatment (mean VAS=5.34+/-2.31, median=6.0) and 4 h later (mean=3.79+/-2.35, median=4.0) than the intralesional group (P<0.0001 and P=0.988, respectively). The pain level in the control group during the cryotreatment did not differ from that in the contact group (P=0.988). In the intralesional, contact and control groups analgesic success (VAS <=3 cm) was achieved in 77.3%, 35.7% and 33.9%, respectively, of cases (P=0.002) during cryotreatment, and in 54.5%, 42.9% and 33.9%, respectively, of cases 4 h after treatment (P=0.24). CONCLUSIONS: The pain control protocol significantly reduced pain severity to tolerable levels (VAS <=3 cm) during and following intralesional and contact cryosurgery. Intralesional cryosurgery caused the least pain during and immediately after treatment. PMID- 21557778 TI - Patient satisfaction with injection devices: a randomized controlled study comparing two different etanercept delivery systems in moderate to severe psoriasis. AB - BACKGROUND: There is limited information regarding the acceptability of injection devices for biological agents. OBJECTIVES: The primary objective of the study was to investigate patients' perceptions on the acceptability of two devices delivering etanercept. The secondary objectives of the study were to explore whether patients' attributes are associated with preferences. METHODS: This was a multicentre, open-label, randomized, parallel-design study. Adult patients with psoriasis were randomized to receive etanercept 50 mg twice-weekly subcutaneously for 12 weeks, either as a pre-filled syringe or as a pre-filled pen. The primary outcome was the patient satisfaction at week 12 with the injection device, as measured on a 0-10-point Likert scale. The study was powered to demonstrate non inferiority of a pen over a syringe for the primary endpoint. RESULTS: A total of 421 patients were randomized. Mean patient satisfaction at week 12 was 8.9 (+/ 1.9) points in the pen group and 7.6 (+/-2.6) points in the syringe group. There was a statistically significant advantage for the pen compared with the syringe. Multiple correspondence analysis showed that very satisfied patients were the oldest and had had psoriasis for a longer duration, while less satisfied patients were the most anxious and depressed. PASI 75 response was achieved by 61% of patients in the pen group and 57% in the syringe group at week 12. CONCLUSIONS: This study showed higher patient satisfaction when injecting etanercept with a pen compared with a syringe. Factors associated with lower satisfaction are younger age, anxiety and depression. PMID- 21557779 TI - Characteristic immune, apoptosis and inflammatory gene profiles associated with intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies. AB - Small bowel transplantation (SBT) is becoming a preferred treatment for patients with irreversible intestinal failure. Despite continuous improvement of immunosuppression, SBT is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need for reliable detection markers and novel immunosuppressive strategies that can achieve better control of ACR. We hypothesized that particular transcriptomes provide critical regulation of the intragraft immune response. The aim of our study was to detect potential molecular biomarkers for identifying ACR in minute mucosal biopsies. We examined 30 intestinal mucosal biopsies (AR/NR; 17/13) obtained from recipients after SBT or multivisceral transplantation. We utilized TaqMan(r) Gene Signature Arrays (immune, inflammation and apoptosis) and investigated the expression of 280 genes. As one of our validations, we performed immunohistochemistry for selected targets. We detected 252 mRNAs in total, 92 of which were found with significantly different expression levels between the AR and NR groups. Immunohistochemistry showed significantly increased staining for IL1R2, ICAM1, GZMB, and CCL3 (P < 0.05) during ACR. For the first time, we characterize the potential molecular changes that are associated with modulation of histological appearances of intestinal ACR. These differences in transcriptome patterns can be used to identify robust biomarkers and potential novel therapeutic targets for immunosuppressive agents. PMID- 21557780 TI - Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. AB - With improved outcome of allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies, long-term complications gain greater importance. Skeletal complications such as osteoporosis or avascular necrosis (AVN) occur frequently in allogeneic recipients with a cumulative incidence of diminished bone mineral density of 24-50% between 2 and 12 months after allo-SCT and a cumulative incidence of AVN in as many as 19% of patients 3 years after allo-SCT. Here, we present a review as part of the German, Austrian, and Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease, held 2009 in Regensburg. The Consensus Conference aimed to achieve a consensus on the current evidence of diagnosis, prevention, and therapeutic options of late complications after allo-SCT summarizing and discussing the literature on these topics. In this report, we provide recommendations for metabolic bone diseases agreed upon by the working party. This includes guidelines for diagnosis, prevention, and therapeutic options in patients with low bone mass or AVN. PMID- 21557781 TI - Measuring population differentiation using GST or D? A simulation study with microsatellite DNA markers under a finite island model and nonequilibrium conditions. AB - The genetic differentiation of populations is a key parameter in population genetic investigations. Wright's F(ST) (and its relatives such as G(ST) ) has been a standard measure of differentiation. However, the deficiencies of these indexes have been increasingly realized in recent years, leading to some new measures being proposed, such as Jost's D (Molecular Ecology, 2008; 17, 4015). The existence of these new metrics has stimulated considerable debate and induced some confusion on which statistics should be used for estimating population differentiation. Here, we report a simulation study with neutral microsatellite DNA loci under a finite island model to compare the performance of G(ST) and D, particularly under nonequilibrium conditions. Our results suggest that there exist fundamental differences between the two statistics, and neither G(ST) nor D operates satisfactorily in all situations for quantifying differentiation. D is very sensitive to mutation models but G(ST) noticeably less so, which limits D's utility in population parameter estimation and comparisons across genetic markers. Also, the initial heterozygosity of the starting populations has some important effects on both the individual behaviours of G(ST) and D and their relative behaviours in early differentiation, and this effect is much greater for D than G(ST) . In the early stages of differentiation, when initial heterozygosity is relatively low (<0.5, if the number of subpopulations is large), G(ST) increases faster than D; the opposite is true when initial heterozygosity is high. Therefore, the state of the ancestral population appears to have some lasting impacts on population differentiation. In general, G(ST) can measure differentiation fairly well when heterozygosity is low whatever the causes; however, when heterozygosity is high (e.g. as a result of either high mutation rate or high initial heterozygosity) and gene flow is moderate to strong, G(ST) fails to measure differentiation. Interestingly, when population size is not very small (e.g. N >= 1000), G(ST) measures differentiation quite linearly with time over a long duration when gene flow is absent or very weak even if mutation rate is not low (e.g. MU = 0.001). In contrast, D, as a differentiation measure, performs rather robustly in all these situations. In practice, both indexes should be calculated and the relative levels of heterozygosities (especially H(S) ) and gene flow taken into account. We suggest that a comparison of the two indexes can generate useful insights into the evolutionary processes that influence population differentiation. PMID- 21557783 TI - Species delimitation in fungal endophyte diversity studies and its implications in ecological and biogeographic inferences. AB - The estimation of species diversity in fungal endophyte communities is based either on species counts or on the assignment of operational taxonomic units (OTUs). Consequently, the application of different species recognition criteria affects not only diversity estimates but also the ecological hypotheses that arise from those observations. The main objective of the study was to examine how the choice and number of genetic markers and species delimitation criteria influence biodiversity estimates. Here, we compare approaches to defining species boundaries in three dominant species complexes of tropical endophytes, specially Colletotrichum gloeosporioides agg., Pestalotiopsis microspora agg. and Trichoderma harzianum agg., from two Amazonian trees: Hevea brasiliensis and H. guianensis. Molecular tools were used to describe and compare the diversity of the different assemblages. Multilocus phylogenetic analyses [gpd, internal transcribed spacer (ITS) and tef1] and modern techniques for phylogenetic species delimitation were overlaid with ecological data to recognize putative species or OTUs. The results demonstrate that ITS alone generally underestimates the number of species predicted by other nuclear loci. These results question the use of ITS and arbitrary divergence thresholds for species delimitation. PMID- 21557784 TI - Characterization of a genomic divergence island between black-and-yellow and gopher Sebastes rockfishes. AB - Islands of high genomic divergence that contain genes of evolutionary significance may form between diverging species. The gopher rockfish, Sebastes carnatus, and black-and-yellow rockfish, S. chrysomelas, are sympatrically distributed temperate marine species inhabiting rocky reefs and kelp forests on the west coast of the United States. Prior studies documented low levels of genetic divergence between the two species, except at a single microsatellite locus that displayed high divergence, Sra.7-2. To better characterize genome wide divergence, we scored 25 additional microsatellite loci. Mean neutral divergence between species (F(ST) = 0.01) changed little from prior estimates. Sra.7-2 continued to be an extreme divergence outlier. Five novel microsatellites within +/- 15 kb of Sra.7-2 were characterized. High divergence, consistently low diversity in S. chrysomelas, and linkage disequilibrium were detected at these loci, suggesting the influence of recent selection. However, coalescent modelling of divergence at neutral and Sra.7-2 regions showed that initial divergence at Sra.7-2 was ancient, likely predating divergence at neutral regions. It is therefore unlikely that Sra.7-2 divergence represents solely recent ecological divergence within one species and may represent the action of recurrent selection. Introgressive gene flow (2N(E) m) was much higher (>>1) at neutral than Sra.7-2 regions (<<1) despite evidence that two S. carnatus individuals have recently mixed ancestry at the Sra.7-2 region. The Sra.7-2 genomic region is likely one of several regions containing genes involved in initiating and maintaining species integrity. Completion of the final stages of speciation appears to be a slow and ongoing process for these species. PMID- 21557785 TI - Severity of hyperacusis predicts individual differences in speech perception in Williams Syndrome. AB - BACKGROUND: Williams Syndrome (WS) is a neurodevelopmental disorder of genetic origin, characterised by relative proficiency in language in the face of serious impairment in several other domains. Individuals with WS display an unusual sensitivity to noise, known as hyperacusis. METHODS: In this study, we examined the extent to which hyperacusis interferes with the perception of speech in children and adults with WS. Participants were required to discriminate words which differed in one consonant of a cluster when these contrasts were embedded in a background of noise. RESULTS: Although the introduction of noise interfered with performance on a consonant cluster discrimination task equally in the WS and control groups, the severity of hyperacusis significantly predicted individual variability in speech perception within the WS group. CONCLUSIONS: These results suggest that alterations in sensitivity to input mediate atypical pathways for language development in WS, where hyperacusis exerts an important influence together with other non-auditory factors. PMID- 21557782 TI - Gene genealogies reveal cryptic species and host preferences for the pine fungal pathogen Grosmannia clavigera. AB - Grosmannia clavigera is a fungal pathogen of pine forests in western North America and a symbiotic associate of two sister bark beetles: Dendroctonus ponderosae and D. jeffreyi. This fungus and its beetle associate D. ponderosae are expanding in large epidemics in western North America. Using the fungal genome sequence and gene annotations, we assessed whether fungal isolates from the two beetles inhabiting different species of pine in epidemic regions of western Canada and the USA, as well as in localized populations outside of the current epidemic, represent different genetic lineages. We characterized nucleotide variations in 67 genomic regions and selected 15 for the phylogenetic analysis. Using concordance of gene genealogies and distinct ecological characteristics, we identified two sibling phylogenetic species: Gc and Gs. Where the closely related Pinus ponderosa and P. jeffreyi are infested by localized populations of their respective beetles, Gc is present. In contrast, Gs is an exclusive associate of D. ponderosae mainly present on its primary host-tree P. contorta; however, in the current epidemic areas, it is also found in other pine species. These results suggest that the host-tree species and the beetle population dynamics may be important factors associated with the genetic divergence and diversity of fungal partners in the beetle-tree ecosystems. Gc represents the original G. clavigera holotype, and Gs should be described as a new species. PMID- 21557786 TI - Association of a genetic variant of BTN2A1 with chronic kidney disease in Japanese individuals. AB - AIM: Although recent genetic studies suggested that several genetic variants increase the risk for chronic kidney disease (CKD), the genes that underlie genetic susceptibility to this condition remain to be identified definitively. We showed that the C->T polymorphism (rs6929846) of BTN2A1 and A->G polymorphism (rs2569512) of ILF3 were significantly associated with myocardial infarction in Japanese individuals by a genome-wide association study. The purpose of the present study was to examine a possible association of these polymorphisms (rs6929846, rs2569512) with CKD in Japanese individuals. METHODS: A total of 7542 Japanese individuals from two independent populations were examined: Subject panel A comprised 971 individuals with CKD (estimated glomerular filtration rate (eGFR) <60 mL/min 1.73 m(-2)) ) and 2269 controls (eGFR >=60 mL/min 1.73 m(-2) ); and subject panel B comprised 1318 individuals with CKD and 2984 controls. RESULTS: The chi(2) test revealed that rs6929846 of BTN2A1, but not rs2569512 of ILF3, was significantly related to the prevalence of CKD both in subject panels A (P = 0.0383) and B (P = 0.0477). Multivariable logistic regression analysis with adjustment for covariates revealed that the C->T polymorphism (rs6929846) of BTN2A1 was significantly associated with the prevalence of CKD in subject panels A (P = 0.0422; recessive model; odds ratio, 2.36) and B (P = 0.0386; dominant model; odds ratio, 1.21) with the T allele representing a risk for this condition. CONCLUSION: Our results suggest that BTN2A1 may be a susceptibility gene for CKD in Japanese individuals. PMID- 21557787 TI - Exercise training in haemodialysis patients: a systematic review and meta analysis. AB - BACKGROUND: We quantified baseline and observed change in peak VO(2) , quality of life, cardiac function, strength and energy intake following exercise training in haemodialysis patients and optimal exercise delivery for producing greatest adherence, safety and patient improvements. METHODS: A systematic literature search was completed in August 2010 to identify randomized, controlled trials of exercise training studies in haemodialysis patients. A subsequent meta-analysis was conducted and the search repeated in December 2010. RESULTS: Fifteen studies, yielding 565 patients were included. Baseline, peak VO(2) values were 70% of age predicted values, exercise intervention patients improved post-training peak VO(2) to 88% predicted. Exercise training produced mean 26 +/- 12% improvements in eight studies that reported peak VO(2) , mean difference 5.22 mL O(2) /kg per min (95% confidence interval 3.86, 6.59, P < 0.00001). Equivocal results for change in short-form 36 health questionnaire scores were reported post-training. Heart rate variability was improved after exercise training of normal to normal interval, mean difference 1634 milliseconds (95% confidence interval 8.3, 24.3, P < 0.0001). Significant improvements in lean body mass, quadriceps muscle area, knee extension, hip abduction and flexion strength were also reported (all P < 0.0001). Exercise training appears safe, with no deaths directly associated with exercise in 28 400 patient-hours and no differences in withdrawal rates between exercise and control participants, P = 0.98. Exercise training for 6 months or more conveyed larger improvements in peak VO(2) than shorter programmes. Data indicate about 25% of patients were excluded from exercise training studies for medical reasons. CONCLUSION: Exercise training is safe and imparts large improvements in peak VO(2) , and heart rate variability. PMID- 21557788 TI - Reduction of natural killer and natural killer T cells is not protective in cisplatin-induced acute renal failure in mice. AB - AIMS: A recent report showed that fractalkine (CX3CL1), which functions as both a potent chemoattractant and adhesion molecule for monocytes and natural killer (NK) cells was significantly increased in cisplatin-induced acute renal failure (CisARF) in mice. Therefore, we developed the hypothesis that increased CX3CL1 expression in CisARF initiates NK cell infiltration in the kidney. The aim of the present study was to determine the role of NK cells in CisARF in mice. METHODS: Time course of pan-NK positive cells in CisARF was investigated by using immunohistochemistry (IHC) for CD49b. Pan-NK positive cells were reduced by using anti-NK1.1 mAb. The model of pan-NK positive cells reduction was confirmed by flow cytometry of the spleen and IHC of the kidney. The expression of granzyme A and caspase-1 was examined, and the activity of caspase-1 was also determined. We performed a study on whether there was significant protection of renal function after reduction of pan-NK positive cells. RESULTS: (i) Infiltration of pan-NK positive cells was prominent on day 3 after cisplatin administration. (ii) granzyme A expression was significantly increased in CisARF and CisARF+NK1.1 Ab compared to vehicle. (iii) Caspase-1 expression and activity was significantly increased in CisARF mice compared to vehicle and CisARF+NK1.1 Ab. (iv) Reduction of pan-NK positive cells was not protective in cisplatin-induced acute renal failure in mice. CONCLUSIONS: Although infiltration of pan-NK cells was significantly increased in CisARF, reduction of infiltration of pan-NK cells into the kidney was not protective against CisARF in mice. PMID- 21557789 TI - Contemporary management of atherosclerotic renovascular disease: before and after ASTRAL. AB - Atheromatous renovascular disease is an increasingly common diagnosis in our ageing population. Although there is a wide spread of experience in its treatment, the evidence base is heterogeneous and inconclusive. The Angioplasty and Stenting for Renal Artery Lesions trial has provided some, but not all, answers regarding the place of renal revascularization therapy and has also raised more questions and generated further debate. We present a brief review of the significance of atheromatous renovascular disease, discussion of historical treatments, a short analysis of Angioplasty and Stenting for Renal Artery Lesions, and an exploration of where future research lies. PMID- 21557790 TI - Efficacy of the glucagon-like peptide-1 agonist exenatide in the treatment of short bowel syndrome. AB - BACKGROUND: Short bowel syndrome (SBS) is a serious clinical disorder characterized by diarrhea and nutritional deprivation. Glucagon-like peptide-1 (GLP-1) is a key hormone, produced by L-cells in the ileum, that regulates proximal gut transit. When extensive ileal resection occurs, as in SBS, GLP-1 levels may be deficient. In this study, we test whether the use of GLP-1 agonist exenatide can improve the nutritional state and intestinal symptoms of patients with SBS. METHODS: Five consecutive patients with SBS based on <=90 cm of small bowel and clinical evidence of nutritional deprivation were selected. Baseline SBS symptoms, demographic and laboratory data were obtained. Antroduodenal manometry was performed on each subject. Each patient was then started on exenatide and over the following month, the baseline parameters were repeated. KEY RESULTS: The subjects consisted of four males and one female, aged 46-69 years. At baseline, all had severe diarrhea that ranged from 6 to 15 bowel movements per day, often occurring within minutes of eating. After exenatide, all five patients had immediate improvement in bowel frequency and form; bowel movements were no longer meal-related. Total parenteral nutrition was stopped successfully in three patients. Antroduodenal manometry revealed continuous low amplitude gastric contractions during fasting which completely normalized with exenatide. CONCLUSIONS & INFERENCES: Exenatide is a novel and safe treatment option for SBS. It produced substantial improvement in the bowel habits, nutritional status and quality of life of SBS patients. Successful treatment with exenatide may significantly reduce the need for parenteral nutrition and small bowel transplant. PMID- 21557791 TI - Valproate versus diazepam for generalized convulsive status epilepticus: a pilot study. AB - BACKGROUND AND PURPOSE: Evidence-based data to guide the management of status epilepticus (SE) after failure of primary treatment are still scarce and the alternate needs to be found when phenytoin (PHT) is not available or contraindicated. Comparison of intravenous (IV) valproate (VPA) and diazepam (DZP) infusion has not been conducted in adults with SE. This prospective randomized controlled trial is thus designed to evaluate the relative efficacy and safety of IV VPA and continuous DZP infusion as second-line anticonvulsants. METHODS: After failure of first-line anticonvulsants treatment, patients with generalized convulsive status epilepticus (GCSE) were randomized to receive either IV VPA or continuous DZP infusion. Primary outcome was the proportion of patients with effective control. Side effects were also evaluated. RESULTS: There were 66 cases enrolled, with the mean age of 41 +/- 21 years. Seizure was controlled in 56% (20/36) of the DZP group and 50% (15/30) of the VPA group (P = 0.652). No patient in the VPA group developed respiratory depression, hypotension, or hepatic dysfunction, whereas in the DZP group, 5.5% required ventilation and 5.5% developed hypotension. Time (hour) for regaining consciousness after control was near-significantly longer in the DZP group [13(3.15-21.5)] than in the VPA group [3(0.75-11)] (P = 0.057). Virus encephalitis and long duration of GCSE were independent risk factors of drug resistance. CONCLUSIONS: Both IV VPA and continuous DZP infusion are effective second-line anticonvulsants for GCSE. IV VPA was well tolerated and free of respiratory depression and hypotension, which may develop in the DZP group. Outcome parameters were not significantly different between groups. PMID- 21557793 TI - Stroke: a realistic approach to a growing problem in sub-Saharan Africa is urgently needed. AB - Stroke is an increasing problem in sub-Saharan Africa, even in children. High rates of hypertension, diabetes, alcohol abuse, smoking, insufficient fruit and vegetable consumption, sickle cell disease, HIV infection, antiretroviral use and race are likely contributing factors. Although often considered as related to increasing wealth, stroke is more strongly related to poverty, and in turn increases it. Case-fatality rates are high and premature death and years of life lost are a major problem. We propose an approach to stroke prevention and treatment that takes into account the real situation on the ground and can be applied in sub-Saharan Africa, an area where stroke units are largely not feasible and many patients do not reach hospitals. Involvement of community and faith-based organisations, use of simple diagnostic tests, emphasis on clinical examination to differentiate between haemorrhagic and ischaemic stroke, prompt initiation of aspirin therapy and training of community nurses on essential management of stroke should be urgently implemented. PMID- 21557795 TI - Metastatic potential of a renal mass according to original tumour size at presentation. AB - OBJECTIVE: To determine the metastatic potential of renal masses based on original tumour size. MATERIALS AND METHODS: We identified 2651 patients who had undergone surgical resection for a unilateral, sporadic renal tumour between 1990 and 2006. Associations of tumour size with synchronous metastasis at presentation [M1 renal cell carcinoma (RCC)] and development of metastases, death from RCC, and death from any cause after surgery were evaluated using logistic and Cox proportional hazards regression. RESULTS: Of the 2651 patients studied, 182 (6.9%) presented with M1 RCC. Tumour size was significantly greater in patients with M1 RCC than in patients with M0 RCC (a median size of 10 vs 4.5 cm; P < 0.001). Only 1 of the 629 patients (0.2%) with a tumour <3 cm had M1 RCC and that tumour was 2.5 cm. The risk of M1 RCC increased from 1.1% for patients with tumours 3-3.9 cm to 16.5% for patients with tumours >=7 cm. Of the 2124 patients with M0 RCC, 430 developed distant metastases at a median (range) of 1.4 (0.1 16.2) years after surgery. Only 9 of the 498 patients (1.8%) with a tumour <3 cm developed distant metastases after surgery. Each 1-cm increase in tumour size increased the risk of death from RCC by 20%[hazard ratio (HR) 1.20; 95% confidence interval (CI) 1.18-1.22; P < 0.001] and death from any cause by 10% (HR 1.10; 95% CI 1.09-1.12; P < 0.001). For the 1346 patients who were still alive at last follow-up, the median (range) duration of follow-up was 6.9 (0.1 19.7) years. CONCLUSIONS: Tumour size is significantly associated with metastases in patients with renal masses. Patients with tumours <3 cm have a low risk of synchronous metastatic disease. PMID- 21557796 TI - Results from an international multicentre double-blind randomized controlled trial on the perioperative efficacy and safety of bipolar vs monopolar transurethral resection of the prostate. AB - OBJECTIVE: To compare the perioperative efficacy and safety of bipolar (B-) and monopolar transurethral resection of the prostate (M-TURP) in an international multicentre double-blind randomized controlled trial using the bipolar system AUTOCON((r)) II 400 ESU for the first time. PATIENTS AND METHODS: From July 2006 to June 2009, consecutive transurethral resection of the prostate (TURP) candidates with benign prostatic obstruction were prospectively recruited in four academic urological centres, randomized 1:1 into an M-TURP or B-TURP arm and followed up for 6 weeks after surgery. A total of 295 eligible patients were enrolled. Of these, 279 patients received treatment (M-TURP, n= 138; B-TURP, n= 141) and were analysed for immediate postoperative outcomes and perioperative safety. In all, 268 patients (M-TURP, n= 129; B-TURP, n= 139) were analysed for efficacy, which was quantified using changes in maximum urinary flow rate, postvoid residual urine volume and International Prostate Symptom Score at 6 weeks compared with baseline. Safety was estimated using sodium and haemoglobin level changes immediately after surgery and perioperative complication occurrence graded according to the modified Clavien classification system. Secondary outcomes included operation-resection time, resection rate, capsular perforation and catheterization time. RESULTS: No significant differences were detected between each study arm except that postoperative decreases in sodium levels favoured B-TURP (-0.8 vs -2.5 mmol/L, for B-TURP and M-TURP, respectively; P= 0.003). The lowest values were 131 mmol/L (B-TURP) and 106 mmol/L (M-TURP). Nine patients ranged between 125 and 130 mmol/L and the values for three patients were <125 mmol/L after M-TURP. The greatest decrease was 9 mmol/L after B-TURP (two patients). In nine patients (M-TURP) the decrease was between 9 and 34 mmol/L. These results were not translated into a significant difference in TUR-syndrome rates (1/138: 0.7% vs 0/141: 0.0%, for M-TURP and B-TURP, respectively; P= 0.495). CONCLUSIONS: In contrast to the previous available evidence, no clinical advantage for B-TURP was shown. Perioperative efficacy, safety and secondary outcomes were comparable between study arms. The potentially improved safety of B TURP that is attributed to the elimination of dilutional hyponatraemia risk, a risk still present with M-TURP, did not translate into a significant clinical benefit in experienced hands. PMID- 21557798 TI - Population dynamics in changing environments: the case of an eruptive forest pest species. AB - In recent decades we have seen rapid and co-occurring changes in landscape structure, species distributions and even climate as consequences of human activity. Such changes affect the dynamics of the interaction between major forest pest species, such as bark beetles (Coleoptera: Curculionidae, Scolytinae), and their host trees. Normally breeding mostly in broken or severely stressed spruce; at high population densities some bark beetle species can colonise and kill healthy trees on scales ranging from single trees in a stand to multi-annual landscape-wide outbreaks. In Eurasia, the largest outbreaks are caused by the spruce bark beetle, Ips typographus (Linnaeus), which is common and shares a wide distribution with its main host, Norway spruce (Picea abies Karst.). A large literature is now available, from which this review aims to synthesize research relevant for the population dynamics of I. typographus and co occurring species under changing conditions. We find that spruce bark beetle population dynamics tend to be metastable, but that mixed-species and age heterogeneous forests with good site-matching tend to be less susceptible to large-scale outbreaks. While large accumulations of logs should be removed and/or debarked before the next swarming period, intensive removal of all coarse dead wood may be counterproductive, as it reduces the diversity of predators that in some areas may play a role in keeping I. typographus populations below the outbreak threshold, and sanitary logging frequently causes edge effects and root damage, reducing the resistance of remaining trees. It is very hard to predict the outcome of interspecific interactions due to invading beetle species or I. typographus establishing outside its current range, as they can be of varying sign and strength and may fluctuate depending on environmental factors and population phase. Most research indicates that beetle outbreaks will increase in frequency and magnitude as temperature, wind speed and precipitation variability increases, and that mitigating forestry practices should be adopted as soon as possible considering the time lags involved. PMID- 21557799 TI - Obstetric outcome in women with epilepsy: a hospital-based, retrospective study. AB - OBJECTIVE: To report the complications during pregnancy and delivery in women with epilepsy, compared with a control group without epilepsy, with special focus on potential risk factors, such as epilepsy severity and dosage of antiepileptic drugs. DESIGN: Hospital-based retrospective study. SETTING: Data from pregnancy notification forms and hospital case records. POPULATION: Women with a past or present history of epilepsy (n = 205) delivered in Bergen, Norway, in the period 1999-2006, and a matched control group of women (n = 205) without epilepsy. METHODS: Data were compared and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by multiple logistic regression models. MAIN OUTCOME MEASURES: Pre-eclampsia (mild and severe), gestational hypertension, vaginal bleeding (early and late), caesarean section, vaginal operative delivery, postpartum haemorrhage and major malformations. RESULTS: Women with epilepsy using antiepileptic drugs had an increased risk of severe pre-eclampsia (OR, 5.0; 95% CI, 1.3-19.9), bleeding in early pregnancy (OR, 6.4; 95% CI, 2.7-15.2), induction (OR, 2.3; 95% CI, 1.2-4.3) and caesarean section (OR, 2.5; 95% CI, 1.4 4.7) adjusted for maternal age, parity, education, smoking, medical conditions and body mass index >=30 kg/m(2) . There was also an increased risk of malformations in the offspring (OR, 7.1; 95% CI, 1.4-36.6). Women without antiepileptic drug use had increased risks of forceps delivery and preterm birth. Active epilepsy (seizures during the last 5 years) versus nonactive epilepsy did not discriminate for any of these complications; 84.5% of women with epilepsy and antiepileptic drug use were using folate. CONCLUSION: Women with epilepsy using antiepileptic drugs had an increased risk of pregnancy and delivery complications, whereas women not using antiepileptic drugs had few complications. Seizures, high doses of antiepileptic drugs, obesity and lack of folate could not explain these increased risks. PMID- 21557800 TI - Stroke around the world. PMID- 21557801 TI - Blood pressure monitoring in the assessment of old patients with acute stroke. AB - BACKGROUND: Most patients have elevated blood pressure in the early phase of acute stroke that it often returns to normal within approximately seven-days. Most available data on the pattern of blood pressure in acute stroke are based on manual blood pressure measurements. AIMS: The aims of the present study were to assess with 24 h blood pressure monitoring the pattern of blood pressure in acute stroke, and the change in blood pressure during the first week of event in very old patients. METHODS: We studied 99 patients with acute stroke (58 males), mean age 83 +/- 6 years (range 70-97). Casual blood pressure and 24 h blood pressure monitoring were recorded within 24 h of admission, and then after six- to seven days. RESULTS: Casual blood pressure before beginning the 24 h blood pressure monitoring was 154 +/- 23/80 +/- 15 mmHg and the average 24 h blood pressure was 147 +/- 20/74 +/- 11 mmHg. One-week after stroke, casual blood pressure decreased by 15/7 mmHg, whereas 24 h blood pressure decreased by only 7/2 mmHg (P<0.01). Blood pressure decreased remarkably only in those with admission elevated systolic blood pressure. The change in 24 h systolic blood pressure after one week correlated to the 24 h admission systolic blood pressure (R=0.47; P<0.01). CONCLUSIONS: Casual blood pressure may overestimate blood pressure in stroke patients. Very old patients with stroke exhibit a mild increase in blood pressure during the acute phase, and blood pressure decreases spontaneously only in those with elevated blood pressure levels. Use of 24 h blood pressure monitoring may be helpful in elderly patients with acute stroke. PMID- 21557802 TI - Does inflammation predispose to recurrent vascular events after recent transient ischaemic attack and minor stroke? The North West of England transient ischaemic attack and minor stroke (NORTHSTAR) study. AB - BACKGROUND AND HYPOTHESIS: Inflammation is implicated in the pathogenesis and outcome of ischaemic injury. Poststroke inflammation is associated with outcome but it remains unclear whether such inflammation precedes or results from ischaemic injury. We hypothesised that inflammatory markers are associated with an increased risk of recurrent vascular events soon after transient ischaemic attack and minor stroke. METHODS: This was a multicentre, prospective, nested case-control study. Plasma concentrations of C-reactive protein, interleukin-6, interleukin-1-receptor antagonist and fibrinogen, leucocyte counts, erythrocyte sedimentation rate and inflammatory gene allele frequencies were analysed in 711 patients with recent transient ischaemic attack or minor stroke. Cases were defined by the incidence of one or more recurrent vascular events during the three-month follow-up. Association of inflammatory markers with case-status was determined using conditional logistic regression. RESULTS: Plasma concentrations of C-reactive protein, interleukin-1-receptor antagonist and interleukin-6 were not associated with case-status. In secondary analyses, only erythrocyte sedimentation rate was significantly associated with case-status (odds ratio 1.39, 95% confidence interval 1.03-1.85; P=0.03), but this effect did not persist after adjustment for smoking and past history of transient ischaemic attack or stroke. Single nucleotide polymorphisms in four inflammatory genes (interleukin 6, fibrinogen, P-selectin and vascular cell adhesion molecule-1) were nominally associated with case-status. CONCLUSIONS: Circulating inflammatory markers were not associated with recurrent vascular events. Nominally significant associations between genetic markers and case-status will require replication. These data provide little evidence for an inflammatory state predisposing to stroke and other vascular events in a susceptible population. PMID- 21557803 TI - Stroke epidemiology and one-month fatality among an urban population in Iran. AB - OBJECTIVE: Stroke is one of the most common causes of death and disability in Iran. This study evaluated stroke patient profiles with respect to rate, risk factors, and one-month fatality. MATERIAL AND METHOD: A cross-sectional, hospital based study on all stroke patients older than 45 years admitted to hospitals in the city of Qom throughout 2001. RESULTS: Four hundred and sixty patients older than 45 years were admitted as stroke. The annual stroke rate was estimated to 338/100 000 (95% confidence interval, 300-360) inhabitants older than 45 years. The annual rate of stroke was 384/100 000 (95% confidence interval, 381-386) when adjusted to the European population. Stroke subtypes were; ischaemic infarction 75%, intracranial haemorrhage 20.7%, subarachnoid haemorrhage 3%, and undetermined 1.3%. Main risk factors were hypertension in 74.6% and diabetes in 55.7%. Mortality rate was 24.6% within the first month. CONCLUSION: Stroke incidence was higher than in Western countries. Hypertension and diabetes mellitus were considerably more frequent in our studied stroke patients than in other developing countries. Our findings need to be addressed in future health education programmes in Iran identifying patients at risk and focusing on more aggressive prevention programmes to lower stroke incidence. PMID- 21557804 TI - Small intracerebral haemorrhages are associated with less haematoma expansion and better outcomes. AB - BACKGROUND AND PURPOSE: Haematoma expansion following intracerebral haemorrhage is a major determinant of early neurological worsening and poor clinical outcome. This has created interest in improving patient selection for therapies targeting haematoma expansion. Based on prior observations, we hypothesised that intracerebral haemorrhage volumes under 10 ml would be less likely to expand. We additionally sought to define a baseline haematoma volume below which significant growth was not observed. METHODS: Patient data were obtained from the Virtual International Stroke Trials Archive. Patients with intracerebral haemorrhage presented within six-hours of symptom onset had baseline clinical, radiological and laboratory data, and computed tomographic scan at 72 h and three-month follow up. The predictor of interest was baseline haematoma volume. Primary outcomes were absolute and relative haematoma growth. Secondary outcomes were early neurological worsening, good functional outcome, and 90-day mortality. RESULTS: The final dataset consisted of 496 patients. Baseline haematoma volumes under 10 ml were associated with much lower odds of absolute expansion compared to larger haematomas. Smaller haematomas were associated with significantly decreased odds of early neurological worsening and three-month mortality, and increased odds of good functional outcome. The smallest haematoma to double in size was 3.97 ml. Among the 34 subjects with very small haematomas (<3 ml), none had early neurological worsening and most had good three-month outcome (73.5%, mRS<=3). CONCLUSIONS: This study provides observational evidence that very small haematomas are unlikely to expand, by commonly used absolute growth definitions, and may represent a subgroup of patients with intracerebral haemorrhage destined towards good clinical outcomes. PMID- 21557805 TI - The unmet need of patients with atrial fibrillation: AVERROES and the novel oral anticoagulants. PMID- 21557806 TI - Cilostazol: a drug particularly effective for Asians? AB - Cilostazol is an antiplatelet drug often used in Asia; however, it is rarely used in the western hemisphere, particularly for stroke patients. Further studies of cilostazol in other ethnicities are required to prove or disprove whether this drug is also beneficial in non-Asian populations. PMID- 21557807 TI - Early Neurological Deterioration (END) after stroke: the END depends on the definition. AB - Neurological worsening poststroke is a serious clinical condition that occurs in up to one-third of patients. This brief report summarizes several of the current issues faced by neurologists in recognizing and managing patients who experience a worsening neurological status following hospital admission. PMID- 21557808 TI - Treatment issues in spontaneous cervicocephalic artery dissections. AB - The management of cervicocephalic arterial dissections raises many unsolved issues such as: how to best acutely treat patients who present with ischemic stroke or occasionally with sub-arachnoid hemorrhage? How to best prevent ischemic stroke in patients who present with purely local signs such as headache, painful Horner Syndrome or neck pain? How long and how should patients be treated after cervicocephalic arterial dissections? Can patients resume their sports activities and when? The consensus is that, given the well-established initial thromboembolic risk, an urgent antithrombotic treatment is required in patients with a recent nonhemorrhagic cervicocephalic arterial dissection, but the type of antithrombotic treatment - anticoagulants or aspirin - as well as the indication for a local arterial treatment such as angioplasty/stenting remain debated. Evidence from a randomized clinical trial would be welcome but such a trial raises major issues of methodology, feasibility and funding. Meanwhile, cervicocephalic arterial dissection remains a situation when a bedside clinician should use, on a case-by-case basis, best clinical judgment and adopt a stepped care approach in the minority of patients who deteriorate despite initial treatment. PMID- 21557809 TI - Epidemiology of stroke in Italy. AB - This study reviews available data on stroke epidemiology in Italy. Data were identified through Medline/PubMed, Embase, and from reference lists, related articles, and citation lists of each of the retrieved papers. Nineteen papers were considered, referring to selected stroke-registers performed in seven different geographical areas: Acquaviva-Casamassima county, Aeolian Islands, Aosta district, Belluno district, L'Aquila district, Trasimeno area, and Vibo Valentia district. Registers covered a total population of 2 262 940 people, with a hospitalization rate from 82% to 98%. The mean age at stroke onset was 74.6 +/- 1.1 years, 72.3 years in men and 76.6 years in women. Among all strokes: * 67.3 82.6% were classified ischemic * 9.9-19.6% as primary intracerebral hemorrhage * 1.6-4.0% as sub-arachnoid hemorrhage, and * 1.2-17.7% as undetermined. Annual incidence rates standardized to the Italian population ranged from 175/1 00 000 to 360/1 00 000 in men and from 130/1 00 000 to 273/1 00 000 in women. Thirty-day case-fatality rates for all strokes ranged from 18.1% to 33.0% while one-year case-fatality rates ranged from 37.9% to 40.2%. Data from selected Italian registers on stroke incidence and case-fatality indicate the great burden of the disease on our national healthcare system. The continuous implementation of preventive strategies, either population-based or addressed to the single patient at a high risk of stroke, is important to reduce the burden of the disease. PMID- 21557810 TI - The practical management of intracerebral hemorrhage associated with oral anticoagulant therapy. AB - Oral anticoagulant-associated intracerebral hemorrhage is increasing in incidence and is the most feared complication of therapy with vitamin K1 antagonists. Anticoagulant-associated intracerebral hemorrhage has a high risk of ongoing bleeding, death, or disability. The most important aspect of clinical management of anticoagulant-associated intracerebral hemorrhage is represented by urgent reversal of coagulopathy, decreasing as quickly as possible the international normalized ratio to values <=1.4, preferably <=1.2, together with life support and surgical therapy, when indicated. Protocols for anticoagulant-associated intracerebral hemorrhage emphasize the immediate discontinuation of anticoagulant medication and the immediate intravenous administration of vitamin K1 (mean dose: 10-20 mg), and the use of prothrombin complex concentrates (variable doses calculated estimate circulating functional prothrombin complex) or fresh-frozen plasma (15-30 ml/kg) or recombinant activated factor VII (15-120 MUg/kg). Because of cost and availability, there is limited randomized evidence comparing different reversal strategies that support a specific treatment regimen. In this paper, we emphasize the growing importance of anticoagulant-associated intracerebral hemorrhage and describe options for acute coagulopathy reversal in this setting. Additionally, emphasis is placed on understanding current consensus based guidelines for coagulopathy reversal and the challenges of determining best evidence for these treatments. On the basis of the available knowledge, inappropriate adherence to current consensus-based guidelines for coagulopathy reversal may expose the physician to medico-legal implications. PMID- 21557811 TI - Stroke in Myanmar: attitudes and treatment. AB - The burden of stroke in low-middle-income countries has increased during the past few decades but has decreased in developed countries and it is important to know why; though it may be attributed primarily to attitudes toward stroke management and prevention among doctors, and consequently in the population. We have conducted a study to investigate how stroke is managed in Myanmar, south-east Asia, with a population of approximately 60 million. We found that attitude differed markedly from that reflected in international guidelines. We expected this attitude to be reflected in the general population and speculate that the poor development and sub-optimal work on prevention and treatment of stroke stems from these attitudes. PMID- 21557812 TI - Stroke unit care: does ischemic stroke subtype matter? AB - BACKGROUND: Stroke unit care improves outcomes following ischemic stroke. However, it is not known whether all ischemic stroke subtypes benefit equally from stroke unit admission. OBJECTIVE: To determine whether the benefit of stroke unit admission is similar among all ischemic stroke subtypes. Design, setting and patients Prospective cohort study including patients admitted with an acute ischemic stroke between July 2003 and September 2007 to stroke centers participating institutions in the Registry of the Canadian Stroke Network. Ischemic stroke subtype information was determined according to the modified Trial of Org 10 172 in Acute Stroke Treatment criteria and categorized as small vessel disease (lacunar), large artery atherosclerotic disease, cardioembolic, or other (including both other determined and undetermined causes). Main outcome measures The primary outcome measure was all-cause mortality at 30 days after stroke. Secondary outcomes were seven-day mortality and death or institutionalization at discharge. RESULTS: Among 6223 eligible patients with ischemic stroke admitted to regional stroke centers in Ontario, the mean age was 72 years and 52.4% were male. Overall 30-day mortality was 12.2%. The 30-day risk adjusted mortality was lower for stroke unit care across all stroke subtypes (for lacunar stroke 3.0% vs. 5.3%; for large artery disease 7.5% vs. 14.5%; for cardioembolic 15.3% vs. 23.3%; and for other causes 8.9% vs. 15.9%). In multivariable analysis, after controlling for age, gender, medical comorbidities, and stroke severity, there was a significant reduction in stroke mortality associated with stroke unit admission in all stroke subtypes (odds ratio (95% confidence interval) for lacunar stroke 0.48 (0.27-0.88), for large artery atherosclerotic disease 0.39 (0.27-0.56), for cardioembolic 0.46 (0.36-0.59), and for other causes 0.45 (0.29-0.70)). The results remained similar after a sensitivity analysis excluding patients receiving palliative care, and a secondary analysis including 3215 patients with missing Trial of Org 10 172 in Acute Stroke Treatment classification. CONCLUSION: This study provides 'real world' evidence that all ischemic stroke subtypes do benefit from a stroke unit admission regardless of the etiology. There is no justification for withholding access to stroke unit care based on stroke subtype. PMID- 21557813 TI - Singapore ministry of health clinical practice guidelines on stroke and transient ischemic attacks. AB - The primary aim of these guidelines is to assist individual clinicians, hospital departments, and hospital administrators to produce local protocols for the: * assessment, investigation and immediate management of individuals with a transient ischemic attack or acute stroke (other than sub-arachnoid hemorrhage), and * secondary prevention and risk factor management following a transient ischemic attack or acute stroke. The secondary aim of these guidelines is to suggest methods for implementation and clinical audit. The workgroup preparing these guidelines was formed by the Ministry of Health, Singapore. It comprised healthcare workers from relevant specialties, family medicine, nursing, occupational therapy, and a lay patient advocate. The Scottish Intercollegiate Guidelines Network's Clinical Practice Guidelines on the Management of Patients with Stroke were reviewed, updated, and modified to meet local needs. The final guidelines are made up of evidence-based recommendations covering the following areas - assessment, investigation, immediate management, secondary prevention, rehabilitation, and implications for service delivery. The guidelines were sent to professional organizations for comments and endorsements. The final version was circulated to all medical practitioners in Singapore. It is hoped that the guidelines will improve the care of patients with stroke and transient ischemic attack. Clinical quality improvement measures are proposed. PMID- 21557814 TI - SYNTHESIS expansion: design of a nonprofit, pragmatic, randomized, controlled trial on the best fast-track endovascular treatment vs. standard intravenous alteplase for acute ischemic stroke. AB - Rationale Reperfusion in ischemic stroke can be pursued by either systemic intravenous thrombolysis or endovascular treatment. However, systemic intravenous thrombolysis with alteplase within 4.5 h of symptom onset in selected patients is the only medication of proven efficacy. No randomized-controlled trials have so far compared the two modalities. To explore this, after a pilot phase, we started the SYNTHESIS Expansion trial. Aims To determine whether endovascular treatment (i.e., intra-arterial thrombolysis with alteplase - if necessary, associated to or substituted by mechanical clot disruption and/or retrieval) compared with systemic intravenous thrombolysis with alteplase, administered according to European labelling, increases the proportion of independent survivors at three months. Design SYNTHESIS Expansion is an open-label, multicenter randomized controlled trial, with blinded follow-up. Eligibility applies to; patients with symptomatic ischemic stroke, seen within 4.5 h of onset; being able to initiate intravenous alteplase immediately, and endovascular treatment as soon as possible (not later than six-hours of stroke onset). The study is pragmatically based on the 'uncertainty principle' between endovascular treatment and systemic intravenous thrombolysis for patients eligible for intravenous alteplase. There are no prespecified clinical or instrumental criteria to further select a patient, although investigators are left free to use them. Enrollment will be completed with 350 randomized patients. Primary analysis is on an intent-to-treat basis. Study outcomes Primary: modified Rankin scale score of 0 or 1 at three months. Secondary: neurological deficit seven-days after thrombolysis and the safety of the procedure on the basis of events reported within seven-days following thrombolysis - symptomatic cerebral hemorrhage, fatal and nonfatal stroke, death from any cause, neurological deterioration. PMID- 21557815 TI - The rationale and design of the Giant Intracranial Aneurysm Registry: a retrospective and prospective study. AB - AIMS AND HYPOTHESIS: Giant intracranial aneurysms have a poor prognosis mainly due to their high risk of rupture. Because their incidence is low, clinical trial evidence for adequate treatment is lacking. The Giant Intracranial Aneurysm Registry is designed to document current treatment strategies in giant aneurysm care and to monitor the course of the disease over five-years. It aims to evaluate the hypothesis that all three possible branches of therapy (conservative/endovascular/surgical) lead to equal rupture rates. DESIGN: The Giant Intracranial Aneurysm Registry is an interdisciplinary multicenter observational study. Each center recruits patients diagnosed with a giant intracranial aneurysm both prospectively and retrospectively. Primary outcome will be the aneurysm rupture rate at five-years of follow-up. STUDY OUTCOME: Patient enrollment has begun at 20 neurovascular centers throughout Germany, with 19 further centers applying for local ethics approval to take part in the study. The first nine months are designed as a pilot phase followed by the integration of study centers throughout the EU and the initiation of separate sub-studies. DISCUSSION: Giant intracranial aneurysms have often been ignored or marginalized due to their low incidence. The Giant Intracranial Aneurysm Registry aims to lead to a better understanding of these complex lesions and to serve as a basis for the development of future clinical studies. PMID- 21557816 TI - International normalised ratio normalisation in patients with coumarin-related intracranial haemorrhages--the INCH trial: a randomised controlled multicentre trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex--study design and protocol. AB - BACKGROUND: Intracerebral haemorrhage is the most feared complication in patients who are on treatment with vitamin K antagonists. Vitamin K antagonist related intracerebral haemorrhage occurs in about 10% of patients. Intracerebral haemorrhage has the worst prognosis of all subtypes of stroke including spontaneous intracerebral haemorrhage, and a mortality rate of up to about 65%. The higher rate of haematoma expansion due to rebleeding is thought to be responsible for the higher mortality. Current international treatment recommendations include fresh frozen plasma and prothrombin complex concentrate. It is known that these substances lower the international normalised ratio, and thus it is assumed that normalisation of coagulopathy may lead to haemostasis and reduction of rebleeding. However, the issue of whether to use fresh frozen plasma or prothrombin complex concentrate for urgent reversal of vitamin K antagonists is unresolved: safety and efficacy of these treatments have never been studied in a randomised controlled trial. Our questions are: how effective are the two substances in normalisation of the international normalized ratio? How feasible is it to apply either of these treatments in an acute situation? What is the safety profile of each of these substances? Is there a difference in haematoma growth and clinical outcome? METHOD: We designed a prospective, randomised, controlled multicentre trial to compare biological efficacy and safety of fresh frozen plasma and prothrombin complex concentrate in vitamin K antagonist related intracerebral haemorrhage. The study is observer-blinded for laboratory, neuroradiological, and clinical outcomes. Patients will be included if a computed tomography scan shows an intraparenchymal or subdural haematoma within 12 h after onset of symptoms, if the patient is on treatment with vitamin K antagonists, and the international normalized ratio is >=2. Primary endpoint is the normalisation of the international normalized ratio (<=1.2) within three-hours after the start of antagonising therapy. Main exclusion criteria are secondary intracerebral haemorrhage, other known coagulopathies, and known acute ischaemic events. DISCUSSION: We discuss the rationale of our trial on the basis of the current recommendations and specific aspects of trial design as, time window, choice of endpoints, dosing of fresh frozen plasma and prothrombin complex concentrate, monitoring and analysis of safety parameters, and rescue treatment. CONCLUSION: This will be the first prospective trial comparing fresh frozen plasma and prothrombin complex concentrate in the indication of vitamin K antagonist related intracerebral hemorrhage. Recruitment of subjects started in August 2009. Until now, 19 patients have been included. PMID- 21557817 TI - Hyperglycemia in thrombolysed acute ischemic stroke patients. PMID- 21557819 TI - A new ultrasound method for evaluating dysphagia in acute stroke patients. PMID- 21557820 TI - Role of vasodilation in cognitive impairment. PMID- 21557822 TI - Recombinant WNTs differentially activate beta-catenin-dependent and -independent signalling in mouse microglia-like cells. AB - AIM: The objective of this study was to compare the efficacy of different recombinant, commercially available Wingless/Int-1 (WNTs) with regard to WNT/beta catenin signalling, dishevelled (DVL) and G protein activation and the induction of cell proliferation in a microglia-like cell line called N13. METHODS: For detection of activated signalling molecules, cell lysates are analysed by immunoblotting. Furthermore, we used a [gamma(35)S] GTP binding assay to monitor the exchange of GDP for GTP in heterotrimeric G proteins in N13 membrane preparations. Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay measuring mitochondrial function, which is proportional to the amount of viable cells. RESULTS: Of the WNTs tested (WNT-3A, 4, -5A, -5B, -7A,-9B), only WNT-3A activated WNT/beta-catenin signalling in N13 cells. All WNTs induced the formation of phosphorylated and shifted DVL (PS-DVL) and the activation of heterotrimeric G proteins with variable efficacies. WNT-5A and WNT-9B, which had the highest efficacy in the G protein assay, also induced N13 cell proliferation. CONCLUSION: WNTs show significant differences in their efficacy to activate beta-catenin-dependent and -independent signalling. The WNTs tested are present during maturation of the central nervous system and/or in the adult brain and are thus potential regulators of microglia-mediated neuroinflammation. PMID- 21557823 TI - [A woman with a mass in her abdomen]. AB - A 43-year-old woman was referred; she had felt an abdominal mass on her left side. Imaging showed a cystic lesion. The lesion was removed via laparotomy. Pathological examination showed a benign mucinous cyst. PMID- 21557824 TI - [Congenital toxoplasmosis: severe ocular and neurological complications]. AB - Two infants with congenital toxoplasmosis are presented. A girl born prematurely was treated postnatally after the mother had received antimicrobial treatment during pregnancy for acute toxoplasmosis. Apart from being small for gestational age, she remained without symptoms and treatment was ceased after 13 months. A 2 month-old boy presented with hydrocephalus and chorioretinitis, consistent with congenital toxoplasmosis. Despite antimicrobial treatment, at 12 months of age he suffered from epilepsy, cerebral palsy and vision impairment. Most infants with congenital toxoplasmosis (2 per 1000 live births in the Netherlands) are asymptomatic at birth. The education of pregnant women is crucial for the prevention of congenital toxoplasmosis. Awareness of antenatal and postnatal presenting signs and symptoms is important for clinicians, because early diagnosis and treatment may minimize sequelae. Untreated, the majority of affected infants will develop chorioretinitis, deafness and/or neurological symptoms. PMID- 21557825 TI - [Treitz and his ligament]. AB - Vaclav (Wenzel) Treitz (1819-1872) grew up in the Czech community that was part of the Habsburg Empire. He studied medicine at the German Karl Ferdinand University in Prague where he specialised in pathological anatomy. He continued this specialisation in Vienna, under Rokitansky. In 1855, after a stint in Krakow (now Poland; then also under Austrian rule), he was appointed Professor of Pathological Anatomy in Prague during which time he discovered a small muscle that connected the duodenojejunal flexure with the coeliac axis. It was called the 'ligament of Treitz' for a long time, but is known today as the musculus suspensorius duodeni (suspensory muscle of duodenum). In addition to this, he focused on internal intestinal herniation alongside a peritoneal duplicature at the duodenojejunal junction ('arch of Treitz'). Treitz taught in Czech and became increasingly involved in patriotic agitations which estranged him from most of his colleagues. Eventually, his mental as well as physical health deteriorated. PMID- 21557826 TI - [Perinatal audit in the North of the Netherlands: the first 2 years]. AB - OBJECTIVE: Description of the implementation of local audit meetings and the identified substandard factors, points of special interest, actions for improvement and the opinion of the participating health care providers. DESIGN: Descriptive study. METHOD: A new organisation and methodology for perinatal mortality audit meetings was introduced in 15 collaborative structures in the northern part of the Netherlands in the period September 2007 to March 2010. During these multidisciplinary audit meetings, cases of perinatal mortality selected by the obstetric collaborative group were discussed in a structured way under the direction of an independent chairman. RESULTS: In total 64 audit meetings were held, in which 677 perinatal health care providers took part at least once, and 112 cases of perinatal death were evaluated. 163 substandard factors were identified. These included : not following the protocol, guideline, standard (31%) or usual care (23%) and insufficient documentation (28%) and communication between health care providers (13%). 442 actions to improve care were reported divided over: 'external collaboration' (15%), 'internal collaboration' (17%), 'practice management' (26%) and 'training and education' (10%). The most valued aspects of the audit meetings were: their multidisciplinary character, the collaborative search for substandard factors, their security, the learning effect and the positive effect on collaboration. CONCLUSION: Cases of perinatal mortality were discussed in all 15 perinatal collaborative structures in the northern part of the Netherlands. Substandard factors were identified, but further analysis of these factors merits attention. The participants concluded that the multidisciplinary approach and the collaboration during the audit meetings improved the cooperation between perinatal health care providers. PMID- 21557827 TI - [Hypertensive disorders in pregnancy: vigilance on the part of general practitioners]. AB - Hypertensive disorders of pregnancy are one of the main causes of maternal morbidity and mortality in the Netherlands. In this paper, we present 3 cases of nulliparous pregnant women, two 25-year-olds and a 31-year-old, who developed symptoms between 27 en 29 weeks of gestation for which they consulted their general practitioner. In spite of available guidelines, there was a significant delay in all cases in the diagnosis and treatment of severe pre-eclampsia. In 2 cases, the delay occurred because blood pressure measurements were not performed; in 1 of these cases proteinuria was mistaken for cystitis and treated as such. In the third case failure to recognize key symptoms led to untimely referral to a gynaecologist. All 3 women delivered preterm and 1 neonate died of necrotizing enterocolitis shortly after delivery. To prevent unnecessary delay we therefore stress the importance of the timely recognition of signs and symptoms of hypertensive disorders of pregnancy in a primary care setting, as well as appropriate early antenatal education and counseling for all pregnant women. PMID- 21557828 TI - [Charles Bonnet syndrome]. AB - BACKGROUND: Charles Bonnet syndrome is characterised by complex visual hallucinations in patients who have visual disturbances but no cognitive disorders. The diagnosis is often missed. CASE DESCRIPTION: An 88-year-old vital woman was referred to the emergency department due to anxiety and restlessness. Her symptoms began after she had started using antipsychotic drugs for visual hallucinations. The patient's visual acuity appeared to be markedly reduced. The antipsychotics were discontinued and the reason behind the patient's symptoms was explained to her: Charles Bonnet syndrome. The anxiety and restlessness disappeared and the frequency of the hallucinations declined. CONCLUSION: This patient had Charles Bonnet syndrome. If visual hallucinations occur for the first time after the 40th year of life, a somatic cause should first be ruled-out. Refraining from treating Charles Bonnet syndrome with pharmacological agents is advised in light of their many side effects and little evidence of being beneficial for this condition. PMID- 21557829 TI - [Effect of emergency intervention team still unclear. More evidence is necessary]. AB - Changes in health care culture are accompanied by a flood of initiatives with respect to patient safety and quality of care. These initiatives are incentives from government, laymen press, health insurance companies and health care providers. This makes evidence-based patient safety an absolute necessity to guide the priorities of policy makers. A medical emergency team (MET), also referred to as a rapid response team (RRT), is an example of a good initiative to improve health care quality that is being embraced rapidly worldwide, but solid evidence of its effectiveness is lacking. The number of cardiopulmonary arrests seems to have decreased, but adequate correction for case mix confounders has not been done and the effect on patient outcome, i.e. in-hospital mortality, has not been convincingly demonstrated. PMID- 21557830 TI - [Thromboprophylaxis in pregnant women should be individually tailored]. AB - Roeters van Lennep et al. recently evaluated efficacy and safety of thromboprophylaxis with low dose low-molecular-weight heparin (LMWH) in women with intermediate and high risk of pregnancy-related venous thromboembolism (VTE). Lessons to be drawn from this study are that the risk of VTE should be estimated preconceptionally, that the current LMWH prophylaxis is sufficient during pregnancy and the post-partum period for women with an intermediate risk of VTE, that from a haemostatic point of view the post-partum period does not end at 6 weeks but at 3 months, and that the prophylactic LMWH dosage is insufficient in 1 out of 20 women with a high risk of VTE. PMID- 21557832 TI - Is there any evidence of superiority between retropubic, laparoscopic or robot assisted radical prostatectomy? AB - PURPOSE: To compare the perioperative, short-term and long-term postoperative results of radical retropubic prostatectomy (RRP), laparoscopic radical prostatectomy (LRP) and robotic assisted laparoscopic prostatectomy (RALP) in the most recent studies evaluable. MATERIALS AND METHODS: Using PubMed we have undertaken a search based on references from major and recent articles with considerable sample sizes. RESULTS: The operative blood loss and the risk of transfusion were lower in the laparoscopic and robotic-assisted approaches. The surgical duration was shorter in the open and robotic group. Regarding the positive margins, continence and potency no substantial differences between the RRP, LRP, and RALP were found. CONCLUSIONS: Our results suggest that no one surgical approach is superior in terms of functional and early oncologic outcomes. Potential advantages of any surgical approach have to be confirmed through longer-term follow-up and adequately designed clinical studies. PMID- 21557833 TI - Radiation therapy and androgen deprivation in the management of high risk prostate cancer. AB - The combined use of radiation therapy (RT) and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials. PMID- 21557834 TI - Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy. AB - PURPOSE: Metastatic renal cell carcinoma (RCC) is one of the most treatment resistant malignancies and nephrectomy, isolated or combined with systemic chemotherapy typically has limited or no effectiveness. We report our initial results in patients treated with the association of molecular targeted therapy, nephrectomy, and hybrid dendritic-tumor cell (DC) vaccine. MATERIALS AND METHODS: Two male patients diagnosed with metastatic RCC were selected for the study. They were treated with the triple strategy, in which sunitinib (50 mg per day) was given for 4 weeks, followed by radical nephrectomy after two weeks. DC vaccine was initiated immediately after surgery and repeated monthly. Sunitinib was restarted daily after 2 to 3 weeks of surgery with a 7-day interval every 4 weeks. RESULTS: Both patients had complete adherence to the proposed treatment with DC vaccine therapy combined with sunitinib. Follow-up in these patients at 9 and 10 months demonstrated a stable disease in both, as shown by imaging and clinical findings, with no further treatment required. CONCLUSION: The immune response obtained with DC vaccine combined with the antiangiogenic effect of sunitinib and the potential benefits of cytoreductive nephrectomy in advanced disease could represent a new option in the treatment of metastatic RCC. Further prospective trials are needed not only to elucidate the ideal dosing and schedule, but also to better define the proof-of-concept proposed in this report and its role in clinical practice. PMID- 21557835 TI - Personal, professional and financial satisfaction among American women urologists. AB - PURPOSE: Although nearly half of American medical school classes are comprised of women, less than 5% of female medical students enter the surgical subspecialties compared to nearly 20% of male students. Many women are concerned that a career in a surgical field will limit their personal choices. In an effort to evaluate if urology is conducive to a satisfying lifestyle, we surveyed all 365 board certified women urologists in the United States in 2007 to find out how satisfied they are with their choice of urology. MATERIALS AND METHODS: A 114 item anonymous survey was mailed to all 365 American Board Certified female urologists in 2007. Results were analyzed. RESULTS: Of the 244 women (69%) who responded, 86.8% (211) reported being satisfied with their decision to enter urology. Given the choice to repeat the decision, 81% (198) said that they would remain in medicine and 91.4% (222) would choose a surgical subspecialty again. The majority of respondents who stated they would choose a career outside of medicine also stated their family life had been significantly compromised by their career. Those who did not think their family life was compromised reported they would remain in medicine. There was a positive correlation between the level of satisfaction with the work itself and with income level (p = 0.006). CONCLUSIONS: Despite the small number of women who choose a career in urology, the number of satisfied women indicates urology is a career conducive to having a balanced and fulfilling life; professionally, personally and financially. PMID- 21557836 TI - Efficacy of three different alpha 1-adrenergic blockers and hyoscine N butylbromide for distal ureteral stones. AB - PURPOSE: To evaluate hyoscine N-butyl bromide (HBB) and three different alpha-1 blockers in the treatment of distal ureteral stones. MATERIALS AND METHODS: A total of 140 patients with stones located in the distal tract of the ureter with stone diameters of 5 to 10mm were enrolled in the present study and were randomized into 4 equal groups. Group 1 received HBB, Group 2 received alfuzosin, Group 3 received doxazosin and Group 4 received terazosin. The subjects were prescribed diclofenac injection (75 mg) intramuscularly on demand for pain relief and were followed-up after two weeks with x-rays of the kidneys, ureters, bladder and urinary ultrasonography every week. The number of pain episodes, analgesic dosage and the number of days of spontaneous passage of the calculi through the ureter were also recorded. RESULTS: The average stone size for groups 1, 2, 3 and 4 was comparable (6.13, 5.83, 5.59 and 5.48 mm respectively). Stone expulsion was observed in 11%, 52.9%, 62%, and 46% in groups 1, 2, 3 and 4 respectively. The average time to expulsion was 10.55 +/- 6.21 days in group 1, 7.38 +/- 5.55 days in group 2, 7.85 +/- 5.11 days in group 3 and 7.45 +/- 5.32 days in group 4. Alpha blockers were found to be superior to HBB (p < 0.05). CONCLUSIONS: Medical treatment of distal ureteral calculi with alfuzosin, doxazosin and terazosin resulted in a significantly increased stone-expulsion rate and decreased expulsion time when compared with HBB. HBB seems to have a negative effect on stone-expulsion rate. PMID- 21557837 TI - High risk bladder cancer: current management and survival. AB - PURPOSE: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates. MATERIALS AND METHODS: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival. RESULTS: 74/412 (18%) patients with high risk NMIBC underwent a transurethral resection (TUR) as single treatment. Adjuvant treatment after TUR was performed in 90.7% of the patients treated in teaching hospitals versus 71.8% in non-teaching hospitals (p < 0.001). In multivariate analysis, age (60-79 years OR 0.40 and > 80 years OR 0.1 p = 0.001) and treatment in non-teaching hospitals (OR 0.25; p < 0.001) were associated with less adjuvant treatment after TUR. Tumor recurrence occurred in 191/392 (49%) and progression in 84/392 (21.4%) patients. The mean 5-years progression free survival was 71.6% (95% CI 65.5-76.8). CONCLUSION: In this pattern of care study in high risk NMIBC, 18% of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates. PMID- 21557838 TI - Focal therapy with high-intensity focused ultrasound for prostate cancer in the elderly. A feasibility study with 10 years follow-up. AB - PURPOSE: To evaluate the long-term efficacy of prostate cancer control and complication rates, in the elderly, after focal therapy with high-intensity focused ultrasound (HIFU). MATERIALS AND METHODS: Between June 1997 and March 2000, patients with localized prostate cancer were included into a focal therapy protocol. Inclusion criteria were: PSA <= 10 ng/mL, <= 3 positive biopsies with only 1 lobe involved, clinical stage <= T2a, Gleason score <= 7 (3+4), negative CT scan and bone scan. Hemi-ablation of the prostate was performed with the Ablatherm(r) device. Survival, complication rates and urinary continence were evaluated. Control biopsies were performed at 1 year. Treatment failure was defined as a positive biopsy or need for salvage therapy. RESULTS: Twelve patients with a mean age 70 years were included. Median follow-up was 10 years. Control prostate biopsies were negative in 11/12 (91%) patients. Overall survival was 83% (10/12) and cancer specific survival was 100% at 10 years. Two patients died from other causes. Recurrence free survival was 90% (95% CI; 0.71-1) at 5 years, and 38% (95% CI; 0.04-0.73) at 10 years. Five patients had salvage therapy with repeat HIFU (n = 1) or hormonal therapy (n = 4) and all salvage patients were alive at 10 years. No patients developed lymph node or bone metastasis. No patients suffered from urinary incontinence. International Prostate Symptom Score was stable at 1 year. Complications included two urinary tract infections and one episode of acute urinary retention. CONCLUSIONS: Hemi-prostate ablation with HIFU can be safely performed in selected elderly patients with adequate long-term cancer control and low complication rates. Results from larger prospective studies using improved imaging techniques and extensive biopsy protocols are awaited. PMID- 21557839 TI - Correlation of hepatitis C and prostate cancer, inverse correlation of basal cell hyperplasia or prostatitis and epidemic syphilis of unknown duration. AB - PURPOSE: The accuracy of prostate specific antigen (PSA) to detect prostate cancer has not yet been determined. Autopsy evidence suggests one-third of men have evidence of prostate cancer. Correlation between prostate cancer and sexually transmitted infection is indeterminate. MATERIALS AND METHODS: A retrospective database was created of all men who underwent transrectal ultrasound guided prostate biopsy over 3 years. Men were 49% African or African Caribbean, and 51% Central or South American. Information about prostate specific antigen, cholesterol, hepatitis A, B and C, human immunodeficiency virus, syphilis, tuberculin skin testing and histology were collected. RESULTS: Hepatitis C antibody detection correlated with prostate cancer OR 11.2 (95% CI 3.0 to 72.4). The odds of prostate cancer increased annually (p = 0.0003). However, no correlation was found between prostate cancer and the following: PSA, biopsy date, repeat biopsy, more than 12 cores at biopsy, total cholesterol, high density lipoprotein, triglycerides, low density lipoprotein, risk measure reported with free and total PSA, hepatitis B surface antibody, high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation. Histologic prostatitis and basal cell hyperplasia were inversely correlated with prostate cancer. Syphilis of unknown duration occurred in 17% of men with indeterminate correlation to prostate cancer. CONCLUSION: In Inner City men of African and African-Caribbean, or Central and South American descent, prostate specific antigen levels did not correlate with prostate cancer. Hepatitis C antibody detection correlates significantly with prostate cancer. One prostate biopsy is sufficient to diagnose statistically significant prostate cancer. Histologic prostatitis and basal cell hyperplasia decrease odds of prostate cancer. Atypical small acinar proliferation may not correlate to prostate cancer and is pending further investigation. Men should be screened for epidemic syphilis of unknown duration. PMID- 21557840 TI - Epidemiological aspects of penile cancer in Rio de Janeiro: evaluation of 230 cases. AB - PURPOSE: To determine epidemiological characteristics of penile cancer in Rio de Janeiro, its associated risk factors and clinical manifestations. PATIENTS AND METHODS: Between 2002 and 2008 we evaluated 230 patients at three public institutions, considering age, ethnicity, birthplace, marital status, educational level, religion, tobacco smoking, presence of phimosis and practice of circumcision. RESULTS: The ages ranged from 25 to 98 years, with an average of 58.35 years. Of the 230 patients, 167 (72.7%) were from the southeast region of Brazil (which includes Rio de Janeiro) and 45 (19.5%) were from the northeast of the country. Most patients were white (67.3%), married (58.6%), smokers (56.5%) and had not completed primary school (71.3%). The predominant religion was Catholic (74.8%). Of the 46 (20%) circumcised patients, only 1 (2.2%) had undergone neonatal circumcision. Grade I tumors were present in 87 (37.8%) of the patients, grade II in 131 (56.9%) and grade III in 12 (5.3%). Lymphovascular embolization was observed in 63 (27.3%) and koilocytosis in 124 (53.9%) patients. Of the total, 41.3% had corpora cavernosa or corpus spongiosum infiltration, and 40 (17.4%) had urethral invasion. Prophylactic lymphadenectomy was performed on 56 (36.1%), therapeutic lymphadenectomy on 84 (54.2%) and hygienic lymphadenectomy for advanced disease on 15 (9.7%) patients. The median time between the lesion onset and clinical diagnosis was 13.2 months. The mean follow up was 28.8 months. CONCLUSION: Most of our patients were born in this state and had low socioeconomic status. Most of them were white men, married, smokers, uncircumcised, of the Catholic faith and in their sixties or older. Their disease was in most cases diagnosed only in the advanced stages. PMID- 21557841 TI - Chromosomal and molecular abnormalities in a group of Brazilian infertile men with severe oligozoospermia or non-obstructive azoospermia attending an infertility service. AB - PURPOSE: To determine the frequency of genetic alterations in a population of Brazilian infertile men with severe oligozoospermia or non-obstructive azoospermia. MATERIALS AND METHODS: Retrospective study of a group of 143 infertile men with severe oligozoospermia or non-obstructive azoospermia from the Andrology Outpatient Clinic of the Human Reproduction Service at the ABC School of Medicine. Of these patients, 100 had severe oligozoospermia, and 43 non obstructive azoospermia. All patients underwent a genetic study which included karyotype analysis and Y-microdeletion investigation. RESULTS: Genetic abnormalities were found in 18.8% of the studied patients. Chromosomal abnormalities were found in 6.2% of the patients, being more prevalent in the azoospermia group (11.6%) than in the oligozoospermia group (4%). Chromosomal variants were found in 8.3%, and Y-chromosome microdeletions in 4.2% of patients. CONCLUSION: The high frequency of genetic alterations (18.8%) in our series justified performing a genetic investigation in a population with idiopathic infertility, as results may help determine the prognosis, as well as the choice of an assisted reproduction technique. Moreover, a genetic investigation could minimize the risk of transmitting genetic abnormalities to future generations such as genetic male infertility, mental retardation, genital ambiguity and/or birth defects. PMID- 21557842 TI - Arc-to-Arc mini-sling 1999: a critical analysis of concept and technology. AB - PURPOSE: The aim of this study was to critically review the Arc-to-Arc mini-sling (Palma's technique) a less invasive mid-urethral sling using bovine pericardium as the sling material. MATERIALS AND METHODS: The Arc-to-Arc mini-sling, using bovine pericardium, was the first published report of a mini-sling, in 1999. The technique was identical to the "tension-free tape" operation, midline incision and dissection of the urethra. The ATFP (white line) was identified by blunt dissection, and the mini-sling was sutured to the tendinous arc on both sides with 2 polypropylene 00 sutures. RESULTS: The initial results were encouraging, with 9/10 patients cured at the 6 weeks post-operative visit. However, infection and extrusion of the mini-sling resulted in sling extrusion and removal, with 5 patients remaining cured at 12 months. CONCLUSION: The Arc-to-Arc mini-sling was a good concept, but failed because of the poor technology available at that time. Further research using new materials and better technology has led to new and safer alternatives for the management of stress urinary incontinence. PMID- 21557843 TI - Prophylaxis and therapeutic effects of raspberry (Rubus idaeus) on renal stone formation in Balb/c mice. AB - PURPOSE: To evaluate the prophylactic potential of herbal decoction from Rubus idaeus, a medicinal plant widely used in the Middle East to treat kidney stones, by assessing the effect of administration in experimentally induced calcium oxalate (CaOx) nephrolithiasis in mice. MATERIALS AND METHODS: This study was based on administration of glyoxylate and/or herbal treatments simultaneously for 12 days, followed by histological and biochemical tests. Group I was used as a negative control. Group II was only given daily intra-abdominal injection of glyoxylate (80 mg/Kg). Group III and IV were given 100 mg/kg/day and 200 mg/kg/day of aqueous extract of R. idaeus by gavage, respectively in addition to glyoxylate injection. To examine the effect of anti-oxidants on hyperoxaluria induced changes in kidney, the enzymatic and non-enzymatic anti-oxidant levels were assessed. RESULTS: Significant reductions were obtained in the urinary oxalate, calcium and phosphorus values in the herbal-treated groups relative to untreated animals while creatinine excretion increased. Serum oxalate, calcium and creatinine were significantly reduced, while phosphorus was not significantly changed. Kidney content of calcium was higher in the untreated group. Mice in treated groups at 12 days had significantly more superoxide dismutase, catalase, glutathione reductase (GSH) and G6PD activities than the untreated group. Hyperoxaluria-induced generation of malondialdehyde (MDA) and protein carbonyls was significantly prevented in the treated groups. R. idaeus had a significantly high content of vitamin E in the herbal treated groups. The histology showed more CaOx deposition in the kidneys of untreated animals. CONCLUSION: Rubus idaeus has an impressive prophylactic effect on CaOx stones in nephrolithic mice. There is a possible role of lipid peroxidation in CaOx stone formation which may has a relationship with the major risk factors in urine including oxalate, calcium, phosphorus and MDA. Further experimental studies are required to elucidate the chemical constituents of the active ingredients of this interesting plant. PMID- 21557844 TI - Myceleal emphysematous cystitis complicating a renal transplant kidney. PMID- 21557862 TI - Health risk appraisal for older people 4: case finding for hypertension, hyperlipidaemia and diabetes mellitus in older people in English general practice before the introduction of the Quality and Outcomes Framework. AB - BACKGROUND: Early intervention can help to reduce the burden of disability in the older population, but many do not access preventive care. There is uncertainty over what factors influence case finding in older patients in general practice. AIM: To explore factors associated with case finding for hypertension, hyperlipidaemia and diabetes mellitus in older patients. METHOD: Two thousand four hundred and ninety-one patients aged 65 years and above were recruited from three large practices in suburban London before the introduction of the Quality and Outcomes Framework (QOF) completed a questionnaire on health, functional status, health behaviours and preventive care. FINDINGS: Those not reporting heart disease, diabetes or hypertension were included in a secondary data analysis to explore factors influencing uptake of preventive care measures. Approximately one-third denied having had a blood pressure check in the previous year. They were more likely to have had little contact with doctors and to have an unhealthy lifestyle (smoking and a high-fat diet). One-third reported a cholesterol test in the previous five years. Cholesterol measurement was reported more often by men and those with a high body mass index. Those with unhealthy lifestyles (smoking and high-fat diet), those who had only received the state pension and those who limited their activities because of a fear of falling were less likely to report cholesterol measurement. About 10% reported a fasting blood glucose measurement and were more likely to consult more often and have more medications, but they were less likely to have a high-fat diet. Preventive care uptake was associated with frequent contacts with doctors, but overall the uptake of preventive care was low. Older people with healthier lifestyles were more likely to have primary preventative care interventions. These findings provide a baseline against which the effect of the QOF on the care of older people can be measured in future studies. PMID- 21557863 TI - Irish consumers' use and perception of nutrition and health claims. AB - OBJECTIVE: To investigate Irish consumers' use and understanding of and their belief in nutrition and health (NH) claims in the context of the European Union (EU) legislation (Regulation no. 1924/2006), which permits a number of NH claims on food products. DESIGN: An interview-assisted questionnaire was administered to consumers (n 400). Preference for three types of NH claims across six products was tested. Perception of NH claims was assessed across a further eight food products. Claims were categorised as content, structure-function and disease-risk factor reduction claims. SETTING: Six supermarkets in the Republic of Ireland. SUBJECTS: Four hundred adult Irish supermarket consumers. RESULTS: Older (P < 0.001), female (P < 0.01) consumers were more likely to seek NH claims. Structure function and content claims were preferred across six products. Consumers' perception was associated with the health benefit claimed rather than with the strength of the claim itself. Preference for claim type and claim perception differed with gender, age and educational level. CONCLUSIONS: Irish consumers prefer content and simpler NH claims rather than more complex disease-risk factor reduction claims. The food industry may thus be better served using these types of claims. Although the reported levels of understanding were high, evidence of positivity bias and misinterpretation was found. Thus, with regard to Regulation 1924/2006, consumers need more information on both simpler and more complex claims. Public health messages should be targeted according to gender, age and educational level. PMID- 21557864 TI - Race-specific validation of food intake obtained from a comprehensive FFQ: the Adventist Health Study-2. AB - OBJECTIVE: To assess race-specific validity of food and food group intakes measured using an FFQ. DESIGN: Calibration study participants were randomly selected from the Adventist Health Study-2 (AHS-2) cohort by church, and then by subject-within-church. Intakes of forty-seven foods and food groups were assessed using an FFQ and then compared with intake estimates measured using six 24 h dietary recalls (24HDR). We used two approaches to assess the validity of the questionnaire: (i) cross-classification by quartile and (ii) de-attenuated correlation coefficients. SETTING: Seventh-day Adventist church members geographically spread throughout the USA and Canada. SUBJECTS: Members of the AHS 2 calibration study (550 whites and 461 blacks). RESULTS: The proportion of participants with exact quartile agreement in the FFQ and 24HDR averaged 46 % (range: 29-87 %) in whites and 44 % (range: 25-88 %) in blacks. The proportion of quartile gross misclassification ranged from 1 % to 11 % in whites and from 1 % to 15 % in blacks. De-attenuated validity correlations averaged 0.59 in whites and 0.48 in blacks. Of the forty-seven foods and food groups, forty-three in whites and thirty-three in blacks had validity correlations >0.4. CONCLUSIONS: The AHS-2 questionnaire has good validity for most foods in both races; however, validity correlations tend to be higher in whites than in blacks. PMID- 21557865 TI - Dietary patterns among British adults: compatibility with dietary guidelines for salt/sodium, fat, saturated fat and sugars. AB - OBJECTIVE: To examine dietary patterns among British adults, associations with Na and macronutrient intakes, and implications for dietary advice. DESIGN: Principal component analysis of 7 d weighed dietary records. SUBJECTS: Adults aged 19-64 years (n 1724). SETTING: National Diet and Nutrition Survey (2000/2001). RESULTS: High Na intake was associated with more energy-dense diets, higher in fat and SFA (percentage of energy) but lower in non-milk extrinsic sugars (NMES). Eight patterns (PC1 to PC8) explained 40 % of the total variance in food intakes. Three patterns - PC3 (high loadings on bread, fats and cheese), PC2 (meat products, eggs and chips) and PC7 (red meat, sauces and alcohol) - were associated with high Na intake. Of these, PC3 correlated with high Na density and Na:K ratio, while PC2 correlated with fat. By contrast, three patterns - 'health-conscious' (PC1; vegetables, fruit, fruit juice, fish), 'breakfast cereals and milk' (PC6) and 'chicken and rice' (PC8) - were associated with modest Na intake, lower Na density and lower fat and SFA. PC2 was positively correlated, and PC1 was negatively correlated, with adding salt to food. Other patterns were 'tea/coffee and cakes' (PC4; associated with high SFA and NMES) and 'soft drinks and snacks' (PC5; associated with high NMES but not fat or SFA). The dietary patterns of males and females differed slightly. CONCLUSIONS: Dietary patterns PC1, PC6, PC8 (vegetables, fruit, fish, milk, breakfast cereals, poultry) were broadly compatible with guidelines for salt, fat, SFA and NMES. However, other patterns tended to be high in either salt or NMES. PMID- 21557866 TI - Food shopping habits, physical activity and health-related indicators among adults aged >=70 years. AB - OBJECTIVE: To investigate the food shopping habits of older adults in the UK and explore their potential associations with selected health-related indicators. DESIGN: A cross-sectional study including objectively measured physical activity levels, BMI, physical function and self-reported health status and dietary intake. SETTING: Bristol, UK. SUBJECTS: A total of 240 older adults aged >=70 years living independently. RESULTS: Mean age was 78.1 (sd 5.7) years; 66.7 % were overweight or obese and 4 % were underweight. Most (80.0 %) carried out their own food shopping; 53.3 % shopped at least once weekly. Women were more likely to shop alone (P < 0.001) and men more likely to shop with their spouse (P < 0.001). Men were more likely than women to drive to food shopping (P < 0.001), with women more likely to take the bus or be driven (P < 0.001). Most reported ease in purchasing fruit and vegetables (72.9 %) and low-fat products (67.5 %); 19.2 % reported low fibre intakes and 16.2 % reported high fat intakes. Higher levels of physical function and physical activity and better general health were significantly correlated with the ease of purchasing fresh fruit, vegetables and low-fat products. Shopping more often was associated with higher fat intake (P = 0.03); higher levels of deprivation were associated with lower fibre intake (P = 0.019). CONCLUSIONS: These findings suggest a pattern of food shopping carried out primarily by car at least once weekly at large supermarket chains, with most finding high-quality fruit, vegetables and low-fat products easily accessible. Higher levels of physical function and physical activity and better self-reported health are important in supporting food shopping and maintaining independence. PMID- 21557867 TI - Socio-economic differences in weight-control behaviours and barriers to weight control. AB - OBJECTIVE: To examine socio-economic differences in weight-control behaviours (WCB) and barriers to weight control. DESIGN: A cross-sectional study. SETTING: Data were obtained by means of a postal questionnaire. SUBJECTS: A total of 1013 men and women aged 45-60 years residing in Brisbane, Australia (69.8 % response rate). RESULTS: Binary and multinomial logistic regression analyses were performed, adjusted for age, gender and BMI. Socio-economically disadvantaged groups were less likely to engage in weight control (OR for lowest income quartile = 0.60, 95 % CI 0.39, 0.94); among those who engaged in weight control, the disadvantaged group had a likelihood of 0.52 (95 % CI 0.30, 0.90) of adopting exercise strategies, including moderate (OR = 0.56, 95 % CI 0.33, 0.96) and vigorous (OR = 0.47, 95 % CI 0.25, 0.89) physical activities, compared with their more-advantaged counterparts. However, lower socio-economic groups were more likely to decrease their sitting time to control their weight compared with their advantaged counterparts (OR for secondary school or lower education = 1.78, 95 % CI 1.11, 2.84). They were also more likely to believe that losing weight was expensive, not of high priority, required a lot of cooking skills and involved eating differently from others in the household. CONCLUSIONS: Marked socio economic inequalities existed with regard to engaging in WCB, the type of weight control strategies used and the perceived barriers to weight control; these differences are consistent with socio-economic gradients in weight status. These factors may need to be included in health promotion strategies that address socio economic inequalities in weight status, as well as inequalities in weight-related health outcomes. PMID- 21557868 TI - Improvement of meal composition by vegetable variety. AB - OBJECTIVE: Our physical environment influences our daily food choices unconsciously. Strategic changes in the food environment might therefore be potential measures to influence consumers' food selection towards better nutrition, without affecting the consumers' freedom of choice. The present study aimed to examine whether increased vegetable variety enhances healthy food choices and improves meal composition. DESIGN: A randomised experiment. SETTING: Participants were instructed to serve themselves a lunch from a buffet of food replicas. Individuals were randomly assigned to one of three food combinations: condition A - cooked carrots, pasta and chicken; condition B - cooked green garden beans, pasta and chicken; condition AB - carrot sticks, green garden beans, pasta and chicken. Two one-vegetable conditions were compared with one two vegetable condition. Data from Zurich, Switzerland, were analysed using one-way ANOVA. SUBJECTS: Ninety-eight students (fifty-three men; mean age 22.8 (sd 2.2) years, minimum = 19 years, maximum = 29 years). RESULTS: Participants who could choose from two vegetables derived significantly more energy (141 kJ) from vegetables compared with participants in the one-vegetable condition (104 and 84 kJ, respectively). Furthermore, in the two-vegetable condition, the relative energy of the meal derived from vegetables (10.9 %) increased significantly compared with the one-vegetable condition (8 % and 6.1 %, respectively). The total energy content of the meal (mean 1472 (sd 468) kJ) was not affected by the experimental manipulation. CONCLUSIONS: Having a choice of vegetables increases a person's tendency to choose vegetables and leads to the selection of a more balanced meal. Serving an assortment of vegetables as side dishes might be a simple and effective strategy to improve food selection. PMID- 21557869 TI - Changes in socio-economic differences in food habits over time. AB - OBJECTIVE: To examine absolute socio-economic differences in food habits and their changes over time. DESIGN: A longitudinal study using the cohort baseline mail surveys conducted in 2000-2002 (n 8960, response rate 67 %) and the follow up in 2007 (n 7332, response rate 83 %), including data on seven food habits recommended in the national dietary guidelines, as well as socio-economic and sociodemographic variables. SETTING: Data from the Helsinki Health Study survey, followed up for 5-7 years. SUBJECTS: Municipal employees of the City of Helsinki, Finland. RESULTS: Apart from fish and vegetable-based margarine on bread, the proportions of the recommended food items were higher for women than for men. The consumption of the recommended food items either increased or remained stable over the follow-up period. On the basis of the slope index of inequality (SII) it was observed that socio-economic differences widened with regard to the consumption of fresh vegetables and fish and use of vegetable-based margarine or oil in cooking, with the upper classes consuming these foods more often. The largest differences were observed in the consumption of fresh vegetables, for which the SII value among women was 2.38 (95 % CI 1.93, 2.95) at baseline and 2.47 (95 % CI 2.01, 3.03) at follow-up, and 3.36 (95 % CI 1.80, 6.28) and 3.47 (95 % CI 1.95, 6.19) for men, respectively. Socio-economic differences were non existent for milk, and the reverse was observed for dark bread and vegetable based margarine on bread. CONCLUSIONS: Consumption of the recommended food items increased in the examined cohort over time. This increase was mostly similar throughout the socio-economic groups and thus the socio-economic differences remained stable. The upper classes followed the guidelines better with regard to the consumption of vegetables and fish and in the use of vegetable-based margarine or oil in cooking. PMID- 21557870 TI - Socio-economic variables influence the prevalence of inadequate nutrient intake in Brazilian adolescents: results from a population-based survey. AB - OBJECTIVE: To estimate the prevalence of inadequate nutrient intake among adolescents and the association between socio-economic variables and nutritional status. DESIGN: Cross-sectional study with a population-based sample. SETTINGS: The usual nutrient intake distribution was estimated using the Iowa State University method. The Estimated Average Requirement cut-off point method was used to determine the proportion of adolescents with inadequate intake for each nutrient, according to sex, income, parental educational level and nutritional status. SUBJECTS: Twenty-four-hour dietary recalls were applied in 525 male and female Brazilian adolescents aged 14-18 years. RESULTS: The highest prevalence of inadequate nutrient intake was observed for vitamin E (99 % in both sexes). For male and female adolescents, the prevalence of inadequate intake was: Mg, 89 % and 84 %; vitamin A, 78 % and 71 %; vitamin C, 79 % and 53 %; and vitamin B6, 21 % and 33 %, respectively. The prevalence of inadequate intake for niacin, thiamin, riboflavin, Se, Cu and vitamin B12 was <15 %. Individuals in the lower income and lower parental educational level strata had the highest risk of having inadequate intake for P, riboflavin and vitamins A, B6 and B12. Compared with non overweight individuals, overweight individuals had a higher risk of inadequate intake for Mg, vitamin A, P, thiamin and riboflavin. CONCLUSIONS: The present study found a high prevalence of inadequate intake of nutrients that are recognised as being protective against chronic diseases. Adolescents in the lower income and lower parental educational level strata were less likely to have their nutrient intake requirements met. PMID- 21557871 TI - Dietary patterns and their association with obesity and sociodemographic factors in a national sample of Lebanese adults. AB - OBJECTIVE: To identify and characterize dietary patterns in Lebanon and assess their association with sociodemographic factors, BMI and waist circumference (WC). DESIGN: A cross-sectional population-based survey. In a face-to-face interview, participants completed a brief sociodemographic and semiquantitative FFQ. In addition, anthropometric measurements were obtained following standard techniques. Dietary patterns were identified by factor analysis. Multivariate linear regression was used to assess determinants of the various patterns and their association with BMI and WC. SETTING: National Nutrition and Non Communicable Disease Risk Factor Survey (2009), Lebanon. SUBJECTS: A nationally representative sample of 2048 Lebanese adults aged 20-55 years. RESULTS: Four dietary patterns were identified: 'Western', 'Traditional Lebanese', 'Prudent' and 'Fish and alcohol'. Factor scores of the identified patterns increased with age, except for the Western pattern in which a negative association was noted. Women had higher scores for the prudent pattern. Adults with higher levels of education had significantly higher scores for the prudent pattern. The frequency of breakfast consumption was significantly associated with scores of both traditional Lebanese and prudent patterns. Multivariate-adjusted analysis revealed a positive association between scores of the Western pattern and the BMI and WC of study participants. CONCLUSIONS: The findings show the presence of four distinct dietary patterns in the Lebanese population, which were associated with age, sex, education and meal pattern. Only the Western pattern was associated with higher BMI. PMID- 21557872 TI - Relationship of homestead food production with night blindness among children below 5 years of age in Bangladesh. AB - OBJECTIVE: To examine the relationship between homestead food production and night blindness among pre-school children in rural Bangladesh in the presence of a national vitamin A supplementation programme. DESIGN: A cross-sectional study. SETTING: A population-based sample of six rural divisions of Bangladesh assessed in the Bangladesh Nutrition Surveillance Project 2001-2005. SUBJECTS: A total of 158 898 children aged 12-59 months. RESULTS: The prevalence rates of night blindness in children among those who did and did not receive vitamin A capsules in the last 6 months were 0.07 % and 0.13 %, respectively. Given the known effect of vitamin A supplementation on night blindness, the analysis was stratified by children's receipt of vitamin A capsules in the last 6 months. Among children who did not receive vitamin A capsules in the last 6 months, the lack of a home garden was associated with increased odds of night blindness (OR = 3.16, 95 % CI 1.76, 5.68; P = 0.0001). Among children who received vitamin A capsules in the last 6 months, the lack of a home garden was not associated with night blindness (OR = 1.28, 95 % CI 0.71, 2.31; P = 0.4). CONCLUSIONS: Homestead food production confers a protective effect against night blindness among pre-school children who missed vitamin A supplementation in rural Bangladesh. PMID- 21557873 TI - Colostrum avoidance, prelacteal feeding and late breast-feeding initiation in rural Northern Ethiopia. AB - OBJECTIVE: To identify specific cultural and behavioural factors that might be influenced to increase colostrum feeding in a rural village in Northern Ethiopia to improve infant health. DESIGN: Background interviews were conducted with six community health workers and two traditional birth attendants. A semi-structured tape-recorded interview was conducted with twenty mothers, most with children under the age of 5 years. Variables were: parental age and education; mother's ethnicity; number of live births and children's age; breast-feeding from birth through to weaning; availability and use of formula; and descriptions of colostrum v. other stages of breast milk. Participant interviews were conducted in Amharic and translated into English. SETTING: Kossoye, a rural Amhara village with high prevalence rates of stunting: inappropriate neonatal feeding is thought to be a factor. SUBJECTS: Women (20-60 years of age) reporting at least one live birth (range: 1-8, mean: ~4). RESULTS: Colostrum (inger) and breast milk (yetut wotet) were seen as different substances. Colostrum was said to cause abdominal problems, but discarding a portion was sufficient to mitigate this effect. Almost all (nineteen of twenty) women breast-fed and twelve (63 %) reported ritual prelacteal feeding. A majority (fifteen of nineteen, 79 %) reported discarding colostrum and breast-feeding within 24 h of birth. Prelacteal feeding emerged as an additional factor to be targeted through educational intervention. CONCLUSIONS: To maximize neonatal health and growth, we recommend culturally tailored education delivered by community health advocates and traditional health practitioners that promotes immediate colostrum feeding and discourages prelacteal feeding. PMID- 21557874 TI - Young children's food in Liverpool day-care settings: a qualitative study of pre school nutrition policy and practice. AB - OBJECTIVE: To explore nutrition and food provision in pre-school nurseries in order to develop interventions to promote healthy eating in early years settings, especially across deprived communities. DESIGN: An ethnographic approach was used combining participant observation with semi-structured interviews. Research participants were selected purposively using convenience sampling. SETTING: Community pre-school nurseries. SUBJECTS: Nursery managers (n 9), cooks (n 6), staff (n 12), parents (n 12) and children at six nurseries (four private and two attached to children's centres) in Liverpool, UK. RESULTS: Private nurseries had minimal access to information and guidelines. Most nurseries did not have a specific healthy eating policy but used menu planning to maintain a focus on healthy eating. No staff had training in healthy eating for children under the age of 5 years. However, enthusiasm and interest were widespread. The level and depth of communication between the nursery and parents was important. Meal times can be an important means of developing social skills and achieving Early Years Foundation Stage competencies. CONCLUSIONS: Nurseries are genuinely interested in providing appropriate healthy food for under-5s but require support. This includes: improved mechanisms for effective communication between all government levels as well as with nurseries; and funded training for cooks and managers in menu planning, cost-effective food sourcing and food preparation. Interventions to support healthy eating habits in young children developed at the area level need to be counterbalanced by continued appropriate national-level public health initiatives to address socio-economic differences. PMID- 21557875 TI - Middle-school students' school lunch consumption does not meet the new Institute of Medicine's National School Lunch Program recommendations. AB - OBJECTIVE: To compare the school lunch consumption of Texas middle-school students with the 2009 Institute of Medicine's (IOM) school meal report recommendations. These new lunch menu patterns increase fruit to one serving and vegetables to two servings, with 50 % wholegrain food. DESIGN: Lunch food records were collected from middle-school students from four schools in south-east Texas in the spring of 2008, and entered into the Nutrition Data System for Research software. Average intake was calculated for those consuming meals according to the National School Lunch Program (NSLP; n 5414) and for those consuming lunch from other sources (n 239). The percentage of students selecting each food group was calculated. SETTING: Middle schools in south-east Texas. SUBJECTS: Middle school students in south-east Texas. RESULTS: Students consuming NSLP meals reported consuming almost 1/2 serving of fruit, 3/4 serving of vegetables, 8 oz of milk and 1/3 serving of whole grains at lunch. Non-NSLP consumers reported almost no intake of fruit, vegetables or milk, and consumed 1/4 serving of whole grains at lunch. Among NSLP consumers, about 40% selected and consumed a fruit serving. About two-thirds of students selected a vegetable, consuming about 67 %. Less than 4% selected a dark green or orange vegetable. CONCLUSIONS: Students' lunch intake did not meet the new IOM recommendations. Few students selected dark green or orange vegetables, and only 40 % selected fruit. Whole grains consumption was low. Interventions with all stakeholders will be necessary to improve students' food and beverage selections overall when school meal patterns are revised. PMID- 21557876 TI - Supermarket and fast-food outlet exposure in Copenhagen: associations with socio economic and demographic characteristics. AB - OBJECTIVE: To investigate whether exposure to fast-food outlets and supermarkets is socio-economically patterned in the city of Copenhagen. DESIGN: The study was based on a cross-sectional multivariate approach to examine the association between the number of fast-food outlets and supermarkets and neighbourhood-level socio-economic indicators. Food business addresses were obtained from commercial and public business locators and geocoded using a geographic information system for all neighbourhoods in the city of Copenhagen (n 400). The regression of counts of fast-food outlets and supermarkets v. indicators of socio-economic status (percentage of recent immigrants, percentage without a high-school diploma, percentage of the population under 35 years of age and average household income in Euros) was performed using negative binomial analysis. SETTING: Copenhagen, Denmark. SUBJECTS: The unit of analysis was neighbourhood (n 400). RESULTS: In the fully adjusted models, income was not a significant predictor for supermarket exposure. However, neighbourhoods with low and mid-low income were associated with significantly fewer fast-food outlets. Using backwise deletion from the fully adjusted models, low income remained significantly associated with fast-food outlet exposure (rate ratio = 0.66-0.80) in the final model. CONCLUSIONS: In the city of Copenhagen, there was no evidence of spatial patterning of supermarkets by income. However, we detected a trend in the exposure to fast-food outlets, such that neighbourhoods in the lowest income quartile had fewer fast-food outlets than higher-income neighbourhoods. These findings have similarities with studies conducted in the UK, but not in the USA. The results suggest there may be socio-economic factors other than income associated with food exposure in Europe. PMID- 21557877 TI - Does the diet of Tehranian adults ensure compliance with nutritional targets? Observations from the Tehran Lipid and Glucose Study. AB - OBJECTIVE: To analyse dietary compliance with WHO/FAO nutritional objectives, identify food subgroups that contribute to discrepancies between dietary intakes and recommendations, and assess food patterns and risk factor profiles at common nutritional targets. DESIGN: The study was a population-based, cross-sectional assessment of the dietary patterns of Tehranian adults. Usual dietary intake was assessed in relation to common nutritional targets of public health (fat, saturated fat, dietary fibre, fruit and vegetables) using a validated FFQ. Metabolic syndrome (MetS) risk factors were diagnosed based on the Iranian modified diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel III. SETTING: The Tehran Lipid and Glucose Study (2005-2008). SUBJECTS: A total of 2510 individuals (1121 men and 1389 women), aged between 19 and 70 years. RESULTS: Generally, 68.5 % of total grain ounce-equivalents were derived from refined grains, with rice making up 36.6 % of all grains consumed. Solid fat (61.1 %) contributed more to discretionary energy than did added sugars (38.9 %). There was a twofold difference in fruit and vegetable consumption between the lowest and highest quartile categories of dietary fibre intake. The probability of having MetS was significantly lower in the highest quartile of fibre intake v. the lowest (OR = 0.69, 95 % CI 0.58, 0.84 v. OR = 0.92, 95 % CI 0.80, 1.03; P -trend < 0.001), whereas it was higher in the highest quartile of SFA intake v. the lowest (OR = 0.92, 95 % CI 0.78, 0.98 v. OR = 0.71, 95 % CI 0.62, 0.89; P-trend = 0.01). CONCLUSIONS: Complying with common nutritional targets of public health is inversely associated with MetS risk factors in Tehranian adults. These results may initiate measures for future development of regional food-based dietary guidelines. PMID- 21557878 TI - A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. AB - We examined the preliminary feasibility, tolerability and efficacy of single dose, intravenous (i.v.) ketamine in depressed emergency department (ED) patients with suicide ideation (SI). Fourteen depressed ED patients with SI received a single i.v. bolus of ketamine (0.2 mg/kg) over 1-2 min. Patients were monitored for 4 h, then re-contacted daily for 10 d. Treatment response and time to remission were evaluated using the Montgomery-Asberg Depression Rating Scale (MADRS) and Kaplan-Meier survival analysis, respectively. Mean MADRS scores fell significantly from 40.4 (s.e.m.=1.8) at baseline to 11.5 (s.e.m.=2.2) at 240 min. Median time to MADRS score <=10 was 80 min (interquartile range 0.67-24 h). SI scores (MADRS item 10) decreased significantly from 3.9 (s.e.m.=0.4) at baseline to 0.6 (s.e.m. =0.2) after 40 min post-administration; SI improvements were sustained over 10 d. These data provide preliminary, open-label support for the feasibility and efficacy of ketamine as a rapid-onset antidepressant in the ED. PMID- 21557879 TI - Cerebroside-A provides potent neuroprotection after cerebral ischaemia through reducing glutamate release and Ca2+ influx of NMDA receptors. AB - Excessive presynaptic glutamate release after cerebral ischaemia leads to neuronal death mainly through excessive calcium entry of N-methyl-D-aspartate receptors (NMDARs). Our recent study reported that cerebroside can open large conductance Ca2+-activated K+ (BKCa) channels. The present study evaluated the effects of cerebroside-A (CS-A), a single molecule isolated from an edible mushroom, on brain injury after focal or global ischaemia in adult male mice and rats. We herein report that treatment with CS-A after 60-min middle cerebral artery occlusion dose-dependently reduced the cerebral infarction with at least a 6-h efficacious time-window, which was partially blocked by the BKCa channel blocker charybdotoxin (CTX). Treatment with CS-A after 20 min global cerebral ischaemia (four-vessel occlusion) significantly attenuated the death of pyramidal cells in hippocampal CA1 area, which was also sensitive to CTX. CS-A, by opening the BKCa channel, could prevent excessive glutamate release after oxygen-glucose deprivation (OGD). In addition, CS-A could inhibit NMDAR Ca2+ influx, which did not require the activation of the BKCa channel. Furthermore, CS-A blocked the OGD induced NMDAR-dependent long-term potentiation in hippocampal CA1 region. These findings indicate that treatment with CS-A after stroke exerts potent neuroprotection through prevention of excessive glutamate release and reduction of Ca2+ influx through NMDARs. PMID- 21557880 TI - Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults. AB - Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First episode schizophrenia (FES) patients show regional cerebral grey- and white matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey matter differences in cannabis users were within the normal variability of grey matter distribution. By contrast, FES subjects had lower total cerebellar grey matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age matched FES subjects with comorbid cannabis use. Our findings indicate small dose dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology. PMID- 21557881 TI - Does the frequency of follow-up assessments affect clinical trial outcome? A meta analysis and meta-regression of placebo-controlled randomized trials. AB - The number and temporal distribution of follow-up assessments during a clinical trial is a critical factor which may influence the outcome as well as the overall cost of a trial. Therefore, we aimed to examine whether the overall and differential frequency of study observations during the course of a clinical trial affects the risk ratio (RR) of responding to antidepressants vs. placebo, specifically in trials for major depressive disorder (MDD). Medline/Pubmed publication databases were searched for randomized, double-blind, placebo controlled trials of antidepressants for adults with MDD (1 January 1980-11 May 2010). A total of 142 manuscripts involving 256 drug-placebo comparison were pooled (n=38 860). We found that higher overall frequency (OF, frequency of assessments during the entire trial) and higher late frequency (LF, frequency of assessments after the first 3 wk of the trial), but not higher early frequency (EF, frequency of assessments during the first 3 wk of the trial), of follow-up visits predicted a significantly greater RR of responding to antidepressant vs. placebo (coefficient=0.213, p=0.014; coefficient=0.238, p=0.003; and coefficient=0.021, p=0.755, respectively, for OF, LF and EF). None of the measures of frequency examined (OF, EF, LF) significantly predicted the RR of discontinuing antidepressant vs. placebo. These findings suggest that increasing the number of follow-up visits, specifically after the third week rather than within the first 3 wk of the trial, may be an effective approach to improve the likelihood of success in placebo-controlled clinical trials for MDD. PMID- 21557882 TI - Genetic association between helpless trait and depression-related phenotypes: evidence from crossbreeding studies with H/Rouen and NH/Rouen mice. AB - Genetic factors are believed to be involved in the aetiology of unipolar depressive disorders. We have previously described a model built up by selective breeding of mice with different responses in the tail suspension test, a screening test for potential antidepressants. In this model, helpless H/Rouen mice are essentially immobile in this test, as well as in the Porsolt forced-swim test, whereas non-helpless NH/Rouen mice show the opposite behaviour, i.e. very low immobility. However, it is unclear whether or not the other phenotypic differences (forced swim test, locomotor activity, sucrose test, sleep patterns, effect of fluoxetine) observed between H/Rouen and the NH/Rouen mice may be attributed to a genetic drift phenomenon during the selection step, rather than being related to the trait of selection. In this study we used reciprocal crossbreeding between H/Rouen and NH/Rouen mice and obtained a segregating F2 population in order to determine whether phenotypic differences between the two lines co-segregate with the trait of selection. In the segregating F2 population, we found significant and strong genetic correlations between helplessness in the tail suspension test and some phenotypical features associated with depressive disorders such as 'alterations of sleep patterns', behavioural response to fluoxetine, immobility duration in the forced swim test, and anhedonia. Our results converge with clinical observations in depressed humans. These results strengthen the validity of the H/Rouen mouse as a model of depression, notably for preclinical studies with antidepressants. In addition, this model should open the way to identifying genes related to depression-like behaviours. PMID- 21557883 TI - Adjunctive mood stabilizer treatment for hospitalized schizophrenia patients: Asia psychotropic prescription study (2001-2008). AB - Recent studies indicate relatively high international rates of adjunctive psychotropic medication, including mood stabilizers, for patients with schizophrenia. Since such treatments are little studied in Asia, we examined the frequency of mood-stabilizer use and its clinical correlates among hospitalized Asian patients diagnosed with schizophrenia in 2001-2008. We evaluated usage rates of mood stabilizers with antipsychotic drugs, and associated factors, for in-patients diagnosed with DSM-IV schizophrenia in 2001, 2004 and 2008 in nine Asian regions: China, Hong Kong, India, Korea, Japan, Malaysia, Taiwan, Thailand, and Singapore. Overall, mood stabilizers were given to 20.4% (n=1377/6761) of hospitalized schizophrenia patients, with increased usage over time. Mood stabilizer use was significantly and independently associated in multivariate logistic modeling with: aggressive behaviour, disorganized speech, year sampled (2008 vs. earlier), multiple hospitalizations, less negative symptoms, younger age, with regional variation (Japan, Hong Kong, Singapore>Taiwan or China). Co prescription of adjunctive mood stabilizers with antipsychotics for hospitalized Asian schizophrenia patients increased over the past decade, and was associated with specific clinical characteristics. This practice parallels findings in other countries and illustrates ongoing tension between evidence-based practice vs. individualized, empirical treatment of psychotic disorders. PMID- 21557884 TI - Placebo effect after prefrontal magnetic stimulation in the treatment of resistant obsessive-compulsive disorder: a randomized controlled trial. AB - Many patients with obsessive-compulsive disorder (OCD) do not achieve satisfactory symptom improvement with conventional treatments. Here, we evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) applied over the right dorsolateral prefrontal cortex (rDLPFC) in patients with treatment resistant OCD. This was a double-blind randomized trial involving 30 treatment resistant OCD outpatients, allocated to have either sham or active high-frequency rTMS (over the rDLPFC) added to their treatment regimens for 6 wk, with 6 wk of follow-up. Active rTMS consisted of 30 applications (figure-of-eight coil; 10 Hz at 110% of motor threshold; 1 session/d; 40 trains/session; 5 s/train; 25-s intertrain interval). At weeks 0, 2, 6, 8, and 12, we applied the Yale-Brown Obsessive-Compulsive Scale (YBOCS), Clinical Global Impression (CGI) scale, 14 item Hamilton Anxiety Rating Scale (HAMA-14), 17-item Hamilton Depression Rating Scale (HAMD-17), and 36-item Short-form Health Survey. The primary outcome measure was a positive response (>= 30% improvement in YBOCS score, together with a 'much improved' or 'very much improved' CGI - Improvement scale rating). One patient in each group showed a positive response (p=1.00). For YBOCS score, there was significant effect of time (F=7.33, p=0.002) but no significant group effect or group*time interaction. In treatment-resistant OCD, active rTMS over the rDLPFC does not appear to be superior to sham rTMS in relieving obsessive compulsive symptoms, reducing clinical severity, or improving treatment response, although there is evidence of a placebo effect. PMID- 21557886 TI - Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar. AB - Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk. PMID- 21557885 TI - Opposing effects of 5,7-DHT lesions to the core and shell of the nucleus accumbens on the processing of irrelevant stimuli. AB - There is good evidence that forebrain serotonergic systems modulate cognitive flexibility. Latent inhibition (LI) is a cross-species phenomenon which manifests as poor conditioning to a stimulus that has previously been experienced without consequence and is widely considered an index of the ability to ignore irrelevant stimuli. While much research has focused on dopaminergic mechanisms underlying LI, there is also considerable evidence of serotonergic modulation. However, the neuroanatomical locus of these effects remains poorly understood. Previous work has identified the nucleus accumbens (NAc) as a key component of the neural circuit underpinning LI and furthermore, this work has shown that the core and shell subregions of the NAc contribute differentially to the expression of LI. To examine the role of the serotonergic input to NAc in LI, we tested animals with 5,7-dihydroxytryptamine (5,7-DHT) lesions to the core and shell subregions on LI assessed under experimental conditions that produce LI in shams and subsequently with weak stimulus pre-exposure designed to prevent the emergence of LI in shams. We found that serotonergic deafferentation of the core disrupted LI whereas 5,7 DHT lesions to the shell produced the opposite effect and potentiated LI. PMID- 21557887 TI - Diet, insulin-like growth factor-1 and cancer risk. AB - Despite extensive research it has proved difficult to establish the role of diet in the aetiology of common types of cancer. Obesity and alcohol definitely increase the risk for several types of cancer, but the importance of particular foods and nutrients is not clear. Part of the difficulty is our poor understanding of the physiological changes that might mediate the effect of diet on cancer risk. Recent research in prospective studies with biobanks of stored blood samples has shown that the serum concentration of insulin-like growth factor-1 (IGF-1) is positively associated with the risk for both breast cancer in women and prostate cancer in men. It is also known that circulating IGF-1 concentrations can change in response to nutritional changes including energy and protein restriction, and some studies suggest that, even within well-nourished western populations, men and women with relatively high intakes of protein from dairy products have higher blood levels of IGF-1. These observations have led to the hypothesis that high intakes of protein from dairy products might increase the risk for some cancers by increasing the endogenous production of IGF-1. Further evaluation of this hypothesis requires clinical nutritional studies of the effects of diet on IGF-1 metabolism, and large epidemiological studies of cancer risk incorporating reliable measures of diet and serum IGF-1 concentrations. PMID- 21557888 TI - Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study. AB - BACKGROUND: Depression has been associated with limbic hyperactivation and frontal hypoactivation in response to negative facial stimuli. Anxiety disorders have also been associated with increased activation of emotional structures such as the amygdala and insula. This study examined to what extent activation of brain regions involved in perception of emotional faces is specific to depression and anxiety disorders in a large community-based sample of out-patients. METHOD: An event-related functional magnetic resonance imaging (fMRI) paradigm was used including angry, fearful, sad, happy and neutral facial expressions. One hundred and eighty-two out-patients (59 depressed, 57 anxiety and 66 co-morbid depression anxiety) and 56 healthy controls selected from the Netherlands Study of Depression and Anxiety (NESDA) were included in the present study. Whole-brain analyses were conducted. The temporal profile of amygdala activation was also investigated. RESULTS: Facial expressions activated the amygdala and fusiform gyrus in depressed patients with or without anxiety and in healthy controls, relative to scrambled faces, but this was less evident in patients with anxiety disorders. The response shape of the amygdala did not differ between groups. Depressed patients showed dorsolateral prefrontal cortex (PFC) hyperactivation in response to happy faces compared to healthy controls. CONCLUSIONS: We suggest that stronger frontal activation to happy faces in depressed patients may reflect increased demands on effortful emotion regulation processes triggered by mood incongruent stimuli. The lack of strong differences in neural activation to negative emotional faces, relative to healthy controls, may be characteristic of the mild-to-moderate severity of illness in this sample and may be indicative of a certain cognitive-emotional processing reserve. PMID- 21557889 TI - Child-, adolescent- and young adult-onset depressions: differential risk factors in development? AB - BACKGROUND: Previous research reported that childhood adversity predicts juvenile onset but not adult-onset depression, but studies confounded potentially genuine differences in adversity with differences in the recency with which adversity was experienced. The current study paper took into account the recency of risk when testing for differences among child-, adolescent- and young adult-onset depressions. METHOD: Up to nine waves of data were used per subject from two cohorts of the Great Smoky Mountains Study (GSMS; n=1004), covering children in the community aged 9-16, 19 and 21 years. Youth and one of their parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA) between ages 9 and 16; these same youth were interviewed using the Young Adult Psychiatric Assessment (YAPA) at ages 19 and 21. The most common psychosocial risk factors for depression were assessed: poverty, life events, parental psychopathology, maltreatment, and family dysfunction. RESULTS: Consistent with previous research, most childhood psychosocial risk factors were more strongly associated with child-onset than with adolescent-/adult-onset depression. When potentially genuine risk differences among the depression-onset groups were disentangled from differences due to the recency of risk, child- and young adult onset depression were no longer different from one another. Adolescent-onset depression was associated with few psychosocial risk factors. CONCLUSIONS: There were no differences in putative risk factors between child- and young adult-onset depression when the recency of risk was taken into account. Adolescent-onset depression was associated with few psychosocial risk factors. It is possible that some adolescent-onset depression cases differ in terms of risk from child- and young adult-onset depression. PMID- 21557890 TI - The proposed 2/11 symptom algorithm for DSM-5 substance-use disorders is too lenient. PMID- 21557891 TI - Characteristics of and trends in subgroups of prisoner suicides in England and Wales. AB - BACKGROUND: The suicide rate is higher in prisoners compared with the general population. The aim was to describe the characteristics of and longitudinal trends in prisoner suicides in England and Wales. METHOD: A case series was ascertained from the Safer Custody and Offender Policy Group at the Ministry of Justice and included a 9-year (1999-2007) national census of prisoner suicides. Questionnaires were completed by prison staff on sociodemographic, custodial, clinical and service-level characteristics of the suicides. RESULTS: There was a fall in the number of prison suicides and a decline in the proportion of young prisoner (18-20 years) suicides over time. Females were over-represented. Upward trends were found in prisoners with a history of violence and with previous mental health service contact. A downward trend was found in those with a primary psychiatric diagnosis of drug dependence. Drug dependence was found to be significant in explaining suicides within the first week of custody. CONCLUSIONS: The findings provide an important insight to aid a target set in the National Suicide Prevention Strategy in England to reduce suicides in the prisoner population by 20% and highlight an important area for policy development in mental health services. Examining trends identified subgroups that may require improved mental healthcare and recognized those that appeared to be having their treatment needs more adequately met. Evidence suggests that targeted suicide prevention strategies for subgroups of prisoners are required. PMID- 21557892 TI - Common limbic and frontal-striatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis. AB - BACKGROUND: Direct comparisons of brain function between obsessive compulsive disorder (OCD) and other anxiety or OCD spectrum disorders are rare. This study aimed to investigate the specificity of altered frontal-striatal and limbic activations during planning in OCD, a prototypical anxiety disorder (panic disorder) and a putative OCD spectrum disorder (hypochondriasis). METHOD: The Tower of London task, a 'frontal-striatal' task, was used during functional magnetic resonance imaging measurements in 50 unmedicated patients, diagnosed with OCD (n=22), panic disorder (n=14) or hypochondriasis (n=14), and in 22 healthy subjects. Blood oxygen level-dependent (BOLD) signal changes were calculated for contrasts of interest (planning versus baseline and task load effects). Moreover, correlations between BOLD responses and both task performance and state anxiety were analysed. RESULTS: Overall, patients showed a decreased recruitment of the precuneus, caudate nucleus, globus pallidus and thalamus, compared with healthy controls. There were no statistically significant differences in brain activation between the three patient groups. State anxiety was negatively correlated with dorsal frontal-striatal activation. Task performance was positively correlated with dorsal frontal-striatal recruitment and negatively correlated with limbic and ventral frontal-striatal recruitment. Multiple regression models showed that adequate task performance was best explained by independent contributions from dorsolateral prefrontal cortex (positive correlation) and amygdala (negative correlation), even after controlling for state anxiety. CONCLUSIONS: Patients with OCD, panic disorder and hypochondriasis share similar alterations in frontal-striatal brain regions during a planning task, presumably partly related to increased limbic activation. PMID- 21557893 TI - Neural response to angry and disgusted facial expressions in bulimia nervosa. AB - BACKGROUND: Processing emotional facial expressions is of interest in eating disorders (EDs) as impairments in recognizing and understanding social cues might underlie the interpersonal difficulties experienced by these patients. Disgust and anger are of particular theoretical and clinical interest. The current study investigated the neural response to facial expressions of anger and disgust in bulimia nervosa (BN). METHOD: Participants were 12 medication-free women with BN in an acute episode (mean age 24 years), and 16 age-, gender- and IQ-matched healthy volunteers (HVs). Functional magnetic resonance imaging (fMRI) was used to examine neural responses to angry and disgusted facial expressions. RESULTS: Compared with HVs, patients with BN had a decreased neural response in the precuneus to facial expressions of both anger and disgust and a decreased neural response to angry facial expressions in the right amygdala. CONCLUSIONS: The neural response to emotional facial expressions in BN differs from that found in HVs. The precuneus response may be consistent with the application of mentalization theory to EDs, and the amygdala response with relevant ED theory. The findings are preliminary, but novel, and require replication in a larger sample. PMID- 21557894 TI - Life history theory as a possible explanation for teenage pregnancy. PMID- 21557895 TI - Panic disorder and its subtypes: a comprehensive analysis of panic symptom heterogeneity using epidemiological and treatment seeking samples. AB - BACKGROUND: Panic disorder (PD) is a heterogeneous syndrome that can present with a variety of symptom profiles that potentially reflect distinct etiologic pathways. The present study represents the most comprehensive examination of phenotypic variance in PD with and without agoraphobia for the purpose of identifying clinically relevant and etiologically meaningful subtypes. METHOD: Latent class (LC) and factor mixture analysis were used to examine panic symptom data ascertained from three national epidemiologic surveys [Epidemiological Catchment Area (ECA), National Comorbidity Study (NCS), National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), Wave 1], a twin study [Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD)] and a clinical trial (Cross-National Collaborative Panic Study [CNCPS]). RESULTS: Factor mixture models (versus LC) generally provided better fit to panic symptom data and suggested two panic classes for the ECA, VATSPSUD and CNCPS, with one class typified by prominent respiratory symptoms. The NCS yielded two classes, but suggested both qualitative and quantitative differences. The more contemporary NESARC sample supported a two and three class model, with the three class model suggesting two variants of respiratory panic. The NESARC's three class model continued to provide the best fit when the model was restricted to a more severe form of PD/panic disorder with agoraphobia. CONCLUSIONS: Results from epidemiologic and clinical samples suggest two panic subtypes, with one subtype characterized by a respiratory component and a second class typified by general somatic symptoms. Results are discussed in light of their relevance to the etiopathogenesis of PD. PMID- 21557896 TI - Cannabis use and psychosis: re-visiting the role of childhood trauma. AB - BACKGROUND: Cannabis consumption continues to be identified as a causal agent in the onset and development of psychosis. However, recent findings have shown that the effect of cannabis on psychosis may be moderated by childhood traumatic experiences. METHOD: Using hierarchical multivariate logistic analyses the current study examined both the independent effect of cannabis consumption on psychosis diagnosis and the combined effect of cannabis consumption and childhood sexual abuse on psychosis diagnosis using data from the Adult Psychiatric Morbidity Survey 2007 (n=7403). RESULTS: Findings suggested that cannabis consumption was predictive of psychosis diagnosis in a bivariate model; however, when estimated within a multivariate model that included childhood sexual abuse, the effect of cannabis use was attenuated and was not statistically significant. The multivariate analysis revealed that those who had experienced non-consensual sex in childhood were over six times [odds ratio (OR) 6.10] more likely to have had a diagnosis of psychosis compared with those who had not experienced this trauma. There was also a significant interaction. Individuals with a history of non-consensual sexual experience and cannabis consumption were over seven times more likely (OR 7.84) to have been diagnosed with psychosis compared with those without these experiences; however, this finding must be interpreted with caution as it emerged within an overall analytical step which was non-significant. CONCLUSIONS: Future studies examining the effect of cannabis consumption on psychosis should adjust analyses for childhood trauma. Childhood trauma may advance existing gene-environment conceptualisations of the cannabis-psychosis link. PMID- 21557897 TI - Abnormalities of object visual processing in body dysmorphic disorder. AB - BACKGROUND: Individuals with body dysmorphic disorder (BDD) may have perceptual distortions for their appearance. Previous studies suggest imbalances in detailed relative to configural/holistic visual processing when viewing faces. No study has investigated the neural correlates of processing non-symptom-related stimuli. The objective of this study was to determine whether individuals with BDD have abnormal patterns of brain activation when viewing non-face/non-body object stimuli. METHOD: Fourteen medication-free participants with DSM-IV BDD and 14 healthy controls participated. We performed functional magnetic resonance imaging (fMRI) while participants matched photographs of houses that were unaltered, contained only high spatial frequency (HSF, high detail) information or only low spatial frequency (LSF, low detail) information. The primary outcome was group differences in blood oxygen level-dependent (BOLD) signal changes. RESULTS: The BDD group showed lower activity in the parahippocampal gyrus, lingual gyrus and precuneus for LSF images. There were greater activations in medial prefrontal regions for HSF images, although no significant differences when compared to a low-level baseline. Greater symptom severity was associated with lower activity in the dorsal occipital cortex and ventrolateral prefrontal cortex for normal spatial frequency (NSF) and HSF images. CONCLUSIONS: Individuals with BDD have abnormal brain activation patterns when viewing objects. Hypoactivity in visual association areas for configural and holistic (low detail) elements and abnormal allocation of prefrontal systems for details are consistent with a model of imbalances in global versus local processing. This may occur not only for appearance but also for general stimuli unrelated to their symptoms. PMID- 21557898 TI - [Effect of miR-146a on IL-18 expression in mouse macrophage]. AB - AIM: To investigate the effect of miR-146a on the Th1/Th2 cytokine expression in mouse RAW264.7 cell line and primary peritoneal macrophage. METHODS: miR-146a mimics, mimics negative control (NC mimics), inhibitor miR-146a and inhibitor negative control (NC inhibitor) were transfected into RAW264.7 cells and freshly isolated peritoneal macrophage. IL-18, IL-5 and IL-10 expressions in the cells were measured by real time PCR. RESULTS: MiR-146a mimics suppressed IL-18 expression (P<0.05), and miR-146a specific inhibitor increased IL-18 expression significantly (P<0.05). However, IL-5 and IL-10 expressions were not affected by both miR-146a mimics and miR-146a inhibitor transfections. CONCLUSION: These data demonstrate at first time that miR-146a can regulate Th1 cytokine IL-18 expression, but not affect Th2 cytokine IL-5 and IL-10 expressions. PMID- 21557899 TI - [Effects of natural killer cells stimulated with immobilized MHC class I chain related antigen A on activities of dendritic cells]. AB - AIM: To observe the effects of NK cells stimulated with immobilized MHC class I chain-related antigen A (iMICA) on activities of dendritic cells (DCs). METHODS: Firstly fresh allogeneic NK cells, or iMICA-stimulated allogeneic NK cells, and autologous NK cells stimulated with IL-2 or IL-2 and iMICA were co-cultured with immature DCs (iDCs) at the ratio of 5:1 for 24 hours. Frequencies of HLA-DR positive or CD86 positive DCs were detected by flow cytometry. Next autologous NK cells stimulated with iMICA were co-cultured with iDCs at the ratio of 1:5 for 24 hours. Variation of HLA-DR or CD86 expression on dendritic cells was measured. Lastly IFN-gamma neutralizing antibody was added into the NK-DCs co-culture system to observe HLA-DR or CD86 expression on DCs. RESULTS: When NK:iDCs ratio was 5:1, both fresh allogeneic and activated autologous NK cells killed iDCs efficiently. iMICA did not synergize this cytotoxicity. However, when NK:iDCs ratio was 1:5, NK cells activated by iMICA promoted HLA-DR and CD86 expression on DCs. IFN-gamma antibody down-regulated HLA-DR and CD86 expression on DCs which were co-cultured with iMICA-activated NK cells. CONCLUSION: iMICA is redundant as fresh allogeneic or activated autologous NK cells killed iDCs. However, if numbers of NK cell are less than those of DCs, iMICA can stimulate NK cells to produce IFN-gamma for DCs maturation. PMID- 21557900 TI - [Analysis of TCR gene rearrangement for identification of T cell leukemia clone by using fine-tiling aCGH]. AB - AIM: To establish a new method which analyzes T cell receptor (TCR) gene rearrangement for identification of T cells acute lymphoblastic leukemia (T-ALL) clone, it will provide the basis for the study of T-ALL including the chromosome translocation involving TCR loci. METHODS: Total DNA was isolated from peripheral blood mononuclear cells (PBMC) of one case with T-ALL. Using the fine-tiling array comparative genomic hybridization (fine-tiling aCGH) to analyze the genomic DNA differences of the case and control group, we could find the breakpoints and their position in the chromosomes. According to the preliminary results, we could design the specific primers for the positions of the breakpoints relative to sequence. Furthermore, the ligation-mediated PCR (LM-PCR) and sequence analysis were used to identify the TCR gene rearrangement. And TCR gene expression was detected by RT-PCR. RESULTS: The fine-tiling aCGH results of the T-ALL showed that the TCRalpha/delta locus of chromosome 14 appeared four breakpoints, corresponding to TCR Vdelta1, Vdelta2, Jdelta1 and Jdelta2. By LM-PCR, sequencing and sequence analysis, TCR gene of the case of T-ALL was involved in Vdelta1Ddelta2Ddelta3Jdelta1, Vdelta2Ddelta3Jdelta2 rearrangement. RT-PCR results also confirmed the expression of these TCR gene rearrangements. CONCLUSION: The results demonstrated that fine-tiling aCGH and LM-PCR techniques could be used to identify the TCR gene rearrangement as one of the best perfect methods. And it was also a way to find some fusion genes involving in TCR gene. PMID- 21557901 TI - [Activation of tumor necrosis factor receptor-associated factor 6 in anti beta2GPI/beta2GPI-induced tissue factor expression on THP-1 cells]. AB - AIM: To investigate whether tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in anti-beta2GPI/beta2GPI-induced tissue factor (TF) expression on THP-1 cells. METHODS: The total RNA was extracted and the protein lysates were collected from THP-1 cells stimulated with anti-beta2GPI/beta2GPI complex. And then the TF expression on THP-1 cells was detected by real-time quatitative PCR (RT-qPCR) and TF activity kit. TRAF6 mRNA and its protein expression were investigated by RT-qPCR and Western blotting, respectively. The proteasome inhibitor, MG-132, was used for inhibitory assays, in order to demonstrate the effect of anti-beta2GPI/beta2GPI complex on THP-1 cells. RESULTS: The TF expression (both mRNA and activity) on THP-1 cells was significantly up regulated with the treatment of anti-beta2GPI/beta2GPI complex (100 mg/L), compared with untreated cells(P<0.05). The TRAF6 mRNA and protein levels in THP-1 cells were also significantly increased with the treatment of anti beta2GPI/beta2GPI complex. The expression of TRAF6 was shown in a time-dependent manner, with the maximal level at 15 minutes (mRNA) and 30 minutes (protein) respectively. All the stimulating effects of anti-beta2GPI/beta2GPI complex (100 mg/L) on THP-1 cells were inhibited by MG-132 (5 MUmol/L). CONCLUSION: TRAF6 is up-regulated and contributes to TF expression on THP-1 cells induced with anti beta2GPI/beta2GPI complex. PMID- 21557902 TI - [Phenotypic analysis of BCG-specific effector memory CD4+ T cells in PBMCs by eight-color flow cytometry]. AB - AIM: To evaluate cytokine production and subsets in PBMCs from PPD+ normal donors after stimulation with BCG. METHODS: PBMCs were isolated from PPD+ normal individuals, and cytokine production and BCG-specific T cell subsets were assessed by eight-color flow cytometry. RESULTS: Following stimulation with BCG, CD4+ but not CD8+ T cells expressed IFN-gamma, IL-2 and TNF-alpha. Phenotypic analysis indicated that cytokine-producing cells were CD4+CD45RO+CD62L-CD27- and CD4+CD45RO+CD62L-CD27+. CONCLUSION: BCG predominantly induced CD4+ T cells to produce cytokines following stimulation with BCG. Further analysis indicated that these cells are CD4+CD45RO+CD62L- effector memory cells, suggesting that these cells probably played essential role in preventing TB infection. PMID- 21557903 TI - [Construction and expression of the eukaryotic expression vector carrying HSV-1 gC glycoprotein gene]. AB - AIM: To stably express herpes simplex virus type 1 (HSV-1) glycoprotein C (gC) in Chinese hamster ovary cells (CHO-K1). METHODS: The eukaryotic expression vector pCI-mCMV-gC-1-IRES-DHFR-L22R was constructed and transfected into CHO-K1 cells by Lipofectamine 2000. The transfected cells were selected by G418 and methotrexate (MTX). The expression of HSV-1 gC was analyzed by Slot blot. HSV-1 gC proteins were purified with His-Ni Sepharose and then detected by Western blot. RESULTS: The eukaryotic expression vector pCI-mCMV-gC-1-IRES-DHFR-L22R was constructed successfully. CHO-K1 cells stably expressing HSV-1 gC proteins were established and confirmed by Western blot. CONCLUSION: The HSV-1 gC proteins have been expressed successfully and have good bioactivity. The results make it possible for further study and clinical use of HSV-1 gC. PMID- 21557904 TI - [Construction of the eukaryotic expression vector encoding multi-epitope fusion protein of human survivin and its expression in dendritic cells]. AB - AIM: To construct a eukaryotic expression vector encoding the multi-epitope fusion protein of human survivin, and express it in human dendritic cells. METHODS: Recombinant cDNA sequence encoding four HLA-A2-restricted CD8+ CTL epitopes and a CD4+ Th epitope was synthesized and cloned into pBluescript II SK (+) vector. After confirmed by sequencing, the cDNA fragment was inserted to eukaryotic expression vector pIRESneo3.0 to generate the recombinant plasmid pPIRESneo3.0-survivin (4)/Th. The pPIRESneo3.0-survivin (4)/Th was then transfected into human dendritic cells and the transfectants were selected for stable expression. RESULTS: The eukaryotic expression vector encoding the multi epitope fusion protein of survivin was constructed, and successfully transfected into human dendritic cells. CONCLUSION: The eukaryotic expression vector encoding the multi-epitope fusion protein of survivin has been constructed successfully, and stably expressed in human dendritic cells, which provides clues for further research on multi-epitope cancer vaccine. PMID- 21557905 TI - [Construction and expression of a coxsackievirus A16 VP1 gene plasmid which delivered by live attenuated Salmonella]. AB - AIM: To develop a coxsackievirus A16 (Cox A16) VP1 gene plasmid which delivered by live attenuated Salmonella. METHODS: The plasmid which expressed VP1 protein of CoxA16 was constructed by gene recombination. Cellular expression was assessed by Western bloten analysis. Then the recombinant attenuated Salmonella which harboring the plasmid were constructed by electro transformation. RESULTS: CoxA16 VP1 gene sequence was inserted into a eukaryotic expression plasmid. VP1 protein was detected in the culture supernatant. CONCLUSION: The plasmid is constructed successfully and it can be expressed effectively in vitro. The recombinant bacteria are constructed successfully. This has provided a basis for further research of an oral CoxA16 vaccine. PMID- 21557906 TI - [Construction and identification of the expression library of album pollen allergens cDNA]. AB - AIM: To construct and identify the express library of album pollen allergens cDNA. METHODS: Total RNA were extracted from the album pollen with TRIzol reagent and the mRNA was isolate for the amplify followed. A double stranded cDNA (ds cDNA) was synthesized using primers containing Xho I and Poly(dT) sequence by ZAP Express(r)cDNA synthesis kit. The ds cDNA was modified and purified by gel chromatography, and then the cDNA fragment with the length of more than 400 bp containing sticky ends was obtained. The cDNA fragment was ligated with Uni-ZAP XR vector and subsequently treated with in vitro packaging using phage by ZAP cDNA express GigapackIII Gold cloning kit. The express library of album pollen cDNA was constructed by in vitro packaging. The recombination rate and the lengths of fragments inserted of the cDNA library were detected by polymerase chain reaction. RESULTS: The titer and the recombination rate of cDNA expression library constructed were 9.7*10(5) and 100%, respectively. The capacity of the library was 4.85 Pfu. The average length of cDNA fragments inserted was about 1.0 kb. CONCLUSION: Based on the capacity of cDNA expression library constructed and the length of cDNA insertion fragments, the cDNA expression library constructed is qualified to screening target cDNA clone, laying the foundation for preparation of gene recombinant allergen pollen vaccine. PMID- 21557907 TI - [Construction of recombinant eukaryotic expression vector pDsRed1-C3/XAPC7 and cellular localization of XAPC7 protein in different cell lines]. AB - AIM: To construct the recombinant eukaryotic expression vector pDsRed1-C3/XAPC7 and to investigate the cellular localization of XAPC7 protein in 786-O and 293T and Chang liver cell lines. METHODS: The cDNA of XAPC7 was amplified from HBE135 E6E7 cell line by RT-PCR method. The aim gene fragment XAPC7 from pMD18-T/XAPC7 was subcloned into eukaryotic expression vector pDsRed1-C3. The recombinant plasmid pDsRed1-C3/XAPC7 was identificated by BamH I/Xho I double digestion and sequence analysis, and then transfected into786-O and 293T and Chang liver cell lines by lipofectamine 2000. The expression and cellular localization of XAPC7 protein were detected by fluorescence microscope. RESULTS: The construction of the recombinant plasmid pDsRed1-C3/XAPC7 was proved successfully by restriction enzyme digestion analysis and DNA sequencing. Red fluorescent protein pDsRed1 C3/XAPC7 was distributed granularly in transfected cell lines. Our researches showed that XAPC7 protein was mainly expressed in the cytoplasm of 786-O cell line, rare in its nucleus, evenly distributed in the cytoplasm and nucleus of 293T cell line, and mainly located in the cytoplasm of Chang liver cell line, few in its nucleus. CONCLUSION: The eukaryotic expression plasmid pDsRed1-C3/XAPC7 has been successfully constructed and expressed in the 786-O and 293T and Chang liver cell lines, but there was obvious difference in different cell lines. Our researches will help further studies on the function of human gene XAPC7. PMID- 21557908 TI - [Expression, purification and identification of fusion protein mTSLPR-Ig]. AB - AIM: To construct an adenovirus vector (Ad-mTSLPR-Ig) expressing the fusion protein of the extracellular domain of mouse TSLPR and the Fc fragment of mouse Ig, further purify and assess the soluble fusion protein mTSLPR-Ig. METHODS: The gene of mTSLPR extracellular domain was amplified from cDNA library of mouse thymus by PCR. Then an adenovirus vector (Ad-mTSLPR-Ig) expressing the fusion protein of mTSLPR and the Fc fragment of mouse Ig was constructed. After Ad mTSLPR-Ig was transfected into COS-7 cells, the supernatants were collected. The fusion proteins in the supernatants were detected by double antibody sandwich ELISA. The soluble fusion proteins mTSLPR-Ig were purified by protein A affinity chromatography. RESULTS: The gene sequence of Ad-mTSLPR-Ig was confirmed by DNA sequencing, and the recombinat adenoviruses harboring mTSLPR-Ig were successfully obtained after the infection of Ad-mTSLPR-Ig. Fusion proteins mTSLPR-Ig in the supernatants were detected by ELISA assay. The purified fusion protein were obtained by affinity chromatography, and identified by Western blot. CONCLUSION: The soluble fusion proteins mTSLPR-Ig have been obtained successfully, which enables further study of its biological activity. PMID- 21557909 TI - [Effect of cyclophilin A on monocyte-derived foam cells]. AB - AIM: To observe whether cyclophilin A (CypA)has an effect on macrophage-derived foam cells, and to investigate the involvement of CypA in the development of atherosclerosis. METHODS: The foam cell model was established through incubating the human monocyte line (THP-1 cells) with oxidized low density lipoproteins (ox LDL). The cells were stained with fresh oil red O to study the morphology of the macrophage-derived foam cells. The cell adhesion, invasion and the production of matrix metalloproteinase (MMPs) of the macrophage-derived foam cells were detected by adhesion assay, invasion assay and gelatin zymography respectively both in the absence or presence of different concentrations of purified CypA (50, 100, 200 MUg/L). Then the foam cells were respectively pre-treated with CsA, c7b8f10, HAb18 mAb, and dual treatment of c7b8f10 and HAb18 mAb respectively, to investigate the inhibitory effect on macrophage-derived foam cells. RESULTS: The adhesion, invasion and the production of MMP-9 and MMP-2 were enhanced during the differentiation of monocytes into macrophages (P<0.05). CypA, especially in the concentration of 100 ng/mL, significantly promoted the function of macrophage derived foam cells (P<0.05). CsA, c7b8f10, HAb18 mAb, and c7b8f10- HAb18 mAb combination dramatically inhibited the function of macrophage-derived foam cells both in the absence or presence of CypA (P<0.05). The c7b8f10- HAb18 mAb combination pretreatment had the most obviously suppressive effect on macrophage derived foam cells (P<0.05). CONCLUSION: These findings suggest that CypA up regulates the adhesion, the invasion and the expressions of MMP-2 and MMP-9 in macrophage-derived foam cells. The CypA effect is blocked by the pretreatment of the different antagonists. This research might suggest the correlation between atherosclerosis pathogenesis and the vulnerability of atherosclerotic plaques, and thus give us some good ideas for atherosclerosis therapy in future. PMID- 21557910 TI - [Effect of tetramethylpyrazine on JAK-STAT signal transduction in cardiomyocyte hypertrophy]. AB - AIM: To study the effect of Tetramethylpyrazine (TMZ), the extracts of Chinese Herbs which accelerat blood circulation, on JAK-STAT signal transduction in cardiomyocyte hypertrophy. METHODS: Cardiomyocyte hypertrophy Wistar rats model was established. The cardiomyocytes were seperated from one-day-old neonatal rats. The total RNA of cardiomyocytes was extracted by TRIzol reagent. Then the ANP mRNA were detected by RT-PCR. pJAK2, pJAK1 and pSTAT3 molecules were analysed by Western blot respectively. RESULTS: Statistics analysis showed that TMZ significantly decreased the expression of ANP mRNA in cardiomyocytes (P<0.01), and that TMZ also decreased the levels of pJAK2, pJAK1 or pSTAT3 (P<0.01). CONCLUSION: TMZ has the inhibitory effect on JAK-STAT signal transduction in cardiomyocyte hyertrophy, suggesting the clinical application of traditional Chinese medicine on cardiomyocyte hypertrophy treatment. PMID- 21557911 TI - [Purification of Cyanovirin-N with antiviral activity and preparation as well as modification of its polyclonal antibody]. AB - AIM: To purify the recombinant Cyanovirin-N (CVN) and determine its anti influenza virus A (H1N1) activity, and to prepare the polyclonal antibody of CVN, purify it and label it with an enzyme for future application. METHODS: The recombinant CVN were rapidly purified by two rounds of Ni-NTA chelating chromatography intervened with a SUMO protease cleavage step. Anti-H1N1 activity of CVN was determined using cytopathogenic effect assay (CPE). The rabbits were immunized with the purified CVN and the antibody was identified by ELISA and Western blot. IgG was purified by ammonium sulfate precipitation followed by DEAE chromatography and the purified IgG was labeled by HRP. RESULTS: The purity of the obtained CVN protein which showed obvious Anti-H1N1 activity in vitro was higher than 95%.The polyclonal antibody of CVN was successfully produced in the rabbits and the results of ELISA and Western blot showed that the antiserum had high titer and high specificity. The purified antibody with a titer up to 1:6 400 was successfully obtained and the anti-CVN antibody-HRP conjugate was achieved after labeling the purified antibody with HRP. CONCLUSION: The purified antibody against CVN has been purified and further coniugated with HRP, with can be used for future research. PMID- 21557912 TI - [Expression of VP0 protein of enterovirus 71 in Escherichia coli and generation of the corresponding polyclonal antibodies in guinea pigs]. AB - AIM: To obtain recombinant VP0 protein of enterovirus 71, and generate the corresponding VP0-specific polyclonal antibodies, for molecular detection and characterization of EV71. METHODS: The VP0 gene was amplified by PCR and cloned into vector pET26b to make pET-VP0 for the prokaryotic expression of VP0. The recombinant VP0 protein was expressed in E.coli BL21 harboring pET-VP0, purified from inclusion bodies, renatured, and subsequently used to immunize guinea pigs. The resultant antisera were evaluated for anti-VP0 titer, binding capacity and specificity by ELISA, immunofluorescence staining and Western blot assays. RESULTS: Recombinant protein VP0 was efficiently produced in E.coli. Immunization of guinea pigs with recombinant VP0 elicited high-titer (1:10(6)) VP0-specific antibodies. Western blot analysis showed the resultant anti-VP0 sera reacted with E.coli-expressed VP0 as well as EV71 propagated in Vero cells. Moreover, the antisera positively recognized EV71 infected cells by immunofluorescence staining. CONCLUSION: The recombinant VP0 and the corresponding polyclonal antibodies can be used to identify and characterize EV71, and therefore represent useful agents and tools for the development of new diagnostic methods and vaccines for EV71. PMID- 21557913 TI - [Preparation and identification of monoclonal antibody against human growth differentiation factor 15]. AB - AIM: To prepare the monoclonal antibody (mAb) against human growth differentiation factor 15 (GDF15). METHODS: The expression vector pGEX-4T-2-gdf15 was constructed and transformed into E.coli Top10F' for expression. Then the purified fusion protein was used to immunize the BALB/c mice. The mouse myeloma cells (Sp2/0) were fused with spleen cells from the BALB/c immunized by the purified protein. Subsequently, limited dilution method was used three times to screen hybridoma cell lines. The titer of the mAb was detected by ELISA and its specificity was analyzed by Western blot. The serum level of GDF15 in hepatocellular carcinoma (HCC) and health people was measured by co immunoprecipitation (IP) method. RESULTS: The GST-GDF15 fusion protein was successfully expressed and purified. One hybridoma cell line designated 9G3 against GDF15 was obtained. IP and mass spectrometric analysis revealed that the mAb recognized GDF15 in human sera with high specificity. The level of GDF15 in HCC patients was much higher than that in health people. CONCLUSION: The success in mouse anti-GDF15 mAb preparation provides the basis for further developing HCC diagnose kit. PMID- 21557914 TI - [Preparation and characterization of the anti-HCV HVR1 synthetic peptide monoclonal antibody]. AB - AIM: To prepare monoclonal antibody (mAb) against HCV HVR1 synthetic peptide and characterize its property. METHODS: 8 week-old female BALB/c mice were immunized with HCV HVR1 synthetic peptide which was linked to bovine serum albumin (BSA) as immunogen. The splenocytes of immunized mice were fused with Sp2/0 cells by hybridoma technique. Monoclonal hybridoma cell line was obtained by limiting dilution, HAT and HT -selective culture. The specificity of mAb was identified by indirect ELISA, immunohistochemical staining and inhibitory reactivity. RESULTS: One hybridoma cell (1A9G9F11) was obtained. The mAb belonged to Ig G3. The titers of mAb in ascetic and the relative affinity constant of mAb were 3.125*10(-5) and 1.0*10(6) L/mol respectively.Indirect ELISA detecition demonstrated that the mAb had no cross-reactivates with other viral antigens, such as HBsAg, HBeAg and HAAg, and with other protein, such as BSA, casein and thymopentin. CONCLUSION: One hybridoma cell secreting mAb against-HCV HVR1 has been established successfully, which lays the foundation for for the further study. PMID- 21557915 TI - [The study of CD4+ and CD8+ T subsets in chronic hepatitis B patients]. AB - AIM: To investigate the difference of CD4+ and CD8+ T subsets in different infection status of chronic hepatitis B (CHB) patients. METHODS: 13 Healthy people were chosen as control group. According to infection status, 78 CHB patients were sorted into HBeAg(+) and normal liver function group, HBeAg(+) and abnormal liver function group, and HBeAg(-) group. The percentages of some subsets of CD4+T and CD8+T cells in CHB patients and healthy people were examined by Flow cytometer, and the correlations between the subsets of T cells and the HBVDNA levels and HBeAg were analyzed. RESULTS: As compared with control group, the percentages of CD4+CD25+/CD4+ and CD4+CD95+/CD4+ were increased (P<0.01, P<0.05) in HBeAg(+) and normal liver function group, and the percentages of CD8+CD28-/CD8+ in three patients groups were increased (P<0.01). As compared with the HBeAg(+) and normal liver function group, the percentages of CD4+CD25+/CD4+ in HBeAg(+) and abnormal liver function group, and HBeAg(-) group were decreased (P<0.01), and the percentages of CD8+CD95+/CD8+ in HBeAg(-) group and the percentages of CD8+CD95+/CD8 in HBeAg(+) and abnormal liver function group were decreased (P<0.05, P<0.01). Moreover, there were positive correlations between CD4+CD25+/CD4+, CD4+CD95+/CD4+ and the HBVDNA levels(P<0.01); there were inverse correlations between CD4+CD28+/CD4+ and the HBVDNA levels and HBeAg (P<0.05, P<0.01); there were positive correlations between CD8+CD28-/CD8+ and HBVDNA and HBeAg (P<0.01). CONCLUSION: Some T cell Subsets, including CD4+CD25+, CD4+CD95+ , and CD8+CD28-, are increased in CHB patients, which maybe play some roles in the immune tolerance of chronic HBV infection. PMID- 21557916 TI - [The effect of secondary lymphoid tissue chemokine and its receptor on chemotaxis of peripheral blood lymphocytes in the patients with Sjogren's syndrome]. AB - AIM: To investigate the effect of secondary lymphoid tissue chemokine (SLTC) and its receptor CCL21/CCR7 on chemotaxis of peripheral blood lymphocytes in the patients with Sjogren's syndrome (SS) and explore their roles in the SS pathogenesis. METHODS: Thirty-one SS patients were selected, including 18 primary SS patients (pSS) and 13 secondary SS (sSS) patients. In addition, 20 healthy persons were selected as normal controls. Peripheral blood lymphocytes were isolated from all the SS patients and normal controls. The cell trans-membrane test with 24-well transwells was used to detect the effect of CCL21/CCR7 on the lymphocyte migration. RESULTS: In the presence of CCL21, the chemotactic indexes (CIs) of lymphocytes from pSS and sSS patients were 2.92+/-0.12 and 2.80+/-0.28, respectively. Both of them were significantly higher than that of normal controls (CI=1.32+/-0.11, P<0.01), while there was no difference between pSS and sSS patients. After anti-CCR7 mAb pretreatment, the lymphocyte CIs of pSS and sSS patients respectively, decreased significantly to 1.04+/-0.05 and 1.03+/-0.08 as compared with untreated controls. CONCLUSION: CCR7 is the one of the important factors resulting in lymphocyte migration. CCL21/CCR7 interaction mediates the migration of peripheral lymphocytes in SS patients and may be involved in the gland damage due to the infiltration of massive lymphocytes in exocrine glands in SS patients. PMID- 21557917 TI - Hormonal regulation of spermatogenesis: insights from constructing genetic models. PMID- 21557918 TI - Abnormal expression of uncoupling protein-2 correlates with CYP11A1 expression in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) may result from hypersensitivity to insulin, which is negatively regulated by uncoupling protein (UCP)-2. Because cholesterol side-chain cleavage enzyme (CYP11A1) is closely linked to PCOS, the expression of UCP-2 and CYP11A1 in ovarian tissues from PCOS patients was examined in the present study. Twelve PCOS patients with hyperandrogenaemia who underwent laparoscopic ovarian wedge resection and 12 age-matched control patients who underwent contralateral ovarian biopsy were enrolled in the study. UCP-2 expression in early stage (primordial, primary and secondary) and late stage (sinus and mature) follicles was examined using immunohistochemistry, whereas UCP 2 and CYP11A1 mRNA and protein levels in ovarian tissue were determined using quantitative reverse transcription-polymerase chain reaction and western blot analyses, respectively. UCP-2 expression increased significantly with follicular development in both control and PCOS tissue, with expression in early stage follicles from PCOS patients significantly greater than that in controls. In addition, both UCP-2 and CYP11A1mRNA and protein levels, mean fasting blood glucose concentrations and fasting serum insulin levels were significantly higher in PCOS patients compared with the control group. Finally, a significant correlation between UCP-2 and CYP11A1 expression was found in PCOS but not control patients. In conclusion, in PCOS patients, there was a correlation between UCP-2 and CYP11A1 expression, which was significantly higher than in the control group. These changes in UCP-2 and CYP11A1 expression may mediate follicle development in PCOS. PMID- 21557919 TI - Relationship between late embryonic mortality and the increase in plasma advanced oxidised protein products (AOPP) in dairy cows. AB - The involvement of protein oxidation in embryonic mortality (EM) has been poorly investigated in cows. Advanced oxidation protein products (AOPP) are markers of protein oxidation generated by activated neutrophils and involved in inflammation. The aim of this work was to study AOPP in cow plasma and their relationship with late EM. The outcomes of 158 artificial inseminations (AI) were examined in 72 cows, which were classified ex post on the basis of blood progesterone and pregnancy-associated glycoprotein concentrations and clinical confirmation of pregnancy into the following categories: (1) positive (AI+, resulted in pregnancy, n=58), (2) negative (AI-, did not result in pregnancy, n=86) and (3) embryonic mortality (EM, n=14). Plasma protein fractions, malondialdehyde (MDA), total glutathione and AOPP were measured at AI (Day 0) and on Days 15, 28, 35, 45 and 60. MDA was significantly higher in EM than AI+ and AI animals on Day 45, and than AI+ animals on Day 60 (P<0.05). Mean plasma AOPP concentrations were significantly higher in the EM group (P<0.01) and the ratio of AOPP:albumin was significantly higher in the EM group on Days 15, 28, 45 and 60 (P<0.05). Based on the temporal pattern of the AOPP:albumin ratio, we propose that oxidative stress is implicated in and may possibly be a cause of EM. PMID- 21557920 TI - Gene silencing in bovine zygotes: siRNA transfection versus microinjection. AB - The aim of this study was to compare gene silencing in bovine zygotes when small interfering RNAs (siRNAs) were introduced into bovine zygotes by microinjection or lipid-based transfection. In Experiment 1, E-cadherin siRNA was injected at 100 or 375 uM and compared with PBS-injected and non-injected controls. Embryos were then cultured in vitro for 7 days and periodically assessed for development. For transfection, zona-free zygotes were incubated in transfection medium with siRNA for 1h at 39 degrees C and then cultured to Day 7. Injection of PBS or 375 uM E-cadherin siRNA resulted in a decrease in the number of embryos reaching the 8-cell stage (51.5% and 45.5%) or the blastocyst stage (39.0 and 32.5%) compared with non-injected controls (62.9 and 45.0%, respectively; P<0.05). Messenger RNA abundance was suppressed by 36 and 46% when siRNA targeting E-cadherin was injected at 100 and 375 uM, respectively, compared with controls (P<0.05). Transfection with 100 nM E-cadherin siRNA decreased development to the 8-cell stage (20.3 versus 53.0%) and blastocyst stage (7.2 versus 18.2%) compared with controls (P<0.05). Messenger RNA relative abundance was not different between controls (non-transfected or transfected with GAPDH or scrambled siRNA). However, transfection of zygotes with 100 and 200 nM E-cadherin siRNA led to a 72 and 38% reduction, respectively, in E-cadherin mRNA relative abundance in Day 7 blastocysts compared with controls (P<0.05). PMID- 21557921 TI - Follicle-stimulating hormone receptor (FSHR)-derived peptide vaccine induced infertility in mice without pathological effect on reproductive organs. AB - In a previous study it was found that priming with recombinant human follicle stimulating hormone receptor (rhFSHR) protein (F140) and boosting with a peptide containing amino acids 32-44 from FSHR showed a specific immune response and fertility inhibition in adult male mice. However, this priming and boosting led to damage of the reproductive organs. Therefore, to eliminate this damage, the peptide prime-boost strategy was explored as a possible means of avoiding the pathological change while maintaining infertility. Immunisation with the peptide prime-boost strategy led to decreased fertility 10 weeks after vaccination, which is consistent with Balb/C mice treated with the protein prime-peptide boost regime. In contrast to the cellular swelling and spotty necrosis in spermatogonia observed in the protein-primed mice, the mice receiving peptide priming did not display pathological damage in seminiferous tubules and interstitial cells. Thus, the prime-boost immune regime with the FSHR-derived peptide potentially provides a much safer candidate for a contraceptive vaccine. PMID- 21557922 TI - Differential developmental requirements for individual histone H3K9 methyltransferases in cleavage-stage porcine embryos. AB - Dimethylated H3K9 is a heritable epigenetic mark that is closely linked with transcriptional silencing and known to undergo global remodelling during cleavage development. Five mammalian histone methyltransferases (HMTases), namely Suv39H1, Suv39H2, SetDB1, EHMT1 and EHMT2, have been shown to mediate the methylation of H3K9. The aim of the present study was to determine the developmental requirements of these HMTases during cleavage development in porcine embryos. We hypothesised that knockdown of the abovementioned HMTases would differentially affect porcine cleavage development. To test this hypothesis, IVM and IVF porcine oocytes were divided into one of three treatment groups, including non-injected controls, oocytes injected with a double-stranded interfering RNA molecule specific for one of the HMTases and oocytes injected with a corresponding mutated (control) double-stranded RNA molecule. Nuclei were counted in all embryos 6 days after fertilisation. Although no significant difference in total cell number was detected in embryos injected with EHMT1 and EHMT2 interfering RNAs (compared with their respective control groups), embryos injected with interfering RNAs that targeted Suv39H1, Suv39H2 and SetDB1had significantly lower cell numbers than their respective control groups (P<0.05). This suggests that individual HMTases differentially affect in vitro developmental potential. PMID- 21557923 TI - The early embryo response to intracellular reactive oxygen species is developmentally regulated. AB - In vitro embryo production (IVP) suffers from excessive developmental failure. Its inefficiency is linked, in part, to reactive oxygen species (ROS) brought on by high ex vivo oxygen (O(2)) tensions. To further delineate the effects of ROS on IVP, the intracellular ROS levels of early bovine embryos were modulated by: (1) varying O(2) tension; (2) exogenous H(2)O(2) treatment; and (3) antioxidant supplementation. Although O(2) tension did not significantly affect blastocyst frequencies (P>0.05), 20% O(2) accelerated the rate of first cleavage division and significantly decreased and increased the proportion of permanently arrested 2- to 4-cell embryos and apoptotic 9- to 16-cell embryos, respectively, compared with embryos cultured in 5% O(2) tension. Treatment with H(2)O(2), when applied separately to oocytes, zygotes, 2- to 4-cell embryos or 9- to 16-cell embryos, resulted in a significant (P<0.05) dose-dependent decrease in blastocyst development in conjunction with a corresponding increase in the induction of either permanent embryo arrest or apoptosis in a stage-dependent manner. Polyethylene glycol-catalase supplementation reduced ROS-induced embryo arrest and/or death, resulting in a significant (P<0.05) increase in blastocyst frequencies under high O(2) culture conditions. Together, these results indicate that intracellular ROS may be signalling molecules that, outside an optimal range, result in various developmentally regulated modes of embryo demise. PMID- 21557924 TI - Temporal effects of exogenous oocyte-secreted factors on bovine oocyte developmental competence during IVM. AB - We investigated whether paracrine signalling between the bovine oocyte and cumulus cells is altered during the course of in vitro maturation (IVM). Bovine COCs were cocultured with denuded oocytes or treated with specific oocyte secreted factors, namely recombinant bone morphogenetic protein (BMP)-15 or growth differentiation factor (GDF)-9, beginning from 0 or 9h IVM. To generate a 9-h denuded oocyte (DO) group, COCs were cultured intact for the first 9h of IVM and then denuded. Coculturing intact COCs with DOs denuded immediately after collection or following 9h of maturation did not affect cleavage rate, but improved blastocyst yield (P<0.05) on Day 8 (51 and 61%, respectively; P<0.05) and cell number compared with COCs cultured alone (41%). Significantly, we observed higher levels of endogenous GDF-9 and BMP-15 protein in oocytes of COCs matured for 9h compared with no incubation. The addition of 175 ng mL(-1) GDF-9 or 10%v/v BMP-15 from partially purified transfected 293H cell supernatant for 24h IVM significantly enhanced development to the blastocyst stage from 40% (control) to 51 and 47%, respectively (P<0.05). However, treatment of COCs with GDF-9 or BMP-15 between 9 and 24h of IVM did not increase blastocyst yield. These results provide evidence of quantitative and possibly qualitative temporal changes in oocyte paracrine factor production during IVM. PMID- 21557925 TI - Vitrification of bovine blastocysts pretreated with sublethal hydrostatic pressure stress: evaluation of post-thaw in vitro development and gene expression. AB - Sublethal stress treatment has been reported to enhance gametes' performance in subsequent procedures, such as cryopreservation. The aim of the present study was to evaluate the effect of different equilibration times between the termination of a sublethal hydrostatic pressure (HP) stress treatment and the initiation of vitrification on the post-thaw survival, continued in vitro development, hatching rate and gene expression of selected candidate genes of in vitro-produced (IVP) expanded bovine blastocysts. Day 7 IVP blastocysts were subjected to 600 bar pressure for 60 min at 32 degrees C. Immediately after pressure treatment (HP0h) or after 1 or 2h incubation (HP1h and HP2h groups, respectively), embryos were either vitrified and warmed using the open pulled straw method, followed by 72 h in vitro culture or were stored at -80 degrees C until gene expression analysis. Re-expansion and hatching rates after vitrification-warming were significantly (P<0.05) higher in the HP0h (88 and 76%, respectively) and HP1h (90 and 75%, respectively) groups than in the untreated (82 and 63%, respectively) and HP2h groups (79 and 70%, respectively). Moreover, the HP1h group showed further improvement in the speed of re-expansion and resumption of normal in vitro development. Cumulative analysis of all genes (SC4MOL, HSP1A1A, SOD2 and GPX4) revealed a similar pattern of expression, with a tendency for peak transcript abundance 1h after HP treatment. Application of HP stress treatment was found to be efficient in increasing the in vitro developmental competence of vitrified bovine embryos. PMID- 21557926 TI - Gene expression analysis of bovine blastocysts produced by parthenogenic activation or fertilisation. AB - The processes underlying the very first moments of embryonic development are still not well characterised in mammals. To better define the kinetics of events taking place following fertilisation, it would be best to have perfect synchronisation of sperm entry. With fertilisation occurring during a time interval of 6 to 12h in the same group of fertilised oocytes, this causes a major variation in the time of activation of embryonic development. Bovine parthenogenesis could potentially result in better synchronisation and, if so, would offer a better model for studying developmental competence. In the present study, bovine oocytes were either parthenogenetically activated or fertilised and cultured in vitro for 7 days. Gene expression analysis for those two groups of embryos at early and expanded stages was performed with BlueChip, a customised 2000-cDNA array developed in our laboratory and enriched in clones from various stages of bovine embryo development. The microarray data analysis revealed that only a few genes were differentially expressed, showing the relative similarity between those two kinds of embryos. Nevertheless, the fact that we obtained a similar diversity of developmental stages with parthenotes suggests that synchronisation is more oocyte-specific than sperm entry-time related. We then analysed our data with Ingenuity pathway analysis. Networks of genes involved in blastocyst implantation but also previous stages of embryo development, like maternal-to-embryonic transition, were identified. This new information allows us to better understand the regulatory mechanisms of embryonic development associated with embryo status. PMID- 21557927 TI - Sperm motility activation, sperm heterogeneity and sperm-female tract interactions in Bennett's wallaby (Macropus rufogriseus rufogriseus). AB - Sperm-oviduct interactions in Bennett's wallaby (Macropus rufogriseus rufogriseus) were investigated using in vitro cocultures of cauda epididymal spermatozoa and oviducal epithelial cells. Kidney epithelial cells were used as non-reproductive control tissues. Spermatozoa attached to epithelial cells of both origins, but sperm survival and activity was higher when cocultured with oviducal cells. New findings during live sperm-epithelial interactions included: (1) a high frequency of reversible head movements, from linear (streamlined configuration) to T shape (thumbtack configuration) in swimming spermatozoa immediately after the start of coculture; (2) the loss of sperm tails (tail shedding) increasing with time; and (3) interrupted swimming patterns, where periods of fast movement were interspersed with slower swimming while the spermatozoa interacted with the epithelial cell surface. Sperm motility activation responses were characterised after diluting the epididymal samples in phosphate-buffered saline, medium M199 and Tyrode's medium. The results confirmed that the marsupial oviduct is able to support the viability and motility of a sperm subpopulation for at least 20 h in vitro and suggest that some spermatozoa shed their tails after binding, possibly as a result of a selective process. PMID- 21557928 TI - Two tyrosines that changed the world: Interfacing the oxidizing power of photochemistry to water splitting in photosystem II. AB - Photosystem II (PSII), the thylakoid membrane enzyme which uses sunlight to oxidize water to molecular oxygen, holds many organic and inorganic redox cofactors participating in the electron transfer reactions. Among them, two tyrosine residues, Tyr-Z and Tyr-D are found on the oxidizing side of PSII. Both tyrosines demonstrate similar spectroscopic features while their kinetic characteristics are quite different. Tyr-Z, which is bound to the D1 core protein, acts as an intermediate in electron transfer between the primary donor, P(680) and the CaMn4 cluster. In contrast, Tyr-D, which is bound to the D2 core protein, does not participate in linear electron transfer in PSII and stays fully oxidized during PSII function. The phenolic oxygens on both tyrosines form well defined hydrogen bonds to nearby histidine residues, His(Z) and His(D) respectively. These hydrogen bonds allow swift and almost activation less movement of the proton between respective tyrosine and histidine. This proton movement is critical and the phenolic proton from the tyrosine is thought to toggle between the tyrosine and the histidine in the hydrogen bond. It is found towards the tyrosine when this is reduced and towards the histidine when the tyrosine is oxidized. The proton movement occurs at both room temperature and ultra low temperature and is sensitive to the pH. Essentially it has been found that when the pH is below the pK(a) for respective histidine the function of the tyrosine is slowed down or, at ultra low temperature, halted. This has important consequences for the function also of the CaMn4 complex and the protonation reactions as the critical Tyr-His hydrogen bond also steer a multitude of reactions at the CaMn4 cluster. This review deals with the discovery and functional assignments of the two tyrosines. The pH dependent phenomena involved in oxidation and reduction of respective tyrosine is covered in detail. This article is part of a Special Issue entitled: Photosystem II. PMID- 21557929 TI - Lactobacillus acidophilus S-layer protein-mediated inhibition of Salmonella induced apoptosis in Caco-2 cells. AB - Surface layer (S-layer) proteins are crystalline arrays of proteinaceous subunits present as the outermost component of the cell wall in several Lactobacillus species. The underlying mechanism for how S-layer proteins inhibit pathogen infections remains unclear. To gain insights into the mechanism of the antimicrobial activity of Lactobacillus S-layer proteins, we examined how Lactobacillus S-layer proteins impact Salmonella Typhimurium-induced apoptosis in vitro in Caco-2 human colon epithelial cells. When Caco-2 cells infected with Salmonella Typhimurium SL1344, we found that apoptosis was mediated by activation of caspase-3, but not caspase-1. When Salmonella Typhimurium SL1344 and S-layer proteins were coincubated simultaneously, Caco-2 cell apoptosis was markedly decreased and the cell damage was modified, as evaluated by flow cytometry and microscopy. Detailed analyses showed that the S-layer proteins inhibited the caspase-3 activity and activated the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Taken together, these findings suggest that Lactobacillus S-layer proteins protected against Salmonella-induced apoptosis through reduced caspase-3 activation. In addition, Salmonella-induced apoptotic cell damage was modified by S-layer proteins through the ERK1/2 signaling pathway. This mechanism may represent a novel approach for antagonizing Salmonella infection. PMID- 21557930 TI - Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: possible role in mechanical stress-induced hyperpigmentation. AB - The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1alpha, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress. PMID- 21557931 TI - Characterization of stress sensitivity and chaperone activity of Hsp105 in mammalian cells. AB - Hsp105 is a major mammalian heat shock protein that belongs to the Hsp105/110 family, a diverged subgroup of the Hsp70 family. Hsp105 not only protects the thermal aggregation of proteins, but also regulates the Hsc70 chaperone system in vitro. Recently, it has been shown that Hsp105/110 family members act as nucleotide exchange factors for cytosolic Hsp70s. However, the biological functions of Hsp105/110 family proteins still remain to be clarified. Here, we examined the function of Hsp105 in mammalian cells, and showed that the sensitivity to various stresses was enhanced in the Hsp105-deficient cells compared with that in control cells. In addition, we found that deficiency of Hsp105 impaired the refolding of heat-denatured luciferase in mammalian cells. In contrast, overexpression of Hsp105alpha enhanced the ability to recover heat inactivated luciferase in mammalian cells. Thus, Hsp105 may play an important role in the refolding of denatured proteins and protection against stress-induced cell death in mammalian cells. PMID- 21557932 TI - Adenosine A2B receptor antagonist suppresses differentiation to regulatory T cells without suppressing activation of T cells. AB - Extracellular adenosine activates P1 receptors (A(1), A(2A), A(2B), A(3)) on cellular membranes. Here, we investigated the involvement of P1 receptor-mediated signaling in differentiation to regulatory T cells (Treg). Treg were induced in vitro by incubating isolated CD4(+)CD62L(+) naive murine T cells under Treg skewing conditions. Antagonists of A(1) and A(2B) receptors suppressed the expression of Foxp3, a specific marker of Treg, and the production of IL-10, suggesting the involvement of A(1) and A(2B) receptors in differentiation to Treg. We also investigated the effect of these antagonists on T cell activation, which is essential for differentiation to Treg, and found that A(1) antagonist, but not A(2B) antagonist, suppressed T cell activation. We conclude that A(1) and A(2B) receptors are both involved in differentiation to Treg, but through different mechanisms. Since A(2B) antagonist blocked differentiation to Treg without suppressing T cell activation, it is possible that blockade of A(2B) receptor would facilitate tumor immunity. PMID- 21557933 TI - Mechanisms of transthyretin cardiomyocyte toxicity inhibition by resveratrol analogs. AB - The transthyretin amyloidoses are a subset of protein misfolding diseases characterized by the extracellular deposition of aggregates derived from the plasma homotetrameric protein transthyretin (TTR) in peripheral nerves and the heart. We have established a robust disease-relevant human cardiac tissue culture system to explore the cytotoxic effects of amyloidogenic TTR variants. We have employed this cardiac amyloidosis tissue culture model to screen 23 resveratrol analogs as inhibitors of amyloidogenic TTR-induced cytotoxicity and to investigate their mechanisms of protection. Resveratrol and its analogs kinetically stabilize the native tetramer preventing the formation of cytotoxic species. In addition, we demonstrate that resveratrol can accelerate the formation of soluble non-toxic aggregates and that the resveratrol analogs tested can bring together monomeric TTR subunits to form non-toxic native tetrameric TTR. PMID- 21557934 TI - Peripheral blood DNA methylation detected in the BRCA1 or BRCA2 promoter for sporadic ovarian cancer patients and controls. AB - BACKGROUND: Ovarian cancer is located at the fifth rank of female cancers. Different risk factors including genetic factors with BRCA1 and BRCA2 genes played an important role in the etiology of the ovarian cancer. In most of sporadic ovarian cancer, variation in the expression of BRCA1 and BRCA2 genes was observed and it could be a consequence of epigenetic modifications. This work aimed to study methylation at CpG islands within the promoter of the BRCA1 and BRCA2 genes in sporadic ovarian cancers. METHODS: For this, we conducted a case control study consisted of 51 ovarian cancer cases with no BRCA mutation and 349 healthy women. All participants came from the Auvergne region in France. Genomic DNA was extracted from peripheral blood cells (PBCs) and we used the Quantitative Analysis of Methylated Alleles (QAMA) to estimate the per cent of methylation in the BRCA1 and BRCA2 promoters. RESULTS: BRCA1 methylation is significantly decreased in ovarian cancer by comparison with the control group. The comparison between the two different populations did not show any significant difference regarding BRCA2 methylation but exhibited a trend in the decrease of BRCA2 promoter methylation in peripheral blood DNA of sporadic ovarian cancer. CONCLUSIONS: These results may have implications in better understanding the underlying epigenetic mechanisms in BRCA1 and BRCA2 oncosuppressors in sporadic ovarian cancer. PMID- 21557935 TI - HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. AB - BACKGROUND: Two commercial immunoassays for HE4 have been compared and the diagnostic accuracy of HE4, CA 125 and the combinatory ROMA algorithm for epithelial ovarian cancer (EOC) has been evaluated. METHODS: HE4 and CA125 were measured on sera obtained from 259 women (73 healthy, 90 with benign ovarian or adnexal diseases, 96 with EOC). The ARCHITECT CMIA HE4 assay was compared with the Fujirebio EIA HE4, and the risk for EOC by the combinatory ROMA algorithm (HE4+CA 125) was assessed with both HE4 assays. RESULTS: The CMIA HE4 assay showed a good linearity (r>0.9998) and precision (interassay and total CVs <4%). The correlation with EIA HE4 was linear (r=0.994), with an average bias of 0.4%. By ROC curve analysis, the sensitivity for EOC at a fixed specificity of 90%, 95% and 99% was 89.6%, 84.4% and 79.2% by CMIA HE4, 84.4%, 83.3% and 79.2% by EIA HE4, 86.5%, 76.0% and 59.4% by CMIA CA125. The accuracy of the ROMA algorithm determined by CMIA or EIA HE4 was very similar (AUC 87.1% vs. 87.6%; p=n.s.) and greater in menopause. CONCLUSIONS: The two HE4 assays showed a good correlation and similar clinical value, with a greater precision for CMIA. HE4 was more specific and accurate than CA125, supporting its use in addition to clinical and imaging criteria for the discrimination of benign from malignant ovarian lesions. The ROMA algorithm showed a good accuracy for discriminating women at high risk for EOC. PMID- 21557936 TI - Accuracy of a prediction model for heparin-induced thrombocytopenia (HIT): an analysis based on individual patient data. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction associated with thrombosis, and its paradoxical nature is a challenging issue for the diagnosis. The '4Ts' scoring system represents a simple and efficient way to improve clinical diagnoses of the syndrome. This system classifies patients as having high, intermediate, and low clinical probability for HIT. However, uncertainty remains concerning its clinical meaning, thus weakening the diagnostic value of this screening instrument. METHODS: We analyzed the diagnostic test accuracy based on individual patient data extracted from published primary scientific studies. This study focused on 186 cases of treatment with heparin, which later evolved into a clinical suspicion of HIT. Upon choosing the most appropriate reference laboratory, the accuracy of the 4Ts was analyzed using the receiver operator characteristic curve analysis. RESULTS: Half of the positive cases (57.1%) were classified as having a high score, while 25.5% of the negative cases were classified as a having low score for HIT. Slightly more than half of all patients (53.2%) were classified as having an intermediate score. As such, the pre-test instrument would most likely fail to distinguish between diseased and nondiseased patients in a relevant number of cases. The calculated accuracy of the summary indicates that the 4Ts can be considered a good, but not a defining, test. CONCLUSION: Further studies are warranted regarding clinical score systems, either alone or in combination with laboratory tests, in an attempt to improve the early diagnosis of this adverse drug reaction and to provide better care for at-risk patients. PMID- 21557937 TI - Numb modulates intestinal epithelial cells toward goblet cell phenotype by inhibiting the Notch signaling pathway. AB - Numb was originally identified as an important cell fate determinant that is asymmetrically inherited during mitosis and controls the fate of sibling cells by inhibiting the Notch signaling pathway in neural tissue. The small intestinal epithelium originates from the division of stem cells that reside in the crypt, which further differentiate into goblet cells, absorptive cells, paneth cells, and enteroendocrine cells. However, Numb's involvement in the differentiation process of intestinal epithelium is largely unknown. In the present study, we confirm that both the Numb mRNA and protein isoforms are expressed in adult mouse intestinal mucosa. Numb protein is ubiquitously expressed throughout the crypt villus axis of the small intestinal epithelium and is mainly localized to the cytoplasmic membrane. Down-regulation of endogenous Numb using RNA interference in cultured intestinal LS174T cells increased Notch signaling, leading to the up regulation of Hes1 and the down-regulation of Hath1. Knockdown of Numb alleviated MUC2 protein expression and led to loss of the goblet cell phenotype in LS174Tl cells. Our results provide the first evidence that Numb, an important cell fate determinant, modulates intestinal epithelial cells towards the goblet cell phenotype by inhibiting the Notch signaling pathway. PMID- 21557938 TI - Cryptosporidium spp. in pet birds: genetic diversity and potential public health significance. AB - To characterize the prevalence and assess the zoonotic transmission burden of Cryptosporidium species/genotypes in pet birds in Henan, China, 434 fecal samples were acquired from 14 families of birds in pet shops. The overall prevalence of Cryptopsoridium was 8.1% (35/434) by the Sheather's sugar flotation technique. The Cryptosporidium-positive samples were analyzed by DNA sequence analysis of the small subunit (SSU) rRNA gene. Three Cryptosporidium species and two genotypes were identified, including C. baileyi (18/35 or 51.4%) in five red billed leiothrixes (Leiothrix lutea), four white Java sparrows (Padda oryzivora), four common mynas (Acridotheres tristis), two zebra finches (Taeniopygia guttata), a crested Lark (Galerida cristata), a Gouldian finch (Chloebia gouldiae), and a black-billed magpie (Pica pica); Cryptosporidium meleagridis (3/35 or 8.6%) in a Bohemian waxwing (Bombycilla garrulus), a Rufous turtle dove (Streptopelia orientalis), and a fan-tailed pigeon (Columba livia); Cryptosporidium galli (5/35 or 14.3%) in four Bohemian waxwings (Bombycilla garrulus) and a silver-eared Mesia (Leiothrix argentauris); Cryptosporidium avian genotype III (3/35 or 8.6%) in two cockatiels (Nymphicus hollandicus) and a red billed blue magpie (Urocissa erythrorhyncha); and Cryptosporidium avian genotype V (6/35 or 17.1%) in six cockatiels (Nymphicus hollandicus). Among the pet birds, 12 species represented new hosts for Cryptosporidum infections. The presence of C. meleagridis raises questions on potential zoonotic transmission of cryptosporidiosis from pet birds to humans. PMID- 21557939 TI - Cytokines in rats experimentally infected with Trypanosoma evansi. AB - The aim of this study was to measure the levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1) and interleukin 6 (IL-6) in the serum of rats experimentally infected with Trypanosoma evansi and to correlate these levels with hematological parameters. Initially, 48 rats (group T) were intraperitoneally inoculated with cryopreserved blood containing 1*10(6) trypomastigotes per animal. Twenty-eight animals (group C) were used as negative controls and received 0.2 mL of saline by the same route. The experimental groups were formed according to the time after infection and the degree of parasitemia as follows: four control subgroups (C3, C5, C10 and C20) with seven non-inoculated animals each and four test subgroups (T3, T5, T10 and T20) with 10 animals each inoculated with T. evansi. The blood samples were collected by cardiac puncture at days 3 (C3, T3), 5 (C5, T5), 10 (C10, T10) and 20 (C20, T20) post-infection (PI) to perform the complete blood count and the determination of IFN-gamma, TNF-alpha, IL-1 and IL-6 levels using an ELISA quantitative sandwich. Infected rats showed normocytic normochromic anemia during the experimental period. T. evansi infection in rats caused a serum increase (P<0.01) of IFN-gamma, TNF-alpha, IL-1 and IL-6 levels at days 3, 5, 10 and 20 PI compared to the controls. The multiple linear regressions showed a reduction of 24% in the hematocrit as a consequence of the increased IFN-gamma, TNF-alpha and IL-1. Therefore, we conclude that the infection caused by T. evansi causes an increase in the pro-inflammatory cytokines. These results suggest a synergism among IL-1, TNF-alpha and IFN-gamma contributing to the development of anemia. This increase is associated with the regulation of immune responses against the parasite. PMID- 21557940 TI - Aurora kinase A critically contributes to the resistance to anti-cancer drug cisplatin in JAK2 V617F mutant-induced transformed cells. AB - JAK2 V617F mutant induces transformation through aberrant activation of various transcription factors. We found that the expression of Aurora kinase A (Aurka) was significantly induced by mutant JAK2 through c-Myc expression. Interestingly, mutant JAK2 enhanced resistance to cisplatin (CDDP)-induced DNA damage, and effectively suppressed apoptosis. Ectopic expression of Aurka in Ba/F3 cells exhibited similar resistance to CDDP, and this required kinase activity. Conversely, knockdown and inhibition of Aurka in cells expressing mutant JAK2 abolished the resistance to CDDP. Taken together, Aurka is most likely critical for resistance to DNA damage in cells transformed by JAK2 V617F mutant. PMID- 21557941 TI - A mechanism for regulation of chloroplast LHC II kinase by plastoquinol and thioredoxin. AB - State transitions are acclimatory responses to changes in light quality in photosynthesis. They involve the redistribution of absorbed excitation energy between photosystems I and II. In plants and green algae, this redistribution is produced by reversible phosphorylation of the chloroplast light harvesting complex II (LHC II). The LHC II kinase is activated by reduced plastoquinone (PQ) in photosystem II-specific low light. In high light, when PQ is also reduced, LHC II kinase becomes inactivated by thioredoxin. Based on newly identified amino acid sequence features of LHC II kinase and other considerations, a mechanism is suggested for its redox regulation. PMID- 21557942 TI - The central role of RNA in human development and cognition. AB - It appears that the genetic programming of humans and other complex organisms has been misunderstood for the past 50 years, due to the assumption that most genetic information is transacted by proteins. However, the human genome contains only about 20,000 protein-coding genes, similar in number and with largely orthologous functions as those in nematodes that have only 1000 somatic cells. By contrast, the extent of non-protein-coding DNA increases with increasing complexity, reaching 98.8% in humans. The majority of these sequences are dynamically transcribed, mainly into non-protein-coding RNAs, with tens if not hundreds of thousands that show specific expression patterns and subcellular locations, as well as many classes of small regulatory RNAs. The emerging evidence indicates that these RNAs control the epigenetic states that underpin development, and that many are dysregulated in cancer and other complex diseases. Moreover it appears that animals, particularly primates, have evolved plasticity in these RNA regulatory systems, especially in the brain. Thus, it appears that what was dismissed as 'junk' because it was not understood holds the key to understanding human evolution, development, and cognition. PMID- 21557943 TI - Are retinoids potential therapeutic agents in disorders of social cognition including autism? AB - Increasing evidence suggests that the nonapeptide, oxytocin (OT), helps shape social and affiliative behaviors not only in lower mammals but also in humans. Recently, an essential mediator of brain OT release has been discovered, ADP ribosyl cyclase and/or CD38. We have subsequently shown that polymorphisms across the CD38 gene are associated with autism spectrum disorders (ASD). Notably, CD38 expression in lymphoblastoid cells (LBC) is reduced in cell lines derived from ASD subjects compared to parental cell lines. Intriguingly, a correlation was observed between CD38 expression and measures of social function in ASD. Finally, we have shown that all-trans retinoic acid (ATRA), a known inducer of CD38 transcription, can rescue low CD38 expressing LBC lines derived from ASD subjects and restore normal levels of transcription of this ectoenzyme providing 'proof of principle' in a peripheral model that retinoids are potential therapeutic agents in ASD. PMID- 21557944 TI - Functional genetics in Apicomplexa: potentials and limits. AB - The Apicomplexans are obligate intracellular protozoan parasites and the causative agents of severe diseases in humans and animals. Although complete genome sequences are available since many years and for several parasites, they are replete with putative genes of unassigned function. Forward and reverse genetic approaches are limited only to a few Apicomplexans that can either be propagated in vitro or in a convenient animal model. This review will compare and contrast the most recent strategies developed for the genetic manipulation of Plasmodium falciparum, Plasmodium berghei and Toxoplasma gondii that have taken advantage of the intrinsic features of their respective genomes. Efforts towards the improvement of the transfection efficiencies in malaria parasites, the development of approaches to study essential genes and the elaboration of high throughput methods for the identification of gene function will be discussed. PMID- 21557945 TI - Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohn's disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor). METHODS: In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls. RESULTS: Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Ralpha, were significantly decreased in IBD compared to control (P<.001) and disease controls (irritable bowel syndrome; P<.001; rheumatoid arthritis; P<.025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohn's disease (P<.05), was independent of disease activity (P>.05), and was not influenced by current medications (P>.05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P<.001). CONCLUSIONS: These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor. PMID- 21557947 TI - Differential activity of bone marrow hematopoietic stem cell subpopulations for EPC development and ischemic neovascularization. AB - Although endothelial progenitor cells (EPCs) differentiate from minor populations of stem cells in bone marrow (BM), the differential role of hematopoietic stem cell (HSC) subpopulations in EPC development is largely unclear. Morphological characterization of EPC colonies has revealed that c-kit+/Sca-1+/lineage (Lin) (KSL) cells mainly develop small EPC-colony forming units (CFUs) not large EPC CFUs. In contrast, c-kit+/Sca-1-/Lin- (KL) cells develop large EPC-CFUs not small EPC-CFUs. Neither c-kit-/Sca-1+/Lin- (SL) cells nor c-kit-/Sca-1-/Lin- (L) cells develop EPC-CFUs to an appreciable extent. Hindlimb ischemia enhances formation of large EPC-CFUs from all HSC subpopulations, suggesting an important role for ischemia in functional EPC development. Real time RT-PCR analysis shows that KSL, KL and SL cells but not L cells express various factors at high levels, maintaining a BM-EPC pool. In hindlimb ischemia, transplanted KSL, KL and SL cells efficiently differentiate into endothelial lineage cells in situ and augment capillary density. The percentage of Ki-67+ cycling cells among transplanted cells in ischemic tissue was also greater for KSL, KL and SL cells than L cells. Moreover, the frequency of VEGF- or SDF-1-expressing cells was higher transplanted KSL, KL or SL cells than L cells. Thus, KSL, KL and SL cells are not different in their angiogenic competence under ischemic conditions. In conclusion, although KSL cells are clearly the most potent contributors to EPC development, KL and SL cells may also contribute to neovascularization via both autocrine and paracrine mechanisms in response to ischemic signals. PMID- 21557946 TI - Effects of reproductive status on behavioral and endocrine responses to acute stress in a biparental rodent, the California mouse (Peromyscus californicus). AB - In several mammalian species, lactating females show blunted neural, hormonal, and behavioral responses to stressors. It is not known whether new fathers also show stress hyporesponsiveness in species in which males provide infant care. To test this possibility, we determined the effects of male and female reproductive status on stress responsiveness in the biparental, monogamous California mouse (Peromyscus californicus). Breeding (N=8 females, 8 males), nonbreeding (N=10 females, 10 males) and virgin mice (N=12 females, 9 males) were exposed to a 5 min predator-urine stressor at two time points, corresponding to the early postpartum (5-7 days postpartum) and mid/late postpartum (19-21 days postpartum) phases, and blood samples were collected immediately afterwards. Baseline blood samples were obtained 2 days prior to each stress test. Baseline plasma corticosterone (CORT) concentrations did not differ among male or female groups. CORT responses to the stressor did not differ among female reproductive groups, and all three groups showed distinct behavioral responses to predator urine. Virgin males tended to increase their CORT response from the first to the second stress test, while breeding and nonbreeding males did not. Moreover, virgin and nonbreeding males showed significant behavioral changes in response to predator urine, whereas breeding males did not. These results suggest that adrenocortical responses to a repeated stressor in male California mice may be modulated by cohabitation with a female, whereas behavioral responses to stress may be blunted by parental status. PMID- 21557948 TI - The acute inotropic effects of cardiac contractility modulation (CCM) are associated with action potential duration shortening and mediated by beta1 adrenoceptor signalling. AB - Despite promising results in clinical trials conducted to date, little is known about how cardiac contractile modulation (CCM) mediated inotropic enhancement occurs and how CCM affects the electrophysiological characteristics of the heart. The aims of the present study were to 1) investigate how the stimulation parameters of the CCM signal and the location of stimulus delivery influence the contractile response, 2) characterise the effect of CCM on ventricular electrophysiology, and 3) investigate the potential physiological mechanisms underlying these acute inotropic and electrophysiological effects. Experiments were conducted in isolated rabbit hearts with simultaneous measurement of ventricular contractility and monophasic action potential duration (MAPD). Biphasic square wave pulses were applied to the left ventricle, timed to coincide with the absolute refractory period. CCM mediated responses were assessed over a range of signal amplitudes (2-30 mA), durations (2-15 ms) and delays from the activation of the locally recorded monophasic action potential (0-30 ms). Responses were assessed during perfusion with the beta1-adrenoceptor antagonist metoprolol (1.8 MUM) and HMR 1556 (500 nM), an inhibitor of the slow delayed rectifying potassium current. Norepinephrine content was collected and assessed by ELISA from samples of coronary effluent collected during CCM. CCM induced a significant increase in left ventricular pressure (LVP) in a manner dependent upon the amplitude and duration of the CCM signal but independent of the delay of the stimulus within the action potential plateau and was associated with an increase in norepinephrine in coronary effluent (Mean: 46+/-9 pg/ml). CCM promoted a shortening of MAPD-90% close to the site of stimulation (-19+/-3%) but had no effect on those recorded at distant sites (0+/-1%). The increase in LVP (4.7+/-1.8 vs. 0.7+/-0.9%, P<0.01) and shortening of local MAPD-90% (-15+/-3 vs. 1+/-1%, P<0.01) was abolished with metoprolol. Perfusion with HMR 1556 caused a significant inhibition of local MAPD shortening (-27+/-2 vs. -21+/-3 ms, P<0.05). CCM is associated with a shortening of ventricular MAPD in a manner dependent upon beta-adrenoceptor stimulation resulting from catecholamine release, a finding which may be of clinical significance in regard to the development of malignant ventricular arrhythmias. This article is part of a Special Issue entitled Possible Editorial. PMID- 21557949 TI - Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency. AB - We consider the relationship between the target affinity of a monoclonal antibody and its in vivo potency. The dynamics of the system is described mathematically by a target-mediated drug disposition model. As a measure of potency, we consider the minimum level of the free receptor following a single bolus injection of the ligand into the plasma compartment. From the differential equations, we derive two expressions for this minimum level in terms of the parameters of the problem, one of which is valid over the full range of values of the equilibrium dissociation constant K(D) and the other which is valid only for a large drug dose or for a small value of K(D). Both of these formulae show that the potency achieved by increasing the association constant k(on) can be very different from the potency achieved by decreasing the dissociation constant k(off). In particular, there is a saturation effect when decreasing k(off) where the increase in potency that can be achieved is limited, whereas there is no such effect when increasing k(on). Thus, for certain monoclonal antibodies, an increase in potency may be better achieved by increasing k(on) than by decreasing k(off). PMID- 21557950 TI - Nitric oxide-active compounds modulate the intensity of glutamate-evoked responses in the globus pallidus of the rat. AB - AIM: The effects of local applied NO-active compounds on glutamate (GLU)-evoked responses were investigated in globus pallidus (GP) neurons. MAIN METHODS: Extracellularly recorded single units from anesthetized rats were treated with GLU before and during the microiontophoretic application of S-nitrosoglutathione (SNOG), a NO donor, and Nomega-nitro-l-arginine methyl ester (L-NAME), a NOS inhibitor. KEY FINDINGS: Most GP cells were excited by SNOG whereas administration of L-NAME induced decrease of GP neurons activity. Nearly all neurons responding to SNOG and/or L-NAME showed significant modulation of their excitatory responses to the administration of iontophoretic GLU. In these cells, the changes induced by NO-active drugs in the magnitude of GLU-evoked responses were used as indicators of NO modulation. In fact, when a NO-active drug was co iontophoresed with GLU, significant changes in GLU-induced responses were observed: generally, increased magnitudes of GLU-evoked responses were observed during SNOG ejection, whereas the administration of L-NAME decreased responses to GLU. SIGNIFICANCE: The results suggest that the NO-active drugs modulate the response of GP neurons to glutamatergic transmission. Nitrergic modulation of glutamatergic transmission could play an important role in the control of GP bioelectric activity, considered a fundamental key in the BG function. PMID- 21557951 TI - Involvement of dorsal hippocampal muscarinic cholinergic receptors on muscimol state-dependent memory of passive avoidance in mice. AB - AIMS: In the present study, the effects of bilateral intra-dorsal hippocampal (intra-CA1) injections of cholinergic agents on muscimol state-dependent memory were examined in mice. MAIN METHODS: A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. KEY FINDINGS: Pre-training intra-CA1 administration of a GABA-A receptor agonist, muscimol (0.05 and 0.1 MUg/mouse) dose dependently induced impairment of memory retention. Pre-test injection of muscimol (0.05 and 0.1 MUg/mouse, intra-CA1) induced state-dependent retrieval of the memory acquired under pre-training muscimol (0.1 MUg/mouse, intra-CA1) influence. Pre-test intra-CA1 injection of an acetylcholinesterase inhibitor, physostigmine (0.5 and 1 MUg/mouse, intra-CA1) reversed the memory impairment induced by pre-training administration of muscimol (0.1 MUg/mouse, intra-CA1). Moreover, pre-test administration of physostigmine (0.5 and 1 MUg/mouse, intra-CA1) with an ineffective dose of muscimol (0.025 MUg/mouse, intra-CA1) significantly restored the retrieval and induced muscimol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.25, 0.5 and 1 MUg/mouse) by itself cannot affect memory retention. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (1 and 2 MUg/mouse) 5 min before the administration of muscimol (0.1 MUg/mouse, intra-CA1) dose dependently inhibited muscimol state-dependent memory. Pre-test intra-CA1 administration of atropine (0.5, 1 and 2 MUg/mouse) by itself cannot affect memory retention. SIGNIFICANCE: The results suggest that muscarinic cholinergic mechanism of the CA1 may influence muscimol state-dependent memory. PMID- 21557952 TI - Membrane-initiated actions of thyroid hormones on the male reproductive system. AB - The presence of specific nuclear receptors to thyroid hormones, described in prepubertal Sertoli cells, implies the existence of an early and critical influence of these hormones on testis development. Although the mechanism of action thyroid hormones has been classically established as a genomic action regulating testis development, our research group has demonstrated that these hormones exert several effects in Sertoli cells lacking nuclear receptor activation. These findings led to the identification of non-classical thyroid hormone binding elements in the plasma membrane of testicular cells. Through binding to these sites, thyroid hormones could exert nongenomic effects, including those on ion fluxes at the plasma membrane, on signal transduction via kinase pathways, on amino acid accumulation, on modulation of extracellular nucleotide levels and on vimentin cytoskeleton. The evidence of the participation of different K(+), Ca(2+) and Cl(-) channels in the mechanism of action of thyroid hormones, characterizes the plasma membrane as an important microenvironment able to coordinate strategic signal transduction pathways in rat testis. The physiological responses of the Sertoli cells to hormones are dependent on continuous cross-talking of different signal transduction pathways. Apparently, the choice of the signaling pathways to be activated after the interaction of the hormone with cell surface binding sites is directly related to the physiological action to be accomplished. Yet, the enormous complexity of the nongenomic actions of thyroid hormones implies that different specific binding sites located on the plasma membrane or in the cytosol are believed to initiate specific cell responses. PMID- 21557953 TI - Mouse models of genetic effects on cognition: relevance to schizophrenia. AB - Cognitive dysfunction is a core feature of schizophrenia. Growing evidence indicates that a wide variety of genetic mutations and polymorphisms impact cognition and may thus be implicated in various aspects of this mental disorder. Despite differences between human and rodent brain structure and function, genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Here, we summarize discoveries of genetic modifications in mice that impact cognition. Based on functional hypotheses, gene modifications within five model systems are described: 1) dopamine (D1, D2, D3, D4, D5, DAT, COMT, MAO); 2) glutamate (GluR-A, NR1, NR2A, NR2B, GRM2, GRM3, GLAST); 3) GABA (alpha(5), gamma(2), alpha(4), deltaGABA(A), GABA(B(1)), GAT1); 4) acetylcholine (nAChRbeta2, alpha7, CHRM1); and 5) calcium (CaMKII-alpha, neurogranin, CaMKKbeta, CaMKIV). We also consider other risk-associated genes for schizophrenia such as dysbindin (DTNBP1), neuregulin (NRG1), disrupted-in schizophrenia1 (DISC1), reelin and proline dehydrogenase (PRODH). Because of the presumed importance of environmental factors, we further consider genetic modifications within the stress-sensitive systems of corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF) and the endocannabinoid systems. We highlight the missing information and limitations of cognitive assays in genetically modified mice models relevant to schizophrenia pathology. PMID- 21557954 TI - Evolution of non-speech sound memory in postlingual deafness: implications for cochlear implant rehabilitation. AB - Neurofunctional patterns assessed before or after cochlear implantation (CI) are informative markers of implantation outcome. Because phonological memory reorganization in post-lingual deafness is predictive of the outcome, we investigated, using a cross-sectional approach, whether memory of non-speech sounds (NSS) produced by animals or objects (i.e. non-human sounds) is also reorganized, and how this relates to speech perception after CI. We used an fMRI auditory imagery task in which sounds were evoked by pictures of noisy items for post-lingual deaf candidates for CI and for normal-hearing subjects. When deaf subjects imagined sounds, the left inferior frontal gyrus, the right posterior temporal gyrus and the right amygdala were less activated compared to controls. Activity levels in these regions decreased with duration of auditory deprivation, indicating declining NSS representations. Whole brain correlations with duration of auditory deprivation and with speech scores after CI showed an activity decline in dorsal, fronto-parietal, cortical regions, and an activity increase in ventral cortical regions, the right anterior temporal pole and the hippocampal gyrus. Both dorsal and ventral reorganizations predicted poor speech perception outcome after CI. These results suggest that post-CI speech perception relies, at least partially, on the integrity of a neural system used for processing NSS that is based on audio-visual and articulatory mapping processes. When this neural system is reorganized, post-lingual deaf subjects resort to inefficient semantic- and memory-based strategies. These results complement those of other studies on speech processing, suggesting that both speech and NSS representations need to be maintained during deafness to ensure the success of CI. PMID- 21557955 TI - Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease. AB - The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or obsessive hobbying, which may develop in up to 30% of people taking higher agonist doses. In contrast, treatment with the dopamine precursor, levodopa, in the absence of D3 agonist therapy very rarely provokes such behavioral syndromes. Although these agonist-induced behaviors have been called "impulse control disorders", the problem is not simply loss of impulse control, but rather a novel obsessive-compulsion directed at one or a few behaviors, often taking on pathological proportions. This experience points to the dopamine D3 receptor as a potential therapeutic target for gambling, sex or other addictions occurring spontaneously in the general population. PMID- 21557956 TI - Juvenile stress impairs body temperature regulation and augments anticipatory stress-induced hyperthermia responses in rats. AB - Clinical studies have implicated adolescence as an important and vulnerable period during which traumatic experiences can predispose individuals to anxiety and mood disorders. As such, a stress model in juvenile rats (age 27-29 d) was previously developed to investigate the long-term effects of stress exposure during adolescence on behavior and physiology. This paradigm involves exposing rats to different stressors on consecutive days over a 3-day period. Here, we studied the effects of juvenile stress on long-term core body temperature regulation and acute stress-induced hyperthermia (SIH) responses using telemetry. We found no differences between control and juvenile stress rats in anxiety related behavior on the elevated plus maze, which we attribute to stress associated with surgical implantation of telemetry devices. This highlights the severe impact of surgical stress on the results of subsequent behavioral measurements. Nonetheless, juvenile stress disrupted the circadian rhythmicity of body temperature and decreased circadian amplitude. It also induced chronic hypothermia during the dark phase of the day, when rats are most active. When subjected to acute social defeat stress as adults, juvenile stress had no impact on the SIH response relative to controls. However, 24 h later, juvenile stress rats displayed an elevated SIH response in anticipation of social defeat when re exposed to the social defeat environment. Taken together, our findings indicate that juvenile stress can induce long-term alterations in body temperature regulation and heighten the increase in temperature associated with anticipation of social defeat. The outcomes of behavioral measurements in these experiments, however, are severely affected by surgical stress. PMID- 21557957 TI - Gut fat sensing in the negative feedback control of energy balance--recent advances. AB - Infusions of lipids into the small intestine potently suppress ongoing feeding. Prior work has identified potential roles for gut extrinsic vagal and non-vagal sensory innervation in mediating the ability of gut lipid infusions to reduce food intake, but the local biochemical processes underlying gut lipid sensing at the level of the small intestine remain unclear. This manuscript will summarize recent progress in the identification and characterization of several candidate gut lipid sensing molecules important in the negative feedback control of ingestion, including the fatty acid translocase CD36, peroxisome proliferator activated receptor alpha (PPAR-alpha), and the fatty acid ethanolamide oleoylethanolamide (OEA). In addition, this manuscript addresses a larger role for gut lipid sensing in the overall control of energy availability by modulating not only food intake but also hepatic glucose production. PMID- 21557958 TI - The dark side of food addiction. AB - In drug addiction, the transition from casual drug use to dependence has been linked to a shift away from positive reinforcement and toward negative reinforcement. That is, drugs ultimately are relied on to prevent or relieve negative states that otherwise result from abstinence (e.g., withdrawal) or from adverse environmental circumstances (e.g., stress). Recent work has suggested that this "dark side" shift also is a key in the development of food addiction. Initially, palatable food consumption has both positively reinforcing, pleasurable effects and negatively reinforcing, "comforting" effects that can acutely normalize organism responses to stress. Repeated, intermittent intake of palatable food may instead amplify brain stress circuitry and downregulate brain reward pathways such that continued intake becomes obligatory to prevent negative emotional states via negative reinforcement. Stress, anxiety and depressed mood have shown high comorbidity with and the potential to trigger bouts of addiction like eating behavior in humans. Animal models indicate that repeated, intermittent access to palatable foods can lead to emotional and somatic signs of withdrawal when the food is no longer available, tolerance and dampening of brain reward circuitry, compulsive seeking of palatable food despite potentially aversive consequences, and relapse to palatable food-seeking in response to anxiogenic-like stimuli. The neurocircuitry identified to date in the "dark" side of food addiction qualitatively resembles that associated with drug and alcohol dependence. The present review summarizes Bart Hoebel's groundbreaking conceptual and empirical contributions to understanding the role of the "dark side" in food addiction along with related work of those that have followed him. PMID- 21557959 TI - Development of social familiarity in ewes. AB - We assessed the development of individual discrimination resulting from direct contact/familiarization in ewes. Unfamiliar ewes were introduced during 6, 24 or 72 h in groups of already familiarized ewes. At the end of this contact period, the development of social recognition with the animal that has been introduced was assessed using two different types of tests: a Y-maze preference test and a delayed paired close encounters test where tested ewes are successively and randomly interacting with the familiar animal and an unfamiliar conspecific. The results of both tests showed that ewes developed a recognition of the familiar animal in comparison to a completely unfamiliar female. However, this preference was evidenced after 24 h of contact when using the paired close encounters test whereas it appears only after 72 h when using the Y-maze test, suggesting that the paired close encounters test is a more sensitive methodology to assess the development of social familiarization. The importance of estrogens, in the formation of social familiarization was also evaluated. To this end, social recognition in the paired close encounters test was compared between ovariectomized animals receiving estrogen implants or not. Despite significant high levels of estradiol in estrogen implanted females, no major differences in recognition appeared between groups, suggesting that in our conditions estrogens do not have major influence on social familiarization. PMID- 21557960 TI - Accumulating evidence supports a taste component for free fatty acids in humans. AB - The requisite criteria for what constitutes a taste primary have not been established. Recent advances in understanding of the mechanisms and functions of taste have prompted suggestions for an expanded list of unique taste sensations, including fat, or more specifically, free fatty acids (FFA). A set of criteria are proposed here and the data related to FFA are reviewed on each point. It is concluded that the data are moderate to strong that there are: A) adaptive advantages to FFA detection in the oral cavity; B) adequate concentrations of FFA to serve as taste stimuli; C) multiple complimentary putative FFA receptors on taste cells; D) signals generated by FFA that are conveyed by gustatory nerves; E) sensations generated by FFA that can be detected and scaled by psychophysical methods in humans when non-gustatory cues are masked; and F) physiological responses to oral fat/FFA exposure. On no point is there strong evidence challenging these observations. The reviewed findings are suggestive, albeit not definitive, that there is a taste component for FFA. PMID- 21557961 TI - Investigation of new acyloxy derivatives of cholic acid and their esters as drug absorption modifiers. AB - Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. Intestinal absorption promoters/enhancers are used as excipients in oral formulations of poorly oral-bioavailable drugs. Series of fourteen acyloxy derivatives of 5beta cholic acid as potential drug absorption modifiers was generated by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (R(M)) was determined. The hydrophobicity (logP) and solubility (logS) of the studied compounds were also calculated using two commercially available programs. All the target compounds were tested for their in vitro transdermal penetration activity and as potential intestinal absorption enhancers. The anti-proliferative activity of all the final compounds was also assessed against the human cancer cell lines: T-lymphoblastic leukemia cell line and the breast adenocarcinoma cell line. Their cytotoxicity was also evaluated against the normal human skin fibroblast cells. Two compounds showed anti-proliferative effect on cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC(50)>37 MUM), indicating they would have low cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effects are discussed in this article. PMID- 21557962 TI - Age-related changes in genomic stability of horses. AB - Recently, the old horse has been proposed as a model to study telomere-dependent senescence, immunosenescence and inflamm-aging. In the present paper, we used 80 Hucul and Anglo-Arabian horses divided into 3 age groups (juvenile, adult, old) to evaluate age-dependent changes at the genomic and DNA level and in cell proliferative potential. The level of positive TUNEL cells (both apoptotic and with DNA fragmentation), oxidative DNA damage (8-oxoG immunostaining), sister chromatid exchange and bleomycin-induced chromatid breaks were significantly increased in the combined old group compared to the combined adult group. We observed a negative correlation between micronuclei formation and age, which may be associated with damaged cells undergoing apoptosis, rather than expressing micronuclei. We were unable to show any significant changes in the nuclear division index value, which reflects the proliferative status of the viable cell fraction during aging. Here, we show that breed-independent and age-associated changes in genomic stability may contribute, at least in part, to the aging process in the horse. PMID- 21557963 TI - Chronic ibuprofen treatment does not affect the secondary pathology in the thalamus or improve behavioral outcome in middle cerebral artery occlusion rats. AB - Anti-inflammatory drug ibuprofen decreases the beta-amyloid (Abeta) deposition and associated inflammation in transgenic Alzheimer disease mice. Based on this, we studied whether ibuprofen could modulate the secondary pathology described in the thalamus of middle cerebral artery occlusion (MCAO) rats. Our hypothesis was that ibuprofen could decrease inflammatory reaction and Abeta load in the thalamus of MCAO rats, which in turn is reflected in improved behavioral outcome. Forty male Wistar rats (250-340 g) were subjected to sham-operation or transient occlusion of the right middle cerebral artery (120 min). Ibuprofen (4 0mg/kg/day, per os) was administrated for 27 days beginning the treatment on post-operative day 2. MCAO controls were given vehicle. Sensorimotor impairment was assessed using the limb-placing, tapered ledged beam-walking and cylinder tests during the follow-up. The rats were perfused for histology on postoperative day 29. Histological data showed that ibuprofen did not affect Abeta or calcium load in the thalamus of MCAO rats. In addition, behavioral tests did not show significant difference between vehicle- and ibuprofen-treated MCAO rats. The present data do not support the idea that ibuprofen reduces the secondary Abeta/calcium pathology in the thalamus or associated sensorimotor impairment following cerebral ischemia. PMID- 21557965 TI - Structural characterization and in vitro inhibitory activities in P-selectin mediated leukocyte adhesion of polysaccharide fractions isolated from the roots of Physalis alkekengi. AB - Selectin-mediated leukocyte initial attachment and rolling over vessel endothelial surface are crucial steps for inflammatory responses. As P-selectin is a promising target for anti-inflammation therapeutic strategy, recent works have focused on searching for more potent and non-toxic P-selectin antagonists among various natural carbohydrate products. Here, we isolated three water soluble polysaccharide fractions (PPS-1, PPS-2 and PPS-3) from the roots of Physalis alkekengi by DEAE-cellulose and Sephacryl S-200 chromatography. Their physicochemical and structural characterizations were determined by chemical methods, GC (gas chromatography), HPLC (high performance liquid chromatography), FT-IR (Fourier transform infrared spectrometry), partial acid hydrolysis, methylation and GC-MS (gas chromatography-mass spectrometry) analyses. The inhibitory capacity of the polysaccharide fractions in P-selectin-mediated leukocyte adhesion was evaluated by flow cytometric, static adhesion and laminar flow assays. Results showed that different polysaccharide fractions possess distinct physicochemical and structural properties, including carbohydrate, protein and uronic acid contents, molecular weight, monosaccharide composition and glycosidic linkage type. Among the polysaccharide fractions, PPS-2 could effectively block the interaction between P-selectin and its native ligand. PMID- 21557964 TI - Cognitive enhancers in the treatment of substance use disorders: clinical evidence. AB - Attenuation of drug reward has been the major focus of medication development in the addiction area to date. With the growth of research in the area of cognitive neuroscience, the importance of executive function and inhibitory cognitive control in addictive disorders is becoming increasingly apparent. An emerging strategy in the pharmacotherapy of addictions and other psychiatric disorders involves the use of medications that improve cognitive function. In particular, agents that facilitate inhibitory and attentional control, improve abstraction, planning and mental flexibility could be beneficial in the treatment of substance use disorders. Because there are multiple neurotransmitter systems involved in the regulation of cognitive function, agents from a number of drug classes have been tested. In particular, agents acting through the cholinergic, adrenergic and glutamatergic systems have shown potential for improving cognitive function in a number of psychiatric and neurologic disorders, but most of these agents have not been tested in the treatment of individuals with substance use disorders. This manuscript provides a review of clinical data supporting the use of the major classes of cognitive enhancing agents in substance use disorders. Agents that have shown promise in cognitive enhancement in other disorders, and have a theoretical or mechanistic rationale for application to substance use disorders are also highlighted. PMID- 21557966 TI - Freeze-gelled silk fibroin protein scaffolds for potential applications in soft tissue engineering. AB - Recently tissue engineering has escalated much interest in biomedical and biotechnological applications. In this regard, exploration of new and suitable biomaterials is needed. Silk fibroin protein is used as one of the most preferable biomaterials for fabrication of scaffolds and several new techniques are being adopted to fabricate silk scaffolds with greater ease, efficiency and perfection. In this study, a freeze gelation technique is used for fabrication of silk fibroin protein 3D scaffolds, which is both time and energy efficient as compared to the conventional freeze drying technique. The fabricated silk fibroin freeze-gelled scaffolds are evaluated micro structurally for morphology with scanning electron microscopy which reveals relatively homogeneous pore structure and good interconnectivity. The pore sizes and porosity of these scaffolds ranges between 60-110MUm and 90-95%, respectively. Mechanical test shows that the compressive strength of the scaffolds is in the range of 20-40kPa. The applicability to cell culture of the freeze gelled scaffolds has been examined with human keratinocytes HaCat cells which show the good cell viability and proliferation of cells after 5 days of culture suggesting the cytocompatibility. The freeze-gelled 3D scaffolds show comparable results with the conventionally prepared freeze dried 3D scaffolds. Thus, this technique may be used as an alternative method for 3D scaffolds preparation and may also be utilized for tissue engineering applications. PMID- 21557967 TI - Murine diffusion imaging using snapshot interleaved EPI acquisition at 7T. AB - Diffusion tensor imaging (DTI) is a powerful magnetic resonance imaging tool for quantitative assessment of white matter micro structure. The majority of DTI methods employ Echo Planar Imaging (EPI) because it is insensitive to motion. However, EPI suffers from distortions and signal losses induced by inhomogeneities in magnetic field susceptibility. This is particularly accentuated in murine imaging at very high magnetic fields. The purpose of this study is to demonstrate that a Snapshot Interleaved EPI acquisition block combined with a stimulated echo module for diffusion sensitization can be successfully used to obtain high quality DTI of a mouse brain at 7T. This technique preserves the EPI speed but reduces its susceptibility artifacts and signal losses. Signal to noise ratio is also reduced but remains higher than in the DTI acquisitions based on a fast low angle shot technique. In vivo results using this new approach are presented along with a full description of the methodology. PMID- 21557968 TI - Monopolar vs. bipolar subretinal stimulation-an in vitro study. AB - This study uses an in vitro rd10 mouse model to quantify and compare the ability of the monopolar and the (concentric) bipolar electrode configurations for subretinal stimulation. To allow for results which can be directly compared an identical region of the retina was stimulated due to the circumstance that the bipolar electrode configuration allows also for monopolar stimulation, if the concentric counter-electrode is set potential-free (floating). A ganglion cell, located centrally over the bipolar electrode configuration was selected to extracellularly record action potentials during stimulation. To analyse the recorded action potentials, we introduce a new method which combines the advantages of (a) singular value decomposition (SVD) for weighting similar modulation patterns with which the recorded action potentials are characterized and (b) multi curve fitting to identify a common threshold level, required to finally assemble a strength-duration relationship (SDR). By directly comparing the obtained SDR curves, we found that the efficiency of stimulation with the monopolar electrode configuration is significantly higher than with the bipolar electrode configuration. All obtained SDR curves were fitted using the Lapicque model to estimate the chronaxie times and the rheobase currents. Liquid inclusions, eventually separating the retina from the electrodes are discussed to be a major cause for low ganglion cell responses during stimulation with the bipolar electrode configuration. PMID- 21557969 TI - Comparative inhibitory activity of the stilbenes resveratrol and oxyresveratrol on African swine fever virus replication. AB - Stilbenols are polyphenolic phytoalexins produced by plants in response to biotic or abiotic stress. These compounds have received much attention because of their significant biological effects. One of these is their antiviral action, which has previously been documented for two members of this class, namely resveratrol and oxyresveratrol. Here we tested the antiviral effect of these two compounds on African swine fever virus, the only member of the newly created family Asfarviridae and a serious limitation to porcine production worldwide. Our results show a potent, dose-dependent antiviral effect of resveratrol and oxyresveratrol in vitro. Interestingly, this antiviral activity was found for these synthetic compounds and also for oxyresveratrol extracted from new natural sources (mulberry twigs). The antiviral effect of these two drugs was demonstrated at concentrations that do not induce cytotoxicity in cultured cells. Moreover, these antivirals achieved a 98-100% reduction in viral titers. Both compounds allowed early protein synthesis but inhibited viral DNA replication, late viral protein synthesis and viral factory formation. PMID- 21557970 TI - The role of neurogenesis in olfaction-dependent behaviors. AB - Newly born neurons continuously migrate into the main and accessory olfactory bulbs and modulate the output of projection neurons. Despite some contradictory results, it is becoming clear that these newly born neurons play an important role in the response to some odorant cues. In this minireview, we discuss the recent findings surrounding the functional significance of adult neurogenesis in olfaction-dependent behaviors. PMID- 21557971 TI - Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice. AB - Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3-100 h post-pump removal. Anxiety-like behavior was assessed in the light-dark box 24h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light-dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure. PMID- 21557972 TI - A novel chicken lung epithelial cell line: characterization and response to low pathogenicity avian influenza virus. AB - Avian influenza virus (AIV) infections of the chicken occur via the respiratory route. Unlike ducks which are considered as a natural AIV reservoir, chickens are highly susceptible to AIV infections and do not possess the RIG-I pattern recognition receptor involved in triggering the antiviral interferon response. To study the chicken innate immune response to AIV in the respiratory tract, we established an epithelial cell line (CLEC213) from lung explants of white leghorn chickens. CLEC213 cells exhibited a polyhedral morphology and formed cohesive clusters bound through tight junctions as assessed by electron microscopy. Expression of E-cadherin but not vimentin could be detected as expected for cells of epithelial origin. In addition, CLEC213 cells showed characteristics similar to those of mammalian type II pneumocytes, including the presence of intracytoplasmic vacuoles filled with a mucopolysaccharide material, alkaline phosphatase activity, transcription of chicken lung collectins genes (cLL and SPA), and some intracytoplasmic lamellar-like bodies. CLEC213 cells showed a constitutive expression level of TLR3 and TLR4 and were responsive to stimulation with the respective agonists, poly (I:C) and LPS: between 4h and 24h after treatment, a strong increase in the expression of IFN-alpha, IFN-beta and IL-8 genes could be detected. Furthermore, CLEC213 cells supported efficient growth of the low pathogenicity avian influenza virus H6N2 (A/duck/France/05057a/2005) in the presence or the absence of trypsin in the culture media. At 4h post infection, the H6N2 virus induced highly elevated levels of expression of IFN alpha and IL-8, moderately elevated levels of LITAF, TGF-beta4 and CCL5. However, an increase of IFN-beta gene expression could not be detected in response to AIV infection. In conclusion, like mammalian type II pneumocytes, CLEC213 are able to mount a robust cytokine and chemokine immune response to microbial patterns and viral infection. We hypothesize that they could derive from lung atrial granular cells. The involvement of such type of lung epithelial cells in the respiratory tract defence of the chicken can thus be further studied. PMID- 21557973 TI - Reproductive function of Selenoprotein M in Chinese mitten crabs (Eriocheir sinesis). AB - Selenoproteins are present in all major forms of life, including eukaryotes, bacteria and archaea. In eukaryotic animals, selenoproteins often function as antioxidants, but rare or absent in other phyla, such as plants and fungi (except for the green alga Chlamydomonas). Selenoprotein M (SelM) is a selenocysteine containing protein with redox activity, which is involved in the antioxidant response. However, information remains limited about SelM physiology and function in marine invertebrates, particularly in crustaceans. Hence, we investigated the reproductive functionality of SelM in the Chinese mitten crab (Eriocheir sinensis), which is a commercially important yet disease vulnerable aquaculture species. The full-length SelM cDNA (928bp) strand was cloned by using PCR, based on an initial expressed sequence tag (EST) that was isolated from a hepatopancreatic cDNA library. The SelM cDNA contained a 390bp open reading frame (ORF) that encoded a putative 129 amino acid (aa) protein. SelM mRNA expression in E. sinensis was (a) tissue-specific, with the highest expression observed in the hepatopancreas, testis, ovaries and intestines. Based on this information, we then detected the different stages of tissue expression for SelM in the testis, ovary, and male crab hepatopancreas and hemolymph, and the enzyme activity of SelM in the testis. Overall, SelM was isolated successfully from the Chinese mitten crab, and its involvement in the regulation of reproduction during the period of rapid development in E. sinensis was confirmed. PMID- 21557974 TI - Ileal interposition attenuates the satiety responses evoked by cholecystokinin-8 and -33. AB - One of the possible mechanisms by which the weight-reducing surgical procedure ileal interposition (II) works is by increasing circulating levels of lower gut peptides that reduce food intake, such as glucagon like peptide-1 and peptide YY. However, since this surgery involves both lower and upper gut segments, we tested the hypothesis that II alters the satiety responses evoked by the classic upper gut peptide cholecystokinin (CCK). To test this hypothesis, we determined meal size (MS), intermeal interval (IMI) and satiety ratio (SR) evoked by CCK-8 and 33 (0, 1, 3, 5nmol/kg, i.p.) in two groups of rats, II and sham-operated. CCK-8 and -33 reduced MS more in the sham group than in the II group; CCK-33 prolonged IMI in the sham group and increased SR in both groups. Reduction of cumulative food intake by CCK-8 in II rats was blocked by devazepide, a CCK(1) receptor antagonist. In addition, as previously reported, we found that II resulted in a slight reduction in body weight compared to sham-operated rats. Based on these observations, we conclude that ileal interposition attenuates the satiety responses of CCK. Therefore, it is unlikely that this peptide plays a significant role in reduction of body weight by this surgery. PMID- 21557975 TI - Pardaxin-induced apoptosis enhances antitumor activity in HeLa cells. AB - Pardaxin, a pore-forming antimicrobial peptide that encodes 33 amino acids was isolated from the Red Sea Moses sole, Pardachirus mamoratus. In this study, we investigated its antitumor activity in human fibrosarcoma (HT-1080) cells and epithelial carcinoma (HeLa) cells. In vitro results showed that the synthetic pardaxin peptide had antitumor activity in these two types of cancer cells and that 15MUg/ml pardaxin did not lyse human red blood cells. Moreover, this synthetic pardaxin inhibited the proliferation of HT1080 cells in a dose dependent manner and induced programmed cell death in HeLa cells. DNA fragmentation and increases in the subG1 phase and caspase 8 activities suggest that pardaxin caused HeLa cell death by inducing apoptosis, but had a different mechanism in HT1080 cells. PMID- 21557976 TI - Willingness of pregnant women to vaccinate themselves and their newborns with the HPV vaccine. AB - OBJECTIVE: To evaluate the willingness of pregnant women to accept the HPV vaccine for their newborns as well as themselves. METHODS: An 18-item questionnaire was distributed to antepartum women. Demographic data about the respondent's current pregnancy and her knowledge of HPV and the HPV vaccine was collected. Information about the respondent's HPV and HPV vaccine status as well as her acceptance of the vaccine for herself during pregnancy and her newborn son and/or daughter after delivery was also collected. RESULTS: Three hundred surveys were completed and available for review. Only 6 respondents (2%) had received the HPV vaccine. Despite the small group of patients who had previously been vaccinated, 112 respondents (37.3%) stated that they would receive the HPV vaccine during pregnancy if recommended by an obstetrician. 99 respondents (33%) stated that they would vaccinate their newborn female infant and 83 (27.7%) stated would vaccinate their male infants. CONCLUSION: Providing the HPV vaccine to pregnant women as well as newborns could be an important way to increase the patient population who is protected against HPV. A percentage of pregnant women are willing to accept the vaccine for themselves and their newborns. PMID- 21557977 TI - Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2 immunocytokine that targets exposed phosphatidylserine. AB - Phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane, is immunosuppressive when externalized on the outside of cell membranes. Exposed PS inhibits the maturation and function of dendritic cells (DCs), and induces the production of multiple immunosuppressive mediators. In the present study, we determined whether blocking these effects of PS while simultaneously introducing interleukin-2 (IL-2) could improve the immunogenicity of a whole-cell cancer vaccine. An immunocytokine (2aG4-IL2) was made by genetically linking IL-2 with a PS targeting antibody, 2aG4, that can block the immunosuppressive effects of PS. The 2aG4-IL2/4T1 vaccine was generated by coating the PS exposed on irradiated 4T1 cells with 2aG4-IL2. Tumor growth, spontaneous metastasis, and survival of vaccinated mice challenged with live 4T1 tumor cells were assessed. Eighty percent of mice inoculated with 2aG4-IL2/4T1 vaccine survived free of tumor, as compared with 20% in the 2aG4/4T1 group, 20% in the C44-IL2/4T1 group, and none in the C44/4T1 control group (P=0.001 for 2aG4 IL2/4T1 versus all others groups). The incidence, number of spontaneous lung metastases was significantly lower in the 2aG4-IL2/4T1 vaccinated group than in the other groups. Splenocytes from 2aG4-IL2/4T1 vaccinated mice had significantly higher 4T1 specific cytotoxicity and ability to secrete interferon-gamma (IFNgamma) than did splenocytes from mice in the other groups. These results demonstrate that a potent whole-cell vaccine can be created by coating irradiated tumor cells with 2aG4-IL2. Such vaccine could potentially be an effective treatment modality for patients with residual disease or at "high-risk" for recurrence. PMID- 21557978 TI - Contamination in bluetongue virus challenge experiments. AB - Five cattle and five sheep that had never been exposed to bluetongue virus (BTV), as well as ten animals that had been experimentally infected with BTV-8, were inoculated with BTV-1. Previous exposure to BTV-8 did not prevent a second infection with another serotype. After the experiment, the BTV-1 preparation was found to be contaminated with BTV-15. The inoculum and blood samples taken during the experiment were analysed by serotype-specific real-time RT-PCR. There was 100 fold less BTV-15 than BTV-1 in the inoculum. Unexpectedly, BTV-15 dominated the infection in cattle that had previously been exposed to BTV-8. In sheep of both groups, on the other hand, BTV-1 prevailed over the contaminant. Regardless of the outcome, the incident demonstrates the need for a thorough contamination screening of virus preparations. For this purpose, two type-specific RT-PCR primer sets for each of the 24 established BTV serotypes as well as Toggenburg Orbivirus were designed. PMID- 21557979 TI - IbpA DR2 subunit immunization protects calves against Histophilus somni pneumonia. AB - Histophilus somni is a prevalent cause of pneumonia and septicemia in cattle. Yet evidence for protection against pneumonia by current vaccines is controversial. We have identified a new H. somni virulence factor, IbpA. Previous studies implicated three likely protective subunits or domains in IbpA (A3, A5, and DR2), which were expressed as recombinant GST fusion proteins and purified for systemic vaccination of calves. After two subcutaneous immunizations, calves were challenged intrabronchially with virulent H. somni strain 2336 and clinical signs were monitored for four days before necropsy. Serum samples were collected throughout. At necropsy, the area of gross pneumonia was estimated, bronchial lavage fluid was collected, lesions were cultured and tissue samples were fixed for histopathology. Results showed that calves immunized with IbpA DR2 had a statistically lower percentage of lung with gross lesions than controls, fewer histologic abnormalities in affected areas and no H. somni isolated from residual pneumonic lesions. Calves immunized with the control GST vaccine, IbpA3 or IbpA5 had larger H. somni positive pneumonic lesions. ELISA results for serum antibodies showed that calves immunized with the IbpA DR2 antigen had high IgG1 and IgG2 and lowest IgE responses to the immunizing antigen. Specific IgG responses were also high in the bronchial lavage fluid. High specific serum IgE responses were previously shown to be associated with more severe pneumonia, but high IgG specific anti-IbpA DR2 responses seem to be critically related to protection. Since the IbpA DR2 Fic motif has been shown to cause bovine alveolar cells to retract, we tested the neutralizing ability of pooled serum from the IbpA DR2 immunized group. This pooled serum reduced cytotoxicity by 75-80%, suggesting that the protection was due to antibody neutralization of IbpA cytotoxicity, at least in part. Therefore, IbpA DR2 appears to be an important protective antigen of H. somni. The study shows, for the first time, that immunization with a purified Fic protein protects against disease in a natural host. PMID- 21557980 TI - Delivery of antigen to sialoadhesin or CD163 improves the specific immune response in pigs. AB - Delivery of antigens to antigen presenting cell surface receptors represents a promising strategy to improve immune response to weak immunogenic antigens. We have analyzed the potential of porcine sialoadhesin (Sn) and CD163 as antigen targeting receptors using mouse Igs as surrogate antigens. Sn and CD163 are two endocytic receptors mainly expressed on macrophages located in antigen-sampling zones of secondary lymphoid organs. MAbs to CD163 induced in vitro PBMC proliferation at concentrations 50-80 fold lower than the control mAb when using, as responder cells, cells from pigs immunized with mouse serum IgGs. To evaluate in vivo targeting, pigs were immunized s.c. with anti-Sn, anti-CD163 or control mAbs, and the immune response induced to mouse Ig was analyzed. Two weeks after the first immunization, pigs receiving either anti-Sn or anti-CD163 mAbs started to show higher anti-mouse-IgG serum titres than controls. Boosting 6 weeks later, further increased the anti-IgG titres up to 15-60 fold those of controls. In addition, differences in the relative predominance of IgG1 or IgG2 subclasses in the response depending on Sn or CD163 targeting were observed. Peripheral blood mononuclear cells from pigs immunized with anti-Sn mAb showed a higher proliferative response to mouse IgG than cells from pigs immunized with control mAb. These results show that targeting antigen to Sn or CD163 can enhance the immune response in pigs. PMID- 21557981 TI - Immunoadjuvant efficacy of plasmids with multiple copies of a CpG motif coadministrated with avian influenza vaccine in chickens. AB - Unmethylated CpG motifs are capable of evoking a range of immunostimulatory effects in vertebrates and have tremendous potential to be used as therapeutic agents and adjuvants. This particular type of CpG motif has been demonstrated to be an excellent immune adjuvant mediated by Toll-like receptor 9 (TLR9) in various mammalian vaccines; however, only a few studies confirm its efficacy in avian vaccines. In the present study, immunomodulatory activities of plasmids with various copy numbers of a CpG motif were evaluated in chickens inoculated with an avian influenza vaccine. Results showed that the plasmid with 64 copies of the CpG motif (64CpG-plasmid) significantly enhanced the mRNA expressions of interferon-gamma (IFN-gamma), TLR3 and TLR7 in chicken splenocytes compared to plasmids with lesser copies of the CpG motif in vitro. Chickens inoculated with the H5N2 avian influenza inactivated vaccines (V52) coadministrated with the 64CpG-plasmid (V52-64CpG) showed significant increments of hemagglutination inhibition (HI) titers, peripheral blood mononuclear cell (PBMC) proliferation, and mRNA expressions of IFN-alpha, IFN-gamma, TLR3, TLR7 and TLR21 in splenocytes as compared to those of chickens inoculated with V52 alone, V52 adjuvanted with aluminum gel (V52-gel), or with V52-gel plus vector. Additionally, following challenge with a highly virulent H5N1 strain, a higher survival rate (100%) was observed in chickens inoculated with V52-64CpG as compared to those that received V52-gel (80%) or PBS (0%). The 64CpG-plasmid significantly enhanced chicken immunity in vitro and in vivo; thus it can be a potent adjuvant in an avian influenza vaccine for chickens. PMID- 21557982 TI - A 13-week subchronic toxicity study of hinokitiol administered in the diet to F344 rats. AB - Myocarditis has been reported in male F344 rats given a diet containing hinokitiol (HT). A subchronic toxicity study was here performed to re-evaluate toxic effects of HT in both sexes of F344 rats with dietary administration at concentrations of 0%, 0.02%, 0.07% and 0.2% for 13 weeks. Significant reduction of body weight gain was noted in 0.2% males and 0.07% and above females. Significant decrease in RBC counts, hemoglobin and hematocrit was detected in 0.07% and 0.2% females. Significant increase in MCV was observed in 0.07% and above males and 0.2% females. In the rats given 0.07% and 0.2%, significant increase in total protein and albumin were detected in males, and in total cholesterol in females. Significant increases in total cholesterol, urea nitrogen and creatinine were also detected in the 0.2% males. Significant increase in relative liver weights was detected in the 0.07% and above males and females. Absolute and relative heart weights were significantly decreased in the 0.07% and above males. Based on the above findings the no-observed-adverse-effect level (NOAEL) of HT for both male and female rats was estimated to be 0.02%, translating into 12.7 and 14.8 mg/kg b.w./day, respectively. Myocarditis was not evident in the present study. PMID- 21557983 TI - Preferential binding of insecticide phorate with sub-domain IIA of human serum albumin induces protein damage and its toxicological significance. AB - Phorate, an organophosphorus insecticide is known for its adverse effects on acetylcholinesterase, and other neuronal and pulmonary activities. Most likely, the toxicity of drugs/agrochemicals is modulated through cellular distribution bound to plasma proteins. Therefore, the in vitro interaction of phorate with human serum albumin (HSA) has been investigated, using sensitive techniques like fluorescence spectroscopy and circular dichroism, to ascertain its binding mechanism and toxicological implications. Fluorescence studies revealed the quenching constant (Ksv) as 2.5 * 104 M-1 and binding affinity (Ka) as 2.96 * 104 M-1 (r2 = 0.99), with a primary binding site of phorate at sub-domain IIA of HSA. Circular dichroism (CD) data demonstrated a noticeable reduction in secondary structure (alpha-helical content) of phorate treated HSA. Albumin treated with 200-1000 MUM phorate released significant amounts of acid soluble amino and carbonyl groups, whereas higher concentrations resulted in protein fragmentation. It is postulated that the 1'-O and 3-O alkyl groups of phorate have a role in binding with electrophilic centers of Trp 214, and Arg 218/Lys 195, respectively. Moreover, the significant ultrastructural changes, reactive oxygen species (ROS) generation, mitochondrial damage and cell death in phorate treated cultured human amnion epithelial (WISH) cells, elucidated phorate induced cellular toxicity. PMID- 21557984 TI - Immunomodulation of serum complement (C3) and macrophages by synthetic pyrethroid fenvalerate: in vitro study. AB - Fenvalerate, a type II synthetic pyrethroid, has emerged as one of the most potent indoor toxicants. Despite its widespread usage, the adverse effect of this insecticide on immune defense mechanism has not been comprehensively investigated. In this in vitro study we report the effect of fenvalerate on two pivotal components of the immune network, namely the complement system and macrophages. Fenvalerate treated human sera showed serum complement activation as evident by significant (p<0.05) increase in C3b, C3d and C3a levels and a significant (p<0.05) decline in CH50 levels. Further detailed study demonstrates that the activation of complement system is through alternative pathway. This is possibly responsible for various allergic manifestations often reported in subjects exposed to fenvalerate. In addition, fenvalerate induce cellular apoptosis and cytotoxicity, as demonstrated by cytoplasmic vacuolization, heterochromatin condensation, hypodiploid nuclei and DNA fragmentation in macrophages. Considerable deleterious effects on macrophages in conjunction with uncontrolled serum complement activation are probably one of the major mechanisms contributing for the immunosuppressive effects of fenvalerate. PMID- 21557985 TI - Reliability and failure modes of implant-supported zirconium-oxide fixed dental prostheses related to veneering techniques. AB - OBJECTIVES: To compare fatigue failure modes and reliability of hand-veneered and over-pressed implant-supported three-unit zirconium-oxide fixed-dental prostheses(FDPs). METHODS: Sixty-four custom-made zirconium-oxide abutments (n=32/group) and thirty-two zirconium-oxide FDP-frameworks were CAD/CAM manufactured. Frameworks were veneered with hand-built up or over-pressed porcelain (n=16/group). Step-stress-accelerated-life-testing (SSALT) was performed in water applying a distributed contact load at the buccal cusp-pontic area. Post failure examinations were carried out using optical (polarized reflected-light) and scanning electron microscopy (SEM) to visualize crack propagation and failure modes. Reliability was compared using cumulative-damage step-stress analysis (Alta-7-Pro, Reliasoft). RESULTS: Crack propagation was observed in the veneering porcelain during fatigue. The majority of zirconium oxide FDPs demonstrated porcelain chipping as the dominant failure mode. Nevertheless, fracture of the zirconium-oxide frameworks was also observed. Over pressed FDPs failed earlier at a mean failure load of 696 +/- 149N relative to hand-veneered at 882 +/- 61N (profile I). Weibull-stress-number of cycles unreliability-curves were generated. The reliability (2-sided at 90% confidence bounds) for a 400N load at 100K cycles indicated values of 0.84 (0.98-0.24) for the hand-veneered FDPs and 0.50 (0.82-0.09) for their over-pressed counterparts. CONCLUSIONS: Both zirconium-oxide FDP systems were resistant under accelerated life-time-testing. Over-pressed specimens were more susceptible to fatigue loading with earlier veneer chipping. PMID- 21557986 TI - The role of arousal in the preparation for voluntary movement. AB - Planning and readiness for action are associated with pre-movement brain activity reflected in the readiness potential (RP). Previous research suggests that RP is affected by higher-order cognitive functions. The present study investigated the relationship between arousal and RP. Twenty participants performed a RP paradigm in which they executed self-paced movements approximately every 4-5s. Participants' arousal level was directly manipulated through interaction with the experimenter during the rest breaks preceding the movement task. Skin conductance level (SCL) differed between arousal conditions, indicating that the arousal manipulation was effective. RP was significantly higher under the low arousal than the high arousal condition. This arousal effect also changed depending on whether RP was measured at overall high or low levels of arousal. Our data indicate that arousal does not directly activate structures underlying action preparation. We suggest that the arousal effect may be mediated by the attentional resources allocated to the movement. PMID- 21557987 TI - X-irradiation reduces the proliferation of astrocytes by cell cycle arrest. AB - Reactive astrogliosis is one of the key components of the cellular response to CNS injury and is considered a major impediment to axonal regeneration. Our previous study demonstrated that cell cycle inhibition treatment can reduce astrocyte activation and proliferation in vivo. In this study, we examined whether reactive astrogliosis can be suppressed by X-irradiation in vitro by modulating cell cycle progression. X-irradiation with low dose (4 Gy) suppressed astrocyte proliferation as demonstrated by immunofluorescence staining with BrdU and Ki67 in monolayer astrocyte cultures and those in scratch-wound model. The proportions of BrdU (+) and Ki67 (+) cells at 12, 24, and 48 h after 4 Gy irradiation were significantly lower than those in control group. FACS analysis of monolayer astrocyte cultures showed that X-irradiation decreased the proportion of astrocytes in S phase at 12 and 24h after irradiation with a dose dependent manner. Furthermore, after X-irradiation, higher levels of p53 were observed by western blot as compared to control astrocyte cultures. Taken together, these data support that X-irradiation can decrease astrogliosis via arresting the cell cycle progression, which might constitute an effective therapeutic intervention in diseases characterized by excessive proliferation of glial cells. PMID- 21557988 TI - Transcallosal inhibition dampens neural responses to high contrast stimuli in human visual cortex. AB - Visual cortical areas in the two hemispheres interact via the corpus callosum, but the precise role of the callosal pathway in visual processing remains controversial. Here we have investigated the function of transcallosal projections in human primary visual cortex (V1). Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts were recorded before and after functional inactivation of the occipital cortex of one hemisphere via off line low-frequency repetitive transcranial magnetic stimulation (rTMS; 0.5 Hz stimulation for 20 min). VEPs were recorded in V1 before (T0), immediately after (T1) and 45' following the completion of rTMS (T2). We found that low-frequency rTMS had an inhibitory effect on VEPs amplitudes at all contrasts in the treated side. Remarkably, reduction of VEP amplitudes in the inhibited hemisphere at T1 was accompanied by an increase in VEP amplitudes in the contralateral side only at mid-high contrasts (50-90%). This disinhibitory effect was observed with both central and hemifield stimulation. No changes in VEP amplitudes were observed when rTMS was applied to a cortical site more anterior with respect to V1. These data provide the first evidence that a mechanism of transcallosal inhibition dampens neural responses at high contrasts in human visual cortex. PMID- 21557989 TI - Increased non-quantal release of acetylcholine after inhibition of endocytosis by methyl-beta-cyclodextrin: the role of vesicular acetylcholine transporter. AB - We investigated the role of the vesicular acetylcholine transporter in the mechanism of non-quantal (non-vesicular) secretion of neurotransmitter in the neuromuscular synapse of the rat diaphragm muscle. Non-quantal secretion was estimated electrophysiologically by the amplitude of end-plate hyperpolarization after inhibition of cholinesterase and nicotinic receptors (H-effect) or measured by the optical detection of acetylcholine in the bathing solution. It was shown that 1 mM methyl-beta-cyclodextrin (MCD) reduced both endocytosis and, to much lesser extent, exocytosis of synaptic vesicles (SV) thereby increasing non quantal secretion of acetylcholine with a concurrent decrease in axoplasm pH. During high-frequency stimulation of the motor nerve, that substantially increases vesicles exocytosis, the non-quantal secretion was further enhanced if the endocytosis of SV was blocked by MCD. In contrast, non-quantal secretion of acetylcholine did not increase when the MCD-treated neuromuscular preparations were superfused with either vesamicol, an inhibitor of vesicular transporter of acetylcholine, or sodium propionate, which decreases intracellular pH. These results suggest that the proton-dependent, vesamicol-sensitive vesicular transporters of acetylcholine, which become inserted into the presynaptic membrane during SV exocytosis and removed during endocytotic recycling of SV, play the major role in the process of non-quantal secretion of neurotransmitter. PMID- 21557990 TI - Transient knock down of checkpoint kinase 1 in hematopoietic progenitors is linked to bone marrow toxicity. AB - Checkpoint kinase 1 (Chk1) is required for both intra-S phase and G2/M checkpoints in cell cycle, and plays critical roles in maintaining genomic stability and transducing DNA damage response. Chk1 deficiency has been shown to inhibit T-cell differentiation and resulted in severe anemia in a Chk1 heterozygous mouse model. To date, there has been a good correlation between Chk1 inhibition and in vitro bone marrow toxicity among small molecule inhibitors. To better understand the role of Chk1 in hematopoiesis, we conducted transient Chk1 gene silencing in human bone marrow progenitor cells using siRNA and electroporation. At 48h post electroporation, approximately 70% inhibition of Chk1 was confirmed using real-time RT-PCR and immunoblotting, which resulted in more than 60% reduction in cell count when compared to the non-specific siRNA control on day 6 post-electroporation. This result was confirmed using a colony forming unit assay, where reduced number in both erythroid and granulocyte colonies was observed with Chk1 siRNA treatment. The Chk1 gene inhibition in bone marrow progenitor cells resulted in significant induction of apoptosis, but not cell cycle arrest, as assessed using flow cytometry. In this study an effective method to knock down a gene of interest was established in hard-to-transfect hematopoietic stem cells. Furthermore, our results support a direct role of Chk1 in maintaining normal hematopoiesis in the bone marrow. PMID- 21557991 TI - Stress responses of human dermal fibroblasts exposed to zinc pyrithione. AB - Zinc pyrithione is used as a topical agent in a range of medicinal and cosmetic applications. Despite its extensive use and reported beneficial effects in treatment of various dermal problems, its potential toxicity towards skin cells remains relatively underexplored. In this work we investigated effects of nM zinc pyrithione on cell stress response pathways of primary human skin fibroblasts during 24h of exposure. We demonstrate that zinc pyrithione-induced cytotoxity in dermal fibroblasts is dose-dependent and it associates with increased intracellular zinc concentrations and activated stress response pathways including p53 and stress kinase p38. Higher zinc pyrithione concentrations (500nM and above) stimulate oxidative stress and moderate DNA damage which occur in the presence of activated p38 kinase. Cells further upregulate the expression of p53 which increases its transcriptional activity while mitogenic signaling exemplified by mTOR (mammalian target of rapamycin) expression is suppressed and these steps lead to mitochondrial, caspase-dependent apoptosis. Conversely, lower zinc concentrations (125nM) fail to induce oxidative stress and significant DNA damage; however, treated cells still activate p38 and upregulate the expression and transcriptional activity of p53 and its target gene p21 as well as the expression of p16 in the presence of active mTOR pathway and a changed DNA methylation pattern. The end result is premature senescence phenotype. Specific pharmacological inhibitors as well as gene knockdown technology prove that an interaction between p38, p53 and mTOR might be responsible for these observed endpoints. Taken together, exposure of dermal fibroblasts to varying concentrations of zinc pyrithione may result in either cell death-apoptosis or cellular premature senescence which attests to the ability of this compound to affect this type of cells in an in vitro model system. PMID- 21557992 TI - Developmental immunotoxicity of di-n-octyltin dichloride (DOTC) in an extended one-generation reproductive toxicity study. AB - Developmental immunotoxicity assessment is considered ready for inclusion in developmental toxicity studies. Further evaluation of proposed and additional assays is needed to determine their utility in assessing developmental immunotoxicity. In this study, a wide range of immunological parameters was included in an extended one-generation reproductive toxicity protocol. F(0) Wistar rats were exposed to DOTC via the feed (0, 3, 10, and 30mg/kg) during pre mating, mating, gestation and lactation and subsequently F(1) were exposed from weaning until sacrifice. Immune assessments by several immune parameters were performed at PNDs 21, 42 and 70. The T cell-dependent antibody response to Keyhole Limpet hemocyanin (KLH) was assessed following subcutaneous immunizations with KLH on PNDs 21 and 35 and the delayed-type hypersensitivity response (DTH) against KLH was evaluated at PND 49. No effects were found on PND 21. While effects on lymphocyte subpopulations in the thymus were only observed in the 30mg/kg group on PND 42, effects on lymphocyte subpopulations in the spleen were found in the 30mg/kg group on both PNDs 42 and 70. The DTH response already showed an effect at 3mg/kg and was the overall critical endpoint. The results from this study support the inclusion of splenocyte subpopulation parameters in developmental toxicity studies and identified the DTH response as an important functional parameter. PMID- 21557993 TI - Relative quantification of polyethylene glycol 400 excreted in the urine of male and female volunteers by direct injection electrospray-selected ion monitoring mass spectrometry. AB - The use of polyethylene glycol 400 (PEG 400) as an excipient in oral formulations can have profound and differing effects on drug bioavailability in men and women; therefore an understanding of the pharmacokinetics of this excipient is required. A direct injection electrospray selected ion monitoring mass spectrometry methodology was developed and validated for the quantitation of PEG 400 excreted in human urine after oral administration. The most abundant ions corresponding to PEG 400 oligomers at m/z 365, 409, 453, 497, 541, and 585 were used for selected ion monitoring (SIM). Pre-dose urine of volunteers was spiked with various amounts of PEG 400 to generate calibration curves over the concentration range 2.5-90 MUg/mL for all SIM channels. The relative standard deviations of intra- and inter-day analysis of PEG 400 in human urine were lower than 11.8% and bias percentage was less than 9.7%. This specific method for relative quantitation of PEG 400 was then used to analyse urine samples with minimal sample preparation. Urine samples of twelve healthy volunteers (six men and six women) who received 0.75 g and 1.5 g PEG 400 on two separate occasions were collected over 24h. On average 36.5% of the orally administered dose of PEG 400 was recovered in the urine of the volunteers, with no significant difference observed between men and women. PMID- 21557994 TI - The effect of deafness duration on neurotrophin gene therapy for spiral ganglion neuron protection. AB - A cochlear implant can restore hearing function by electrically exciting spiral ganglion neurons (SGNs) in the deaf cochlea. However, following deafness SGNs undergo progressive degeneration ultimately leading to their death. One significant cause of SGN degeneration is the loss of neurotrophic support that is normally provided by cells within the organ of Corti (OC). The administration of exogenous neurotrophins (NTs) can protect SGNs from degeneration but the effects are short-lived once the source of NTs has been exhausted. NT gene therapy, whereby cells within the cochlea are transfected with genes enabling them to produce NTs, is one strategy for providing a cellular source of NTs that may provide long-term support for SGNs. As the SGNs normally innervate sensory cells within the OC, targeting residual OC cells for gene therapy in the deaf cochlea may provide a source of NTs for SGN protection and targeted regrowth of their peripheral fibers. However, the continual degeneration of the OC over extended periods of deafness may deplete the cellular targets for NT gene therapy and hence limit the effectiveness of this method in preventing SGN loss. This study examined the effects of deafness duration on the efficacy of NT gene therapy in preventing SGN loss in guinea pigs that were systemically deafened with aminoglycosides. Adenoviral vectors containing green fluorescent protein (GFP) with or without genes for Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT3) were injected into the scala media (SM) compartment of cochleae that had been deafened for one, four or eight weeks prior to the viral injection. The results showed that viral transfection of cells within the SM was still possible even after severe degeneration of the OC. Supporting cells (pillar and Deiters' cells), cells within the stria vascularis, the spiral ligament, endosteal cells lining the scala compartments and interdental cells in the spiral limbus were transfected. However, the level of transfection was remarkably lower following longer durations of deafness. There was a significant increase in SGN survival in the entire basal turn for cochleae that received NT gene therapy compared to the untreated contralateral control cochleae for the one week deaf group. In the four week deaf group significant SGN survival was observed in the lower basal turn only. There was no increase in SGN survival for the eight week deaf group in any cochlear region. These findings indicated that the efficacy of NT gene therapy diminished with increasing durations of deafness leading to reduced benefits in terms of SGN protection. Clinically, there remains a window of opportunity in which NT gene therapy can provide ongoing trophic support for SGNs. PMID- 21557995 TI - Extract of the dried heartwood of Caesalpinia sappan L. attenuates collagen induced arthritis. AB - AIM OF THIS STUDY: To confirm the anti-arthritic effect and explore the potential mechanism of the dried heartwood of Caesalpinia sappan L. (HCS) on collagen induced arthritis (CIA) in rats, an animal model of rheumatoid arthritis. MATERIALS AND METHODS: CIA was induced in male Wistar rats by intradermal injection of bovine collagen-II in Freund's incomplete adjuvant (IFA). The rats in the onset of arthritis were treated daily with oral administration of an ethanol extract from HCS (EHCS) at different doses (1.2, 2.4 and 3.6g/kg) or olive oil-vehicle for 10 days. Paw swelling, arthritis index, radiographic and histopathologic changes were evaluated to confirm the anti-arthritic effect of EHCS on CIA in rats. Levels of proinflammatory cytokines interleukin-1 beta (IL 1beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) as well as prostaglandin E2 (PGE2) in blood and expression of cyclooxygenase-2 (COX-2) and transcription factor NF-kappaB p65 in paw cartilage were detected to further study the molecular mechanism of the anti-arthritic effects of EHCS on CIA in rats. In addition, the adverse effects of EHCS on liver and kidney of rats were also evaluated. RESULTS: The results showed that the EHCS markedly attenuated collagen-induced arthritis and reduced the levels of IL-1beta, IL-6, TNF-alpha and PGE2 in serum and the expression of COX-2 and transcription factor NF-kappaB p65 in paw cartilage of CIA rats. EHCS (3.6g/kg) induced slight hepatotoxicity and body weight loss. CONCLUSION: These results indicate that EHCS significantly attenuates CIA in rats by decreasing the levels of IL-1beta, IL-6, TNF-alpha and PGE2 in serum and the expression of COX-2 and transcription factor NF-kappaB in paw cartilage. PMID- 21557996 TI - Hyperaccumulators, arbuscular mycorrhizal fungi and stress of heavy metals. AB - Use of plants, with hyperaccumulating ability or in association with soil microbes including the symbiotic fungi, arbuscular mycorrhiza (AM), are among the most common biological methods of treating heavy metals in soil. Both hyperaccumulating plants and AM fungi have some unique abilities, which make them suitable to treat heavy metals. Hyperaccumulator plants have some genes, being expressed at the time of heavy metal pollution, and can accordingly localize high concentration of heavy metals to their tissues, without showing the toxicity symptoms. A key solution to the issue of heavy metal pollution may be the proper integration of hyperaccumulator plants and AM fungi. The interactions between the soil microbes and the host plant can also be important for the treatment of soils polluted with heavy metals. PMID- 21557997 TI - Modelling acute oral mammalian toxicity. 1. Definition of a quantifiable baseline effect. AB - Quantitative structure-activity relationships (QSARs) provide a useful tool to define a relationship between chemical structure and toxicity and allow for the prediction of the toxicity of untested chemicals. QSAR models based upon an anaesthetic or narcosis mechanism represent a baseline, or minimum, toxicity, i.e. unless a chemical acts by another, more specific, mechanism, its toxicity will be predicted by such models. The aim of this investigation was to develop baseline models for the acute toxicity of chemicals to mammals (rat and mouse) following the oral route of administration. The availability of such baseline toxicity models for mammalian species can provide a probe for testing new chemicals with respect to their molecular mechanism of toxicity. Multiple regression type structure-toxicity relationships were derived . (i.e., from oral log LD(50)(-1) data for mammalian species (rat and mouse) and the 1-octanol/water partition coefficient (log P) of classic non-polar narcotics). Subsequently, these models were used to distinguish between reactive chemicals of different mechanistic domains and baseline toxic chemicals. Comparison of measured toxicity data for oral rat and mouse LD(50) with predictions from baseline QSAR provides a means of identifying mechanistic categories and for categorising more specific acute mechanisms. PMID- 21557998 TI - Sulforaphane induces cytotoxicity and lysosome- and mitochondria-dependent cell death in colon cancer cells with deleted p53. AB - Mechanisms and pathways responsible for cytotoxicity of sulforaphane (SF) in colon cancer cells with deleted p53 were investigated during 48 h of exposure. SF showed dose-dependent cytotoxicity and proapoptotic activity in the present model. In addition, in HCT-116 p53KO cells SF induced DNA damage with the subsequent cellular response and signaling not including p53 and caspase-2 pathways. Conversely, in SF-treated cells JNK was activated which led to an early lysosomal membrane permeabilization, release of cathepsin B and D and activation of Bid by specific cleavage. Concomitantly, the expression of Bax increased in the presence of JNK-mediated Bcl-2 inhibition which was followed by mitochondrial release of cytochrome c and activation of apoptosis. These results suggest that SF may be useful as a chemopreventive agent in colon cancer with inactivated or lost p53. PMID- 21557999 TI - Depletion of cytosolic or mitochondrial thioredoxin increases CYP2E1-induced oxidative stress via an ASK-1-JNK1 pathway in HepG2 cells. AB - Thioredoxin is an important reducing molecule in biological systems. Increasing CYP2E1 activity induces oxidative stress and cell toxicity. However, whether thioredoxin protects cells against CYP2E1-induced oxidative stress and toxicity is unknown. SiRNA were used to knockdown either cytosolic (TRX-1) or mitochondrial thioredoxin (TRX-2) in HepG2 cells expressing CYP2E1 (E47 cells) or without expressing CYP2E1 (C34 cells). Cell viability decreased 40-60% in E47 but not C34 cells with 80-90% knockdown of either TRX-1 or TRX-2. Depletion of either thioredoxin also potentiated the toxicity produced either by a glutathione synthesis inhibitor or by TNFalpha in E47 cells. Generation of reactive oxygen species and 4-HNE protein adducts increased in E47 but not C34 cells with either thioredoxin knockdown. GSH was decreased and adding GSH completely blocked E47 cell death induced by either thioredoxin knockdown. Lowering TRX-1 or TRX-2 in E47 cells caused an early activation of ASK-1, followed by phosphorylation of JNK1 after 48 h of siRNA treatment. A JNK inhibitor caused a partial recovery of E47 cell viability after thioredoxin knockdown. In conclusion, knockdown of TRX-1 or TRX-2 sensitizes cells to CYP2E1-induced oxidant stress partially via ASK-1 and JNK1 signaling pathways. Both TRX-1 and TRX-2 are important for defense against CYP2E1-induced oxidative stress. PMID- 21558001 TI - Increased efflux of oxidized glutathione (GSSG) causes glutathione depletion and potentially diminishes antioxidant defense in sickle erythrocytes. AB - Erythrocytes are both an important source and target of reactive oxygen species in sickle cell disease. Levels of glutathione, a major antioxidant, have been shown to be decreased in sickle erythrocytes and the mechanism leading to this deficiency is not known yet. Detoxification of reactive oxygen species involves the oxidation of reduced glutathione (GSH) into glutathione-disulfide (GSSG) which is actively transported out of erythrocyte. We questioned whether under oxidative conditions, GSSG efflux is increased in sickle erythrocytes. Erythrocytes of 18 homozygous sickle cell patients and 9 race-matched healthy controls were treated with 2,3-dimethoxy-l,4-naphthoquinone, which induces intracellular reactive oxygen species generation, to stimulate GSSG production. Intra- and extracellular concentrations of GSH and GSSG were measured at baseline and during 210-minute 2,3-dimethoxy-l,4-naphthoquinone stimulation. While comparable at baseline, intracellular and extracellular GSSG concentrations were significantly higher in sickle erythrocytes than in healthy erythrocyte after 210 minute 2,3-dimethoxy-l,4-naphthoquinone stimulation (69.9 +/- 3.7 MUmol/l vs. 40.6 +/- 6.9 MUmol/l and 25.8 +/- 2.7 MUmol/l vs. 13.6 +/- 1.7 MUmol/l respectively, P<0.002). In contrast to control erythrocytes, where GSH concentrations remained unchanged (176 +/- 8.4 MUmol/l vs. 163 +/- 13.6 MUmol/l, NS), GSH in sickle erythrocytes decreased significantly (from 167 +/- 8.8 MUmol/l to 111 +/- 11.8 MUmol/l, P<0.01) after 210-minute 2,3-dimethoxy-l,4 naphthoquinone stimulation. Adding multidrug resistance-associated protein-1 inhibitor (MK571) to erythrocytes blocked GSSG efflux in both sickle and normal erythrocytes. GSSG efflux, mediated by multidrug resistance-associated protein-1, is increased in sickle erythrocytes, resulting in net loss of intracellular glutathione and possibly higher susceptibility to oxidative stress. PMID- 21558000 TI - The role of glutathione S-transferase P in signaling pathways and S glutathionylation in cancer. AB - Glutathione S-transferase P is abundantly expressed in some mammalian tissues, particularly those associated with malignancies. While the enzyme can catalyze thioether bond formation between some electrophilic chemicals and GSH, novel nondetoxification functions are now ascribed to it. This review summarizes recent material that implicates GSTP in mediating S-glutathionylation of specific clusters of target proteins and in reactions that define a negative regulatory role in some kinase pathways through ligand or protein:protein interactions. It is becoming apparent that GSTP participates in the maintenance of cellular redox homeostasis through a number of convergent and divergent mechanisms. Moreover, drug platforms that have GSTP as a target have produced some interesting preclinical and clinical candidates. PMID- 21558002 TI - Lipid nanocapsules for dermal application: a comparative study of lipid-based versus polymer-based nanocarriers. AB - Lipid nanocapsules (LNC) are colloidal carriers providing controlled release profiles and improved bioavailability for many drug substances and diverse administration routes. However, they have not been explored before for transdermal application. Here, we study the behavior of LNC as a transdermal drug delivery system using ibuprofen as a model drug. A comparison to other lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and polymeric nanocarriers has been made. It was found that LNC could increase the flux rate of ibuprofen 21.9+/-0.5 compared to 5.8+/-0.4 MUg/cm(2)h in case of drug solution. Similar flux rates were obtained for SLN and NLC with average values of 22.9+/-0.5 and 22.5+/-2.0 MUg/cm(2)h, respectively. On the other side, comparison to polymeric nanoparticles showed that the polymer based carriers of the same particle size had lower permeation-enhancing effect with a flux rate of 10.62+/-1.84 MUg/cm(2)h. Polymeric carriers had fourfold higher accumulation in the skin compared to that of the LNC and twice the accumulation of SLN and NLC. These results would suggest that the LNC can be considered as efficient as SLN and NLC for the transdermal drug delivery while polymeric nanoparticles are more suitable for localized drug delivery to the skin. PMID- 21558003 TI - Integration of steroid research: perspectives on environment factors, homeostasis in health, and disease treatment. PMID- 21558004 TI - Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia-ischemia in newborn piglet striatum. AB - Na+,Ca2+-permeable acid-sensing ion channel 1a (ASIC1a) is involved in the pathophysiologic process of adult focal brain ischemia. However, little is known about its role in the pathogenesis of global cerebral ischemia or newborn hypoxia ischemia (H-I). Here, using a newborn piglet model of asphyxia-induced cardiac arrest, we investigated the effect of ASIC1a-specific blocker psalmotoxin-1 on neuronal injury. During asphyxia and the first 30min of recovery, brain tissue pH fell below 7.0, the approximate activation pH of ASIC1a. Psalmotoxin-1 injection at 20min before hypoxia, but not at 20min of recovery, partially protected the striatonigral and striatopallidal neurons in putamen. Psalmotoxin-1 pretreatment largely attenuated the increased protein kinase A-dependent phosphorylation of DARPP-32 and N-methyl-d-aspartate (NMDA) receptor NR1 subunit and decreased nitrative and oxidative damage to proteins at 3h of recovery. Pretreatment with NMDA receptor antagonist MK-801 also provided partial neuroprotection in putamen, and combined pretreatment with psalmotoxin-1 and MK-801 yielded additive neuroprotection. These results indicate that ASIC1a activation contributes to neuronal death in newborn putamen after H-I through mechanisms that may involve protein kinase A-dependent phosphorylation of NMDA receptor and nitrative and oxidative stress. PMID- 21558005 TI - Expression in Escherichia coli and purification of human recombinant connexin-43, a four-pass transmembrane protein. AB - We have recently shown, using a well-defined in vitro model, that connexin 43 (Cx43) is directly involved in human cytotrophoblastic cell fusion into a multinucleated syncytiotrophoblast. Cx43 appears to interact with partner proteins within a fusogenic complex, in a multi factorial and dynamic process. This fusogenic complex remains to be characterized and constituent proteins need to be identified. In order to identify proteins interacting with the entire Cx43 molecule (extracellular, transmembrane and intracellular domains), we produced and purified full-length recombinant Cx43 fused to glutathione S-transferase (GST Cx43) and used it as "bait" in GST pull-down experiments. Cx43 cDNA was first cloned into the pDEST15 vector in order to construct a GST-fusion protein, using the Gateway system. The fusion protein GST-Cx43 was then expressed in Escherichia coli strain BL21-AITM and purified by glutathione-affinity chromatography. The purified fusion protein exhibited the expected size of 70 kDa on SDS-PAGE, western blot and GST activity. A GST pull-down assay was used to show the capacity of the full-length recombinant protein to interact with known partners. Our results suggest that this method has the capacity to produce sufficient full length recombinant protein for investigations aimed at identifying Cx43 partner proteins. PMID- 21558006 TI - Expression of plectasin in Pichia pastoris and its characterization as a new antimicrobial peptide against Staphyloccocus and Streptococcus. AB - Recombinant plectasin, the first fungus defensin, was expressed in Pichia pastoris and purified, and its physical, chemical and antimicrobial characteristics were studied. Following a 120 h induction of recombinant yeast, the amount of total secreted protein reached 748.63 MUg/ml. The percentage of recombinant plectasin was estimated to be 71.79% of the total protein. After purification with a Sephadex G-25 column and RP-HPLC, the identity of plectasin was verified by MALDI-TOF MS. Plectasin exhibited strong antimicrobial activity against the Gram-positive bacteria Staphyloccocusaureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus suis. At a concentration of 2560 MUg/ml, this peptide showed approximately equal activity against S. aureus, S. epidermidis, S. suis, and S. pneumoniae, when compared to 320 MUg/ml vancomycin, 640 MUg/ml penicillin, 320 MUg/ml vancomycin and 160 MUg/ml vancomycin, respectively. In addition, plectasin showed anti-S. aureus activity over a wide pH range of 2.0 and 10.0, a high thermal stability at 100 degrees C for 1h and remarkable resistance to papain and pepsin. The expression and characterization of recombinant plectasin in P. pastoris has potential to treat Streptococcus and Staphyloccocus infections when most traditional antibiotics show no effect on them. Our results indicate that plectasin can be produced in large quantities, and that it has pharmaceutical importance for the prevention and clinical treatment of Staphyloccocus and Streptococcus infections. PMID- 21558007 TI - Molecular characterization and expression analysis of the channel catfish cathepsin D genes. AB - Cathepsin D is a lysosomal aspartic proteinase that participates in various degradation functions of the cell. In this study, we characterized the cathepsin D genes in channel catfish and found two genes encoding catfish cathepsin D, referred to as cathepsin D1 and D2 genes. These two genes are highly similar in genomic structure and organization, sharing a moderate level of amino acid sequence similarity (56%). Genomic Southern analysis suggested the presence of a single copy of each of the cathepsin D1 and D2 genes. Phylogenetic analysis provided strong evidence that two cathepsin D genes are present in most of the teleost lineage, with cathepsin D2 likely having been lost in some higher vertebrate lineages. The catfish cathepsin D1 and D2 genes are expressed in virtually all the 11 tested tissues (brain, gill, heart, head kidney, trunk kidney, intestine, liver, muscle, skin, spleen, and stomach) on the transcript level, but appear to exhibit greater levels of expression in immune-related tissues and organs. Upon infection with Edwardsiella ictaluri, the expression of the catfish cathepsin D genes showed the most significant changes in liver and head kidney, with time points and magnitude of transcript changes varying between the two genes. We additionally examined bacterially-mediated changes of expression in gill, intestine, and trunk kidney. The fact that bacterial infection can induce expression of the cathepsin D genes and that they appeared to be expressed naturally at higher levels in immune-related organs may suggest that they are an important component of the innate immune response of catfish against bacterial infections. PMID- 21558008 TI - Dynamics underlying spontaneous human alpha oscillations: a data-driven approach. AB - Although the cognitive and clinical correlates of spontaneous human alpha oscillations as recorded with electroencephalography (EEG) or magnetoencephalography (MEG) are well documented, the dynamics underlying these oscillations is still a matter of debate. This study proposes a data-driven method to reveal the dynamics of these oscillations. It demonstrates that spontaneous human alpha oscillations as recorded with MEG can be viewed as noise perturbed damped harmonic oscillations. This provides evidence for the hypothesis that these oscillations reflect filtered noise and hence do not possess limit cycle dynamics. To illustrate the use of the model, we apply it to two data-sets in which a decrease in alpha power can be observed across conditions. The associated differences in the estimated model parameters show that observed decreases in alpha power are associated with different kinds of changes in the dynamics. Thus, the model parameters are useful dynamical biomarkers for spontaneous human alpha oscillations. PMID- 21558009 TI - Evolutionary patterns of diversification in the Andean hummingbird genus Adelomyia. AB - The patterns of genetic diversity and morphological variation are of central importance in understanding the evolutionary process that drive diversification. We use molecular, morphological, and ecological data to explore the influence of geography and ecology in promoting speciation in the widespread Andean hummingbird genus Adelomyia. Six monophyletic clades were recovered which show distributional limits at well-defined geographic barriers. Percentage sequence divergence ranged between 5.8% and 8.2% between phylogroups separated by large (>4000 km) and small (<50 km) distances respectively, suggesting that geographic isolation may be influential at very different scales. We show that morphological traits in independent phylogroups are more related to environmental heterogeneity than to geographic barriers. We provide a molecular reconstruction of relationships within Adelomyia and recommend its use in future comparative studies of historical biogeography and diversification in the Andes. PMID- 21558010 TI - Phylogenetic informativeness profiling of 12 genes for 28 vertebrate taxa without divergence dates. PMID- 21558011 TI - Forebrain-specific constitutively active CaMKKalpha transgenic mice show deficits in hippocampus-dependent long-term memory. AB - The Ca(2+)/calmodulin (CaM) kinase cascade is activated by Ca(2+) influx through the voltage-dependent Ca(2+) channels and the NMDA receptor. CaM kinase kinase (CaMKK), the most upstream kinase of the CaM kinase cascade, phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, resulting in activation of cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription. Using transgenic techniques, we created mutant mice in which a constitutively active form of CaMKK1, the autoinhibitory domain truncated protein, is over-expressed specifically in the forebrain. In these mice, although performance was normal in basal activity and short-term memory, specific impairments were shown in hippocampus-dependent long-term memory after training in spatial memory tasks and after contextual fear conditioning. In cultured neurons of these mice, phosphorylation of CaMKI was significantly increased in basal states, whereas the activity range of CaMKI phosphorylation by brain-derived neurotrophic factor (BDNF) and KCl stimulation was significantly diminished in mutant mice. Our results define a critical role for CaMKKalpha in synaptic plasticity and the retention of hippocampus-dependent long-term memory. PMID- 21558012 TI - Mig1 is involved in mycelial formation and expression of the genes encoding extracellular enzymes in Saccharomycopsis fibuligera A11. AB - The MIG1 gene of Saccharomycopsis fibuligera A11 was cloned from its genomic DNA using the degenerated primers and inverse PCR. The MIG1 gene (1152bp, accession number: HM450676) encoded a 384-amino acid protein very similar to Mig1s from other fungi. Besides their highly conserved zinc fingers, the Mig1 proteins displayed short conserved motifs of possible significance in glucose repression. The MIG1 gene in S. fibuligera A11 was disrupted by integrating the HPT (hygromycin B phosphotransferase) gene into ORF (Open Reading Frame) of the MIG1 gene. The disruptant A11-c obtained could grow in the media containing hygromycin and 2-deoxy-d-glucose, respectively. alpha-Amylase, glucoamylse, acid protease and beta-glucosidase production by the disruptant and expression of their genes in the disruptant were greatly enhanced. This confirms that Mig1, the transcriptional repressor, indeed regulates expression of the genes and production of the extracellular enzymes in S. fibuligera A11. At the same time, it was found that cell budding was enhanced and mycelial formation was reduced in the disruptant. PMID- 21558013 TI - Selection and optimization of PCR-based methods for the detection of Histoplasma capsulatum var. capsulatum. AB - BACKGROUND: Current methods for the laboratory diagnosis of histoplasmosis are problematic in terms of their sensitivity, specificity and runtime. OBJECTIVES: Thus, in this study, we sought to select and optimize methods for the detection of Histoplasma capsulatum var. capsulatum by polymerase chain reaction (PCR). METHODS: Three DNA extraction methods and three PCR methods were evaluated. We optimised the concentration of the components of this PCR reaction and determined its sensitivity and specificity using blood samples to which H. capsulatum had been added. RESULTS: The DNA extraction method that yielded the highest-quality DNA used silica membranes (DNeasy Blood & Tissue Kit, Qiagen, Hilden, Germany), and the amplification method with the best detection capacity used a target gene encoding a 100-kDa protein. Our optimisation of the PCR conditions indicated that the reaction works over a significant range of component concentrations; in addition, it was able to detect H. capsulatum better than traditional culture techniques, with a detection limit of only 10 pg of DNA. CONCLUSIONS: In our experimental conditions, the PCR method selected in this work (instead of nested PCR) is a tool sensitive enough for the diagnosis of histoplasmosis. PMID- 21558015 TI - Diabetes: New conductors for the peroxisome proliferator-activated receptor gamma (PPARgamma) orchestra. AB - The PPARgamma nuclear receptor orchestrates fatty acid storage and glucose metabolism by coordinating the expression of genes involved in lipid uptake, adipogenesis and inflammation. It is a target for the insulin-sensitising thiazolidinediones (TZDs) which have been used to treat diabetes since the late nineties. Adverse secondary effects of TZDs have underpinned continued investigations into the molecular details governing PPARgamma regulation and new therapeutic approaches which represent the focus of this article. Recent findings position Cdk5 as a lead conductor of PPARgamma. Cdk5 regulates PPARgamma directly, via phosphorylation, and may also inhibit it indirectly, via phosphorylation and activation of phospholipase D2 (PLD2) which generates the endogenous inhibitor cyclic phosphatidic acid (CPA). Whilst the multifunctional nature of Cdk5 precludes it from therapeutic targeting all is not lost as selective PPARgamma modulators (SPPARMs) have shown promising preclinical and clinical results heralding a new generation of drugs to conduct a more refined PPARgamma program. PMID- 21558014 TI - Structural requirements for the inhibition of calcium mobilization and mast cell activation by the pyrazole derivative BTP2. AB - Mast cells play a critical role in the development of the allergic response. Upon activation by allergens and IgE via the high affinity receptor for IgE (FcERI), these cells release histamine and other functional mediators that initiate and propagate immediate hypersensitivity reactions. Mast cells also secrete cytokines that can regulate immune activity. These processes are controlled, in whole or part, by increases in intracellular Ca(2+) induced by the FcERI. We show here that N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-methyl-1,2,3 thiadiazole-5-carboxamide (BTP2), a pyrazole derivative, inhibits activation induced Ca(2+) influx in the rat basophil cell line RBL-2H3 and in bone marrow derived mast cells (BMMCs), without affecting global tyrosine phosphorylation of cellular proteins or phosphorylation of the mitogen-activated protein kinases Erk1/2, JNK and p38. BTP2 also inhibits activation-induced degranulation and secretion of interleukin (IL)-2, IL-3, IL-4, IL-6, IL-13, tumor necrosis factor (TNF)-alpha, and granulocyte macrophage-colony stimulating factor (GM-CSF) by BMMCs, which correlates with the inhibition of Nuclear Factor of Activated T cells (NFAT) translocation. In vivo, BTP2 inhibits antigen-induced histamine release. Structure-activity relationship analysis indicates that substitution at the C3 or C5 position of the pyrazole moiety on BTP2 (5-trifluoromethyl-3-methyl pyrazole or 3-trifluoromethyl-5-methyl-pyrazole, respectively) affected its activity, with the trifluoromethyl group at the C3 position being critical to its activity. We conclude that BTP2 and related compounds may be potent modulators of mast cell responses and potentially useful for the treatment of symptoms of allergic inflammation. PMID- 21558016 TI - Potentiation strategies of dendritic cell-based antitumor vaccines: combinational therapy takes the front seat. AB - Despite recent attempts to take advantage of dendritic cell (DC)-based vaccines for cancer immunotherapy, the results of clinical studies have been disappointing. This is mainly as a result of the diverse immune escape mechanisms used by the tumor together with the insufficient ability of DCs to mount an effective immune response against these mechanisms. In this regard, several approaches have been devised to improve the efficacy of DC-based vaccines. However, the application of each individual approach per se might not be sufficient to overwhelm the diverse immune escape mechanisms. In this review, we focus on current strategies for the ex vivo potentiation of DC-based vaccines, with an emphasis on combinational therapy methods as a promising alternative for tumor immunotherapy. PMID- 21558017 TI - Driving operational excellence across research. PMID- 21558018 TI - Postreplication repair mechanisms in the presence of DNA adducts in Escherichia coli. AB - During bacterial replication, DNA polymerases may encounter DNA lesions that block processive DNA synthesis. Uncoupling the replicative helicase from the stalled DNA polymerase results in the formation of single-stranded DNA (ssDNA) gaps, which are repaired by postreplication repair (PRR), a process that involves at least three mechanisms that collectively remove, circumvent or bypass lesions. RecA mediated excision repair (RAMER) and homologous recombination (HR) are strand-exchange mechanisms that appear to be the predominant strategies for gap repair in the absence of prolonged SOS induction. During RAMER, RecA mediates pairing of damaged ssDNA with an undamaged homologous duplex and subsequent exchange of strands between the damaged and undamaged DNA. Repair of the lesion occurs in the context of the strand-exchange product and is initiated by UvrABC excinuclease; the resulting patch is filled by DNA synthesis using the complementary strand of the homologous duplex as a template. HR uses a complementary strand of an undamaged homologous duplex as a transient template for DNA synthesis. HR requires the formation and resolution of Holliday junctions, and is a mechanism to circumvent the lesion; lesions persisting in one of the daughter DNA duplexes will normally be repaired prior to subsequent rounds of replication/cell division. Translesion DNA Synthesis (TLS) does not involve strand-exchange mechanisms; it is carried out by specialized DNA polymerases that are able to catalyze nucleotide incorporation opposite lesions that cannot be bypassed by high-fidelity replicative polymerases. Maximum levels of TLS occur during prolonged SOS induction generally associated with increased mutagenesis. RAMER, HR and TLS are alternative mechanisms for processing a common intermediate the ssDNA gap containing a RecA nucleofilament. The actual pathway that is utilized will be strongly influenced by multiple factors, including the blocking/coding capacity of the lesion, the nature of the gene products that can be assembled at the ssDNA gap, the availability of a homologous partner for RAMER and HR, and protein:protein interactions and post-translational modifications that modulate the mutagenic activity of Pol-IV and Pol-V. PMID- 21558019 TI - Determining the benefits of oncologic surgery after endoscopic removal of submucosal invasive colorectal carcinoma. PMID- 21558020 TI - Natural Leishmania donovani/Leishmania aethiopica hybrids identified from Ethiopia. AB - Natural hybridization events have been demonstrated between closely and distantly related Leishmania groups despite a predominantly clonal and endogamically sexual mode of reproduction. Here we report the first natural hybrid between Leishmania aethiopica and Leishmania donovani, as evidenced from the analysis of several clones from strain MHOM/ET/94/ABAUY. Targeted species-identification PCRs revealed the presence of both genotypes, and amplified fragment length polymorphisms indicated that the clones are genetically in an intermediate position between both parental species, being more closely related to L. aethiopica. The possible scenario facilitating hybrid formation is not clear, but is discussed in relation to epidemiological data. PMID- 21558021 TI - Management of refractory anti-phospholipid syndrome. AB - Anti-phospholipid syndrome (APS) is an autoimmune prothrombotic disorder characterised by the predisposition to venous and/or arterial thrombosis and obstetric morbidity. Management of APS centres on attenuating the procoagulant state whilst balancing the risks of anticoagulant therapy. Cases of recurrent thromboses and obstetric complications occur despite optimum therapy. Alternative therapies for refractory cases are subject to disparity among clinicians due to the current lack of clinical evidence present. This review aims to address the current management strategies for refractory thrombotic and obstetric cases and future therapeutic interventions. The role and current clinical evidence of using long term low molecular weight heparin (LMWH) as an alternative to warfarin therapy for refractory thromboses is evaluated. Potential alternatives for thromboses including statins, hydroxychloroquine, Rituximab are reviewed as well as the additional avenues to target in the future as the pathogenic mechanisms of APS are unveiled. The optimal management for refractory obstetric APS cases is subject to controversy. This review focuses and assesses the current evidence for the uses of low dose prednisolone, intravenous immunoglobulin and hydroxycholoroquine in obstetric cases. The treatment modalities for the management of refractory APS require further clinical evidence. PMID- 21558023 TI - A standard orientation for metallopeptidases. AB - Visualization of three-dimensional structures is essential to the transmission of information to the general reader and the comparison of related structures. Therefore, it would be useful to provide a common framework. Based on the work of Schechter and Berger, and the finding that most peptidases bind their substrates in extended conformation, we suggest a "standard orientation" for the overall description of metallopeptidases (MPs) as done before for peptidases of other classes. This entails a frontal view of the horizontally-aligned active-site cleft. A substrate is bound N- to C-terminally from left (on the non-primed side of the cleft) to right (on the primed side), and the catalytic metal ion resides at the cleft bottom at roughly half width. This view enables us to see that most metalloendopeptidases are bifurcated into an upper and a lower sub-domain by the cleft, whose back is framed by a nearly horizontal "active-site helix." The latter comprises a short zinc-binding consensus sequence, either HEXXH or HXXEH, which provides two histidines to bind the single catalytic metal and the general base/acid glutamate required for catalysis. In addition, an oblique "backing helix" is observed behind the active-site helix, and a mixed beta-sheet of at least three strands is positioned in the upper sub-domain paralleling the cleft. The lowermost "upper-rim" strand of the sheet runs antiparallel to the substrate bound in the cleft and therefore contributes both to delimitating the cleft top and to binding of the substrate main-chain on its non-primed side through beta ribbon-like interactions. In contrast, in metalloexopeptidases, which chop off N- or C-terminal residues only, extensive binding on both sides of the cleft is not required and a different overall scaffold is generally observed. This consists of an alphabetaalpha-sandwich, which is reminiscent of, but clearly distinct from, the archetypal alpha/beta-hydrolase fold. Metalloexopeptidases have their active sites at the C-terminal end of a central, eight-stranded twisted beta-sheet, and can contain one or two catalytic metal ions. As the zinc-binding site and the residues engaged in substrate binding and catalysis are mainly provided by loops connecting the beta-sheet strands and the helices on either side, the respective standard orientations vary with respect to the position of the sheets. The standard orientation of eight prototypic MP structures is presented and discussed. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome. PMID- 21558022 TI - Activities of human genioglossus motor units. AB - Upper airway muscles play an important role in regulating airway lumen and in increasing the ability of the pharynx to remain patent in the face of subatmospheric intraluminal pressures produced during inspiration. Due to the considerable technical challenges associated with recording from muscles of the upper airway, much of the experimental work conducted in human subjects has centered on recording respiratory-related activities of the extrinsic tongue protudor muscle, the genioglossus (GG). The GG is one of eight muscles that invest the human tongue (Abd-El-Malek, 1939). All eight muscles are innervated by the hypoglossal nerve (cranial nerve XII) the cell bodies of which are located in the hypoglossal motor nucleus (HMN) of the caudal medulla. Much of the earlier work on the respiratory-related activity of XII motoneurons was based on recordings obtained from single motor axons dissected from the whole XII nerve or from whole muscle GG EMG recordings. Detailed information regarding respiratory related GG motor unit activities was lacking until as recently as 2006. This paper examines key findings that have emerged from the last decade of work conducted in human subjects. Wherever appropriate, these results are compared with results obtained from in vitro and in vivo studies conducted in non-human mammals. The review is written with the objective of facilitating some discussion and some new thoughts regarding future research directions. The material is framed around four topics: (a) motor unit type, (b) rate coding and recruitment, (c) motor unit activity patterns, and (d) a compartment based view of pharyngeal airway control. PMID- 21558025 TI - Sequencing batch biofilter granular reactor for textile wastewater treatment. AB - Textile wastewater is difficult to treat as it usually contains considerable amounts of different pollutants, which are often recalcitrant, toxic and inhibitory. Therefore, complex treatment schemes based on the sequence of various steps are usually required for an effective treatment. This explains why textile effluents are often treated in centralized plants and sometimes mixed with municipal wastewater. The adoption of new technologies for on-site treatment, instead, would be optimal, deeply reducing treatment costs. An innovative technology exhibiting several characteristics appropriate for the attainment of such a goal is sequencing batch biofilter granular reactor (SBBGR). To assess the suitability of this technology, two lab-scale reactors were operated, treating mixed municipal-textile wastewater and a pure textile effluent, respectively. Results have demonstrated that mixed wastewater can be successfully treated with very low hydraulic retention times (less than 10 hours). Furthermore, SBBGR shows to be an effective pre-treatment for textile wastewater for discharge into sewer systems. The economic evaluation of the process showed operative costs of 0.10 and 0.19 ? per m(3) of mixed wastewater and textile wastewater, respectively. PMID- 21558026 TI - Induction of hypoxia inducible factor (HIF-1alpha) in rat kidneys by iron chelation with the hydroxypyridinone, CP94. AB - Hypoxia inducible factor (HIF-1alpha) is a master regulator of tissue adaptive responses to hypoxia whose stability is controlled by an iron containing prolyl hydroxylase domain (PHD) protein. A catalytic redox cycle in the PHD's iron center that results in the formation of a ferryl (Fe(+4)) intermediate has been reported to be responsible for the hydroxylation and subsequent degradation of HIF-1alpha under normoxia. We show that induction of HIF-1alpha in rat kidneys can be achieved by iron reduction by the hydroxypyridin-4 one (CP94), an iron chelator administered intraperitoneally in rats. The extent of HIF protein stabilization as well as the expression of HIF target genes, including erythropoietin (EPO), in kidney tissues was comparable to those induced by known inhibitors of the PHD enzyme, such as desferrioxamine (DFO) and cobalt chloride (CoCl(2)). In human kidney cells and in vitro PHD activity assay, we were able to show that the HIF-1alpha protein can be stabilized by addition of CP94. This appears to inactivate PHD; and thus prevents the hydroxylation of HIF-1alpha. In conclusion, we have identified the inhibition of iron-binding pocket of PHD as an underlying mechanism of HIF induction in vivo and in vitro by a bidentate hydroxypyridinone. PMID- 21558028 TI - From the editor's perspective... PMID- 21558029 TI - Ultrasound-assisted thrombolysis of thrombus and pulmonary embolus. PMID- 21558027 TI - Wiring and rewiring of the retinogeniculate synapse. AB - The formation and refinement of synaptic circuits are areas of research that have fascinated neurobiologists for decades. A recurrent theme seen at many CNS synapses is that neuronal connections are at first imprecise, but refine and can be rearranged with time or with experience. Today, with the advent of new technologies to map and monitor neuronal circuits, it is worthwhile to revisit a powerful experimental model for examining the development and plasticity of synaptic circuits--the retinogeniculate synapse. PMID- 21558030 TI - Impact of a supervised strength training or walking training over a subsequent unsupervised therapy period on walking capacity in patients with claudication. AB - Previous studies have demonstrated that supervised strength training (ST) or walking training (WT) improve walking capacity in patients with claudication. However, it remains unknown whether these improvements would be sustained over a subsequent unsupervised period. This article reports the findings of a study to analyze whether the improvements in walking capacity, achieved with a supervised ST or WT, would be sustained over a subsequent unsupervised therapy period in patients with claudication. Patients were initially randomized to supervised exercise consisting of ST (n = 15) or WT (n = 15) for 12 weeks. After this period, 12 patients in each group consented to be followed for an additional 12 weeks of unsupervised therapy. Initial claudication distance (ICD) and total walking distance (TWD) were measured at baseline, after the supervised period (Week 12) and after the unsupervised period (Week 24). In comparison with baseline values, both groups similarly increased ICD and TWD at Week 12. From Week 12 to Week 24, both groups similarly decreased ICD (ST: -55 +/- 110 m and WT: -82 +/- 142 m, P =.04) and TWD (ST: -68 +/- 186 m and WT: -128 +/- 112 m, P < .01). However, in both groups, ICD (ST: +126 +/- 149 m and WT: +50 +/- 167 m, P = .01) and TWD (ST: +104 +/- 162 m and WT: +45 +/- 139 m, P =.01) at Week 24 remained greater than baseline values. The conclusion is that supervised ST or WT followed by an unsupervised therapy period similarly decreased walking capacity in patients with claudication. However, after the unsupervised period, walking capacity remained at a higher level than before the onset of the supervised exercise-training period. PMID- 21558031 TI - Integrating complementary and alternative medicine: use of essential oils in hypertension management. PMID- 21558032 TI - Review of an article: oral rivaroxaban for symptomatic venous thromboembolism. The EINSTEIN Investigators et al. N Engl J Med 2010; 363(26):2499-2510. PMID- 21558033 TI - Balancing spinal stability and future mobility in the cervical spine: surgical treatment of a case of osteoblastoma with secondary aneurysmal bone cyst. AB - BACKGROUND CONTEXT: The combination of osteoblastoma and aneurysmal bone cyst (ABC) in the cervical spine is a relatively rare occurrence in the general population. The diagnosis and surgical management of osteoblastoma and ABCs have been previously described in a small number of case reports/series and orthopedic texts. Lesions of the cervical spine pose challenges to surgeons that require preoperative planning and intraoperative decisions to ensure an appropriate patient outcome. Complete resection has been shown to be the most effective method for preventing recurrence; however, balancing spinal stability, future mobility, and complete resection is especially important in active young patients. PURPOSE: We describe a modern approach to the surgical management of osteoblastoma with secondary ABC of the cervical spine with 4-year clinical and radiographic follow-up. Included in this report is a comprehensive review of the literature related to osteoblastoma, ABCs, and surgical issues pertinent to them. STUDY DESIGN: An independent retrospective case review combined with a review of current literature was performed. PATIENT SAMPLE: A single patient with a combination of osteoblastoma and secondary ABC is presented. OUTCOME MEASURES: During 4 years of follow-up, the patient has been evaluated with plain radiographs for subluxation or rotation of the cervical spine. Postoperative assessments for pain and range of motion were also collected. METHODS: The medical, pathologic, and radiographic records of a case of osteoblastoma with secondary aneursymal bone cyst of the cervical spine were reviewed. A computer based literature search of the PubMed database was used to compile a comprehensive review of the topic. RESULTS: The diagnosis and surgical treatment of osteoblastoma with secondary ABC in the cervical spine are discussed in the context of a literature review. The surgical management of this lesion was dictated by the size and location of the mass as well as the impact of the surgical resection on surrounding structures in terms of spinal stability and future mobility. CONCLUSIONS: The combination of osteoblastoma and ABC in the cervical spine is an uncommon occurrence in the general population. In the cervical spine, careful surgical planning and a case-by-case evaluation must be implemented to minimize morbidity and recurrence for every patient. PMID- 21558034 TI - Modic changes and associated features in Southern European chronic low back pain patients. AB - BACKGROUND CONTEXT: Conflicting reports exist regarding the prevalence of Modic changes among low back pain (LBP) patients and factors associated with their existence. PURPOSE: To assess the prevalence of Modic changes and other findings on lumbar magnetic resonance imaging (MRI) among Spanish adult chronic LBP patients and the patient characteristics and radiological findings associated with Modic changes. STUDY DESIGN: A cross-sectional imaging study among chronic LBP patients. PATIENT SAMPLE: Four hundred eighty-seven patients (263 women and 224 men) undergoing lumbar spine MRI examination for chronic LBP. OUTCOME MEASURES: Gender, age, body mass index (BMI), lifetime smoking exposure, degree of physical activity, and image features (disc degeneration, type and extension of Modic changes, disc contour, annular tears, spinal stenosis, and spondylolisthesis). METHODS: Ten radiologists from six hospitals across six cities in Spain consecutively recruited adult patients in whom lumbar MRI had been prescribed for LBP lasting >=3 months. Patients' characteristics and imaging findings were assessed through previously validated instruments. A multivariate logistic regression model was developed to assess the features associated with Modic changes. RESULTS: Modic changes were found in 81% of the patients. The most common was Type II (51.3%), affecting only the end plate. Variables associated with Type I changes were disc contour abnormalities, spondylolisthesis, and disc degeneration. The same variables were associated with a higher risk of Type II or any type of Modic changes, as well as being male, and having a higher BMI. CONCLUSIONS: Modic changes are found in 81% (95% confidence interval, 77-85) of adult Spanish patients in whom an MRI is prescribed for chronic LBP. Modic changes are more likely to be found in males with a high BMI, who also show disc contour abnormalities, spondylolisthesis, or disc degeneration. PMID- 21558035 TI - Upright magnetic resonance imaging measurement of prevertebral soft tissue in the cervical spine of normal volunteers. AB - BACKGROUND CONTEXT: Anteroposterior width of prevertebral soft tissues (PVSTs) in the cervical spine has long been considered a valuable radiographic measurement for evaluation of occult cervical spine pathology. These measurements, generally obtained from lateral radiographs of the cervical spine, have been used clinically as references for the evaluation of patients with traumatic, neoplastic, or other cervical spine disorders. Magnetic resonance imaging (MRI) offers a subtle delineation of the soft-tissue structures anterior to the vertebral column, with the potential for more accurate and sensitive determination of PVST width. Upright magnetic resonance images permit comparison with and validation of previously reported upright lateral radiographic measurements of PVST width. To our knowledge, evaluation of cervical spine PVST width using upright MRI has not been previously published in the English literature. PURPOSE: The purposes of this study were to validate lateral radiographic measurements of PVST width using upright weight-bearing MRI in healthy subjects and quantify effects of spinal level and gender. STUDY DESIGN: Clinical study in asymptomatic volunteers. METHODS: Eleven male and eight female volunteers consented and were enrolled in the study. All volunteers were asymptomatic and had no history of cervical spine injury or degenerative disease. Prevertebral soft-tissue width was measured at each cervical level from C2 to C7 using upright weight-bearing MRI. Statistically significant differences in PVST width based on spinal level and gender were determined using two-factor analysis of variance. RESULTS: Width magnitudes were significantly dependent on gender (p<.0001) and spinal level (p<.0001). All C3 and C6 measurements were below the traditionally accepted values of 7 and 20 mm, respectively, that would be considered "abnormal." Prevertebral soft-tissue width was greater in men at upper and lower extents of the cervical spine. Prevertebral soft-tissue widths reported in the present study were similar in magnitude and level-by-level trends to measurements of asymptomatic volunteers obtained using lateral radiography. CONCLUSION: The present study validated the use of lateral radiography to measure PVST width, presented level-by-level and gender-specific normative data, and provided a weighted statistical analysis of differences between normal volunteers and injured patients. PMID- 21558036 TI - Comparison of clinical effectiveness of cervical transforaminal steroid injection according to different radiological guidances (C-arm fluoroscopy vs. computed tomography fluoroscopy). AB - BACKGROUND CONTEXT: Transforaminal steroid injection using C-arm fluoroscopy has been regarded as a useful method of treatment for cervical herniated disc. But C arm fluoroscopy cannot identify soft tissue; so there is controversy about its safety and efficacy. Computed tomography (CT) fluoroscopy permits precise anatomical resolution and has the potential to offer a safer technique compared with C-arm fluoroscopy. PURPOSE: This study was to identify the clinical effectiveness of CT fluoroscopy guidance in cervical transforaminal steroid injection compared with C-arm fluoroscopy guidance. STUDY DESIGN/SETTING: Prospective randomized controlled study/spine hospital. PATIENTS SAMPLE: Patients with neck pain and radiating upper limb pain resulting from cervical disc herniation participated in the study. They were allocated into either the CT (CT group, N=51) or C-arm (C group, N=65) fluoroscopy guidance group. OUTCOME MEASURE: Numeric Rating Scale (NRS) pain score and Neck Disability Index (NDI) values were measured at pretreatment and 8 weeks after treatment. Successful pain relief and functional improvement were defined as a 50% or more reduction in NRS and at least 40% reduction in NDI compared with pretreatment one. Numeric Rating Scale and NDI efficiency were also calculated by the difference between pre and 8 weeks after treatment to validate the degree of change in pain reduction and functional improvement. RESULTS: After 8 weeks, both groups showed pain reduction and functional improvement. The CT group showed significantly the better outcomes in reduction of NRS for arm pain score and improvement of NDI. Whereas the CT group had no cases of side effects, the C group had 10 cases. CONCLUSIONS: The CT group, without any side effects, showed the better effectiveness than the C-arm group in the improvement of radiating pain and functional status in patients with cervical disc herniation. Therefore, CT fluoroscopy can be a substitute for C-arm fluoroscopy in transforaminal steroid injection when treating patients with cervical disc herniation. PMID- 21558037 TI - Re: Ponnusamy KE, Iyer S, Gupta G, Khanna AJ. Instrumentation of the osteoporotic spine: biomechanical and clinical considerations. Spine J 2011;11:54-63. PMID- 21558041 TI - Auditory enhancement of visual perception at threshold depends on visual abilities. AB - Whether or not multisensory interactions can improve detection thresholds, and thus widen the range of perceptible events is a long-standing debate. Here we revisit this question, by testing the influence of auditory stimuli on visual detection threshold, in subjects exhibiting a wide range of visual-only performance. Above the perceptual threshold, crossmodal interactions have indeed been reported to depend on the subject's performance when the modalities are presented in isolation. We thus tested normal-seeing subjects and short-sighted subjects wearing their usual glasses. We used a paradigm limiting potential shortcomings of previous studies: we chose a criterion-free threshold measurement procedure and precluded exogenous cueing effects by systematically presenting a visual cue whenever a visual target (a faint Gabor patch) might occur. Using this carefully controlled procedure, we found that concurrent sounds only improved visual detection thresholds in the sub-group of subjects exhibiting the poorest performance in the visual-only conditions. In these subjects, for oblique orientations of the visual stimuli (but not for vertical or horizontal targets), the auditory improvement was still present when visual detection was already helped with flanking visual stimuli generating a collinear facilitation effect. These findings highlight that crossmodal interactions are most efficient to improve perceptual performance when an isolated modality is deficient. PMID- 21558042 TI - PAH body burden and biomarker responses in mussels (Mytilus edulis) exposed to produced water from a North Sea oil field: laboratory and field assessments. AB - In order to study the impact of produced water (PW) from a North Sea oil field on blue mussels (Mytilus edulis), chemical and biological markers were selected. A laboratory exposure (0.125%, 0.25% and 0.5% of PW) and a field study (6 stations 0.2-2 km from a PW discharge point) were conducted. In the laboratory study, PAH bioaccumulation increased in mussel soft tissue even at the lowest exposure dose. Micronuclei frequency demonstrated a dose-response pattern, whereas lysosomal membrane stability showed tendency towards a dose-response pattern. The same markers were assessed in the field study, biomarker analyses were consistent with the contamination level, as evaluated by mussel polycyclic aromatic hydrocarbons body burden. Overall, obtained results confirmed the value of an ecotoxicological approach for a scientifically sound characterisation of biological effects induced by offshore oilfield operational discharges. PMID- 21558043 TI - Modelling sediment-microbial dynamics in the South Nation River, Ontario, Canada: Towards the prediction of aquatic and human health risk. AB - Runoff from agricultural watersheds can carry a number of agricultural pollutants and pathogens; often associated with the sediment fraction. Deposition of this sediment can impact water quality and the ecology of the river, and the re suspension of such sediment can become sources of contamination for reaches downstream. In this paper a modelling framework to predict sediment and associated microbial erosion, transport and deposition is proposed for the South Nation River, Ontario, Canada. The modelling framework is based on empirical relationships (deposition and re-suspension fluxes), derived from laboratory experiments in a rotating circular flume using sediment collected from the river bed. The bed shear stress governing the deposition and re-suspension processes in the stream was predicted using a one dimensional mobile boundary flow model called MOBED. Counts of live bacteria associated with the suspended and bed sediments were used in conjunction with measured suspended sediment concentration at an upstream section to allow for the estimation of sediment associated microbial erosion, transport and deposition within the modelled river reach. Results suggest that the South Nation River is dominated by deposition periods with erosion only occurring at flows above approximately 250 m(3) s(-1) (above this threshold, all sediment (suspended and eroded) with associated bacteria are transported through the modelled reach). As microbes are often associated with sediments, and can survive for extended periods of time, the river bed is shown to be a possible source of pathogenic organisms for erosion and transport downstream during large storm events. It is clear that, shear levels, bacteria concentrations and suspended sediment are interrelated requiring that these parameters be studied together in order to understand aquatic microbial dynamics. It is important that any management strategies and operational assessments for the protection of human and aquatic health incorporate the sediment compartments (suspended and bed sediment) and the energy dynamics within the system in order to better predict the concentration of indicator organism. PMID- 21558044 TI - A regioselective synthesis of some new pyrazol-1'-ylpyrazolo[1,5-a]pyrimidines in aqueous medium and their evaluation as antimicrobial agents. AB - An efficient and environmental benign regioselective synthesis of some new pyrazol-1'-ylpyrazolo[1,5-a]pyrimidines (7b-h) has been accomplished via treatment of 3(5)-amino-5(3)-hydrazinopyrazole dihydrochloride (5) with several unsymmetrical 1,3-diketones (6b-h) using water as a solvent without any catalysts or additives. The structure of 7b-h was established on the basis of rigorous analysis of (1)H, (13)C NMR, IR spectral data and MS. Eight compounds (7a-h) were screened for their antibacterial activity against two gram-positive and two gram negative bacteria and compounds (7a, b, d and e) for antifungal activity against four phytopathogenic fungi. Compounds 7c and 7e manifest rather broad antibacterial activity than standard antibiotics. One lead compound, 7a (10mg/ml and 200mg/ml) exhibited equipotent or more potent antifungal activity against all tested microorganisms than standard drug. PMID- 21558045 TI - Computational investigation of the enzymatic mechanisms of phosphothreonine lyase. AB - SpvC, a virulence effector injected through type III secretion system by some Salmonella serovars, belongs to the newly discovered enzyme family, phosphothreonine lyase. Previous experimental studies have demonstrated that SpvC irreversibly inactivates mitogen-activated protein kinases by removing the phosphate group from phosphothreonine-containing substrate through a beta elimination mechanism, and results in a beta-methyldehydroalanine product. Interestingly, further biochemical investigations also indicated a secondary reaction occurring other than elimination, where a covalently bound complex is formed. Here, we employed molecular dynamics simulations and quantum mechanics calculations to gain insights on the microscopic details of such novel reaction mechanisms. Our theoretical results are consistent with the experimental observations, in which the critical stages of SpvC catalyzed reaction are revealed and the roles of several important binding site residues are reconciled. The deprotonation and precise position of the catalytic base K136 are facilitated by the formation of the fully desolvated active site upon substrate binding. The abstraction of the alpha hydrogen by K136 and the elimination of the phosphate group occur nearly simultaneously, promoted by the proton donation from the catalytic acid H106, and thus strongly supports an E2-like mechanism. K104, which is not directly involved in the enzymatic reaction, stabilizes the transition state and facilitates the reaction to occur. Remarkably, the subsequent deprotonation of K136 happens to be a natural sequel of the primary elimination reaction, restores its nucleophile capacity to attack the double bond containing elimination product, and leads to a covalently bound complex via a Michael addition mechanism. The reaction mechanism used by phosphothreonine lyases might serve as a method of programmed regulation to fine tune their enzymatic activity. PMID- 21558046 TI - Red meat and colon cancer: should we become vegetarians, or can we make meat safer? AB - The effect of meat consumption on cancer risk is a controversial issue. However, recent meta-analyses show that high consumers of cured meats and red meat are at increased risk of colorectal cancer. This increase is significant but modest (20 30%). Current WCRF-AICR recommendations are to eat no more than 500 g per week of red meat, and to avoid processed meat. Moreover, our studies show that beef meat and cured pork meat promote colon carcinogenesis in rats. The major promoter in meat is heme iron, via N-nitrosation or fat peroxidation. Dietary additives can suppress the toxic effects of heme iron. For instance, promotion of colon carcinogenesis in rats by cooked, nitrite-treated and oxidized high-heme cured meat was suppressed by dietary calcium and by alpha-tocopherol, and a study in volunteers supported these protective effects in humans. These additives, and others still under study, could provide an acceptable way to prevent colorectal cancer. PMID- 21558047 TI - USA300 methicillin-resistant Staphylococcus aureus bacteremia and the risk of severe sepsis: is USA300 methicillin-resistant Staphylococcus aureus associated with more severe infections? AB - USA300 methicillin-resistant Staphylococcus aureus (MRSA) is increasing as a cause of severe community-associated bacteremic infections. We assessed severe sepsis in response to infection in patients with USA300 MRSA compared to non USA300 MRSA bacteremia. A cohort study was conducted from 1997 to 2008 comparing sepsis in response to infection in 271 patients with MRSA bacteremia from 4 VA hospitals. Sixty-seven (25%) patients with MRSA bacteremia were USA300 MRSA; 204 (75%) were non-USA300 MRSA. The proportion of MRSA bacteremia caused by USA300 MRSA increased over time (chi2 P < 0.0001). Adjusting for age and nosocomial infection, patients with USA300 MRSA bacteremia were more likely to have severe sepsis or septic shock in response to infection than patients with non-USA300 MRSA bacteremia (adjusted relative risk = 1.82; 95% confidence interval, 1.16 2.87; P = 0.01). This suggests that patients with USA300 MRSA are more likely to develop severe sepsis in response to their infection, which could be due to host or bacterial differences. PMID- 21558048 TI - Comparative in vitro antimicrobial susceptibilities and synergistic activities of antimicrobial combinations against carbapenem-resistant Acinetobacter species: Acinetobacter baumannii versus Acinetobacter genospecies 3 and 13TU. AB - Therapeutic options for the treatment of infections caused by carbapenem resistant Acinetobacter baumannii (CRAB) are limited. In vitro activity of amikacin, ciprofloxacin, colistin (polymyxin E), ampicillin-sulbactam, and tigecycline alone and in combination with imipenem against CRAB and carbapenem resistant Acinetobacter genospecies 3 and 13TU was investigated. Colistin (97% susceptible) and tigecycline (88% and 44% susceptible by US Food and Drug Administration [FDA] and European Committee on Antimicrobial Susceptibility Testing [EUCAST] breakpoints for Enterobacteriaceae, respectively) were the 2 most active agents against CRAB, followed by minocycline (66%), ampicillin/sulbactam (16%), and amikacin (13%). Compared with CRAB isolates, carbapenem-resistant Acinetobacter genospecies 3 and 13TU isolates had higher antimicrobial susceptible rates to ciprofloxacin (88%), amikacin (63%), tigecycline (100% by FDA breakpoint and 88% by EUCAST breakpoint for Enterobacteriaceae, respectively), minocycline (100%), and ampicillin/sulbactam (75%). For the 12 tested CRAB isolates, the checkerboard titration method demonstrated synergy between imipenem and colistin (42%), tigecycline (25%), amikacin (16%), and ampicillin/sulbactam (16%). Time-kill assays revealed antimicrobial synergism for imipenem in combination with colistin (75%), tigecycline (50%), ampicillin/sulbactam (42%), amikacin (42%), and ciprofloxacin (16%). However, antimicrobial synergism between imipenem and combined agents was not present among CRAB isolates with an imipenem MIC >= 32 mg/L. The combination of tigecycline and colistin showed good in vitro synergy for CRAB with high imipenem resistance. Our results demonstrate accurate identification of prevalent Acinetobacter species and highlight their different antimicrobial susceptibilities. This knowledge will enable clinicians to select appropriate regimens for treating these infections. PMID- 21558049 TI - Analysis of multilocus sequence typing schemes for 35 different bacteria revealed that gene loci of 10 bacteria could be replaced to improve cost-effectiveness. AB - Although multilocus sequence typing (MLST) has been widely used for bacterial typing, the contribution of the gene loci to the discriminatory power of each MLST scheme is unknown. We analyzed the discriminatory powers of 36 MLST schemes using all combinations of the 7 loci and contributions of each locus to the schemes. In 10 schemes, sequencing 6 loci can achieve the discriminatory powers of 7 loci. For the other 26 schemes, the median marginal increase in discriminatory power when 7 instead of 6 loci were used is 0.0004. Sequencing the 7 loci of 50 strains each of Pseudomonas aeruginosa and Acinetobacter baumannii revealed that the discriminatory power for P. aeruginosa was 0.9861 when either 6 (without trp) or 7 loci were used and that for A. baumannii was 0.9363 when 5, 6, or 7 loci were used. Genes that have no additional or minimal contribution to the overall discriminatory powers should be replaced. PMID- 21558050 TI - Prosthetic valve endocarditis caused by Bartonella quintana in a patient during immunosuppressive therapies for collagen vascular diseases. AB - Bartonella quintana, known to cause various clinical symptoms, is increasingly recognized as one important cause of culture-negative endocarditis. We report a case of infectious endocarditis with B. quintana on the prosthetic valve, accompanied by proteinase 3-antineutrophil cytoplasmic antibody-positive collagen vascular disease-like symptoms 1 year earlier. PMID- 21558051 TI - Achilles allograft reconstruction for recurrent dislocation in total hip arthroplasty. AB - Recurrent dislocation secondary to posterior soft tissue deficiency is a challenging complication of total hip arthroplasty. We describe the use of an Achilles allograft sling to improve hip stability. Eight patients treated with the sling were followed an average of 5 years. Seven patients had no recurrent instability and good postoperative range of motion. One graft failed in a patient with a neuropathic hip. Cadaveric biomechanical testing was also performed to investigate the stiffness and torque to failure of the sling in 6 specimens. Allograft slings can be used to improve hip stability. The technique is relatively easy to perform and does not limit postoperative range of motion. The graft decreases joint stiffness and has a greater torque to failure than the intact capsule. PMID- 21558052 TI - A low frequency variant within the GWAS locus of MTNR1B affects fasting glucose concentrations: genetic risk is modulated by obesity. AB - Two common variants (rs1387153, rs10830963) in MTNR1B have been reported to have independent effects on fasting blood glucose (FBG) levels with increased risk to type 2 diabetes (T2D) in recent genome-wide association studies (GWAS). In this investigation, we report the association of these two variants, and an additional variant (rs1374645) within the GWAS locus of MTNR1B with FBG, 2h glucose, insulin resistance (HOMA IR), beta-cell function (HOMA B), and T2D in our sample of Asian Sikhs from India. Our cohort comprised 2222 subjects [1201 T2D, 1021 controls]. None of these SNPs was associated with T2D in this cohort. Our data also could not confirm association of rs1387153 and rs10830963 with FBG phenotype. However, upon stratifying data according to body mass index (BMI) (low <= 25 kg/m(2) and high > 25 kg/m(2)) in normoglycemic subjects (n = 1021), the rs1374645 revealed a strong association with low FBG levels in low BMI group (beta = -0.073, p = 0.002, Bonferroni p = 0.01) compared to the high BMI group (beta = 0.015, p = 0.50). We also detected a strong evidence of interaction between rs1374645 and BMI with respect to FBG levels (p = 0.002). Our data provide new information about the significant impact of another MTNR1B variant on FBG levels that appears to be modulated by BMI. Future confirmation on independent datasets and functional studies will be required to define the role of this variant in fasting glucose variation. PMID- 21558053 TI - An integrated MBR-TiO2 photocatalysis process for the removal of Carbamazepine from simulated pharmaceutical industrial effluent. AB - This paper aims to demonstrate that integrating biological process and photocatalytic oxidation in a system operated in recycling mode can be a promising technology to treat pharmaceutical wastewater characterized by simultaneous presence of biodegradable and refractory/inhibitory compounds. A lab scale system integrating a membrane bioreactor (MBR) and a TiO(2) slurry photoreactor was fed on simulated wastewater containing 10mg/L of the refractory drug Carbamazepine (CBZ). Majority of chemical oxygen demand (COD) was removed by the MBR, while the photocatalytic oxidation was capable to degrade CBZ. CBZ degradation kinetics and its impacts on the biological process were studied. The adoption of a recycling ratio of 4:1 resulted in removal of up to 95% of CBZ. Effluent COD reduction, sludge yield increase and respirometric tests suggested that the oxidation products were mostly biodegradable and not inhibiting the microbial activity. These results evidenced the advantages of the proposed approach for treating pharmaceutical wastewater and similar industrial effluents. PMID- 21558054 TI - Kinetics of the pyrolytic and hydrothermal decomposition of water hyacinth. AB - The kinetics of water hyacinth decomposition using pyrolysis and hydrothermal treatment was compared. With pyrolysis, initial vaporization occurred at 453 K as determined by thermogravimetric analysis, while initial solubilisation occurred at 433 K with subcritical hydrothermal treatment. The "kinetic triplet" was determined for the ranges of 423-483 K (range I) and 473-553 K (range II) using the Coats-Redfern method for both treatments. The calculated activation energies for ranges I and II were 110 and 116 kJ/mol for conventional pyrolysis and 145 and 90 kJ/mol for hydrothermal treatment. The similar activation energies for the two temperature ranges observed for pyrolysis implied that only hemicellulose decomposition occurred. For hydrothermal treatment, both hemicellulose and cellulose decomposition occurred in temperature range II, in which a notable lower activation energy was observed. This implied hydrothermal treatment was more suitable for conversion lignocellulosic biomass under these conditions. PMID- 21558055 TI - Combination of canonical correlation analysis and empirical mode decomposition applied to denoising the labor electrohysterogram. AB - The electrohysterogram (EHG) is often corrupted by electronic and electromagnetic noise as well as movement artifacts, skeletal electromyogram, and ECGs from both mother and fetus. The interfering signals are sporadic and/or have spectra overlapping the spectra of the signals of interest rendering classical filtering ineffective. In the absence of efficient methods for denoising the monopolar EHG signal, bipolar methods are usually used. In this paper, we propose a novel combination of blind source separation using canonical correlation analysis (BSS_CCA) and empirical mode decomposition (EMD) methods to denoise monopolar EHG. We first extract the uterine bursts by using BSS_CCA then the biggest part of any residual noise is removed from the bursts by EMD. Our algorithm, called CCA_EMD, was compared with wavelet filtering and independent component analysis. We also compared CCA_EMD with the corresponding bipolar signals to demonstrate that the new method gives signals that have not been degraded by the new method. The proposed method successfully removed artifacts from the signal without altering the underlying uterine activity as observed by bipolar methods. The CCA_EMD algorithm performed considerably better than the comparison methods. PMID- 21558056 TI - Substitute voice production: quantification of PE segment vibrations using a biomechanical model. AB - After total larynx excision due to laryngeal cancer, the tracheoesophageal substitute tissue vibrations at the intersection between the pharynx and the esophagus [pharyngoesophageal segment (PE segment)] serve as voice generator. The quality of the substitute voice significantly depends on the vibratory characteristics of the PE segment. For improving voice rehabilitation, the relationship between the PE dynamics and the resulting substitute voice quality is a matter of particular interest. Precondition for a comprehensive analysis of this relationship is an objective quantification of the PE vibrations. For quantification purposes, a method is proposed, which is based on the reproduction of the tissue vibrations by means of a biomechanical model of the PE segment. An optimization procedure for an automatic determination of appropriate model parameters is suggested to adapt the model dynamics to tissue movements extracted from high-speed (HS) videos. The applicability of the optimization procedure is evaluated with ten synthetic data sets. A mean error of 8.2% for the determination of previously defined model parameters was achieved as well as an overall stability of 7.1%. The application of the model to six HS recordings presented a mean correlation of the vibration patterns of 82%. PMID- 21558057 TI - Adaptive learning control for finite interval tracking based on constructive function approximation and wavelet. AB - Using a constructive function approximation network, an adaptive learning control (ALC) approach is proposed for finite interval tracking problems. The constructive function approximation network consists of a set of bases, and the number of bases can evolve when learning repeats. The nature of the basis allows the continuous adaptive learning of parameters when the network undergoes any structural changes, and consequently offers the flexibility in tuning the network structure. The expandability of the bases guarantees precision of the function approximation and avoids the trial-and-error procedure in structure selection for any fixed structure network. Two classes of unknown nonlinear functions, namely, either global L(2) or local L(2) with a known bounding function, are taken into consideration. Using the Lyapunov method, the existence of solution and the convergence property of the proposed ALC system are discussed in a rigorous manner. By virtue of the celebrated orthonormal and multiresolution properties, wavelet network is used as the universal function approximator, with the weights tuned by the proposed adaptive learning mechanism. PMID- 21558058 TI - Stability and dissipativity analysis of distributed delay cellular neural networks. AB - In this brief, the problems of delay-dependent stability analysis and strict (Q,S,R)-alpha-dissipativity analysis are investigated for cellular neural networks (CNNs) with distributed delay. First, by introducing an integral partitioning technique, two new forms of Lyapunov-Krasovskii functionals are constructed, and improved distributed delay-dependent stability conditions are established in terms of linear matrix inequalities. Based on this criterion, a new sufficient delay and alpha-dependent condition is given to guarantee that the CNNs with distributed delay are strictly (Q,S,R)-alpha-dissipative. The results developed in this brief can tolerate larger allowable delay than existing ones in the literature, which is demonstrated by several examples. PMID- 21558059 TI - Efficient algorithm for training interpolation RBF networks with equally spaced nodes. AB - This brief paper proposes a new algorithm to train interpolation Gaussian radial basis function (RBF) networks in order to solve the problem of interpolating multivariate functions with equally spaced nodes. Based on an efficient two-phase algorithm recently proposed by the authors, Euclidean norm associated to Gaussian RBF is now replaced by a conveniently chosen Mahalanobis norm, that allows for directly computing the width parameters of Gaussian radial basis functions. The weighting parameters are then determined by a simple iterative method. The original two-phase algorithm becomes a one-phase one. Simulation results show that the generality of networks trained by this new algorithm is sensibly improved and the running time significantly reduced, especially when the number of nodes is large. PMID- 21558060 TI - Real-time upper limb motion estimation from surface electromyography and joint angular velocities using an artificial neural network for human-machine cooperation. AB - A current challenge with human-machine cooperation systems is to estimate human motions to facilitate natural cooperation and safety of the human. It is a logical approach to estimate the motions from their sources (skeletal muscles); thus, we employed surface electromyography (SEMG) to estimate body motions. In this paper, we investigated a cooperative manipulation control by an upper limb motion estimation method using SEMG and joint angular velocities. The SEMG signals from five upper limb muscles and angular velocities of the limb joints were used to approximate the flexion-extension of the limb in the 2-D sagittal plane. The experimental results showed that the proposed estimation method provides acceptable performance of the motion estimation [normalized root mean square error (NRMSE) <0.15, correlation coefficient (CC) >0.9] under the noncontact condition. From the analysis of the results, we found the necessity of the angular velocity input and estimation error feedback due to physical contact. Our results suggest that the estimation method can be useful for a natural human machine cooperation control. PMID- 21558061 TI - Interoperability of medical device information and the clinical applications: an HL7 RMIM based on the ISO/IEEE 11073 DIM. AB - Medical devices are essential to the practice of modern healthcare services. Their benefits will increase if clinical software applications can seamlessly acquire the medical device data. The need to represent medical device observations in a format that can be consumable by clinical applications has already been recognized by the industry. Yet, the solutions proposed involve bilateral mappings from the ISO/IEEE 11073 Domain Information Model (DIM) to specific message or document standards. Considering that there are many different types of clinical applications such as the electronic health record and the personal health record systems, the clinical workflows, and the clinical decision support systems each conforming to different standard interfaces, detailing a mapping mechanism for every one of them introduces significant work and, thus, limits the potential health benefits of medical devices. In this paper, to facilitate the interoperability of clinical applications and the medical device data, we use the ISO/IEEE 11073 DIM to derive an HL7 v3 Refined Message Information Model (RMIM) of the medical device domain from the HL7 v3 Reference Information Mode (RIM). This makes it possible to trace the medical device data back to a standard common denominator, that is, HL7 v3 RIM from which all the other medical domains under HL7 v3 are derived. Hence, once the medical device data are obtained in the RMIM format, it can easily be transformed into HL7-based standard interfaces through XML transformations because these interfaces all have their building blocks from the same RIM. To demonstrate this, we provide the mappings from the developed RMIM to some of the widely used HL7 v3-based standard interfaces. PMID- 21558062 TI - Natural supplements for H1N1 influenza: retrospective observational infodemiology study of information and search activity on the Internet. AB - BACKGROUND: As the incidence of H1N1 increases, the lay public may turn to the Internet for information about natural supplements for prevention and treatment. OBJECTIVE: Our objective was to identify and characterize websites that provide information about herbal and natural supplements with information about H1N1 and to examine trends in the public's behavior in searching for information about supplement use in preventing or treating H1N1. METHODS: This was a retrospective observational infodemiology study of indexed websites and Internet search activity over the period January 1, 2009, through November 15, 2009. The setting is the Internet as indexed by Google with aggregated Internet user data. The main outcome measures were the frequency of "hits" or webpages containing terms relating to natural supplements co-occurring with H1N1/swine flu, terms relating to natural supplements co-occurring with H1N1/swine flu proportional to all terms relating to natural supplements, webpage rank, webpage entropy, and temporal trend in search activity. RESULTS: A large number of websites support information about supplements and H1N1. The supplement with the highest proportion of H1N1/swine flu information was a homeopathic remedy known as Oscillococcinum that has no known side effects; supplements with the next highest proportions have known side effects and interactions. Webpages with both supplement and H1N1/swine flu information were less likely to be medically curated or authoritative. Search activity for supplements was temporally related to H1N1/swine flu-related news reports and events. CONCLUSIONS: The prevalence of nonauthoritative webpages with information about supplements in the context of H1N1/swine flu and the increasing number of searches for these pages suggest that the public is interested in alternatives to traditional prevention and treatment of H1N1. The quality of this information is often questionable and clinicians should be cognizant that patients may be at risk of adverse events associated with the use of supplements for H1N1. PMID- 21558063 TI - Technical approaches for mouse models of human disease. AB - The mouse is the leading organism for disease research. A rich resource of genetic variation occurs naturally in inbred and special strains owing to spontaneous mutations. However, one can also obtain desired gene mutations by using the following processes: targeted mutations that eliminate function in the whole organism or in a specific tissue; forward genetic screens using chemicals or transposons; or the introduction of exogenous transgenes as DNAs, bacterial artificial chromosomes (BACs) or reporter constructs. The mouse is the only mammal that provides such a rich resource of genetic diversity coupled with the potential for extensive genome manipulation, and is therefore a powerful application for modeling human disease. This poster review outlines the major genome manipulations available in the mouse that are used to understand human disease: natural variation, reverse genetics, forward genetics, transgenics and transposons. Each of these applications will be essential for understanding the diversity that is being discovered within the human population. PMID- 21558064 TI - Mouse models of myeloproliferative neoplasms: JAK of all grades. AB - In 2005, several groups identified a single gain-of-function point mutation in the JAK2 kinase that was present in the majority of patients with myeloproliferative neoplasms (MPNs). Since this discovery, much effort has been dedicated to understanding the molecular consequences of the JAK2V617F mutation in the haematopoietic system. Three waves of mouse models have been produced recently (bone marrow transplantation, transgenic and targeted knock-in), which have facilitated the understanding of the molecular pathogenesis of JAK2V617F positive MPNs, providing potential platforms for designing and validating novel therapies in humans. This Commentary briefly summarises the first two types of mouse models and then focuses on the more recently generated knock-in models. PMID- 21558066 TI - Does the prophylactic administration of magnesium sulphate to patients undergoing thoracotomy prevent postoperative supraventricular arrhythmias? A randomized controlled trial. AB - BACKGROUND: Supraventricular arrhythmias (SVA) are common after thoracic surgery and are associated with increased morbidity and mortality. This prospective, randomized, double-blind, placebo-controlled trial examined the effects of perioperative magnesium on the development of postoperative SVA. METHODS: Two hundred patients undergoing thoracotomy for lobectomy, bi-lobectomy, pneumonectomy, or oesophagectomy were recruited and randomly allocated into two groups. The treatment group received magnesium (5 g daily) intraoperatively, and on days 1 and 2 after operation, the control group received placebo. The primary outcome of the study was the development of SVA within the first 5 days after operation. RESULTS: There were 100 patients in each arm of the study, with one withdrawal and three lost to follow-up in the treatment group and four withdrawals in the control group. Ninety-six patients received magnesium and 96 received placebo. There was no difference in the incidence of SVA between the treatment and control groups, 16.7% (16/96) vs 25% (24/96), P=0.16. In the predefined subgroup analysis, patients at highest risk of arrhythmias (those undergoing pneumonectomy) had a significant reduction in the frequency of SVA, 11.1% (2/18) vs 52.9% (9/17), P=0.008. There were no differences in hospital length of stay or mortality. Patients receiving i.v. magnesium experienced a higher frequency of minor side-effects (stinging at injection site). The treatment was otherwise well tolerated. CONCLUSIONS: Overall, prophylactic magnesium did not reduce the incidence of SVA in patients undergoing thoracotomy. However, it reduced the incidence of SVA in the high-risk cohort of patients undergoing pneumonectomy. (ISRCTN22028180.). PMID- 21558065 TI - Mouse models of graft-versus-host disease: advances and limitations. AB - The limiting factor for successful hematopoietic stem cell transplantation (HSCT) is graft-versus-host disease (GvHD), a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT) that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future. PMID- 21558067 TI - Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. AB - Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain. The efficacy and safety of i.v. formulations of paracetamol is unclear. We performed a systematic search (multiple databases, bibliographies, any language, to May 2010) for single-dose, randomized, controlled clinical trials of propacetamol or i.v. paracetamol for acute postoperative pain in adults or children. Thirty-six studies involving 3896 patients were included. For the primary outcome, 37% of patients (240/367) receiving propacetamol or i.v. paracetamol experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo (number needed to treat=4.0; 95% confidence interval, 3.5-4.8). The proportion of patients in propacetamol or i.v. paracetamol groups experiencing at least 50% pain relief diminished over 6 h. Patients receiving propacetamol or paracetamol required 30% less opioid over 4 h and 16% less opioid over 6 h than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events (AEs). Similar comparisons between propacetamol or i.v. paracetamol and active comparators were either not statistically significant, not clinically significant, or both. AEs occurred at similar rates with propacetamol or i.v. paracetamol and placebo. However, pain on infusion occurred more frequently in those receiving propacetamol compared with placebo (23% vs 1%). A single dose of either propacetamol or i.v. paracetamol provides around 4 h of effective analgesia for about 37% of patients with acute postoperative pain. Both formulations are associated with few AEs, although patients receiving propacetamol have a higher incidence of pain on infusion. PMID- 21558068 TI - Effect of patient sex on general anaesthesia and recovery. AB - BACKGROUND: Numerous studies have shown that women emerge faster from general anaesthesia than men, and differ in their postoperative recovery profile. The extent and underlying mechanisms for these sex-related differences in general anaesthesia are unclear. METHODS: In a multicentre, prospective, matched cohort study, 500 ASA physical status I or II patients of either sex undergoing general anaesthesia for elective surgery were recruited. All subjects received a general anaesthetic through inhalation. Anaesthetic drugs and doses used, bispectral index (BIS) scores, recovery times, pain scores, and 40-item quality of recovery (QoR-40) scores for 3 days after general anaesthesia were recorded. RESULTS: Women had higher BIS scores at similar concentrations of anaesthesia (P<0.05). Time to eye-opening (P<0.01) and time to obeying commands (P<0.01) were shorter in women. Duration of recovery room stay was longer in women, who also had higher pain scores and need for treatment of nausea and vomiting (all P<0.001). QoR-40 scores for the first 3 days after general anaesthesia were lower in women (P<0.001). Plasma progesterone concentrations in women negatively correlated with the time to eye-opening (rho=-0.53, P=0.01). CONCLUSIONS: Patient sex is an independent factor influencing the response to anaesthesia and recovery after surgery. Women emerged faster from general anaesthesia but their overall quality of recovery was poorer. Female sex hormones, particularly progesterone, might be involved, with premenopausal women having faster recovery time but poor overall recovery. PMID- 21558069 TI - Telemonitoring of implantable cardiac devices: hurdles towards personalised medicine. PMID- 21558070 TI - The 10 commandments of troponin, with special reference to high sensitivity assays. PMID- 21558071 TI - MIBG and risk stratification. PMID- 21558072 TI - Functional state of rat cardiomyocytes and blood antioxidant system under psycho emotional stress. AB - We studied the functionality of the antioxidant system in laboratory rat cardiomyocytes and blood under psycho-emotional stress. It was found that 40-day isolation and violation of diurnal cycle among the animals were accompanied by the intensification of lipid peroxidation process and marked with a reduced activity of antioxidant system enzymes, such as catalase and superoxide dismutase activity. The results suggested that psycho-emotional stress was accompanied by oxidative stress, causing a reduction in the intensity of energy metabolism in cardiomyocytes, which was further strengthened by the fact that the activity of the enzymes involved in ATP synthesis in mitochondria was reduced. Based on the results, we proposed that psychological stress is one of the factors contributing to the development of various cardiac diseases. PMID- 21558073 TI - Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. AB - Glioblastoma multiforme (GBM) is a devastating disease, and the current therapies have only palliative effect. Evidence is mounting to indicate that brain tumor stem cells (BTSCs) are a minority of tumor cells that are responsible for cancer initiation, propagation, and maintenance. Therapies that fail to eradicate BTSCs may ultimately lead to regrowth of residual BTSCs. However, BTSCs are relatively resistant to the current treatments. Development of novel therapeutic strategies that effectively eradicate BTSC are, therefore, essential. In a previous study, we used patient-derived GBM sphere cells (stemlike GBM cells) to enrich for BTSC and identified maternal embryonic leucine-zipper kinase (MELK) as a key regulator of survival of stemlike GBM cells in vitro. Here, we demonstrate that a thiazole antibiotic, siomycin A, potently reduced MELK expression and inhibited tumor growth in vivo. Treatment of stemlike GBM cells with siomycin A resulted in arrested self-renewal, decreased invasion, and induced apoptosis but had little effect on growth of the nonstem cells of matched tumors or normal neural stem/progenitor cells. MELK overexpression partially rescued the phenotype of siomycin A-treated stemlike GBM cells. In vivo, siomycin A pretreatment abraded the sizes of stemlike GBM cell-derived tumors in immunodeficient mice. Treatment with siomycin A of mice harboring intracranial tumors significantly prolonged their survival period compared with the control mice. Together, this study may be the first model to partially target stemlike GBM cells through a MELK-mediated pathway with siomycin A to pave the way for effective treatment of GBM. PMID- 21558074 TI - Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab. AB - Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial. All patients underwent MRI and neurocognitive testing at baseline and every 6 weeks thereafter. Memory, visuomotor scanning speed, and executive function were evaluated using the Hopkins Verbal Learning Test-Revised, the Trail Making Test, and the Controlled Oral Word Association test, respectively. NCF relative to baseline for patients with an OR, PFS >6 months, or disease progression was evaluated at time of OR, 24 weeks, and time of progression, respectively. For patients with an OR or PFS >6 months, median standardized test scores were examined from baseline to week 24. Most patients with an OR or PFS >6 months had poorer NCF performance compared to the general population at baseline and had improved or stable NCF at the time of response or at the 24-week assessment, respectively; most patients with progressive disease had neurocognitive decline at the time of progression. For patients with an OR or PFS >6 months, median standardized test scores were largely stable across the first 24 weeks on study. Neurocognitive testing was an objective, valid, and feasible method of monitoring NCF in patients with recurrent glioblastoma. PMID- 21558075 TI - Profiles and motives for PGD: a prospective cohort study of couples referred for PGD in the Netherlands. AB - BACKGROUND: PGD is nowadays a well-established alternative to prenatal diagnosis. However, information with respect to couples' motives and profiles for choosing PGD is scarce. METHODS: A prospective cohort of 264 couples referred for PGD was interviewed semi-structurally after intake, and follow-up data were collated after 6-8 years. Outcome measures were: the primary choice shortly after intake (PGD intention), and their definitive use, until maximum 8 years later (PGD use). Logistic regression analysis was performed with clinical impact of the genetic disorder, couples' experiences, obstetric history and psychosocial factors as putative predictors. RESULTS: About 53.4% of the couples showed PGD intention. The experience of one or more miscarriages, the loss of an affected child and the absence of (acceptable) alternatives for the female partner positively contributed to PGD intention. For PGD use (45.8% of couples), infertility, a history of pregnancy termination(s) and the absence of alternatives according to the female partner were positive determinants. A living affected child reduced PGD use. Mode of inheritance and clinical impact of the disorder did not contribute. CONCLUSIONS: Fewer than 50% of the referred couples actually started PGD treatment. Personal experiences and reproductive history [the presence of a living affected child, infertility or a history of termination of pregnancy (TOP)] were more important determinants of eventual PGD use than the mode of inheritance or the expected clinical impact of the disorder. PMID- 21558076 TI - Evidence that carbonyl stress by methylglyoxal exposure induces DNA damage and spindle aberrations, affects mitochondrial integrity in mammalian oocytes and contributes to oocyte ageing. AB - BACKGROUND: Highly reactive carbonyl compounds formed during glycolysis, such as methylglyoxal (MG), can lead to the formation of 'advanced glycation end products' (AGE) and carbonyl stress. Toxic AGEs are suspected to accumulate and play a role in reducing quality and developmental potential of mammalian oocytes of aged females and in PCOS and diabetic patients. Whether and how MG and AGE affect young and aged oocytes at the cellular level is unknown. METHODS: The study consists of three parts. In Part A expression of MG-detoxifying enzymes glyoxalases 1 and 2 was analysed by RT-PCR at different stages of maturation in denuded oocytes (DO), cumulus-enclosed oocytes (CEO) and metaphase (M)II oocytes of the CD-1 mouse to obtain information on stage-specific susceptibility to carbonyl stress. DO and CEO from young and aged females and from stimulated cycles were exposed to MG during maturation in vitro to assess also age-related changes in sensitivity to carbonyl stress induced by MG. Induction of apoptosis by MG on in vitro maturing DO was assessed by terminal deoxynucleotidyl transferase-mediated dUDP nick-end labelling test. In Part B of the study, DO from large antral follicles of ovaries of adult, young MF-1 mice in late diestrous were exposed to MG to assess direct influences of MG and AGEs formed during continuous exposure to MG on rate and kinetics of maturation to MII, on DNA integrity (by gamma-H2AX staining) in the germinal vesicle (GV) stage, and on spindle formation and chromosome alignment (by tubulin and pericentrin immunofluorescence and polarization microscopy), and chromosome segregation (by C banding) during in vitro maturation. Since MG and AGEs can affect functionality of mitochondria in Part C, mitochondrial distribution and membrane potential was studied using JC-1 probe. Expression of a redox-sensitive mito-Grx1-roGFP2 protein in mitochondria of maturing oocytes by confocal laser scanning microscopy was employed to determine the inner mitochondrial glutathion (GSH)/glutathion disulfide (GSSG)-dependent redox potential. RESULTS: Part A revealed that mRNA for glyoxalases decreases during meiotic maturation. Importantly, cumulus from aged mice in CEO obtained from stimulated cycles does not protect oocytes efficiently from MG-induced meiotic arrest during in vitro maturation. Part B showed that the MG-induced meiotic delay or arrest is associated with significant rises in spindle aberrations, chromosome congression failure and aberrant telophase I in oocytes. MG exposure of meiotically arrested GV-stage oocytes significantly increases the numbers of gamma-H2AX spots in the nucleus suggesting increased DNA damage, while MG exposure during maturation affects chromatin condensation and induces chromosome lagging at anaphase I. Moreover, Part C revealed that carbonyl stress by chronic exposure to MG is associated with delays in changes in mitochondrial distribution and altered inner-mitochondrial GSH/GSSG redox potential, which might be particularly relevant for cytoskeletal dynamics as well as processes after fertilization. Sensitivity to a meiotic block by MG appears dependent on the genetic background. CONCLUSIONS: The sensitivity to carbonyl stress by MG appears to increase with maternal age. Since MG-exposure induces DNA damage, meiotic delay, spindle aberrations, anaphase I lagging and epimutation, aged oocytes are particularly at risk for such disturbances in the absence of efficient protection by cumulus. Furthermore, disturbances in mitochondrial distribution and redox regulation may be especially critical for fertilization and developmental competence of oocytes exposed to MG and carbonyl stress before or during maturation, for instance, in aged females, or in PCOS or diabetic patients, in agreement with recent suggestions of correlations between poor follicular and embryonic development, lower pregnancy rate and presence of toxic AGEs in serum, irrespective of age. PMID- 21558077 TI - Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. AB - The objective of this phase II study was to evaluate the efficacy and safety of subcutaneous octreotide therapy for the treatment of recurrent meningioma and meningeal hemangiopericytoma. Octreotide is an agonist of somatostatin receptors, which are frequently expressed in meningioma, and reports have suggested that treatment with somatostatin agonists may lead to objective response in meningioma. Patients with recurrent/progressive meningioma or meningeal hemangiopericytoma were eligible for enrollment; those with atypical/anaplastic meningioma or hemangiopericytoma must have experienced disease progression despite radiotherapy or have had a contraindication to radiation. Patients received subcutaneous octreotide with a goal dose of 500 MUg 3 times per day, as tolerated. Imaging was performed every 3 months during therapy. The primary outcome measure was radiographic response rate. Eleven patients with meningioma and 1 with meningeal hemangiopericytoma were enrolled during the period 1992 1998. Side effects included diarrhea (grade 1 in 4 patients and grade 2 in 2), nausea or anorexia (grade 1 in 4 patients), and transaminitis (grade 1 in 1 patient). One patient developed extra hepatic cholangiocarcinoma, which was likely unrelated to octreotide therapy. No radiographic responses were observed. Eleven of the 12 patients experienced progression, with a median time to progression of 17 weeks. Two patients experienced long progression-free intervals (30 months and >=18 years). Eleven patients have died. Median duration of survival was 2.7 years. Immunohistochemical staining of somatostatin receptor Sstr2a expression in a subset of patients did not reveal a correlation between level of expression and length of progression-free survival. Octreotide was well tolerated but failed to produce objective tumor response, although 2 patients experienced prolonged stability of previously progressive tumors. PMID- 21558078 TI - Convection-enhanced delivery of a transforming growth factor-beta2 inhibitor trabedersen for recurrent high-grade gliomas: efficacy real or imagined?, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142). PMID- 21558079 TI - Trabedersen to target transforming growth factor-beta: when the journey is not the reward, in reference to Bogdahn et al. (Neuro-Oncology 2011;13:132-142). PMID- 21558081 TI - Community level composting in a developing country: case study of KIWODET, Tanzania. AB - Environmentally sustainable waste management practices have a limited relevance and viability in developing countries. Despite a technological potential, composting initiatives often share this fate. Little is known about the functioning of community level composting, which is reportedly the optimal level for viable compost production. This paper presents a multidisciplinary analysis of factors influencing the success and failure of the composting initiative of KIWODET, a community based organization in Dar es Salaam, Tanzania. The results show that despite the ready availability and good compostability of the waste stream, not all fractions of municipal organic wastes qualify as feedstock. Negative consumer attitude hindered the acceptance of compost produced from residential wastes. KIWODET did manage to successfully implement a composting operation for commercial organic wastes. Their additional waste collection and sorting activities also contributed to an increased feedstock control as well as the integration of informal waste collecting activities. When KIWODET was forced to suspend its composting activities because of land use issues, their diversified waste sector activities proved crucial in reducing the negative financial impact on their overall performance. This paper emphasizes that successful composting initiatives can arise from local capacity in developing countries. However, the lack of municipal integration and support leaves such technically viable initiatives strongly vulnerable to external factors. PMID- 21558082 TI - Potential applications of silk sericin, a natural protein from textile industry by-products. AB - Silk is composed of two major proteins, fibroin (fibrous protein) and sericin (globular, gumming protein). Fibroin has been used in textile manufacturing and for several biomaterial applications, whereas sericin is considered a waste material in the textile industry. Sericin has recently been found to activate the proliferation of several cell-lines and has also shown various biological activities. Sericin can form a gel by itself; however, after mixing with other polymers and cross-linking it can form a film or a scaffold with good characteristics that can be used in the cosmetic and pharmaceutical industries. Sericin is proven to cause no immunological responses, which has resulted in a more acceptable material for biological applications. PMID- 21558083 TI - Influence of the impact assessment method on the conclusions of a LCA study. Application to the case of a part made with virgin and recycled HDPE. AB - Recent legislation has stressed the need to decide the best end-of-life (EoL) option for post-consumer products considering their full life-cycle and the corresponding overall environmental impacts. The life cycle assessment (LCA) technique has become a common tool to evaluate those impacts. The present study aimed to contribute to the better understanding of the application of this technique, by evaluating the influence of the selection of the life cycle impact assessment (LCIA) method in its results and conclusions. A specific case study was chosen, using previous information related to an anti-glare lamellae (AGL) for highway use, made with virgin and recycled high-density polyethylene (HDPE). Five distinct LCIA methods were used: Eco-indicator 99, CML 2 (2000), EPS 2000, Eco-indicator 95 and EDIP 97. Consistent results between these methods were obtained for the Climate change, Ozone layer depletion, Acidification and Eutrophication environmental indicators. Conversely, the Summer smog indicator showed large discrepancies between impact assessment methods. The work sheds light on the advantages inherent in using various LCIA methods when doing the LCA study of a specific product, thus evidencing complementary analysis perspectives. PMID- 21558084 TI - Relationship of blood pressure and obesity with inflammatory cytokines among African Americans. AB - OBJECTIVES: Hypertension and obesity are major public health issues. Both conditions are highly prevalent among African Americans and contribute to the increased burden of cardiovascular disease in this group. Inflammation is considered to be an underlying process in both conditions. The authors sought to determine if there is an interaction between high blood pressure (HBP) and obesity that is associated with markedly elevated plasma levels of proinflammatory cytokines in African American adults. METHODS: This study examined 484 African Americans, aged 18-45 years, including people with and without obesity, and also with and without HBP. People known to have diabetes were not enrolled. Plasma levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), plasminogen activator inhibitor 1, tumor necrosis factor alpha (TNF-alpha), and adiponectin were measured. Participants also underwent an oral glucose tolerance test and measurement of blood pressure and body mass index (BMI). RESULTS: There was no statistically significant interaction between obesity and HBP on plasma levels of adiponectin or the inflammatory cytokines. When both conditions were present, HBP and obesity had additive associations with the expected geometric mean ratios for IL-6 (1.44, 95% CI 1.18 to 1.75), TNF alpha (1.31, 95% CI 1.11 to 1.53), hsCRP (2.55, 95% CI 1.99 to 3.26) and negative association with adiponectin (0.61, 95% CI 0.52 to 0.71). Compared with HBP, obesity had the predominant association with cytokine levels. An increase in cytokine plasma levels was detectable when BMI exceeded 25 kg/m2. CONCLUSIONS: Biomarkers of inflammation in African Americans are strongly associated with BMI. A modest additive effect is found with HBP. Interventions to reduce obesity related inflammation may impact cardiovascular disease outcomes. PMID- 21558085 TI - Beneficial effects of angiotensin (1-7) in diabetic rats with cardiomyopathy. AB - OBJECTIVE: This study was designed to investigate the effect of angiotensin (1 7), a Mas receptor agonist, and A-779, a Mas receptor antagonist, in rats with diabetic cardiomyopathy (DC). METHODS: Rats treated with a single injection of streptozotocin (50 mg/kg, intraperitoneal), developed DC after 8 weeks. The extent of DC was assessed by measuring the left ventricular weight/body weight (LVW/BW) ratio, absolute LVW, left ventricular developed pressure (LVDP), maximum change in left ventricular pressure over time (dp/dtmax), minimum change in left ventricular pressure over time (dp/dtmin), left ventricular (LV) protein content, LV collagen content, lipid profile, and serum nitrite/nitrate concentration. Test drug treatment was given from week 4 to week 8. RESULTS: Angiotensin (1-7) treatment attenuated DC by significantly increasing LVDP, dp/dtmax, dp/dtmin, serum nitrite/nitrate concentration and significantly decreasing the LVW/BW ratio and LV collagen content. For the first time, this study has documented that endogenous angiotensin (1-7) regulates lipid profile in rats, and that treatment with angiotensin (1-7) significantly attenuates diabetes-induced changes in lipid profile. However, LV protein content and absolute LVW remain unaffected after treatment. CONCLUSION: Angiotensin (1-7) significantly attenuates DC in rats because of vasodilatory, antiproliferative and anifibrotic properties but also because of a significant decrease in dyslipidemia, the major culprit for cardiac dysfunctions in diabetes. PMID- 21558086 TI - Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. AB - Tuberculosis (TB) remains one of the leading public health problems worldwide. Declared as a global emergency in 1993 by the WHO, its control is hampered by the emergence of multidrug resistance (MDR), defined as resistance to at least rifampicin and isoniazid, two key drugs in the treatment of the disease. More recently, severe forms of drug resistance such as extensively drug-resistant (XDR) TB have been described. After the discovery of several drugs with anti-TB activity, multidrug therapy became fundamental for control of the disease. Major advances in molecular biology and the availability of new information generated after sequencing the genome of Mycobacterium tuberculosis increased our knowledge of the mechanisms of resistance to the main anti-TB drugs. Better knowledge of the mechanisms of drug resistance in TB and the molecular mechanisms involved will help us to improve current techniques for rapid detection and will also stimulate the exploration of new targets for drug activity and drug development. This article presents an updated review of the mechanisms and molecular basis of drug resistance in M. tuberculosis. It also comments on the several gaps in our current knowledge of the molecular mechanisms of drug resistance to the main classical and new anti-TB drugs and briefly discusses some implications of the development of drug resistance and fitness, transmission and pathogenicity of M. tuberculosis. PMID- 21558087 TI - Phosphatase assay for multi-phosphorylated substrates using phosphatase specific motif antibody. AB - Protein phosphorylation plays central roles in a wide variety of signal transduction pathways and most phosphorylated proteins contain multi phosphorylated sites. PPM1 type Ser/Thr protein phosphatase family is known to show rigid substrate specificity unlike other Ser/Thr phosphatase PPP family including PP1, PP2A and PP2B. PPM1 type phosphatases are reported to play important roles in growth regulation and in cellular stress signalling. In this study, we developed a phosphatase assay of PPM1D using phosphatase motif-specific antibody. PPM1D is a member of PPM1 type Ser/Thr phosphatase and known to dephosphorylate Ser(P)-Gln sequence. The gene amplification and overexpression of PPM1D were reported in many human cancers. We generated the monoclonal antibody specific for the Ser(P)-Gln sequence, named 3G9-H11. The specificity of this method using ELISA enables the convenient measurement of the dephosphorylation level of only PPM1D target residues of substrate peptides with multiple phosphorylated sites in the presence of multiple phosphatases. In addition, the antibody was applicable to immunoblotting assay for PPM1D function analysis. These results suggested that this method should be very useful for the PPM1D phosphatase assay, including high-throughput analysis and screening of specific inhibitors as anti-cancer drugs. The method using phosphatase motif-specific antibody can be applied to other PPM1 phosphatase family. PMID- 21558088 TI - Encountering unpredicted off-target effects of pharmacological inhibitors. AB - With the emergence of chemical biology, the use of pharmacological inhibitors in biological research has been expanding. SP600125 is a low-molecular weight compound that has been widely used to inhibit c-Jun-N-terminal kinase (JNK). A recent publication by Tanemura et al. (J. Biochem. 145:345-354, 2009) indicated that SP600125 also inhibits phosphatidylinositol 3-kinase (PI3K) in an isoform selective fashion: it efficiently inhibited the delta isoform of p110 catalytic subunit (p110delta), which is primarily expressed in leucocytes, but neither of the ubiquitously expressed isoforms, p110alpha and p110gamma. Here, I discuss what we learn from such unpredicted off-target effects of pharmacological inhibitors. PMID- 21558089 TI - Atorvastatin improving renal ischemia reperfusion injury via direct inhibition of active caspase-3 in rats. AB - Caspase-3 is a key molecule involved in the inflammation and apoptosis of ischemia reperfusion (IR) injury. Statins are known to inhibit IR injury, but the mechanism of action remains uncertain. In the present study, the effect and underlying mechanism of ischemia alone, and reperfusion with or without atorvastatin (AT) as a timed intervention were examined, since clinically the kidney is only exposed to drug delivery during reperfusion. Male Sprague-Dawley rats were subjected to 45-min clamping of the left renal hilus followed by four hours reperfusion with a right nephrectomy. AT 10 mg/kg was intravenously administered after clamping the renal hilus, but prior to kidney reperfusion. Ischemia alone did cause tubulointerstitial damage (TID), protein carbonylation and caspase-3 activation with an increase in 12 kDa subunit, while reperfusion further enhanced TID, monocyte (ED-1+ cell) infiltration, apoptosis and necrosis together with caspase-3 activity and 17 kDa subunit, but reversed protein carbonylation. AT significantly reduced TID (26%), ED-1+ cell infiltration (74%), tubular apoptosis (47%) and necrosis (73%), and interstitial apoptosis (64%), as well as caspase-3 activity (26%), but did not change serum creatinine and cholesterol. Importantly, without affecting either caspase-3 active protein cleavage or S-nitrosylation, AT directly inhibited caspase-3 active enzyme in a dose-dependent manner in vitro. In conclusions, IR and AT exerted opposing effects on caspase-3 activity by differing mechanisms, with IR stimulating caspase-3 proteolytic cleavage and AT inhibiting active caspase-3 enzyme. This new inhibitory mechanism of AT may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients. PMID- 21558090 TI - Glutathione S-transferase M1 polymorphism and bladder cancer risk: a meta analysis involving 33 studies. AB - Glutathione S-transferase M1 (GSTM1) might be involved in inactivation of procarcinogens that contribute to the genesis and progression of cancers. GSTM1 null status has been extensively studied as a risk factor in bladder cancer susceptibility. The aim of this study is to evaluate the role of GSTM1 null genotype in bladder cancer risk. All available studies were considered in this meta-analysis, including 7301 cases and 9405 controls from 33 studies. Significantly increased risk was detected between GSTM1 deletion and bladder cancer susceptibility in all subjects (odds ratio [OR] = 1.409 [1.267-1.568], P < 0.001). The same patterns were observed in Caucasians (OR = 1.434 [1.212-1.697], P < 0.001) and Asians (OR = 1.485 [1.295-1.704], P < 0.001). When stratified with study design, a positive association was also found in hospital-based studies (OR = 1.552 [1.382-1.744], P < 0.001), but no association in population-based ones (OR = 1.088 [0.970-1.221], P = 0.151). In summary, our meta-analysis suggested that GSTM1 null status is associated with a high increase in the risk of bladder cancer, and further studies based on population design are necessary to confirm our conclusion. PMID- 21558091 TI - Polo-like kinases and DNA damage checkpoint: beyond the traditional mitotic functions. AB - Polo-like kinases (Plks) are a family of serine-threonine kinases that play a pivotal role in cell cycle progression and in cellular response to DNA damage. The Plks are highly conserved from yeast to mammals. There are five Plk family members (Plk1-5) in humans, of which Plk1, is the best characterized. The Plk1 isoform is being aggressively pursued as a target for cancer therapy, following observations that this protein is overexpressed in human tumors and is actively involved in malignant transformation. The roles of Plks in mitotic entry, spindle pole functions and cytokinesis are well established and have been the subject of several recent reviews. In this review, we discuss functions of Plks other than their classical roles in mitotic progression. When cells incur DNA damage, they activate checkpoint mechanisms that result in cell cycle arrest and allow time for repair. If the damage is extensive and cannot be repaired, cells will undergo cell death by apoptosis. If the damage is repaired, cells can resume cycling, as part of the process known as checkpoint recovery. If the damage is not repaired or incompletely repaired, cells can override the checkpoint and resume cycling with damaged DNA, a process called checkpoint adaptation. The Plks play a role in all three outcomes and their involvement in these processes will be the subject of this review. PMID- 21558092 TI - Telomerase-based immortalization modifies the angiogenic/inflammatory responses of human coronary artery endothelial cells. AB - Telomerase reverse transcriptase (TERT) is fundamental in determining the life span by regulating telomere length of chromosomes. To address the question whether the enhancement of the proliferative potential hampers cell differentiation, we generated TERT-over-expressing endothelial cells (ECs) and analyzed in vitro their (1) barrier function; (2) low-density lipoprotein uptake; (3) expression pattern of six selected marker proteins; (4) angiogenic potential in four assays; and (5) inflammatory responses. In contrast to investigations with focus on other cell parameters, we demonstrate that immortalization of ECs by over-expression of TERT resulted in different angiogenic and inflammatory behavior in comparison to cells with low native telomerase levels. PMID- 21558093 TI - Relapsing typhilitis to CFHR5 nephropathy: the thrill of discovery. PMID- 21558094 TI - Tuberculosis: a forgotten plague? PMID- 21558095 TI - Art and the thyroid gland. PMID- 21558096 TI - The identification of CFHR5 nephropathy. PMID- 21558097 TI - Frederick Treve's first surgical operation for appendicitis. PMID- 21558098 TI - Work and common psychiatric disorders. AB - Psychiatric disorders are now the most common reason for long-term sickness absence. The associated loss in productivity and the payment of disability benefits places a substantial burden on the economies of many developed countries. The occupational dysfunction associated with psychiatric disorders can also lead to poverty and social isolation. As a result the area of work and psychiatric disorders is a high priority for policymakers. There are two main agendas: for many researchers and clinicians the focus is on the need to overcome stigma and ensure people with severe psychiatric disorders have meaningful work; however the public health agenda predominantly relates to the more common disorders such as depression and anxiety, which contribute a greater burden of disability benefits and pensions. In this review we attempt to address this second agenda. The relatively sparse evidence available reveals a complex field with significant interplay between medical, psychological social and cultural factors. Sick leave can be a 'process' as well as an 'event'. In this review we propose a staged model where different risk and protective factors contribute to the onset of psychiatric disorders in the working population, the onset of short term sickness absence, and the transition from short- to long-term absence. We also examine strategies to manage psychiatric disorder in the workforce with a view towards returning the employee to work. Our aim in this review is to highlight the complexity of the area, to stimulate debate and to identify important gaps in knowledge where further research might benefit both patients and wider society. PMID- 21558099 TI - Can an electronic prescribing system detect doctors who are more likely to make a serious prescribing error? AB - OBJECTIVES: We aimed to assess whether routine data produced by an electronic prescribing system might be useful in identifying doctors at higher risk of making a serious prescribing error. DESIGN: Retrospective analysis of prescribing by junior doctors over 12 months using an electronic prescribing information and communication system. The system issues a graded series of prescribing alerts (low-level, intermediate, and high-level), and warnings and prompts to respond to abnormal test results. These may be overridden or heeded, except for high-level prescribing alerts, which are indicative of a potentially serious error and impose a 'hard stop'. SETTING: A large teaching hospital. PARTICIPANTS: All junior doctors in the study setting. MAIN OUTCOME MEASURES: Rates of prescribing alerts and laboratory warnings and doctors' responses. RESULTS: Altogether 848,678 completed prescriptions issued by 381 doctors (median 1538 prescriptions per doctor, interquartile range [IQR] 328-3275) were analysed. We identified 895,029 low-level alerts (median 1033 per 1000 prescriptions per doctor, IQR 903 1205) with a median of 34% (IQR 31-39%) heeded; 172,434 intermediate alerts (median 196 per 1000 prescriptions per doctor, IQR 159-266), with a median of 23% (IQR 16-30%) heeded; and 11,940 high-level 'hard stop' alerts. Doctors vary greatly in the extent to which they trigger and respond to alerts of different types. The rate of high-level alerts showed weak correlation with the rate of intermediate prescribing alerts (correlation coefficient, r = 0.40, P = <0.001); very weak correlation with low-level alerts (r = 0.12, P = 0.019); and showed weak (and sometimes negative) correlation with propensity to heed test-related warnings or alarms. The degree of correlation between generation of intermediate and high-level alerts is insufficient to identify doctors at high risk of making serious errors. CONCLUSIONS: Routine data from an electronic prescribing system should not be used to identify doctors who are at risk of making serious errors. Careful evaluation of the kinds of quality assurance questions for which routine data are suitable will be increasingly valuable. PMID- 21558100 TI - Danish contributions to the evaluation of serum therapy for diphtheria in the 1890s. PMID- 21558101 TI - Practising medicine in China: an unsolved dilemma. PMID- 21558103 TI - Prevalence of autism spectrum disorders in a total population sample. AB - OBJECTIVE: Experts disagree about the causes and significance of the recent increases in the prevalence of autism spectrum disorders (ASDs). Limited data on population base rates contribute to this uncertainty. Using a population-based sample, the authors sought to estimate the prevalence and describe the clinical characteristics of ASDs in school-age children. METHOD: The target population was all 7- to 12-year-old children (N=55,266) in a South Korean community; the study used a high-probability group from special education schools and a disability registry and a low-probability, general-population sample from regular schools. To identify cases, the authors used the Autism Spectrum Screening Questionnaire for systematic, multi-informant screening. Parents of children who screened positive were offered comprehensive assessments using standardized diagnostic procedures. RESULTS: The prevalence of ASDs was estimated to be 2.64% (95% CI=1.91-3.37), with 1.89% (95% CI=1.43-2.36) in the general-population sample and 0.75% (95% CI=0.58-0.93) in the high-probability group. ASD characteristics differed between the two groups: the male-to-female ratios were 2.5:1 and 5.1:1 in the general population sample and high-probability group, respectively, and the ratios of autistic disorders to other ASD subtypes were 1:2.6 and 2.6:1, respectively; 12% in the general-population sample had superior IQs, compared with 7% in the high-probability group; and 16% in the general-population sample had intellectual disability, compared with 59% in the high-probability group. CONCLUSIONS: Two-thirds of ASD cases in the overall sample were in the mainstream school population, undiagnosed and untreated. These findings suggest that rigorous screening and comprehensive population coverage are necessary to produce more accurate ASD prevalence estimates and underscore the need for better detection, assessment, and services. PMID- 21558104 TI - The relationship of knowledge, health value and health self-efficacy with men's intentions to receive the human papillomavirus (HPV) vaccine. AB - The aim of the present study was to determine whether it was possible to predict Human Papillomavirus (HPV) vaccination intentions an Australian male sample. One hundred and twenty one males aged 18 to 26 (M = 22.3, SD = 2.06), completed an online survey assessing HPV-related knowledge, health beliefs and health self efficacy. HPV knowledge and health self-efficacy were significant independent predictors of vaccine acceptance. A moderating effect was found between HPV knowledge and health self-efficacy. It was concluded that the results of previous research into the predictors of HPV vaccination intentions can largely be applied to an Australian male population. PMID- 21558105 TI - Editorial: all you need is love? PMID- 21558106 TI - Organizational ethics: a literature review. AB - The aim of the study was to report the results of a systematically conducted literature review of empirical studies about healthcare organizations' ethics and management or leadership issues. Electronic databases MEDLINE and CINAHL yielded 909 citations. After a two stage application of the inclusion and exclusion criteria 56 full-text articles were included in the review. No large research programs were identified. Most of the studies were in acute hospital settings from the 1990s onwards. The studies focused on ethical challenges, dilemmas in practice, employee moral distress and ethical climates or environments. Study samples typically consisted of healthcare practitioners, operational, executive and strategic managers. Data collection was mainly by questionnaires or interviews and most of the studies were descriptive, correlational and cross sectional. There is need to develop conceptual clarity and a theoretical framework around the subject of organizational ethics and the breadth of the contexts and scope of the research needs to be increased. PMID- 21558107 TI - Moral margins concerning the use of coercion in psychiatry. AB - In the closed wards of mental health institutions, moral decisions are made concerning the use of forced seclusion. In this article we focus on how these moral decisions are made and can be improved. We present a case study concerning moral deliberations on the use of seclusion and its prevention among nurses of a closed mental health ward. Moral psychology provides an explanation of how moral judgments are developed through processes of interaction. We will make use of the Social Intuitionist Model of Jonathan Haidt that emphasizes the role of emotions, intuitions and the social context in moral judgments and reasoning. We argue that this model can help to explain social dynamics in the context of enforced seclusion. In the discussion we explore how moral psychology can be complemented with the normative perspective of dialogical ethics to develop strategies for improving psychiatric practices. We conclude that social processes play an important role in moral deliberations and that moral development can be fostered by bringing in new perspectives in the dialogue. Moral case deliberation provides a practical tool to systematically organize moral reflections among nurses on the work floor. PMID- 21558108 TI - Burnout in palliative care: a systematic review. AB - Burnout is a phenomenon characterized by fatigue and frustration, usually related to work stress and dedication to a cause, a way of life that does not match the person's expectations. Although it seems to be associated with risk factors stemming from a professional environment, this problem may affect any person. Palliative care is provided in a challenging environment, where professionals often have to make demanding ethical decisions and deal with death and dying. This article reports on the findings of a systematic review aimed at identifying described burnout levels in palliative care nurses and physicians, and the related risks and protective factors. The main findings indicate that burnout levels in palliative care, or in health care settings related to this field, do not seem to be higher than in other contexts. PMID- 21558109 TI - Organizing moral case deliberation experiences in two Dutch nursing homes. AB - Moral case deliberation (MCD) is a specific form of clinical ethics, aiming to stimulate ethical reflection in daily practice in order to improve the quality of care. This article focuses on the implementation of MCD in nursing homes and the questions how and where to organize MCD. The purpose of this study was to evaluate one way of organizing MCD in two Dutch nursing homes. In both of these nursing homes the MCD groups had a heterogeneous composition and were organized apart from existing institutional communication structures. As part of a naturalistic evaluation, systematic observations, interviews and focus groups were completed. The findings indicate that the heterogeneous composition and MCD meetings separate from existing structures have benefits. However, the participants also reported negative experiences. This gives rise to the question whether a mixed MCD group which meets separately is an effective way to embed MCD as an instrument for reflection on moral issues in daily practice. We conclude that there is no single answer to that question. In the end, the two implementation strategies (i.e. within existing communication structures and a mixed MCD group) can be complementary to each other. PMID- 21558110 TI - How nurses and physicians face ethical dilemmas--the Croatian experience. AB - The aim of this study was to assess nurses' and physicians' ethical dilemmas in clinical practice. Nurses and physicians of the Clinical Hospital Centre Rijeka were surveyed (N=364). A questionnaire was used to identify recent ethical dilemma, primary ethical issue in the situation, satisfaction with the resolution, perceived usefulness of help, and usage of clinical ethics consultations in practice. Recent ethical dilemmas include professional conduct for nurses (8%), and near-the-end-of-life decisions for physicians (27%). The main ethical issue is limiting life-sustaining therapy (nurses 15%, physicians 24%) and euthanasia and physician-assisted suicide (nurses 16%, physicians 9%). The types of help available are similar for nurses and physicians: obtaining complete information about the patient (37% vs. 50%) and clarifying ethical issues (31% vs. 39%). Nurses and physicians experience similar ethical dilemmas in clinical practice. The usage of clinical ethics consultations is low. It is recommended that the individual and team consultations should be introduced in Croatian clinical ethics consultations services. PMID- 21558111 TI - Health professionals' attitude towards information disclosure to cancer patients in China. AB - A self-designed questionnaire was given to 634 health professionals in a large teaching hospital in Hubei Province in mainland China, to clarify the participants' attitude towards information disclosure to cancer patients. Statistic description was used to analyze the data. The item 'inappropriate information about cancer easily leads to medical disputes' scored highest at 3.86, while the scores of such items as 'advantages of fully informing patients outweigh disadvantages', 'if their family members demand nondisclosure, you will find it difficult to cooperate in good faith with patients', and 'telling white lies to patients disturbs you a lot' were less than 3. The health care staff placed a high value on both the desire and priority of patients to know the truth, though most of them did not think that patients had received enough information about their disease. In order to improve cancer patients' current state of knowledge, health professionals should learn more about informed consent, and special methods and guidelines compatible with Chinese culture are urgently required in China. PMID- 21558112 TI - Placebo use in clinical practice by nurses in an Iranian teaching hospital. AB - The present study was carried out to explore Iranian nurses' use of placebos in clinical practice and their knowledge and attitude towards its use. A cross sectional, descriptive study was conducted using self-report questionnaires. All nurses working in a university hospital in Arak (n=342) were invited to participate in the study. Among 295 respondents, 221 (75%) reported that they had used at least one placebo within the past year and 179 (81%) told patients they were receiving actual medication. The most common reason and symptom for placebo use were after unjustified demand for medication and pain, respectively. Only 60 (20.33%) of the nurses believed that placebos should never be used. Results showed that most nurses in our study had used placebos and probably will continue to use them. Placebo use is viewed as ethically permissible among nurses. Some patients benefit from the placebos, but their use raises ethical questions. The role of placebo treatment, its mechanisms, and its ethics issues should be taught to nurses. PMID- 21558113 TI - Dignified end-of-life care in the patients' own homes. AB - Nowadays it is increasingly common that the patients in the end of life phase choose to be cared for in their own home. Therefore it is vital to identify significant factors in order to prevent unnecessary suffering for dying patients and their families in end-of-life homecare. This study aimed to describe 10 nurses' perceptions of significant factors that contribute to good end-of-life care in the patients own home. The transcribed texts from the interviews' were analyzed using phenomenological hermeneutical method, which focuses on the life world of human beings. The results demonstrate that good end-of-life care presupposes that the aim of the caring staff is to provide safety, autonomy and integrity for the patient and family in order to create the respect required for as good and dignified a death as possible. PMID- 21558114 TI - Rationing home-based nursing care: professional ethical implications. AB - The purpose of this study was to investigate nurses' decisions about priorities in home-based nursing care. Qualitative research interviews were conducted with 17 nurses in home-based care. The interviews were analyzed and interpreted according to a hermeneutic methodology. Nurses describe clinical priorities in home-based care as rationing care to mind the gap between an extensive workload and staff shortages. By organizing home-based care according to tight time schedules, the nurses' are able to provide care for as many patients as possible. Furthermore, legal norms set boundaries for clinical priority decisions, resulting in marginalized care. Hence, rationing care jeopardizes important values in the nurse-patient relationship, in particular the value of individualized and inclusive nursing care. The findings are highly relevant for clinical practice, since they have major implications for provision of nursing care. They revive debates about the protection of values and standards of care, and nurses' role and responsibility when resources are limited. PMID- 21558115 TI - Feminist intersectionality: bringing social justice to health disparities research. AB - The principles of autonomy, beneficence, non-maleficence, and justice are well established ethical principles in health research. Of these principles, justice has received less attention by health researchers. The purpose of this article is to broaden the discussion of health research ethics, particularly the ethical principle of justice, to include societal considerations--who and what are studied and why?--and to critique current applications of ethical principles within this broader view. We will use a feminist intersectional approach in the context of health disparities research to firmly establish inseparable links between health research ethics, social action, and social justice. The aim is to provide an ethical approach to health disparities research that simultaneously describes and seeks to eliminate health disparities. PMID- 21558116 TI - Home-based nursing: an endless journey. AB - The aim of this study was to explore metaphors for discovering values and norms held by nurses in home-based nursing care. Ten interviews were analysed and interpreted in accordance with a metaphor analytical method. In the analysis, metaphoric linguistic expressions and two entailments emerged, grounded in the conceptual metaphor 'home-based nursing care is an endless journey', which were created in a cross-domain mapping between the two conceptual domains of home based nursing care and travel. The metaphor exposed home-based nursing care as being in constant motion, thereby requiring nurses to adjust to circumstances that demand ethical maturity. The study focuses on the importance of developing further theories supporting nurses' expressions of their experiences of everyday ethical issues. PMID- 21558117 TI - Blended learning in ethics education: a survey of nursing students. AB - Nurses are experiencing new ethical issues as a result of global developments and changes in health care. With health care becoming increasingly sophisticated, and countries facing challenges of graying population, ethical issues involved in health care are bound to expand in quantity and in depth. Blended learning rather as a combination of multiple delivery media designed to promote meaningful learning. Specifically, this study was focused on two questions: (1) the students' satisfaction and attitudes as members of a scenario-based learning process in a blended learning environment; (2) the relationship between students' satisfaction ratings of nursing ethics course and their attitudes in the blended learning environment. In total, 99 senior undergraduate nursing students currently studying at a public nursing college in Taiwan were invited to participate in this study. A cross-sectional survey design was adopted in this study. The participants were asked to fill out two Likert-scale questionnaire surveys: CAAS (Case Analysis Attitude Scale), and BLSS (Blended Learning Satisfaction Scale). The results showed what students felt about their blended learning experiences - mostly items ranged from 3.27-3.76 (the highest score is 5). Another self-assessment of scenario analysis instrument revealed the mean scores ranged from 2.87-4.19. Nearly 57.8% of the participants rated the course 'extremely helpful' or 'very helpful.' This study showed statistically significant correlations (r=0.43) between students' satisfaction with blended learning and case analysis attitudes. In addition, results testified to a potential of the blended learning model proposed in this study to bridge the gap between students and instructors and the one between students and their peers, which are typical of blended learning, and to create meaningful learning by employing blended pedagogical consideration in the course design. The use of scenario instruction enables students to develop critical analysis and problem solving skills through active learning and social exchange of ideas. PMID- 21558118 TI - Perceptions of moral integrity: contradictions in need of explanation. AB - The incidence of moral distress, compromised moral integrity, and leaving nursing is highest among nurses new to the profession. Understanding perceptions of moral integrity may assist in developing strategies to reduce distress and promote workforce retention. The purpose of this study was to determine how newly graduated baccalaureate prepared nurses perceive moral integrity and how prepared they feel to manage challenges to it. The design was qualitative descriptive using a confidential short answer online survey. Data were analyzed using conventional content analysis. Moral integrity was perceived as acting like, becoming, and being a certain kind of person who was honest, trustworthy, consistently doing and standing up for what is right, despite the consequences but also expected to set aside their values and beliefs and do what others ask, even if this would mean acting contrary to their conscience. The contradiction within this perception needs explanation. PMID- 21558119 TI - Educational content in nurse education in Japan: a Delphi study. AB - The purpose of this study was to clarify the minimum necessary educational content in the area of nursing ethics in a basic nursing education program, and the level of students' mastery of this content, based on a Delphi study in both educational and clinical settings. A Delphi study was conducted in three rounds with faculty members who teach nursing ethics at all 158 four-year nursing universities in Japan as targeted panelists. In this study the opinions on nursing ethics of nursing instructors responsible for hospital education at all 82 special functioning hospitals were reflected in the panelists' opinions. Consensus was obtained on 41 items from a total of 63 items in 4 proposed frameworks. There were 20 items related to the Concept of nursing ethics, 7 items related to Ethical codes, 13 items related to Ethical issues and methods to resolve them, and 1 item related to Efforts and issues in practical and educational settings. Consensus as to desired level of mastery was reached on a total of 40 items. This agreed-upon level involved understanding of the concept for 22 items, the ability to explain the concept for 16 items, and the ability to act based on the concept for 2 items. PMID- 21558120 TI - Questions for debate. What is the role of moral theory in everyday nursing ethics? Is it right that Research Ethics Committees make judgements about the scientific quality of research proposals? PMID- 21558123 TI - A common genetic variant in the 3'-UTR of vacuolar H+-ATPase ATP6V0A1 creates a micro-RNA motif to alter chromogranin A processing and hypertension risk. AB - BACKGROUND: The catecholamine release-inhibitor catestatin and its precursor chromogranin A (CHGA) may constitute "intermediate phenotypes" in the analysis of genetic risk for cardiovascular disease such as hypertension. Previously, the vacuolar H(+)-ATPase subunit gene ATP6V0A1 was found within the confidence interval for linkage with catestatin secretion in a genome-wide study, and its 3' UTR polymorphism T+3246C (rs938671) was associated with both catestatin processing from CHGA and population blood pressure. We explored the molecular mechanism of this effect by experiments with transfected chimeric photoproteins in chromaffin cells. METHODS AND RESULTS: Placing the ATP6V0A1 3'-UTR downstream of a luciferase reporter, we found that the C (variant) allele decreased overall gene expression. The 3'-UTR effect was verified by coupled in vitro transcription/translation of the entire/intact human ATP6V0A1 mRNA. Chromaffin granule pH, monitored by fluorescence of CHGA/EGFP chimera during vesicular H(+) ATPase inhibition by bafilomycin A1, was more easily perturbed during coexpression of the ATP6V0A1 3'-UTR C-allele than the T-allele. After bafilomycin A1 treatment, the ratio of CHGA precursor to its catestatin fragments in PC12 cells was substantially diminished, though the qualitative composition of such fragments was not affected (on immunoblot or matrix-assisted laser desorption ionization (MALDI) mass spectrometry). Bafilomycin A1 treatment also decreased exocytotic secretion from the regulated pathway, monitored by a CHGA chimera tagged with embryonic alkaline phosphatase. 3'-UTR T+3246C created a binding motif for micro-RNA hsa-miR-637; cotransfection of hsa-miR-637 precursor or antagomir/inhibitor oligonucleotides yielded the predicted changes in expression of luciferase reporter/ATP6V0A1-3'-UTR plasmids varying at T+3246C. CONCLUSIONS: The results suggest a series of events whereby ATP6V0A1 3'-UTR variant T+3246C functioned: ATP6V0A1 expression probably was affected through differential micro RNA effects, altering vacuolar pH and consequently CHGA processing and exocytotic secretion. PMID- 21558124 TI - Thyroid autoantibodies, preterm birth, and miscarriage. PMID- 21558125 TI - New recommendations on autism spectrum disorder. PMID- 21558127 TI - Smothering in commercial free-range laying hens: a preliminary investigation. PMID- 21558126 TI - Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. AB - OBJECTIVES: To evaluate the association between thyroid autoantibodies and miscarriage and preterm birth in women with normal thyroid function. To assess the effect of treatment with levothyroxine on pregnancy outcomes in this group of women. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Library, and SCISEARCH (inception-2011) without any language restrictions. We used a combination of key words to generate two subsets of citations, one indexing thyroid autoantibodies and the other indexing the outcomes of miscarriage and preterm birth. STUDY SELECTION: Studies that evaluated the association between thyroid autoantibodies and pregnancy outcomes were selected in a two stage process. Two reviewers selected studies that met the predefined and explicit criteria regarding population, tests, and outcomes. DATA SYNTHESIS: Odds ratios from individual studies were pooled separately for cohort and case-control studies with the random effects model. RESULTS: 30 articles with 31 studies (19 cohort and 12 case-control) involving 12,126 women assessed the association between thyroid autoantibodies and miscarriage. Five studies with 12,566 women evaluated the association with preterm birth. Of the 31 studies evaluating miscarriage, 28 showed a positive association between thyroid autoantibodies and miscarriage. Meta-analysis of the cohort studies showed more than tripling in the odds of miscarriage with the presence of thyroid autoantibodies (odds ratio 3.90, 95% confidence interval 2.48 to 6.12; P < 0.001). For case-control studies the odds ratio for miscarriage was 1.80, 1.25 to 2.60; P = 0.002). There was a significant doubling in the odds of preterm birth with the presence of thyroid autoantibodies (2.07, 1.17 to 3.68; P = 0.01). Two randomised studies evaluated the effect of treatment with levothyroxine on miscarriage. Both showed a fall in miscarriage rates, and meta-analysis showed a significant 52% relative risk reduction in miscarriages with levothyroxine (relative risk 0.48, 0.25 to 0.92; P=0.03). One study reported on the effect of levothyroxine on the rate of preterm birth, and noted a 69% relative risk reduction (0.31, 0.11 to 0.90). CONCLUSION: The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks. PMID- 21558128 TI - Hypertrophic feline muscular dystrophy: diagnostic overview and a novel immunohistochemical diagnostic method using formalin-fixed tissue. AB - This paper describes a case of hypertrophic feline muscular dystrophy (HFMD) in the UK. The cat under investigation died unexpectedly following routine vaccination, and postmortem investigation revealed myopathy, particularly affecting the diaphragm as well as multiple skeletal muscles. The right lung lobes were also partially collapsed and this was considered secondary to the effect of the muscular dystrophy. Pathological and immunohistochemical findings are described, macroscopic and microscopic findings are compared with other recorded cases in the literature and a diagnostic overview of HFMD is given. Possible causes of death are also discussed and a novel immunohistochemical method of demonstrating dystrophin deficiency using formalin-fixed tissue is described. PMID- 21558129 TI - Acute phase proteins in milk in naturally acquired bovine mastitis caused by different pathogens. AB - The concentrations of haptoglobin (Hp) and serum amyloid A (SAA) and the activity of N-acetyl-beta-D-glucosaminidase (NAGase) in milk from 234 cows with spontaneous mastitis caused by different pathogens were measured to assess whether they corresponded with the clinical signs of mastitis and whether there were any differences between pathogens. Ninety-eight of the cows had clinical mastitis and 136 had subclinical mastitis. There were statistically significant positive correlations between the concentrations of SAA and Hp and the activity of NAGase. Significant differences in the concentrations of acute phase proteins and NAGase activity were found in milk from cows with mastitis caused by different pathogens. The highest concentrations of Hp and NAGase were found in cases of mastitis caused by Escherichia coli and Arcanobacterium pyogenes, and the lowest concentrations were from cases of mastitis caused by coagulase negative staphylococci. Very low SAA concentrations were found in milk from the cases caused by A pyogenes, in contrast to cases caused by other major mastitis pathogens. The median concentration of SAA was over 10 times higher in cases of mastitis caused by E coli than in mastitis caused by other pathogens. There were significant differences in the mean Hp concentration and NAGase activity between clinical and subclinical mastitis. In approximately one-third of the samples, the Hp concentration was below the detection limit, potentially compromising the use of Hp as a mastitis marker. PMID- 21558130 TI - Evaluation of a human generic formulation of ciclosporin in the treatment of canine atopic dermatitis with in vitro assessment of the functional capacity of phagocytic cells. AB - To compare the efficacy, tolerability and safety of a generic formulation of ciclosporin for human beings with prednisone in the treatment of canine atopic dermatitis), human generic ciclosporin A (hgCsA) (5 mg/kg daily) and prednisone (1 mg/kg daily for seven days, followed by 1 mg/kg every second day) were administered to 13 and seven dogs with atopic dermatitis, respectively, for 42 days. Skin changes were assessed using a modified canine atopic dermatitis extent and severity index (mCADESI-01) and a pruritus intensity scale system. The in vitro functional capacity of phagocytic cells was assessed using the tetrazolium reductase activity and zymosan-stimulated tetrazolium reductase activity tests, as well as measurements of the percentage phagocytic activity and the ingestion capacity of phagocytic cells. Haematological and biochemical parameters were also monitored. There was a greater than or equal to 50 per cent reduction from the baseline in mCADESI-01 scores in 84.6 and 100 per cent of dogs, and a greater than or equal to 50 per cent reduction from the baseline in pruritus scores in 76.9 and 85.7 per cent of dogs, treated with hgCsA and prednisone, respectively. No important adverse physical, haematological or biochemical effects occurred with either drug and no statistically significant changes were detected in any of the four tests assessing the functional activity of phagocytes. The generic formulation of ciclosporin was effective in reducing the severity of physical signs of canine atopic dermatitis and was well tolerated. PMID- 21558131 TI - Influence of N-acetylcysteine against dimethylnitrosamine induced hepatotoxicity in rats. AB - This study evaluates the hepatoprotective and antioxidant properties of N acetylcysteine (NAC) on dimethylnitrosamine (DMN) induced hepatotoxicity in male Wistar albino rats. A single intraperitoneal dose of DMN (5 mg/kg b.w.) caused a significant increase in the levels of the serum marker enzymes (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamyl transpeptidase (gamma-GT)) and a subsequent decrease in AST, ALT, ALP and increase in LDH and gamma-GT in the liver tissue indicating hepatocellular damage. Elevation in the status of lipid peroxidation, fall in the activities of the enzymic (superoxide dismutase, catalase) and non enzymic antioxidants (vitamin C, vitamin E) in the liver tissue further confirms oxidative stress and hepatocellular damage induced on DMN administration. Oral administration of NAC (50 mg/kg b.w.) for 7 days significantly prevented the above alterations in the status of the marker enzymes of hepatotoxicity and antioxidant parameters and restored them towards normalcy, which was further substantiated by the histopathological studies of the liver tissue. These results suggest that NAC offers hepatoprotection by ameliorating DMN-induced oxidative stress and hepatotoxicity and this protective effect was attributed to its antioxidant and free radical scavenging properties. PMID- 21558132 TI - Gender-specific acute organ toxicity during intensified preoperative radiochemotherapy for rectal cancer. AB - Patients with locally advanced rectal cancer (cUICC stages II/III) are typically treated with preoperative 5-fluorouracil-based (5-FU-based) radiochemotherapy (RCT). However, trials are currently being conducted to improve the complete remission rates and the systemic control by combining 5-FU with oxaliplatin. The primary objective was to identify the subgroups of rectal cancer patients who were at risk for high-grade toxicity. All 196 patients who were included in the present study were treated with 50.4 Gy and chemotherapy that included either 5 FU (n = 115) or 5-FU+oxaliplatin (n = 81). The preoperative RCT was followed by a total mesorectal excision and adjuvant chemotherapy. Acute toxicity was monitored weekly and a toxicity grade >=3 (Common Toxicity Criteria) for a skin reaction, cystitis, proctitis, or enteritis was defined as high-grade acute organ toxicity. After RCT with 5-FU+oxaliplatin, complete tumor remission was achieved in 13.6% of the patients and in 11.3% after RCT with 5-FU alone. Complete irradiation dosages of 50.4 Gy were given to 99% (5-FU) and 95% (5-FU+oxaliplatin) of the patients. Concomitant chemotherapy was fully administered in 95% of the patients treated with 5-FU compared with the 84% of patients treated with 5 FU+oxaliplatin. A significantly higher proportion of acute organ toxicity was found in the patients who were treated with 5-FU+oxaliplatin compared with those who were treated with 5-FU. Additionally, women with a low body mass index were at the highest risk for acute organ toxicity. These results suggest that there are basic clinical parameters, such as gender and body mass index, that may be potential markers for generating individual risk profiles of RCT-induced toxicity. PMID- 21558133 TI - Preoperative chemotherapy for operable breast cancer improves surgical outcomes in the community hospital setting. AB - BACKGROUND: Preoperative chemotherapy (PC) for operable breast cancer has demonstrated significant benefits in clinical trials. Many patients are treated in the community setting and some may question the applicability of PC outside the university setting. The potential benefits of PC in terms of surgical outcomes in a community practice were examined. METHODS: A retrospective review was performed of stage II and stage IIIA breast cancer patients from January 1, 2002 to July 31, 2009. Surgical outcomes of margin status, volume of lumpectomy, rate of lumpectomy, and re-excision lumpectomy were evaluated. RESULTS: There were 212 patients included. Seventy-nine percent of patients who underwent PC had a clinical response and 25% had a pathologic complete response. For clinical stage T2 and stage T3 tumors, the PC group underwent lumpectomy more often than patients in the adjuvant chemotherapy (AC) group (78% versus 50%; p = .016 and 60% versus 29%; p = .015, respectively). The rate of close or positive margins in the PC group was half the rate in the AC group (23% versus 46%; p = .04) and this resulted in fewer re-excisions (p = .01). The volume of tissue removed was also smaller in the PC group (143.6 cm3 versus 273.9 cm3; p = .003). Conclusions. PC for operable breast cancer can significantly improve surgical outcomes in community-based practice. PMID- 21558134 TI - Preoperative chemotherapy for operable breast cancer is associated with better compliance with adjuvant therapy in matched stage II and IIIA patients. AB - INTRODUCTION: Preoperative chemotherapy (PC) for operable breast cancer has shown significant benefits in prospective trials. Many patients are treated in the community setting and some may question the applicability of PC outside the university setting. METHODS: Retrospective review was performed of stage II and IIIA breast cancer patients treated from January 2002 to July 2009. Fifty-three of 57 patients who underwent PC were matched based on age, tumor size, and hormone receptor status with 53 patients who did not undergo PC. Differences in patient compliance with physician recommendations for all types of adjuvant therapy were evaluated. Crude odds ratios and adjusted odds ratios derived from conditional logistic regression models were calculated. RESULTS: There were 106 patients included. Patient compliance with chemotherapy was better in the PC group than in the adjuvant chemotherapy (AC) group (100% versus 70%; p = .0001). Similarly, more patients in the PC group completed radiation therapy (96% versus 65%; p = .0003) and initiated hormonal therapy (100% versus 62%; p = .0001). Conditional logistic regression revealed that higher pathologic stage and current cigarette smoking were associated with poorer compliance with chemotherapy. For radiation therapy, the univariate model revealed that compliance with chemotherapy and being employed were associated with completion of radiation, whereas current cigarette smoking and larger pathologic size were associated with poorer compliance with radiation. For hormonal therapy, current cigarette smokers were more likely to be noncompliant with initiation of hormonal therapy. CONCLUSIONS: PC for operable breast cancer can improve patient compliance with chemotherapy. Current cigarette smokers were more likely to be noncompliant with all types of adjuvant therapy. PMID- 21558135 TI - Micronutrient levels in children exposed to secondhand tobacco smoke. AB - INTRODUCTION: Antioxidant micronutrients are the body's primary defense against the oxidative stress of secondhand smoke (SHS). Micronutrient levels have been associated with lung function; decreased levels of vitamin C and beta-carotene have been associated with SHS exposure in children. We sought to determine the association between SHS exposure and micronutrient levels in children. METHODS: Data from the 2003-2004 National Health and Nutrition Examination Survey (NHANES) were analyzed. Serum cotinine levels were categorized into no (<0.015 ng/mL), moderate (0.015 to <2.0 ng/mL), and high (2.0-15.0 ng/mL) smoke exposure; t-tests determined associations between exposure and levels of micronutrients. Significant bivariate associations were tested further using linear regression. RESULTS: In all, 2,218 children, aged 6-18 years, were included (response rate of 82%); 17% had no, 76% moderate, and 7% high exposure. Children with no exposure had higher levels of vitamin A, C, and E, cis- and trans-beta-carotene, and folate, while levels of vitamins B(6), B(12), and D did not differ. In regression analysis, higher cotinine levels were negatively associated with levels of vitamin C (beta = -.03; p < .01), cis-beta-carotene (beta = -.04; p < .01), trans beta-carotene (beta = -.7; p < .01), folate (beta = -.5; p < .001) and vitamin A (beta = -.6; p < .01). CONCLUSIONS: Children exposed to SHS have lower levels of antioxidants controlling for dietary and supplement intake. This antioxidant depletion may increase systemic inflammation and sensitivity to other oxidant stresses. Parents should be counseled on these specific risks from SHS exposure for their children, and the importance of smoking cessation and eliminating children's exposure to tobacco smoke. PMID- 21558136 TI - Pathological gambling and primary antiphospholipid (Hughes) syndrome: a unique neuropsychiatric association. AB - Neuropsychiatric conditions are common in patients with primary antiphospholipid syndrome (APS) with or without vascular thrombosis of the central nervous system. There are frequent descriptions of memory alterations, cognition and mood disorders, such as depression, anxiety, and even conditions of mania and psychosis preceding the diagnosis of primary APS. However, this study is the first to present primary or secondary APS associated with habit or impulse control disorders. The authors describe the case of a 53-year-old male patient who had been a pathological gambler since adulthood and who has had APS for more than 20 years. We describe the case and review its characteristics, criteria for diagnosis and treatment offered for patients with this specific subtype of impulse disorder. PMID- 21558137 TI - Predictors of mortality in diffuse alveolar haemorrhage associated with systemic lupus erythematosus. AB - The objective of this study was the evaluation of clinical, demographic and treatment-associated mortality factors in patients with diffuse alveolar haemorrhage (DAH) associated with systemic lupus erythematosus (SLE). Clinical, laboratory test, SLEDAI-2K, predictors of mortality (APACHE II) and different treatments including cyclophosphamide, methylprednisolone and rituximab were evaluated in SLE patients who were diagnosed with DAH, to determine potential association with mortality. Twenty-nine episodes of DAH in 22 SLE patients were included (one patient with four episodes, four patients with two episodes (seven recurrences)), 15 died. Mean age was 25.1 years and 1.5 years of SLE evolution with haemoglobin drop 3.4 g/dl. In 4 of 22 patients, the DAH diagnosis was confirmed by autopsy. Six episodes were in patients under 18 years of age (2 patients with recurrence). DAH was the initial manifestation of SLE in 10 patients. Of the 22 patients, 17 were women and 22/29 had DAH episodes. Dyspnoea and nephritis occurred in all patients, less common were arthritis (75.9%) and fever (65.5%); haemoptysis was present only in 44.8%. Through evaluation of all included factors, only thrombocytopenia, renal failure, requirement for mechanical ventilation and high APACHE II were associated with higher mortality. Cyclophosphamide use was associated with less mortality (not statistically significant). PMID- 21558138 TI - Elevated circulating CD4+ ICOS+ Foxp3+ T cells contribute to overproduction of IL 10 and are correlated with disease severity in patients with systemic lupus erythematosus. AB - In this work, we aimed to investigate the frequency, possible categories and clinical significance of circulating CD4+ ICOS+ FoxP3+ T cells in patients with systemic lupus erythematosus (SLE). The frequency of circulating CD4+ ICOS+ FoxP3+ T cells was analysed by flow-cytometric analysis in 32 SLE patients, 10 rheumatoid arthritis patients and 32 healthy controls. Production of IL-10 and mTGF-beta by different CD4+ T-cell populations was determined by intracellular cytokine staining. Plasma levels of IL-10 and TGF-beta were determined by enzyme linked immunosorbent assay (ELISA). The frequency of circulating CD4+ ICOS+ FoxP3+ T cells was significantly increased in SLE patients as compared with control groups. The elevated frequency of CD4+ ICOS+ FoxP3+ T cells had a positive correlation with SLE Disease Activity Index (SLEDAI) scores and serum anti-dsDNA but a negative correlation with serum C3. Additionally, the CD4+ ICOS+ Foxp3+ T cells contained significantly higher percentages of IL-10-producing cells than CD4+ ICOS- Foxp3+ T cells. A significant positive correlation was also observed between the frequency of CD4+ ICOS+ Foxp3+ T cells and the plasma level of IL-10 in SLE patients. In conclusion, an increased frequency of circulating CD4+ ICOS+ Foxp3+ T cells was observed in patients with SLE, suggesting its potential importance in the immunopathogenesis of SLE. Analysis of the CD4+ ICOS+ FoxP3+ T-cell population may be useful for the evaluation of lupus disease severity. PMID- 21558139 TI - Expression and function of Cbl-b in T cells from patients with systemic lupus erythematosus, and detection of the 2126 A/G Cblb gene polymorphism in the Mexican mestizo population. AB - Systemic lupus erythematosus (SLE) is characterized by abnormalities in the function of T and B lymphocytes and in the signaling pathways induced through their receptors. Cbl-b is an intracellular adaptor protein that plays a key role in the negative regulation of lymphocyte activity. We explored the expression and function of Cbl-b in T lymphocytes from SLE patients. In addition, the possible association of SLE and a single nucleotide polymorphism (SNP) of the Cblb gene was determined. We studied 150 SLE patients, 163 healthy individuals, and 14 patients with rheumatoid arthritis (RA). The expression of Cbl-b was analyzed in the peripheral blood mononuclear cells, and the negative regulatory function of Cbl-b was assessed by analyzing actin polymerization and the phosphorylation of JNK and c-Jun induced through CD3. Furthermore, the 2126(A/G) SNP of the Cblb gene was detected by real-time polymerase chain reaction. We found a significant small reduction in the expression of Cbl-b as well as increased levels of activation of c-Jun and actin polymerization in T lymphocytes from patients with SLE compared with healthy controls or RA patients. In addition, a significant association between the 2126(A/G) SNP and SLE was detected. Our data suggest that Cbl-b may contribute to the deregulated activation of T lymphocytes observed in SLE. PMID- 21558140 TI - Density of ghrelin-producing cells is higher in the gastric mucosa of morbidly obese patients. AB - BACKGROUND: Ghrelin is a peptide mainly secreted by gastric mucosa and has been implicated in the regulation of eating behavior and weight balance. Obesity and Helicobacter pylori infection are associated with changes in plasma ghrelin levels. OBJECTIVE: This study was designed to evaluate the density of ghrelin producing cells in the gastric mucosa of morbidly obese and dyspeptic non-obese patients, with and without H. pylori infection. METHODS: Gastric biopsies of the antral and oxyntic mucosa were obtained from 50 morbidly obese patients (BMI >40, 21 with metabolic syndrome (MS)), 17 dyspeptic overweight subjects (25